Advanced Textiles for Wound Care

Woodhead Publishing in Textiles: Number 85

Advanced textiles for wound care Edited by S. Rajendran

Oxford

© 2009 Woodhead Publishing Limited

Cambridge

New Delhi

The Textile Institute and Woodhead Publishing The Textile Institute is a unique organisation in textiles, clothing and footwear. Incorporated in England by a Royal Charter granted in 1925, the Institute has individual and corporate members in over 90 countries. The aim of the Institute is to facilitate learning, recognise achievement, reward excellence and disseminate information within the global textiles, clothing and footwear industries. Historically, The Textile Institute has published books of interest to its members and the textile industry. To maintain this policy, the Institute has entered into partnership with Woodhead Publishing Limited to ensure that Institute members and the textile industry continue to have access to high calibre titles on textile science and technology. Most Woodhead titles on textiles are now published in collaboration with The Textile Institute. Through this arrangement, the Institute provides an Editorial Board which advises Woodhead on appropriate titles for future publication and suggests possible editors and authors for these books. Each book published under this arrangement carries the Institute’s logo. Woodhead books published in collaboration with The Textile Institute are offered to Textile Institute members at a substantial discount. These books, together with those published by The Textile Institute that are still in print, are offered on the Woodhead web site at: www.woodheadpublishing.com. Textile Institute books still in print are also available directly from the Institute’s website at: www.textileinstitutebooks.com. A list of Woodhead books on textile science and technology, most of which have been published in collaboration with The Textile Institute, can be found at the end of the contents pages.

© 2009 Woodhead Publishing Limited

Published by Woodhead Publishing Limited in association with The Textile Institute Woodhead Publishing Limited, Abington Hall, Granta Park, Great Abington Cambridge CB21 6AH, UK www.woodheadpublishing.com Woodhead Publishing India Private Limited, G-2, Vardaan House, 7/28 Ansari Road, Daryaganj, New Delhi – 110002, India Published in North America by CRC Press LLC, 6000 Broken Sound Parkway, NW, Suite 300, Boca Raton, FL 33487, USA First published 2009, Woodhead Publishing Limited and CRC Press LLC © Woodhead Publishing Limited, 2009 The authors have asserted their moral rights. This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. Reasonable efforts have been made to publish reliable data and information, but the authors and the publishers cannot assume responsibility for the validity of all materials. Neither the authors nor the publishers, nor anyone else associated with this publication, shall be liable for any loss, damage or liability directly or indirectly caused or alleged to be caused by this book. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfi lming and recording, or by any information storage or retrieval system, without permission in writing from Woodhead Publishing Limited. The consent of Woodhead Publishing Limited does not extend to copying for general distribution, for promotion, for creating new works, or for resale. Specific permission must be obtained in writing from Woodhead Publishing Limited for such copying. Trademark notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation, without intent to infringe. British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library. Library of Congress Cataloging in Publication Data A catalog record for this book is available from the Library of Congress. Woodhead Publishing ISBN 978-1-84569-271-1 (book) Woodhead Publishing ISBN 978-1-84569-630-6 (e-book) CRC Press ISBN 978-1-4200-9489-3 CRC Press order number WP9489 The publishers’ policy is to use permanent paper from mills that operate a sustainable forestry policy, and which has been manufactured from pulp which is processed using acid-free and elemental chlorine-free practices. Furthermore, the publishers ensure that the text paper and cover board used have met acceptable environmental accreditation standards. Typeset by SNP Best-set Typesetter Ltd., Hong Kong Printed by TJ International Limited, Padstow, Cornwall, UK

© 2009 Woodhead Publishing Limited

Contents

Contributor contact details Woodhead Publishing in Textiles Preface

Part I The use of textiles in particular aspects of wound care 1 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 2

2.1 2.2 2.3 2.4 2.5 2.6 2.7

xi xv xxi

1

Wound management and dressings S. Ather and K. G. Harding, Cardiff University, UK

3

Introduction Types of wound Mechanism of wound healing Factors affecting wound healing: why wounds fail to heal Wound healing: treatment options Future trends Conclusions References

3 3 4

Testing dressings and wound management materials S. T. Thomas, formerly of Surgical Materials Testing Laboratory, Medetec, UK Introduction The need for laboratory testing Fluid-handling tests Low-adherence tests Conformability tests Microbiological tests Odour control tests

11 13 17 18 18

20

20 21 23 36 37 38 42 v

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Contents

2.8 2.9

Biological tests References

3

3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 3.10 3.11 3.12 4

4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9 5 5.1 5.2 5.3 5.4

Textile materials and structures for wound care products B. S. Gupta, North Carolina State University, USA, and J. V. Edwards, United States Department of Agriculture – Agricultural Research Service, USA Introduction The role of wound dressings Categorization of wounds Minor wounds Healing mechanisms Wound dressings Types of dressings available Bandages Materials used in dressings and bandages Textile processes involved in formation of dressings and bandages Acknowledgement References Interactive dressings and their role in moist wound management C. Weller, Monash University, Australia

44 45

48

48 49 50 51 53 55 60 70 71 79 92 92

97

Introduction Normal wound healing Wound characteristics Dressings Interactive wound dressings Future trends Conclusions Sources of further information and advice References

97 98 100 102 105 110 111 112 112

Bioactive dressings to promote wound healing G. Schoukens, Ghent University, Belgium

114

Introduction Physiology of wound healing Principles and roles of bioactive dressings Types and structures of bioactive dressings

114 115 117 118

© 2009 Woodhead Publishing Limited

Contents 5.5 5.6 5.7 5.8 6

Example of bioactive dressing: di-O-butyrylchitin (DBC) Future trends Acknowledgements References

vii

127 144 146 146

Advanced textiles for wound compression S. Rajendran and S. C. Anand, University of Bolton, UK

153

6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 6.9

Introduction Elastic compression bandages Venous leg ulcers Venous leg ulcer treatment Applications of bandages Present problems and novel bandages Three-dimensional spacer compression bandages Conclusions References

153 154 155 157 163 165 169 175 175

7

Antimicrobial textile dressings in managing wound infection Y. Qin, Jiaxing College, China

179

7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 8

8.1 8.2 8.3 8.4

Introduction Topical antimicrobial agents in wound care Main types of antimicrobial wound dressings Wound dressings containing silver Applications of modern antimicrobial wound dressings containing silver Future trends Sources of further information and advice References Novel textiles in managing burns and other chronic wounds H. Onishi and Y. Machida, Hoshi University, Japan Introduction: current practice in the management of deep skin wounds or ulcers Normal treatment options for deep skin wounds or ulcers Novel wound dressings for managing deep skin wounds or ulcers Future trends

© 2009 Woodhead Publishing Limited

179 181 183 187 190 193 195 195

198

198 201 205 212

viii

Contents

8.5 8.6

Sources of further information and advice References

Part II Types of advanced textiles for wound care 9

215 215

221

Drug delivery dressings P. K. Sehgal, R. Sripriya and M. Senthilkumar, Central Leather Research Institute, India

223

9.1 9.2 9.3 9.4 9.5 9.6 9.7 9.8 9.9

Introduction Wounds: defi nition and types Wounds which require drug delivery Delivering drugs to wounds Types of dressings for drug delivery Applications of drug delivery dressings Future trends Conclusions References

223 224 226 231 235 240 244 246 247

10

The use of ‘smart’ textiles for wound care J. F. Kennedy and K. Bunko, Advanced Science and Technology Institute, UK

254

10.1 10.2 10.3 10.4 10.5 10.6 10.7 10.8 10.9

Introduction Basic principles and types of smart textiles Characteristics of smart textiles Textiles in control of exudate from wounds Examples of ‘smart’ textiles for wound care Response of dressings to bacteria Future trends Sources of further information and advice References

254 255 256 262 265 267 268 271 272

11

Composite dressings for wound care M. Joshi and R. Purwar, Indian Institute of Technology Delhi, India

275

11.1 11.2 11.3 11.4

Introduction Defi nition of composite dressings Structure of composite dressings Materials and textile structures used in composite dressings

275 276 277

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Contents

ix

11.5 11.6 11.7 11.8

Types of composite dressings Trends in composite dressings: embroidery technology Conclusions References

284 286 288 288

12

Textile-based scaffolds for tissue engineering M. Kun, C. Chan and S. Ramakrishna, National University of Singapore, Singapore

289

12.1 12.2 12.3 12.4

Introduction: principles of tissue engineering Properties required for fibrous scaffolds Materials used for scaffolds Relationship between textile architecture and cell behavior Textiles used for tissue scaffolds and scaffold fabrication Applications of textile scaffolds in tissue engineering Future trends Sources of further information and advice References

289 290 293

12.5 12.6 12.7 12.8 12.9

© 2009 Woodhead Publishing Limited

294 298 303 308 310 312

Contributor contact details

(* = main contact)

Chapter 3

Chapter 1

Professor Bhupender S Gupta* Department of Textile Engineering, Chemistry & Science College of Textiles North Carolina State University Raleigh, NC 27695-8301 USA

Shahzad Ather and Keith G Harding* Wound Healing Research Unit Department of Surgery Cardiff University Cardiff UK E-mail: [email protected]

Chapter 2 Dr Stephen Thomas MEDETEC 1 Radyr Farm Road Radyr Cardiff CF15 8EH UK

E-mail: [email protected] Dr J Vincent Edwards USDA-ARS Southern Regional Research Center 1100 Robert E Lee Blvd New Orleans LA 70124 USA E-mail: [email protected]. gov

E-mail: [email protected] [email protected]

xi

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xii

Contributor contact details

Chapter 4

Chapter 7

Carolina Weller Department of Epidemiology and Preventative Medicine School of Public Health and Preventative Medicine Monash University Level 3 Burnet Building, DEPM The Alfred 89 Commercial Road Melbourne Vic 3004 Australia

Dr Yimin Qin Biochemical Materials Research and Development Center Jiaxing College 56 Yuexiu Road South Jiaxing 314001 Zhejiang Province China

E-mail: Carolina.Weller@med. monash.edu.au

Chapter 5 Professor Gustaaf Schoukens Ghent University Faculty of Engineering Sciences Department of Textiles Technologiepark 907 B-9052 Zwijnaarde (Gent) Belgium E-mail: gustaaf.schoukens@ UGent.be

Chapter 6 Dr S Rajendran* and S C Anand Centre for Materials Research and Innovation University of Bolton Bolton BL3 5AB UK E-mail: [email protected]

© 2009 Woodhead Publishing Limited

E-mail: [email protected]

Chapter 8 Hiraku Onishi* and Yoshiharu Machida Department of Drug Delivery Research Hoshi University 2-4-41, Ebara Shinagawa-ku Tokyo 142-8501 Japan E-mail: [email protected]

Chapter 9 Dr P K Sehgal*, Dr R Sripriya and Dr M Senthilkumar Bioproducts Laboratory Central Leather Research Institute Adyar, Chennai 600 020 Tamil Nadu India E-mail: [email protected]

Contributor contact details

xiii

Chapter 10

Chapter 11

John F Kennedy* and Katarzyna Bunko Advanced Science and Technology Institute 5 The Croft, Buntsford Drive Stoke Heath, Bromsgrove Worcestershire B60 4JE UK

M Joshi* and Roli Purwar Department of Textile Technology Indian Institute of Technology Delhi New Delhi 110016 India

E-mail: [email protected]

Chapter 12

Formerly of Chembiotech Laboratory University of Birmingham Research Park Vincent Drive Birmingham B15 2SQ UK

E-mail: [email protected] [email protected]

Ma Kun, Casey K. Chan and Seeram Ramakrishna* Division of Bioengineering & Dept. of Mechanical Engineering, Faculty of Engineering National University of Singapore Singapore 119077 E-mail: [email protected]

© 2009 Woodhead Publishing Limited

Woodhead Publishing in Textiles

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Watson’s textile design and colour Seventh edition Edited by Z. Grosicki Watson’s advanced textile design Edited by Z. Grosicki Weaving Second edition P. R. Lord and M. H. Mohamed Handbook of textile fi bres Vol 1: Natural fi bres J. Gordon Cook Handbook of textile fi bres Vol 2: Man-made fi bres J. Gordon Cook Recycling textile and plastic waste Edited by A. R. Horrocks New fi bers Second edition T. Hongu and G. O. Phillips Atlas of fi bre fracture and damage to textiles Second edition J. W. S. Hearle, B. Lomas and W. D. Cooke Ecotextile ’98 Edited by A. R. Horrocks Physical testing of textiles B. P. Saville Geometric symmetry in patterns and tilings C. E. Horne Handbook of technical textiles Edited by A. R. Horrocks and S. C. Anand Textiles in automotive engineering W. Fung and J. M. Hardcastle Handbook of textile design J. Wilson High-performance fi bres Edited by J. W. S. Hearle Knitting technology Third edition D. J. Spencer

xv

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xvi 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38

Woodhead Publishing in Textiles Medical textiles Edited by S. C. Anand Regenerated cellulose fi bres Edited by C. Woodings Silk, mohair, cashmere and other luxury fi bres Edited by R. R. Franck Smart fi bres, fabrics and clothing Edited by X. M. Tao Yarn texturing technology J. W. S. Hearle, L. Hollick and D. K. Wilson Encyclopedia of textile fi nishing H-K. Rouette Coated and laminated textiles W. Fung Fancy yarns R. H. Gong and R. M. Wright Wool: Science and technology Edited by W. S. Simpson and G. Crawshaw Dictionary of textile fi nishing H-K. Rouette Environmental impact of textiles K. Slater Handbook of yarn production P. R. Lord Textile processing with enzymes Edited by A. Cavaco-Paulo and G. Gübitz The China and Hong Kong denim industry Y. Li, L. Yao and K. W. Yeung The World Trade Organization and international denim trading Y. Li, Y. Shen, L. Yao and E. Newton Chemical fi nishing of textiles W. D. Schindler and P. J. Hauser Clothing appearance and fit J. Fan, W. Yu and L. Hunter Handbook of fi bre rope technology H. A. McKenna, J. W. S. Hearle and N. O’Hear Structure and mechanics of woven fabrics J. Hu Synthetic fi bres: nylon, polyester, acrylic, polyolefi n Edited by J. E. McIntyre Woollen and worsted woven fabric design E. G. Gilligan Analytical electrochemistry in textiles P. Westbroek, G. Priniotakis and P. Kiekens

© 2009 Woodhead Publishing Limited

Woodhead Publishing in Textiles 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Bast and other plant fi bres R. R. Franck Chemical testing of textiles Edited by Q. Fan Design and manufacture of textile composites Edited by A. C. Long Effect of mechanical and physical properties on fabric hand Edited by Hassan M. Behery New millennium fi bers T. Hongu, M. Takigami and G. O. Phillips Textiles for protection Edited by R. A. Scott Textiles in sport Edited by R. Shishoo Wearable electronics and photonics Edited by X. M. Tao Biodegradable and sustainable fi bres Edited by R. S. Blackburn Medical textiles and biomaterials for healthcare Edited by S. C. Anand, M. Miraftab, S. Rajendran and J. F. Kennedy Total colour management in textiles Edited by J. Xin Recycling in textiles Edited by Y. Wang Clothing biosensory engineering Y. Li and A. S. W. Wong Biomechanical engineering of textiles and clothing Edited by Y. Li and D. X-Q. Dai Digital printing of textiles Edited by H. Ujiie Intelligent textiles and clothing Edited by H. Mattila Innovation and technology of women’s intimate apparel W. Yu, J. Fan, S. C. Harlock and S. P. Ng Thermal and moisture transport in fi brous materials Edited by N. Pan and P. Gibson Geosynthetics in civil engineering Edited by R. W. Sarsby Handbook of nonwovens Edited by S. Russell Cotton: Science and technology Edited by S. Gordon and Y-L. Hsieh Ecotextiles Edited by M. Miraftab and A. Horrocks

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xviii 61 62 63 64 65 66 67 68 69 70 71 72 73 74

75 76 77 78 79 80 81

Woodhead Publishing in Textiles Composite forming technologies Edited by A. C. Long Plasma technology for textiles Edited by R. Shishoo Smart textiles for medicine and healthcare Edited by L. Van Langenhove Sizing in clothing Edited by S. Ashdown Shape memory polymers and textiles J. Hu Environmental aspects of textile dyeing Edited by R. Christie Nanofi bers and nanotechnology in textiles Edited by P. Brown and K. Stevens Physical properties of textile fi bres Fourth edition W. E. Morton and J. W. S. Hearle Advances in apparel production Edited by C. Fairhurst Advances in fi re retardant materials Edited by A. R. Horrocks and D. Price Polyesters and polyamides Edited by B. L. Deopora, R. Alagirusamy, M. Joshi and B. S. Gupta Advances in wool technology Edited by N. A. G. Johnson and I. Russell Military textiles Edited by E. Wilusz 3D fi brous assemblies: Properties, applications and modelling of three-dimensional textile structures J. Hu Medical textiles 2007 Edited by J. Kennedy, A. Anand, M. Miraftab and S. Rajendran Fabric testing Edited by J. Hu Biologically inspired textiles Edited by A. Abbott and M. Ellison Friction in textile materials Edited by B. S. Gupta Textile advances in the automotive industry Edited by R. Shishoo Structure and mechanics of textile fi bre assemblies Edited by P. Schwartz Engineering textiles: Integrating the design and manufacture of textile products Edited by Y. E. El-Mogahzy

© 2009 Woodhead Publishing Limited

Woodhead Publishing in Textiles 82 83 84 85 86 87

Polyolefi n fi bres: industrial and medical applications Edited by S. C. O Ugbolue Smart clothes and wearable technology Edited by J. McCann and D. Bryson Identification of textile fi bres Edited by M. Houck Advanced textiles for wound care Edited by S. Rajendran Fatigue failure of textile fi bres Edited by M. Miraftab Advances in carpet technology Edited by K. Goswami

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xix

Preface

It is apparent that quality of life is a key issue in the healthcare of people. Textile materials play an important and crucial role in designing appropriate structures for the healthcare of people and medical companies. With the increasing threat from new strains of bacteria and viruses and the growing problems such as Deep Vein Thrombosis (DVT) and leg ulcers, it is vital that new or enhanced medical devices should be developed to cope with the situation. The market potential for medical textile products is considerable. The UK has one of the largest medical device markets in the world. The market is dominated by the National Health Service (NHS), accounting for approximately 80% of healthcare expenditure. There is a considerable high market potential for advanced wound dressings. The wound care industry generated between US$3.5 and 4.5 billion for the period between 2003 and 2006, mostly from the USA and Europe. The wound care market is predicted to grow to US$12.5 billion in 2012 and the global advanced wound care segment is the fastest growing area with growth of 10% a year. In Europe the advanced wound care market is expected to grow by an average of 12.4% a year to US$1.23 billion in 2010. The growth forecast for antimicrobial wound dressing is 25.9% per annum. In the USA alone there are over 100 000 surgeries performed daily which can result in surgical wounds. Ageing population creates increased demand for all types of surgical intervention. In 1991 the estimated annual cost of treating pressure ulcers in the UK was over £750 million, and in 2004 the total costs were £1.4– £2.1 billion or 4% of the total NHS budget. The annual cost of treating diabetic foot ulceration accounts for 5% of the total NHS budget in the UK. The annual cost for treating venous leg ulceration in Britain is £650 million and in the USA it is around $1 billion. While traditional dressings currently dominate the wound care market, raising awareness of the clinical benefits provided by advanced wound dressings is bound to widen their uptake. Continued research and development into developing high-tech wound dressings that fulfi l the principal xxi

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Preface

essential requirements of keeping the wound moist to accelerate healing, being nonadherent to wound bed and having antibacterial and antiodour properties not only promotes wound healing with special reference to difficult-to-heal wounds but also reduces the treatment cost considerably which, in turn, has a direct impact on the economy. Wound management is a global problem and the need for a comprehensive book which links textiles and wounds for better wound management has been felt for a long time. This interdisciplinary state-of-the art book has been designed to meet the growing challenges in advanced wound care management. The chapters are carefully written by multinational authors who have vast experience in medical and/or textile disciplines. During editing I found that the chapters not only provide a wealth of information on wound management but also problem-solving techniques. The book is organised into two parts. The chapters in Part I address the principles and physiology of wounds and wound healing, and how textiles play a vital role in managing acute and chronic wound healing. Part I emphasises the fact that wound healing depends not only on medication but also on the use of proper dressing techniques and suitable dressing materials. Dressings vary with the type of wound and wound management, and no single dressing is universally applicable in enhancing wound healing. The role of interactive dressings, bioactive dressings, antimicrobial dressings and special dressings for managing burn wounds is critically discussed in Part I. In addition, a chapter in Part I demonstrates that textile bandages are the only treatment option to enhance the healing of difficult-to-heal venous leg ulcers. The testing and characterisation of wound dressings are also critically reviewed taking account of the real laboratory scenario. The high-tech dressings such as drug delivery dressings, temperature control dressings, smart dressings and composite dressings are focused in Part II. A unique last chapter covers the cultivation of human organs and body parts on textile scaffolds. Each chapter includes a wealth of bibliographical information which can serve as a ‘ready reckoner’ for finding additional information in specific subject area. Efforts have been exerted to edit the chapters to be easily readable by medical professionals, textile scientists and researchers as well as wound dressing manufacturers. This book provides readers with much needed information in the interdisciplinary subject areas of nursing and textiles. I am deeply indebted to the authors of this publication and have no doubt that their contribution will be a useful resource document making a greater contribution to this emerging discipline. S. Rajendran The University of Bolton

© 2009 Woodhead Publishing Limited

1 Wound management and dressings S. AT H E R and K. G. H A R DI NG, Cardiff University, UK

Abstract: The various types of wounds and their mechanisms of healing are described and factors affecting the management of wound healing are outlined. For chronic wounds, a number of factors when present in combination lead to the non-healing of wounds. Wound management should therefore be multifactorial and aim at correcting the underlying abnormalities. Options for treatment are described with no single treatment being universally effective owing to the multiple molecular and cellular events involved so that a combination of different therapies is required. Future trends include application of gene therapy and stem cell therapy. Key words: wound healing, wound management, chronic wounds.

1.1

Introduction

A wound is defi ned as a break in the epithelial integrity of the tissues. This disruption can be deeper and involve subepithelial tissues including dermis, fascia and muscle. They can be caused accidentally, intentionally or be a part of a disease process.1 A wound is caused by physical trauma where the skin is torn, cut or punctured (an open wound), or where a blunt force trauma causes a contusion (a closed wound). The history of wound care spans from prehistory to modern medicine and has evolved from simple wound covers ranging from vinegar-soaked dressings, through topical antibiotics to topically applied growth factors. 2 Even during early historical periods several factors were noted that speeded up or assisted the process of healing. The necessity for hygiene, the prevention of bleeding and, later on, the germ theory of disease paved the way for modern wound management.

1.2

Types of wound

Wounds can be classified in many ways, by acute or chronic, by cause (e.g., pressure, trauma, venous leg ulcer, diabetic foot ulcer), by the depth of tissue involvement, or other characteristics such as closure (primary or secondary intention). 3

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Advanced textiles for wound care

1.2.1 Acute wound An acute wound is defi ned as a recent wound that has yet to progress through the sequential stages of wound healing. 3 An acute wound is acquired as a result of an incision or trauma and heals in a timely and orderly manner. Surgically created wounds include all incisions, excisions, and wounds that are surgically debrided. Surgical wounds include all skin lesions that occur as a result of trauma (e.g. burns, falls), as a result of an underlying condition (e.g. leg ulcers), or as a combination of both.

1.2.2 Chronic wounds Wounds that fail to heal in an anticipated time frame and orderly fashion and often recur are considered chronic. 3 Venous leg ulcers, pressure ulcers and diabetic foot ulcers are some examples of chronic wounds.

1.2.3 Open and closed wounds Wounds are also differentiated as open or closed wound types: Open wounds: examples include incision or incised wounds, laceration, abrasions, punctured wounds and penetrating wounds, Closed wounds: examples include contusions, haematoma and crush injuries.

1.3

Mechanism of wound healing

The aim of wound healing is homeostasis and restoration of tissue integrity. It is a well-orchestrated and complex process which is triggered by tissue injury and ends by regeneration or repair. Typically healing is divided into categories based on the anticipated nature of the repair process (Fig. 1.1).

1.3.1 Healing by primary intention Wound edges are approximated with sutures, staples or adhesive within hours of its creation with no defect. This enables closure to occur quickly with minimal tissue needed to repair the defect and minimal scarring.

1.3.2 Healing by secondary intention The wound is left open and no formal closure is done. Healing occurs by epithelialisation and contraction, e.g. healing associated with a large and/or deep wound in which the tissue edges cannot be approximated. The

© 2009 Woodhead Publishing Limited

Wound management and dressings

5

Differential wound healing Wound healing

Scarless Foetal skin, oral mucosa

Scarring Adult skin

Non-healing Chronic wounds

Excessive scarring Hypertrophic scars, keloid scars

1.1 Differential wound healing.

size of the gap determines the degree of new tissue matrix and epidermal surface needed for complete closure.4

1.3.3 Delayed primary/tertiary healing Wound closure is delayed for several days; this is usually employed for infected wounds. Irrespective of the cause, wounds heal in a very similar fashion. Studying this process and how to optimise this remains the central focus of attention for the clinicians. It is a dynamic and interactive process that involves a variety of blood and parenchymal cells, extracellular matrices and soluble mediators. During this process, wound healing passes through four phases of haemostasis, inflammation, proliferation and remodelling. These phases are clinically indistinct and overlap in time. Tissue injury sets in motion a cascade of cellular and biochemical activities which leads to healing of the wound. In the following sections, stages in the process of wound healing are described (Fig. 1.2).

1.3.4 Haemostasis The fi rst step in the process (immediate up to 2–4 h) of inflammation is haemostasis, which is characterised by vasoconstriction and coagulation. It starts soon after injury and is usually completed within the first few hours. Injury to the tissues causes disruption of blood vessels and lymphatics exposing the platelets to fibrin and collagen. This activates the

© 2009 Woodhead Publishing Limited

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Advanced textiles for wound care Wound biology Injury

Platelet activation Fibrin clot

Macrophages

Provisional Growth factors matrix Proteases ECM production Re-epithelialisation Migration Granulation tissue

Fibroblast ↓ ↓ ↑ ↑ ↑

Cellular density Blood supply Contraction Collagen orientation Epithelial thickness

Scar formation/ maturation

1.2 Biology of wound healing.

platelets and complement cascade. Platelets also interact with the injured tissue, causing the release of thrombin, which converts soluble, circulating fibrinogen to fibrin, which in turn traps, and activates platelets and forms the physical entity of the hemostatic ‘plug’. 5 The activated platelet releases cytokines and growth factors including thromboxane A-2 and serotonin which are important inflammatory mediators and also cause vasoconstriction The clot also serves to concentrate the elaborated cytokines and growth factors including platelet-derived growth factor (PDGF) and transforming growth factor (TGF) β1.6 Coagulation leads to hemostasis, which initiates healing by leaving behind messengers that bring on an inflammatory process. Deficiency of clotting factors (Factor VII. IX, XII) leads to impaired wound healing.7

1.3.5 Inflammation The stage of inflammation starts soon after haemostasis (immediate up to 2–5 days) and is usually completed within the fi rst 48 to 72 h but it may last as long as 5 to 7 days. 8 The initial vasoconstriction is followed by vasodilatation and increased vascular permeability in response to histamine and other vasoactive mediators. Role of neutrophils The net result of this change in vascular permeability is an influx of polymorphonuclear cells (PMN) and monocytes in the injured area in a protein-

© 2009 Woodhead Publishing Limited

Wound management and dressings Phases of wound repair

Maximum response

I Inflammation

II Cell proliferation and matrix deposition

7

III Matrix remodelling

Fibroplasia Angiogenesis Re-epithelialization Extracellular matrix synthesis -Collagens Extracellular matrix -Fibronectin synthesis, degradation -Proteoglycans and remodelling Granulocytes ↑ Tensile strength Bleeding Phagocytosis ↓ Cellularity Coagulation ↓ Vascularity Platelet activation Complement activation Macrophages Cytokines

0.1

0.3

1

3 10 30 Days after wounding (log scale)

100

300

1.3 Wound biology: phases of wound repair.

rich fluid. Neutrophils phagocytise debris and bacteria, they also kill bacteria by releasing caustic proteolytic enzymes and free radicals in a process called ‘respiratory burst’.9 The surrounding tissue matrix in unwounded tissue is protected by protease inhibitors which can be overwhelmed and penetrated if the inflammatory response is extremely robust leading to damage to normal tissue. Unless stimuli for neutrophil recruitment persist at the wound site, the neutrophil infi ltration ceases after a few days, they undergo apoptosis and are engulfed and degraded by macrophages.10 Macrophages Macrophages start appearing in the wound two days after the injury and dominate the wound cell population over the next few days. Beside resident macrophages, the majority of macrophages at the wound site are recruited from the blood. Monocytes extravasate from the blood vessel, become activated and differentiate into mature tissue macrophages. Macrophages are crucial to wound healing and perform a number of functions. They act as antigen-presenting cells and remove debris and dead cells by phagocytosis. Perhaps their more important role in the process of healing is synthesis of numerous potent growth factors, such as TGF-β, TGF-α, basic fibroblast growth factor (bFGF), platelet-derived growth factor, and vascular endothelial growth factor, which promote cell proliferation and the synthesis of extracellular matrix molecules by resident skin cells.11 These factors also help in angiogenesis, migration and activation of

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Advanced textiles for wound care

fibroblast thus setting the stage of proliferation.12 It has been shown experimentally that macrophage depletion using antisera results in a significant delay in healing.13 Role of inflammatory mediators Inflammatory mediators play a central and major role in the process of wound healing. They include a collection of soluble factors present either in plasma in an inactive form or released by damaged and nearby cells and leukocytes in an attempt to control the damage and initiate healing. Mechanisms of inflammatory resolution Inflammation performs several important functions. It clears the wound of infectious organism and debris, and brings about a change in the micro-environment of the wound to set the stage for proliferation. However, successful repair after injury requires resolution of the inflammatory response. The mechanisms controlling this down-regulation of the inflammatory response are poorly understood and for years it was thought that the inflammatory response would just ‘burn itself out’. Recent evidence, however, suggests that this process is organised as a series of reactions to produce stop signals referred to as ‘check point controllers of inflammation’.14 Lipoxins and aspirin-triggered lipoxins are the stop signals for inflammation. Autocoids also display potent anti-inflammatory actions and are termed resolvins.15 Down-regulation of pro-inflammatory mediators and the reconstitution of normal microvascular permeability, which contributes to the cessation of local chemoattractants, synthesis of antiinflammatory mediators, apoptosis, and lymphatic drainage also play their role. An excessive or prolonged inflammatory response results in increased tissue injury and poor healing.

1.3.6 Proliferation This phase starts around the second or third day after injury and continues for up to 3 or 4 weeks. This is marked by the appearance of fibroblasts in the wound and overlaps with the inflammatory phase. As in other phases, the changes in this phase do not occur in a series, but overlap in time. Granulation tissue formation Fibroblasts start to appear in the wound from the third to fourth day and their numbers peak between the seventh and fourteenth days. They migrate from the wound margins using the fibrin-based provisional matrix created

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during the inflammatory phase of healing. Under the influence of bFGF, TGF-β, and PDGF secreted by macrophages they proliferate and synthesise glycosaminoglycans and proteoglycans, elastins and fibronectin, the building blocks of the new extracellular matrix of granulation tissue, and collagen. As the number of macrophages diminishes, fibroblasts themselves begin to secrete bFGF, TGF-β, and PDGF. They also begin producing keratinocyte growth factor and insulin like growth factor I. After secretion of collagen molecules, they are organised in the form of collagen fibres which are then cross-linked into bundles. Collagen gives the wound its tensile strength and, in addition, cells involved in inflammation, angiogenesis, and connective tissue construction attach to, grow and differentiate on the collagen matrix laid down by fibroblasts.16 Collagen deposition increases the tensile strength of the wound. Initially collagen levels in the wound increase, but later on homeostasis is reached as the collagen is also being degraded by collagenases. Angiogenesis Angiogenesis accompanies the fibroplasia phase and is essential to scar formation. Endothelial cells located at intact venules are stimulated by vascular endothelial growth factor (VEGF) which is secreted mainly by keratinocytes at the wound edge and also by macrophages, fibroblasts and platelets in response to hypoxia and the presence of lactic acid. Endothelial cells originating from parts of uninjured blood vessels develop pseudopodia and push through the extracellular matrix (ECM) into the wound site. They produce the degradation agents including plasminogen activator and collagenase and invade the wound by the enzymatic degradation of fibrin clot once the new granulation tissue (i.e., extracellular matrix, collagen, capillaries) is laid down.17 Through this activity, they establish new blood vessels which later on join to form capillary loops and establish blood flow in the wound. Cells, when adequately perfused, stop producing angiogenic factors, and migration and proliferation of endothelial cells is reduced.17 Eventually, blood vessels that are no longer needed die by apoptosis; this explains the change in color seen in scar tissue as it matures. Epithelialisation The initial event in epithelialisation is migration of undamaged epithelial cells from the wound margins. Keratinocytes at the wound edges are stimulated by EGF and TGF-α produced by activated platelets and macrophages,15 they proliferate and begin their migration across the wound bed within 12 to 24 h after injury.18 The fi rst step of migration involves separation of the keratinocytes from each other and their anchors to the cell

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basement membrane.19 The process of migration continues until the migrating cells from opposing sides of the wound touch each other. At the point of contact, migration ceases in a process known as contact inhibition.19 Once this process is complete, keratinocytes stabilise them by forming firm attachments to each other and the new basement membrane. 20 All these changes in the wound lead to the formation of granulation tissue which consists of inflammatory cells, fibroblasts and new vasculature in a hydrated matrix of glycoproteins, collagen and glycosaminoglycans, the components of a new, provisional ECM. The provisional ECM is different in composition from the ECM in normal tissue and includes fibronectin, collagen, glycosaminoglycans and proteoglycans. 21 Contraction About a week after the injury, the fibroblast differentiates into myofibroblasts, pulls the edges of the wound together and the wound begins to contract. 22 Contraction peaks at 5 to 15 days post wounding and continues even after the wound is completely re-epithelialised. 23 Contraction reduces the size of the wound and, thus, reduces the amount of ECM needed to fi ll the wound 24 and facilitates re-epithelialisation by reducing the distance which migrating keratinocytes must travel. At the end of the granulation phase, fibroblasts begin to undergo apoptosis, converting granulation tissue from an environment rich in cells to one that consists mainly of collagen.23

1.3.7 Maturation and remodelling Maturation and remodelling of the collagen into an organised and wellmannered network is the fi nal stage of the healing process (from day 8 up to 2 years). If this is compromised, then the wound’s strength will be greatly affected. On the other hand, excessive collagen synthesis can lead to the formation of a hypertrophic scar or keloid. The maturation phase can last for two years or longer, depending on the size of the wound and whether it was initially closed or left open. This phase is characterised by the removal of type III collagen and its replacement by mature type I collagen. There is a rapid production of type I collagen but there is no net gain as the old collagen is also being degraded by collagenases. New collagen fibres are rearranged, cross-linked, and aligned along tension lines but they can never become as organised as the collagen found in uninjured skin. 25 The second characteristic feature of this stage is programmed cell death or apoptosis and, thus the number of cell types such as macrophages, keratinocytes, fibroblasts, and myofibroblasts is reduced.18,20 Remodelling is regulated by fibroblasts through the synthesis of ECM components and MMPs that control cell

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differentiation. 26 All of these changes produce a cell-deficient environment with excessive connective tissue. Blood vessels that are no longer required die by apoptosis and the remainder acquire a basement membrane and become relatively impermeable. All of these factors lead to the increase in tensile strength, decrease in erythema and scar tissue bulk, and the fi nal appearance of the healed scar.

1.4

Factors affecting wound healing: why wounds fail to heal

In most cases, wound healing is a natural, uneventful process which leads to the restoration of tissue integrity. But, in some cases, wounds fail to heal and become a complex medical problem requiring specialised care and treatment. If a wound has not improved significantly in four weeks, or if it has not completed the healing process in eight weeks, it is considered a chronic, non-healing wound. Wound healing is dependent on the interaction of different cells, mediators and growth factors. Alterations in one or more of these components may account for the impaired healing observed in chronic wounds. Chronic wounds may be arrested in any of the healing phases but, most commonly, disruption occurs in the inflammatory or proliferative phase27 with the accumulation of excessive extracellular matrix and matrix metalloproteinases such as collagenase and elastase, which result in premature degradation of collagen and growth factors. 28 An optimum microenvironment and the absence of cytotoxic factors are essential for healing of wounds. Many local and systemic factors have been implicated in the delayed healing of wounds.

1.4.1 Local factors Infection Infection is the commonest local cause for delayed wound healing. Bacteria delay wound healing by activating the alternative complement pathway and exaggerating and prolonging the inflammatory phase of wound healing. The bacteria, themselves elaborate toxins and proteases, also compete for oxygen and nutrients, and this ultimately damages the cells. Tissue ischaemia Local hypoxia is detrimental to cellular proliferation, resistance to infection and collagen production. This may be the result of foreign bodies, infection, suture material, or the presence of peripheral vascular disease.

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Poor surgical technique Proper tissue handling and closure with appropriate sutures is very important. Wound healing is affected if the tissues are devitalised, strangulated with sutures or improperly debrided. Others Formation of haematomas, presence of foreign bodies and mechanical pressure are some of the other local factors in the pathophysiology of delayed wound healing.

1.4.2 Systemic factors Ageing Healing in the elderly is generally delayed but the fi nal result is qualitatively similar in elderly people. There are many physiological changes associated with ageing which can lead to delayed healing. Reduced skin elasticity and collagen replacement influence healing. Reduced immunity and other chronic diseases can also affect the healing process. Nutritional status Deficiency of various nutrients and vitamins can affect the wound healing process. Proteins are required for all the phases of wound healing and are particularly important for collagen synthesis. In protein deficiency states, cellular and humoral immune responses are blunted, fibroplasia and all aspects of matrix formation are delayed. Glucose balance is essential for wound healing and it provides the energy required for cell function. Insulin may act as a fibroblast growth factor and its deficiency leads to suppression of collagen deposition in the wound. 29 Deficiency of fatty acids can also impair healing. Vitamins Vitamin A deficiency has been associated with slowed re-epithelisation, decreased collagen synthesis and stability and an increased susceptibility to infection. Vitamin C (ascorbic acid) is an essential cofactor during collagen biosynthesis. In scurvy, the collagen formed is unhydroxylated, relatively unstable and subject to collagenolysis. Vitamin K deficiency results in a deficiency in the production of the clotting factors (factors II, VII, IX and X) that are vitamin K dependent

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resulting in bleeding diathesis, hematoma formation and secondary detrimental effects on wound healing. Iron is required to transport oxygen. Other minerals like zinc and copper are important for enzyme systems and immune systems. Zinc deficiency contributes to disruption in granulation tissue formation. Underlying diseases Diabetes, arthritis, renal disease, heart disease, cancer, immune disorder, lung disease blood disorders and surgery all affect the process of wound healing. Medication Anti-inflammatory, cytotoxic, immunosuppressive and anticoagulant drugs all reduce healing rates by interrupting cell division or the clotting process.

1.5

Wound healing: treatment options

1.5.1 Basic care Wound repair requires the timed and balanced activity of inflammatory, vascular, connective tissue, and epithelial cells and their mediators. It is important to provide an environment that is conducive to wound healing, to treat the underlying origin of the wound, and to correct associated abnormalities.

1.5.2 Wound dressings Dressings do not heal wounds; properly selected dressings do, however, promote healing and prevent further harm to the wound. Wound dressings are passive, active or interactive. 30 Passive dressings simply provide cover while active or interactive dressings are believed to be capable of modifying the physiology of the wound environment. Interactive dressings include hydrocolloids, hydrogels, alginates and foams. An ideal dressing should maintain a moist environment at the wound interface and act as a barrier to micro-organisms. Commonly available dressings include. Alginate These dressings are highly absorbent and are composed of calcium and sodium salts of alginic acid, obtained from seaweed. They are useful in

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medium to heavily exuding wounds and are also good for bleeding wounds. Examples include Kaltostat, Sorbsan and Algisite. Hydrogels Hydrogels have a high water content which creates a moist wound surface and helps in the debridement of wounds by hydration and promotion of autolysis. As absorption of exudate is poor, they can cause maceration. Examples include Aquafoam, Intrasite, Nu-Gel, Purilon and Sterigel. 31 Hydrocolloids Hydrocolloids are composed of a matrix of cellulose and other gel-forming agents, including gelatin and pectin. These dressings promote autolysis and aid granulation. Examples include sheets such as Alione, Combiderm and Duoderm; paste such as GranuGel; and hydrofibre such as Aquacel and Versiva. 31 Semipermeable fi lms Semipermeable dressings are good for low to medium exuding wounds. Examples include Opsite, Flexiguard, Tegaderm, Melfilm and Bioclusive. Foam dressings Foam dressings are useful for moderately exudating wounds as they prevent ‘strike through’ of exudate to the wound surface. They also provide cushion and support to the wound. Examples include Allevyn, Lyofoam, Tielle plus and Biatin Adhesive. Antimicrobial dressings Antimicrobial dressings are good for infected wounds especially in diabetics. Examples include Acticoat, Aquacell Ag, Arglaes, Inadine and iodoflex.

1.5.3 Bioengineered skin Bioengineered skin is generally divided into: 1. 2.

permanent, such as autografts and temporary, such as allografts (including de-epidermised cadaver skin and in vitro reconstructed epidermal sheets), xenografts (i.e. conserved pig skin) and synthetic dressings

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Allogenic grafts are produced from neonatal fibroblasts and keratinocytes. Available in the form of dermal, epidermal or composite grafts, they are better than traditional skin grafts as they are non-invasive, do not require anaesthesia and avoid potential donor site problems. Epidermal grafts Available in both autograft and allogenic forms, epidermal grafts include Epicell, Laserskin, CellSpray, Bioseed-S and LyphoDerm. 27 They are useful for coverage of large skin defects with acceptable cosmetic results and are indicated for burns and leg ulcers. Their main disadvantages include fragility and difficulty in handling owing to a lack of backing material. They are unsuitable for deep wounds as they only provide temporary cover. They are most successful when placed on a dermal bed. Dermal grafts Dermal grafts are either cellular or acellular, and allogenic in nature, and, hence, available for immediate use. Products include Integra, Alloderm, Biobrane, Transcyte and Dermagraft.27 They are indicated for burns, deep wounds, and for cosmetic procedure. However, they cannot be generated in large quantities and are susceptible to infections. Composite grafts Composite grafts are bilayered skin grafts and contain epidermal and dermal components. Apligraft is a commercially available product and is indicated for diabetic and venous ulcers. It lacks skin adnexal structures but produces all the cytokines and growth factors that are produced by normal skin. Allergy to bovine collagen, limited shelf-life and infection can limit their use. 27

1.5.4 Non-surgical innovations Vacuum assisted closure Vacuum-assisted closure (VAC) therapy entails placing an open-cell foam dressing into the wound cavity and applying a controlled subatmospheric pressure. This produces negative pressure in the wound, leading to improved blood flow and oxygenation. It also helps in removing excessive fluid and slough. 32 This stimulates granulation tissue formation, wound contraction and early closure of wound.

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Intermittent pneumatic compression This is an effective treatment for chronic ulcers on legs with severe oedema. It provides compression (at 20–120 mm Hg) at preset intervals. 33 It improves lymphatic and venous flow and helps in the healing of chronic ulcers. Hyperbaric oxygen Hyperbaric oxygen is thought to expedite healing as it has been shown that ischaemic lesions heal less well34 and certain growth factors do not work in hypoxic conditions. 35 Debate continues on its value in certain wound conditions. Other therapies Laser, ultrasound, hydrotherapy, versijet, electromagnetic therapy and electrotherapy are some other therapies which are used to stimulate healing.

1.5.5 Drug therapy Drugs affect wound healing by assisting or interfering with specific phases. Drugs can reduce peripheral vascular resistance, reduce blood viscosity and cause local or systemic vasodilatation leading to improved tissue perfusion and oxygenation. Currently available drugs include pentoxifylline, which decreases platelet aggregation leading to decreased viscosity and improved capillary microcirculation. It is useful in patients with chronic venous ulcers who cannot tolerate compression. Iloprost a vasodilator and prostacyclin analogue is good in the treatment of arterial and vasculitic ulcers. 33 Calcium channel blockers and glyceryl trinitrate (GTN) ointment have also been used as vasodilators in cases of vaculitic ulcers caused by Raynaud’s disease and ischaemic ulcers, respectively.

1.5.6 Growth factors Growth factors are soluble signalling proteins which influence wound healing through their inhibitory or stimulatory effect during different stages of the wound healing process. Produced by different cells they act on inflammatory cells, fibroblasts, and endothelial cells to direct the processes involved in wound healing. Recombinant human-platelet derived growth factor-bb (rhPDGF-BB, Becaplermin) is the only FDA-approved

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growth factor available for clinical use. In clinical trials, this has been shown to increase the incidence of complete wound closure and decrease the time to achieve complete wound healing. Basic fibroblast growth factor (available commercially in Japan) stimulates endothelial cell migration and proliferation. Its topical application leads to faster granulation tissue formation and epidermal regeneration in burn wounds. However, this effect is not seen in diabetic foot ulcers. Preclinical trials have shown promising results for epidermal growth factor and keratinocyte growth factor in venous ulcers and fibroblast growth factor platelet derived growth factor (PDGF) for pressure ulcers. Despite promising preclinical data, results of the clinical trials are disappointing. Inherent instability of these proteins in the hostile environment of the wound makes them ineffective. Time of application, dosage, mode of delivery or the combination of the growth factors may be incorrect and further evaluation is required.

1.6

Future trends

1.6.1 Gene therapy To be clinically effective a high concentration of growth factors is needed, which requires frequent and high dosing, but it is prohibitively expensive. Introduction of the gene rather than the product (growth factor) is thought to be cheaper and more efficient in treating non-healing wounds. It can lead to a sustained local availability of these proteins and can be cost effective. The technology to introduce genes through physical or biological vectors has existed for some time. Long-term expression of the therapeutic gene remains a challenge but only a transient gene expression is required for wound repair. Phase I studies are being conducted at the moment and their results will dictate any further course of action in this field.

1.6.2 Stem cells therapy Stem cells which are thought to be present in every tissue are characterised by their prolonged self-renewal capacity and by their asymmetric replication. There is potential that stem cells may reconstitute dermal, vascular and other elements required for optimum wound healing. Han et al.36 showed the potential of human bone marrow stromal cells to accelerate wound healing in vitro by measuring the amount of collagen synthesis and the levels of basic fibroblast growth factor. Though the technique is still in its infancy, Badiavas et al.37 have shown that direct application of autologous bone marrow and its cultured cells may accelerate the healing process.

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1.7

Conclusions

Chronic wounds do not have a unique defect but a number of factors, which, when present in combination, lead to the non-healing of wounds. Wound management should therefore be multifactorial and aim at correcting the underlying abnormalities. No single treatment is universally effective owing to multiple molecular and cellular events involved and a combination of different therapies is required.

1.8

References

1. robson mc, Wound infection: a failure of wound healing, caused by an imbalance of bacteria. Surg Clin North Am 1997; 77:637–50. 2. janis je and attinger ce, Current concepts in wound healing. Plast Reconstr Surg 2006; 117(7 Suppl):4S–5S. 3. attinger ce, janis je, steinberg j, schwartz j, al-attar a and couch k, Clinical approach to wounds: debridement and wound bed preparation including the use of dressings and wound-healing adjuvants. Plast Reconstr Surg 2006 Jun; 117(7 Suppl):72S–109S. 4. iocono ja, ehrlich hp and gottrup f et al., The biology of healing. In: DL Leaper and KG Harding, Editors, Wounds: biology and management, Oxford University Press, Oxford, England (1998), pp. 12–22. 5. kerstein md, The scientific basis of healing. Adv Wound Care 1997; 10(4):30–36. 6. singer aj and clark ra, Cutaneous wound healing, N Engl J Med 1999; 341:738–746. 7. beck e, duckert f and ernst m, The influence of fibrin stabilizing factor on the growth of fibroblasts in vitro and wound healing. Thromb Diath Haemorrh 1961; 6:485. 8. haas af, Wound healing, Dermatol Nurs 1995; 7:28–34. 9. greenhalgh dg, The role of apoptosis in wound healing. The International J Biochem Cell Biol 1998; 30(9):1019–1030. 10. martin p and leibovich sj, Inflammatory cells during wound repair: the good, the bad and the ugly. Trends Cell Biol 1998; 15(11):599–607. 11. dipietro la and polverini pj, Role of the macrophage in the positive and negative regulation of wound neovascularisation. Am J Pathol 1993; 143:678–684. 12. witte m and barbul a, Role of nitric oxide in wound repair. Am J Surg 2002; 183:406. 13. leibovich sj and ross r, The role of the macrophage in wound repair. Am J Pathol 1975; 78:71–100. 14. trengove nj, stacey mc and macauley s, Analysis of acute and chronic wound environment: The role of protease and their inhibitors. Wound Repair Regen 1999; 7:442. 15. lawrence w and diegelmann r, Growth factors in wound healing. Clin Dermatol 1994; 12:157. 16. ruszczak z, Effect of collagen matrices on dermal wound healing. Adv Drug Deliv Rev 2003; 55(12):1595–1611.

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17. greenhalgh dg, The role of apoptosis in wound healing. Int J Biochem Cell Biol 1998; 30(9):1019–1030. 18. iocono ja, ehrlich hp and gottrup f et al., The biology of healing. In: DL Leaper and KG Harding, Editors, Wounds: Biology and Management, Oxford University Press, Oxford, England (1998), pp. 12–22. 19. garrett b, Re-epithelialisation, J Wound Care 1998; 7:358–359. 20. clark raf, Wound repair: Overview and general considerations (ed 2). In: RAF Clark, Editor, The Molecular and Cellular Biology of Wound Repair, Plenum Press, New York, NY (1995), pp. 3–50. 21. ruszczak z, Effect of collagen matrices on dermal wound healing. Adv Drug Del Rev 2003; 55(12):1595–1611. 22. eichler mj and carlson ma, Modeling dermal granulation tissue with the linear fibroblast-populated collagen matrix: A comparison with the round matrix model. J Dermatol Sci 2005; 41(2):97–108. 23. stadelmann wk, digenis ag and tobin gr, Physiology and healing dynamics of chronic cutaneous wounds. Am J Surg 1998; 176(2):26S–38S. 24. calvin m, Cutaneous wound repair, Wounds 1998; 10:12–15. 25. lorenz hp and longaker mt, Wounds: biology, pathology, and management. Stanford University Medical Center, 2003. 26. streuli c, Extracellular matrix remodeling and cellular differentiation, Curr Opin Cell Biol 1999; 11:634–640. 27. enoch s, grey je and harding kg, Recent advances and emerging treatments. BMJ Apr 2006; 332:962–965. 28. diabetes care, american diabetes association. Consensus development conference on diabetic foot wound care. 1999; 22:1354–1360. 29. eaglestein wh and mertz pm, ‘Inert’ vehicles do affect wound healing. J Invest Dermatol 1980; 74:90. 30. hanson c, Interactive wound dressings. A practical guide to their use in older patients. Drugs Aging 1997; 11:271–284. 31. jones v, grey je and harding kg, Wound dressings. BMJ Apr 2006; 332:777–780. 32. fleck tm, fleck m, moidl r, czerny m, koller r, giovanoli p, hiesmayer mj, zimpfer d, wolner e and grabenwoger m, The vacuum-assisted closure system for the treatment of deep sternal wound infections after cardiac surgery. Ann Thoracic Surg 2002, 74(5):1596–1600. 33. enoch s, grey je and harding kg, Non-surgical and drug treatments. BMJ Apr 2006; 332:900–903. 34. jonsson k, hunt tk and mathes sj, Oxygen as an isolated variable influences resistance to infection. Ann Surg 1988; 208(6):783–787. 35. wu l et al., Effects of oxygen on wound responses to growth factors: Kaposi’s FGF but not basic FGF stimulates repair in ischemic wounds. Growth Factors 1995; 12(1):29–35. 36. han sk et al., Potential of human bone marrow stromal cells to accelerate wound healing in vitro. Ann Plast Surg 2005; 55:414–419. 37. badiavas ev and falanga v, Treatment of chronic wounds with bone marrowderived cells. Arch Dermatol 2003; 139(4):510–516.

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2 Testing dressings and wound management materials S. T. T HOM A S, formerly of Surgical Materials Testing Laboratory, Medetec, UK

Abstract: The development of modern dressings is briefly reviewed and a description is given of how new test methods and specifications have evolved to characterise various key aspects of the performance of the products concerned. For thousands of years man has applied a variety of materials to his wounds to control bleeding and promote healing. For much of that time many of the materials used were largely those that occurred naturally, or which were developed and used primarily for another purpose. Only in the last thirty to fi fty years have large number of increasing complex products been developed specifically for application to open wounds of all types. These new dressings vary widely in composition and construction and, as a result, new families of performance-based test methods and specifications have been developed in order in order to characterise their performance. Key words: wound dressings, wound management, fluid handling, hydrocolloids.

2.1

Introduction

The use of materials to cover or treat wounds stretches back into antiquity but the use of standards and specifications to characterise these materials is relatively new. The fi rst standards that were used to characterise dressings were very simple and concentrated primarily upon the structure rather than the function of the products concerned. As new, ever-more sophisticated dressings were introduced, there was an increasing need for test systems to demonstrate that these materials perform in a consistent manner and delivered the performance claimed for, and expected of them. Whilst it is undoubtedly true that ultimately it is how a product performs clinically that will determine its acceptability and commercial success, well-designed laboratory tests can provide a useful performance indicator, particularly in comparative terms. In this chapter, the need for dressing standards is discussed and how these standards have evolved, and briefly outlines test methods that can be 20

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used to assess key aspects of the performance of many different types of products.

2.2

The need for laboratory testing

Laboratory tests for dressings are required for a number of reasons: •

To demonstrate compliance with national or international standards or specifications. • To ensure product meets ‘in-house’ manufacturing standards. • To facilitate comparisons with competitive products. • To generate data to support allocation of shelf life (stability/storage). There are essentially three types of standards or specifications.

• Structural standards, which defi ne the structure and/or composition of a product. • Performance standards, which describe one or more key aspects of the function of a dressing. • Safety standards, designed to ensure that a product, when used appropriately, is unlikely to adversely affect the health or wellbeing of the individual to whom it is applied.

2.2.1 The development of dressings For centuries mankind had little option but to apply readily available natural substances to his wounds to staunch bleeding, absorb exudate or promote healing. Initially, these would have consisted of simple materials such as honey, animal oils or fat, cobwebs, mud, leaves, moss or animal dung applied in the crude form in which they were found, but later these and other ‘raw materials’ began to be combined together, either to make them easier to handle, or to improve their clinical effectiveness. Whilst most of these early preparations were probably of little or no value, others, such as honey, used alone or mixed with oils or waxes, undoubtedly conferred some real clinical benefits to the user. Up to the end of the 19th century, whenever dressings were required to cover wounds, absorb exudate or remove blood during a surgical procedure, practitioners of the time used whatever materials were to hand, often recycling old pieces of cloth or linen fabric for this purpose. This was sometimes fi rst unravelled to form short ends of thread called ‘charpie’, or the surface was scraped with knives to produce ‘soft lint’, a soft fluffy material not dissimilar to absorbent cotton (cotton wool) which could be used to pack cavities and soak up exudate or blood. The fi rst product to be manufactured commercially for use as a dressing was absorbent (sheet) lint. This was formed by scraping sheets of old linen

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with sharp knives to raise a fibrous ‘nap’ on one surface, increasing the absorbency of the cloth but decreasing its tensile properties. Initially a manual process, a lint-making machine was developed in the fi rst half of the 19th century which used new, specially woven, fabric for the purpose. This resulted in a more consistent product with, it is assumed, a considerably lower bioburden! Originally lint was formed from linen but this was eventually replaced by cotton by the middle of the 20th century.

2.2.2 The first standards for dressings As new types of dressings were developed and the production of surgical materials became more mechanised, it became necessary to develop formal standards to ensure that these were consistently produced to an agreed of level of quality. The fi rst of these appeared in two supplements to the British Pharmaceutical Codex (BPC) of 1911 and these were later incorporated into the 1923 edition of this publication. Over 80 products were described, the majority of which consisted of cotton fibre, both medicated and unmedicated, and a variety of cotton fabrics together with a few more complex products such as emplastrums (plasters) and oiled silk. The BPC remained the principal source of standards for surgical dressings within the United Kingdom for over 50 years, but, in 1980, these were transferred to the British Pharmacopoeia (BP). When, as a result of European legislation, dressings became classified as Medical Devices, monographs for these materials were subsequently omitted from the BP.

2.2.3 The importance of performance-based specifications The early pharmacopeial monographs consisted almost entirely of structural specifications supplemented by limit tests for potential contaminants. Whilst such standards undoubtedly have a value as quality control checks to ensure that products which have previously been shown to meet a specific clinical need are produced in a consistent way from a range of well-characterised materials, they do not facilitate comparisons between the performances of different types of dressings. Their proscriptive and inflexible nature also prevents or delays the introduction of new and more innovative products which may be structurally different from the standard materials. Recognising these limitations, in the early 1990s, the Surgical Dressings Manufacturing Association (SDMA) set up a series of working groups, comprising technical staff from the industry and the NHS, to devise a new family of performance-based test methods and specifications. These were based on a number of instances upon work that had been pioneered within the Surgical Materials Testing Laboratory (SMTL), an NHS facility that specialised in testing wound dressings and other medical disposables for the

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NHS in Wales. This group published test methods for bandages, alginates, fi lms, hydrocolloids and hydrogels, many of which subsequently became incorporated into the BP and/or adopted as European Standards. The types of tests required to characterise the performance of a dressing should be determined by the nature and condition of the wound to which the product is to be applied. The functions of a dressing have been described more fully in the past,1 but for the purpose of this chapter the principal requirements are summarised below. • • • • • •

Exudate management/environmental control Control or prevention of infection Provide a bacterial barrier Odour control Low-adherence Freedom from toxicity.

2.3

Fluid-handling tests

The effective management of the moisture content of a wound and the surrounding skin is perhaps the most important requirements of any dressing system. In the case of exuding wounds, this implies the removal of excess wound fluid, but, in dry or lightly exuding wounds, the dressing may be required to conserve moisture in order to maintain the exposed tissue in the optimum state of hydration to facilitate epithelialisation or promote autolytic debridement. The ability to control the loss of moisture from a wound is commonly determined by the moisture vapour permeability of the dressing or dressing system. Because excessive exudate can cause maceration of the periwound skin, which in turn can lead to infection, considerable attention has been given by the industry to the development of highly absorbent products that are able to prevent fluid from spreading over the surrounding healthy tissue. Some dressings, such as hydrophilic polyurethane fi lms, are very permeable to water vapour and thus permit the passage of a significant quantity of the aqueous component of exudate from the wound to the environment by evaporation. In practice, however, most permeable products are unable to cope with the volume of fluid that is produced by heavily exuding leg ulcers, burns or malignant wounds. In such situations, products that have the ability to absorb or otherwise retain significant quantities of liquid are required, although many also combine this absorptive function with a significant degree of moisture vapour permeability. These two values determine the ability of a dressing to cope with wound exudate and are described as its fluid handling capacity (FHC). 2 Numerous different tests have been described to characterise the fluid handling properties of dressings, which vary from simple ‘dunk and drip’

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tests to more sophisticated techniques in which a suitable test fluid is applied to a sample of dressing under controlled conditions, some of which have been incorporated in the European Standard (BS EN 13726-1) 3 described below.

2.3.1 Free swell absorptive capacity This, the fi rst standard test described in BS EN 13726-1, measures the uptake of fluid by fibrous dressings such as those made from alginate fibre presented either in sheet or rope form. The dressing is placed in a Petri dish together with a quantity of test solution equivalent to 40 times the weight of the test sample, and held for 30 min at 37 °C after which it is gently removed from the dish, allowed to drain for 30 s and reweighed. The absorbency is then expressed as the mass of solution retained per 100 cm 2 (for sheet dressings) or per gram of sample for cavity dressings. Unless otherwise stated, all absorbency tests are performed using ‘Test solution A’, a mixture of sodium chloride and calcium chloride solutions containing 142 mmol of sodium ions and 2.5 mmol of calcium ions as the chloride salts. This solution has an ionic composition similar to human serum or exudate. The presence of both sodium and calcium ions is required as these both have a marked effect upon the gelling characteristics of alginate fibres. It will immediately be seen that a serious criticism of this method is that the alginate is tested in the absence of any pressure, which means that the results obtained bear little relation to the volume of exudate that the dressing will take up under normal conditions of use. (This point is returned to later.) In the presence of sodium ions, alginate fibres absorb fluid and swell, sometimes taking on a gel-like appearance. The degree of swelling and dispersion is determined by the chemical structure, ionic content and method of preparation of the dressing. Some alginate products, having a high mannuronic acid content, appear to form an amorphous mass, whilst others with a high guluronic acid content tend to retain their structure and swell to a much lesser degree.4 These properties are quite important as they determine how the dressing will perform when introduced into a wound and BS EN 13726-1 describes two simple tests that help to characterise the alginate and determine its dispersion/solubility.

2.3.2 Fluid-handling capacity This test, also described within BS EN 13726-1, and based on a method published previously, 5 provides information on the amount of test fluid

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both retained and transpired by products such as hydrogel and hydrocolloid sheets and other dressings made from foam which incorporate an integral waterproof backing layer. The method is not suitable for testing fibrous products or permeable absorbents. The test involves the use of a simple piece of apparatus known as a Paddington Cup. This is described in detail in the standard, but, essentially, it consists of a cylinder with an internal cross-sectional area of 10 cm 2 having a flange at each end. To one end of the cylinder is fitted an annular ring, the internal diameter of which is identical to that of the cylinder, and, to the other, a solid plate, which can be clamped into position forming a watertight seal. A piece of dressing under examination is cut to shape and clamped between the annular ring and one of the flanges. The cylinder together with all the associated parts is then weighed. Approximately 20 ml of test fluid is added to the cup and the plate clamped in position. The cup is then weighed again before being placed in an incubator capable of maintaining the internal temperature and humidity within specified limits (37 ± 1) °C and relative humidity <20% throughout the test. After a predetermined period (usually 24 h) the cylinder is reweighed, the plate removed and the excess fluid is allowed to escape after which the cylinder is reweighed once again. From these weighings, it is possible to calculate the amount of fluid lost through the back of the dressing by evaporation during the period of test, and the weight of fluid retained within its structure. The sum of these two values represents the Fluid Handling Capacity of the dressing. By way of illustration, Tables 2.1–2.3 contain the published results of fluid handling tests performed on 12 hydrocolloid dressings over 24, 48 and 96 h. 5 Individually the tables illustrate the differences between products at each time point, but a comparison of the results achieved with individual products at the two time points clearly demonstrates how the products vary in terms of their rate of hydration. Some products reach full absorbency after 24 h, others are still absorbing after 96 h. These differences clearly have potentially important clinical implications for the use of the products concerned.

2.3.3 Moisture vapour transmission rate (MVTR) This same apparatus described in BS EN 13726-1 may be used in a similar although less complicated fashion, to determine the MVTR of permeable fi lm dressings. This method is described in BS EN 13726-2.6 Although the official method specifies that the apparatus shall be incubated with the solution in contact with the test sample, it is also possible

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Table 2.1 Fluid-handling characteristics of hydrocolloid dressings after 24 h*

Tegasorb Thin Tegasorb Cutinova Hydro Askina Biofilm Transparent Askina Transorbent Comfeel Plus Plaques Biseautees Comfeel Plus Transparenter Comfeel Plus Flexibler (sample 1) Comfeel Plus Flexibler (sample 2) Varihesive E Granuflex Hydrocoll Algoplaque

Moisture vapour loss [g (s.d.)]

Weight absorbed [g (s.d.)]

FHC [g (s.d.)]

0.58 0.60 0.67 0.27 3.35 1.33 0.65 0.49

(0.03) (0.22) (0.03) (0.02) (0.51) (0.05) (0.10) (0.05)

2.89 (0.26) 4.40 (0.11) 2.53 (0.05) 0.24 (0.07) 0.80 (0.05) 1.53 (0.04) 3.98 (0.12) 3.27 (0.09)

3.47 (0.26) 5.01 (0.26) 3.21 (0.05) 0.51 (0.08) 4.16 (0.55) 2.86 (0.06) 4.63 (0.16) 3.76 (0.11)

0.77 (0.12)

3.33 (0.06)

4.10 (0.11)

0.03 0.03 0.50 0.22

1.94 (0.11) 1.75 (0.13) 5.62 (0.11) 1.32 (0.14)

1.97 (0.12) 1.78 (0.14) 6.12 (0.12) 1.54 (0.38)

(0.01) (0.02) (0.04) (0.45)

* Reproduced with permission from: A comparative study of the properties of twelve hydrocolloid dressings http://www.worldwidewounds.com/1997/july/ Thomas-Hydronet/hydronet.html.

Table 2.2 Fluid-handling characteristics of hydrocolloid dressings after 48 h* Dressing

Moisture vapour loss [g (s.d.)]

Weight absorbed [g (s.d.)]

FHC [g (s.d.)]

Tegasorb Thin Tegasorb Cutinova Hydro Askina Biofilm Transparent Askina Transorbent Comfeel Plus Plaques Biseautees Comfeel Plus Transparenter Comfeel Plus Flexibler (sample 1) Comfeel Plus Flexibler (sample 2) Varihesive E Granuflex Hydrocoll Algoplaque

1.46 (0.07) 2.27 (1.06) 1.92 (0.02) 0.38 (0.02) 3.90 (0.38) 2.28 (0.21) 3.02 (0.21) 1.55 (0.06) 2.21 (0.12) 0.13 (0.03) 0.10 (0.01) 1.06 (0.05) 0.17 (0.03)

3.70 (0.07) 5.25 (0.39) 2.87 (0.04) 0.12 (0.14) 0.75 (0.03) 4.39 (0.05) 1.68 (0.12) 3.73 (0.09) 3.45 (0.14) 2.77 (0.10) 2.86 (0.08) 6.46 (0.21) 2.81 (0.09)

5.17 (0.08) 7.52 (0.69) 4.80 (0.06) 0.50 (0.13) 4.64 (0.38) 6.67 (0.19) 4.70 (0.28) 5.28 (0.06) 5.66 (0.16) 2.90 (0.11) 2.96 (0.08) 7.52 (0.25) 2.98 (0.07)

* Reproduced with permission from: A comparative study of the properties of twelve hydrocolloid dressings http://www.worldwidewounds.com/1997/july/ Thomas-Hydronet/hydronet.html.

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Table 2.3 Fluid-handling characteristics of hydrocolloid dressings after 96 h* Dressing

Moisture vapour loss [g (s.d.)]

Weight absorbed [g (s.d.)]

FHC [g (s.d.)]

Tegasorb Thin Tegasorb Cutinova Hydro Askina Biofilm Transparent Askina Transorbent Comfeel Plus Plaques Biseautees Comfeel Plus Transparenter Comfeel Plus Flexibler (sample 1) Comfeel Plus Flexibler (sample 2) Varihesive E Granuflex Hydrocoll Algoplaque

3.45 (0.11) 5.50 (0.75) 4.04 (0.07) 0.79 (0.01) 9.89 (0.73) 6.41 (0.31) 9.31 (1.01) 4.28 (0.75) 5.67 (0.58) 0.91 (0.18) 0.63 (0.47) 2.19 (0.11) 0.44 (0.03)

3.59 (0.48) 5.57 (0.66) 2.95 (0.05) 0.19 (0.16) 0.82 (0.05) 4.45 (0.10) 1.45 (0.22) 4.03 (0.24) 3.69 (0.14) 3.35 (0.11) 3.35 (0.36) 5.02 (0.69) 3.81 (0.19)

7.04 (0.51) 11.06 (0.19) 6.99 (0.05) 0.98 (0.17) 10.72 (0.75) 10.85 (0.31) 10.77 (0.81) 8.31 (0.77) 9.36 (0.51) 4.25 (0.19) 3.98 (0.13) 7.19 (0.76) 4.25 (0.20)

* Reproduced with permission from: A comparative study of the properties of twelve hydrocolloid dressings http://www.worldwidewounds.com/1997/july/ Thomas-Hydronet/hydronet.html.

to undertake the test with the cylinder inverted so that the dressing is not in direct contact with the liquid but exposed only to moisture vapour. This is important because the permeability of some types of polyurethane film will increase dramatically whilst in contact with liquid but revert back to previous values when this is removed – a characteristic that has obvious and important implications for its use as a wound dressing when in contact with intact peri-wound skin. 2

2.3.4 Dynamic MVTR The fluid handling and moisture vapour transmission methods described previously, provide a single value for the amount of fluid which is lost through the back of the dressing during the test period. Whilst this may be suitable for fi lm dressings, the permeability of which remain relatively consistent throughout the test period, the test has serious limitations for products such as hydrocolloids in which the permeability of the dressing changes with time as the adhesive mass on the wound contact surface gradually becomes hydrated. This problem can be overcome by a modification to the standard test which has been described previously. 5 A Paddington Cup is set up as

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described and placed upon the pan of a top loading balance located in a controlled humidity cabinet which is connected to a data logger. In this way, the weight of the Paddington Cup can be continuous monitored over the test period, and, from the recorded data, the change in moisture vapour transmission rate may be determined. Depending upon the product this may be virtually zero for a number of hours, gradually increasing to reach a steady state some time during the following 24–48 hours. 5,7 The weight of fluid absorbed by the dressing during this time is determined as previously described. Using this method, it is also possible to demonstrate the marked change in permeability that occurs when a hydrophilic polyurethane membrane is brought into contact with liquid. Two similar absorbent polyurethane foam dressings with semipermeable fi lm backing layers were tested as described and after a 6-h incubation with the dressings uppermost, i.e. not in contact with the test solution, the chambers were inverted so that the test materials were allowed to become wet. The results, shown in Fig. 2.1, show a marked increase in the permeability of one product but not the other. This change in permeability has important implications for the relative fluid-handling properties of the dressings when applied to heavily exuding wounds.

14

Loss of moisture vapour (g/10 cm2)

12 10 8 6 4 2 0 0

2

4

6

8

10 12 14 16 18 20 22 24 Time (h)

2.1 Effect of inversion of the test chamber after 6 h on the moisture vapour transmission rate of two film-backed dressings.

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2.3.5 Shortcomings of existing test methods Although methods described thus far facilitate comparisons of the fluidhandling properties of similar products within specific groups and provide useful quality control tests to confi rm consistency of production, they do not permit direct comparisons between different groups of dressings such as alginates and hydrocolloids. They also cannot be used to investigate the performance of the different dressings when subjected to pressure – a major factor in the treatment of venous leg ulcers where dressings are often subjected to pressures as high as 40 mm Hg. Some dressings, such as foam sheets are like bath sponges, capable of taking up large volumes of fluid, but unable to retain this under even light pressure. Much research has therefore been devoted to maximising the performance of foam dressings by casting the foam from hydrophilic polymers and/or the inclusion of super-absorbents within the porous structure of the foam itself. These developments have resulted in the formation of a family of products that are among the most absorbent and widely used dressings available. Test systems are therefore required to compare these different dressings under varying levels of pressure in simulated clinical conditions. Over the years, numerous methods for measuring the absorbency of wound dressings have been described, most of which consist of variations on a common theme. The dressing under examination is placed on a simple wound model, which usually consists of a metal or acrylic plate with a small hole or depression in the centre. A weight is then applied to the back of the dressing to simulate the pressure applied by a bandage and test fluid is applied to the dressing through the plate by means of a peristaltic pump or syringe driver. In some test systems, the fluid is not actively pumped into the dressing but is absorbed by the dressing itself from some form of constant head apparatus. 8 A particular example of such a test system is the ‘demand wetability’ apparatus that was developed to investigate how fibre pre-treatments and alignment can influence the uptake of water.9 For a surgical dressing, the absorbent capacity is generally taken to be that volume of fluid taken up by the time at which strike-through occurs. Strike-through is defi ned as the point at which absorbed fluid reaches the outer surface or edge of a dressing and this may be determined in a number of different ways. In one early system devised by SMTL,10 the distribution of liquid absorbed by the dressing was monitored electronically by means of sharp steel spikes which penetrated into the body of the dressing. The disruption to the structure of the test sample caused

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by the spikes cast doubt on the validity of this method and so it was abandoned. Many of the other test systems developed previously also suffered from a series of disadvantages: • •

•

•

•

• •

They can be difficult to automate and therefore may not always be suitable for running unattended over extended periods. The application of a weight and/or strike-through detector on the back of the dressing prevents the loss of moisture vapour, an important mechanism by which some dressings cope with exudate production. If moisture vapour transmission is to be measured, it is not possible to apply a weight or strike-through detector on the back of the dressing to simulate the effect of pressure. The use of a positive feed system for the application of test fluid can produce anomalous results. For example, a hydrocolloid dressing that is fi rmly stuck to the acrylic sheet may appear to be capable of absorbing large volumes of test solution when in fact this is simply being trapped under the dressing in the form of a huge bubble. Most simple test systems provide a single value for the total absorbency of a dressing with little indication of how the product performs over a specified period of time (dynamic performance testing). Many wound models are not suitable for testing hydrogels or packing materials. They do not readily enable predictions to be made of clinical wear times of different types of dressings.

2.3.6 Development of the Wrap rig Research undertaken in the SMTL, led to the development of a new test system (called the Wrap rig), which facilitates comparison of the fluid handling properties of most types of dressings irrespective of their structure and composition even whilst under compression. Design requirements of a test system In order to address some of the shortcomings of test methods described previously and produce a system that more closely approximated to the clinical situation, a series of key design criteria for the new model were derived previously.11 •

Fluid should be provided to the test sample by some form of pump or other suitable positive flow device. A passive uptake technique is not acceptable.

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•

•

•

• •

• •

• • • •

31

The fluid should not be presented to the test sample under excessive pressure. Previous test systems have, in effect, injected fluid into the dressing under pressure, although there is no evidence that this occurs in wounds. There must be some suitable method for controlling the temperature of the system for the duration of the test, to reproduce the environmental conditions in the wound. The test should provide some indication of the dynamic performance of the dressing, measuring its fluid-handling capacity profi le over time, and not just a single total absorbency figure. The equipment should be capable of delivering test solution at a range of different flow rates, so that the effect of different rates of exudate can be examined. The apparatus should indicate when either vertical or lateral strikethrough has occurred. The apparatus should be suitable for testing a wide range of different types of dressings to permit direct comparison of the results. Previous methods were frequently dedicated to one type of technology, such as alginates. The equipment should be compatible with a range of different test solutions. Where appropriate, the apparatus should permit the application of varying loads to the test samples in order to determine the effect of external pressure. The apparatus should permit the measurement of moisture vapour transmission by the dressing as an integral part of the test. The test should be easy to perform and provide results that can be reproduced within and between laboratories. The equipment should not be excessively expensive to produce. The test should, ideally, provide an indication of the wear time of a dressing in normal clinical use.

In addition to the primary design criteria, a number of additional features were identified, which, although not essential, are considered desirable features in a wound model. • The apparatus should withstand sterilisation or disinfection. • The apparatus should permit analysis of wound fluid that has been in contact with the dressing to measure changes in ionic composition or changes in concentration of solutes such as proteins caused by selective absorbtion by the dressing. • The apparatus should permit microbiological examination of the local environment during the course of the test.

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2.2 The Wrap rig.

• The test equipment should allow the pressure beneath the dressing to be varied if this is considered desirable. A prototype test system was developed based upon these criteria.11 Following some early validation work, some minor modifications were made and a new version of the rig was produced; the use of this rig has been described in a subsequent publication which also clearly illustrated the effects of compression upon dressing performance.12 Essentially the apparatus consists of a number of separate components. The wound model The Wrap rig model consists of a two-part stainless-steel plate (the ‘wound bed’), mounted on a Perspex table (Fig. 2.2). An electronically controlled heating mat beneath the steel plate keeps the plate and test sample under examination within a narrow temperature band. The central section of the plate is milled from solid stainless steel and includes a shallow circular recess bearing two ports on opposite ends of a 15-mm-long shallow channel. An inlet hole 3 mm in diameter and a outlet hole 7 mm in diameter permit the introduction and unimpaired exit of test solution. The diameter and depth of the circular recess is sufficient to accommodate two thin absorbent pads that ensure the effective transfer of liquid from the channel to the dressing above. Test fluid, introduced by means of a syringe pump, travels along the narrow channel and passes out through the second port, falling verti-

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cally down through a short, wide-bore tube. This tube discharges into a receiver placed on the pan of an electronic balance. The liquid in the receiver is covered with a layer of oil to prevent loss by evaporation. The balance is connected to an electronic data capture device that records changes in the balance reading at predetermined intervals throughout the period of the test. A dressing sample typically measuring 10 cm × 10 cm is secured on to the test plate which is set to a predetermined temperature. Test fluid applied to the test rig passes along the open channel some or all of which will be taken up by the dressing. Any unabsorbed fluid continues to pass along the channel until it falls through the outflow pipe into the receiver, causing a change in the balance reading. The amount of fluid that accumulates in this way is inversely proportional to the absorbency of the dressing. A highly absorbent dressing may take up all the liquid that is applied to it, while less absorbent products will absorb only for a short time or take a little while to reach maximum absorbency. During a test, therefore, the maximum weight of fluid that can be taken up by a dressing is determined by the flow rate of the syringe pump. As this test system is designed to simulate the normal use of a dressing, it is important to ensure that the test conditions employed are as clinically relevant as possible, particularly in relation to the production of exudate. Previous studies have found that a heavily exuding wound typically produces around 5 ml per 10 cm 2 per 24 h,13 but in the presence of infection this value can easily double.14 Although it is possible to run the test with these flow rates, for most tests the syringe pump is normally set to deliver a nominal 1 ml h−1 as this value provides a reasonable compromise between clinical relevance and a need to keep testing times to a minimum for practical reasons. When testing cavity wound dressings, alginate fibre or hydrogel dressings, a simple modification is made to the apparatus. A piece of stainless tube is fi xed inside the recess in the centre of the plate to form a chamber into which the dressing is placed. Although strike-through measurements are not appropriate with such dressings, it is possible to apply pressure to cavity dressings such as alginate packing by means of a weighted stainlesssteel piston, which forms a sliding fit in the tube. In all other respects, the test procedures remain the same. When testing hydrogel dressings, the open end of the chamber is sealed with a piece of aluminium foil held in place with impermeable plastic tape to prevent evaporation. The ability of this test system to differentiate between different hydrocolloid dressings is shown in Fig. 2.3. All the products, which were tested in the same way, are superficially similar in appearance but as the figure clearly indicates, marked differences exist in their ability to absorb and retain test solution.

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Advanced textiles for wound care 8 Fluid uptake (g)

7 6 5 4 3 2 1 0

0

10

20

30 Time (h)

40

50

2.3 Fluid handling properties of four hydrocolloid dressings measured using the Wrap rig.

The pressure/vertical strike-through plate As previously discussed, the application of a weight to the back of the dressing to simulate pressure produced by compression bandages has the undesirable effect of occluding the back of the dressing and preventing the transpiration of moisture vapour, an important part of the function of the dressing. This problem was overcome in this model in a novel way by combining in one piece of apparatus, the functions of strike-through plate, moisture-absorbing-unit, and pressure plate. A stainless-steel box, one surface of which consists of a coarse stainless-steel mesh supported internally by pillars attached to the inner face of the other surface to impart structural rigidity, can be fi lled with silica gel and when placed upon the test sample with the mesh surface downwards it fulfi ls three functions: • It permits the application of pressure to the dressing without occluding the outer surface. • It provides a humidity gradient across the dressing to facilitate passage of moisture vapour. • It acts as an electrical contact to detect strike-through. Recording strike-through A method of recording strike-through was devised that proved to be relatively easy and trouble free. This consisted of a Psion Organiser II (Model XP) fitted with a Digitron Model SF10 Datalogger unit. The SF10 unit plugs into the top of the Psion II, and is a four-channel unit capable of taking up to four external probes to measure temperature, pressure, relative humidity or voltage. For the purpose of this study, a voltage probe,

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capable of recording from 0–2500 mV, was used. A 1.5-V (AA sized) alkaline cell was used to supply the necessary electromotive force. Initial experience with this equipment suggested that the combination provided a simple and reproducible technique for measuring strike-through, recording values that changed instantly from 0 mV to in excess of 1000 mV when strike-through occurred. At this point, the contribution made by the loss of moisture vapour to the fluid-handling properties of the sheet dressings may be determined by measuring the change in weight of the silica gel in the strike-through plate. Lateral strike-through detectors Lateral strike-through may be detected by the use of four brass strips, typically 90 mm × 20 mm × 3.5 mm thick, connected with short lengths of flexible cable. The under-surface of each strip is covered with a layer of insulating tape to prevent it from making electrical contact with the stainless-steel plate. In use, the strips, which are connected to the strikethrough detector, can be pushed gently against the exposed edges of the dressing to detect any moisture that appears at the edge of the dressing. The new test rig is currently being evaluated by a multidisciplinary group comprising representatives from most European dressings companies, in addition to others with an interest in dressing design or performance. This group, which was originally funded by a research grant from the Engineering and Physical Sciences Research Council (EPSRC), is concerned with the development and validation of methodologies for medical device evaluation.

2.3.7 Fluid-affinity test Some hydrogel dressings, both in sheet and amorphous form, have the ability to absorb or donate liquid according to the condition of the underlying tissue. This means that they can absorb fluid from a heavily exuding wound or donate moisture to dry or devitalised tissue to promote autolytic debridement. Test systems are therefore required which can be used to assess both these properties. The material in question is placed in contact with other gels made from varying concentrations of agar or gelatine representing a spectrum of tissue types, and the transfer of liquid to or from the test sample to the standard gels is measured by recording any change in weight of the sample. A fairly basic version of this technique was described in three early publications15–17 but this was gradually refi ned and used as the basis of a standard method described in BS EN 13726-1.

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Advanced textiles for wound care

2.4

Low-adherence tests

2.4.1 Importance of low-adherence The results of a international survey,18 identified that pain and trauma were ranked as the most important factors to consider when changing dressings. A total of 3918 clinicians who responded to a written questionnaire, considered that pain was most commonly associated with dressings drying out or adhering to the wound bed, factors that were also considered to be responsible for wound trauma. Some products like alginates, hydrogels or silicone products show little propensity to adhere to granulating wounds whilst other such as simple gauze or non-woven fabrics perform particularly badly in this context. It is generally believed that there are two mechanisms of adherence. The fi rst is the inherent ‘stickness’ of serum which acts like a simple adhesive that forms a bond between two opposing surfaces. The second mechanism is a little more complex, involving the penetration into the dressing of serous fluid containing cellular debris which dries to form a solid ‘scab’ on the wound surface but which also incorporates some of the structural elements of the dressing which acts like reinforcing bars in concrete. As a result when the dressing is removed the scab, together with underlying new epithelium, is forcibly removed leading to rewounding and delayed healing. Many dressings have therefore been developed with a woundcontact surface that is designed specifically to reduce adherence, examples of which have been described previously.19

2.4.2 Measurement of adherence potential Predicting the way in which dressings will perform clinically in terms of adherence has proved unexpectedly difficult, as no standard laboratory test system has been described for this purpose. In 1982, a method was devised by SMTL in which a cold-cure silicone rubber material was applied onto the surface of a test sample using a plastic former to control the area of application.10 Once the rubber had set, the dressing was removed from the former containing the silicone block by means of a tensiometer to record the applied force, using a 180° peel. Although no absolute values could be applied as limits, the test system was used to rank products in order of their adherence potential. In a later modification to this test, an aqueous solution of gelatine was used to replace the silicone as this more closely represents the in vivo situation. This procedure is still used as a non-official ‘in-house’ test.

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37

Conformability tests

Dressings applied around joints or to other areas of tissue that are subject to movement or distortion must, to some degree, accommodate this movement without causing excess pressure, or in the case of adhesive products, shearing forces that can cause skin trauma. Whilst products such as bandages tend to accommodate changes in body geometry fairly readily, products such as hydrocolloids, semipermeable fi lm dressings and self-adhesive island dressings can sometimes cause clinical problems. 20 A test designed to assess the extensibility and permanent set conformability of primary wound dressings by measuring its extensibility and permanent set is described in BS EN 13726-4. In this test, strips of dressing 25 mm wide with an effective test length of 100 mm are extended by 20% in a constant rate of traverse machine at 300 mm min−1. The maximum load is recorded and the sample is held in this position for 1 min. It is then allowed to relax for 300 s before being remeasured. Further samples taken from a direction perpendicular to the first are also tested in a similar way to account for ‘directionality’ in structure of the material. The standard requires that the test report records the maximum load, the extensibility and the permanent set which are calculated using the formulae provided. An alternative test method, which eliminates the problems of directionality by extending a sample in all directions at once has been developed using a modification of the Apparatus for the Measurement of Waterproofness described in the BP 1993. This consists of a chamber, open at one end, bearing a flange with an internal diameter of 50 mm. A retaining ring with the same internal diameter as the hole in the flange is mounted over the open end of the cylinder which can be lowered down onto the flange by means of a screw thread. A sample of the dressing under examination is placed on the flange and held fi rmly in place by means of the retaining ring. During the course of this test, air is slowly forced into the chamber by means of a large syringe. The resultant rise in the pressure within the chamber causes the dressing to expand and form a hemisphere which gradually increases in size until the upper surface of the dressing comes into contact with a marker placed 20 mm above the dressing surface at the start of the test. This pressure reading is then recorded by means of a transducer. In this test, the conformability of a dressing is considered to be inversely proportional to the pressure required to deform it by a predetermined amount and is represented by the mean inflation pressure of the samples examined. Results of the test performed on a range of hydrocolloid dressings are shown in Table 2.4.

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Table 2.4 Conformability of hydrocolloid dressings* Dressing

Mean inflation pressure [mm Hg (s.d.)]

Tegasorb Thin Tegasorb Cutinova Hydro Askina Biofilm Transparent Askina Transorbent Comfeel Plus Plaques Biseautees Comfeel Plus Transparenter Comfeel Plus Flexibler (sample 1) Comfeel Plus Flexibler (sample 2) Varihesive E Granuflex Hydrocoll Algoplaque

107 (4.6) 187 (32.0) 105 (3.7) 103 (5.7) † 164 (11.8) ‡ 166 (13.0) 161 (8.9) 156 (4.6) 162 (5.3) 194 (20.4) 154 (17.3)

*

Reproduced with permission from: A comparative study of the properties of twelve hydrocolloid dressings http://www.worldwidewounds.com/1997/july/ Thomas-Hydronet/hydronet.html. † Dressing is permeable to air and therefore could not be tested. ‡ Dimensions of dressing were too small for testing.

2.6

Microbiological tests

2.6.1 Bacterial barrier properties Wounds of all types represent a potential source of cross-infection, particularly if they are infected with antibiotic resistant organisms such as MRSA. It is therefore important to ensure that wounds, in so far as is possible, are isolated from the environment to prevent the ingress or egress of pathogenic micro-organisms. Many dressings therefore consist of (or include in their construction) a layer which prevents the transmission of micro-organisms into or out of a wound. Most commonly, this layer consists of a piece of cast polyurethane fi lm but sometimes closed cell foams are used for this purpose. The ability of a bacterium to pass through a dressing is determined by the presence of a liquid pathway. For dry wounds, a thick layer of absorbent cotton or gauze may be sufficient to prevent contamination, but, as soon as this becomes wet, the barrier properties are lost and the dressing becomes useless in this regard. It follows, therefore, that a test system for dressings designed to provide an effective bacterial barrier is required which provides the ‘worst-case’ scenario, and once again a method has been devised within SMTL that has gained widespread acceptance.

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A sterile dressing is aseptically clamped between two sterile flanged hemispheres (closures of reactions vessels are typically used) such that the dressing is maintained in the vertical plain. A microbiological liquid nutrient medium is introduced into both chambers one side of which contains a heavy inoculum of a suitable test organism. The apparatus is then incubated for an appropriate period after which the chamber containing the previously sterile nutrient solution is examined for evidence of growth. If no growth is visible, the dressing is considered to represent an effective bacterial barrier but, if growth is detected, samples are plated out to confi rm that it is the test organism not extraneous contamination from a failure in aseptic technique. This test is currently being evaluated by the industry before being formally proposed as a new European Standard.

2.6.2 Antibacterial properties Some dressings contain agents that have intrinsic antimicrobial activity such as antibiotics, antiseptics, silver ions or materials which possess a significant osmotic pressure capable of inhibiting bacterial growth. In clinical practice, these materials are released from the dressing to exert an antibacterial effect. Such dressings are often recommended or promoted for the treatment or prevention of soft tissue infections. Other products contain antimicrobials that are immobilised or fi xed within the structure or the wound contact surface of the dressing, i.e. not released into the local wound environment. These materials are claimed simply to prevent the proliferation of micro-organisms within the dressing itself. They have no direct effect upon the wound and as such are more suited for preventing crossinfection than for treating existing wound infections.

Tests for immobilised antimicrobial agents A number of methods have been described for evaluating the antimicrobial properties of immobilised antimicrobial agents. A quantitative procedure for the evaluation of the degree of antibacterial activity of fi nishes on textile material has been published by the American Association of Textile Chemists and Colorists. 21 According to this method, swatches of test and control material are inoculated with the test organisms using sufficient test material to absorb the total volume of inoculum (1 ± 0.1 ml) leaving no free liquid. After incubation, the samples are eluted with a suitable extractant containing a neutralising agent and the number of viable organisms present in this solution is determined using standard microbiological techniques.

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Whilst this method may be appropriate for testing a homogeneous mass of material, it is not suitable for evaluating a structured product such as a dressing that has several different components of which only one, the wound contact layer for example, may have antimicrobial activity. Any bacterial suspension that is taken up by the non-medicated part of the dressing will remain unaffected by the antibacterial fi nish on the medicated portion leading to anomalous results. This deficiency in the method is noted in a later test published by ASTM International. 21 This describes an alternative method that ensures good contact between the bacteria and treated substrate by constant agitation of the test specimen in a bacterial suspension for a specified contact time. The suspension is then serially diluted and the number of remaining viable organisms is determined and compared with values obtained using an appropriate control or untreated sample. This method also includes a procedure to ensure that the antimicrobial activity detected is not caused by leaching of the active ingredient as follows. An extract of the dressing is placed into an 8-mm hole in an agar plate inoculated with a test organism and the presence of any zone of inhibition around the well indicates the presence of leaching, thus rendering the test invalid. An alternative test, devised within the SMTL, graphically demonstrates the ability of a dressing to kill or inhibit the growth of micro-organisms that come into contact with it and thereby prevent the transfer of contaminated material into or out of a wound. In this test an agar plate has two channels cut out of it as to effectively form two separate agar areas in the Petri dish. One of the agar blocks is sterile; the other is inoculated with the test organism. A strip of dressing under examination is placed on top of the two blocks forming a bridge. Sterile water is place in the channel on the outer side of the contaminated agar to increase the water content of the gel and provide a ‘driving force’ to encourage the movement of moisture from the contaminated agar along or through the dressing to the sterile agar on the other side of the second channel. The Petri dish is incubated as normal with the dressings in place after which it is examined to detect the presence of growth around the margin of the test sample on the sterile agar surface. This test determines the ability of bacteria to survive on the dressing surface and migrate along it from the contaminated agar to the sterile agar. A positive result in this test suggests that it is possible that micro-organisms could be transported laterally out of a contaminated wound onto the surrounding skin, or potentially move in the opposite direction from the intact skin into the wound itself. No growth on the sterile agar suggests that the dressing does indeed have the ability to kill or prevent the growth of bacteria that come into contact with it.

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Tests for antimicrobial agents released from dressings For products that are designed to kill bacteria within the wound, alternative test systems are required based upon the following considerations. The ability of an antimicrobial dressing to exert a beneficial clinical effect is dependent upon three factors: • • •

The nature and spectrum of activity of the agent concerned The concentration of the material present in the dressing The release characteristics (does the material actually get into the wound?).

In its simplest form, the test can consist of the application of a piece of dressing applied to an agar plate that has previously been seeded with the test organism. Antibacterial activity is indicated by the presence of a halo or zone of inhibition around the sample, the size of which is determined at least in part by the concentration and solubility of the active ingredient. Such tests are easy to perform and can involve the use of different test organisms. 22–25 A possible criticism of this type of simple test is that the moisture content of the agar may be insufficient to facilitate extraction of the active agent from the dressing, or that the affi nity of the dressing for moisture may be such that it effectively retains the moisture within its structure and thus limits the amount that is released onto the agar to exert an inhibitory effect. It is also possible that the active agent may require the presence of sodium or calcium ions normally present in exudate or serous fluid to release or activate the biocidal agent within the dressing. Both of these problems may be overcome by a modification to the method in which a well is cut in the agar plate into which the dressing sample is inserted. The residual volume within the well is then fi lled with Solution A (used in absorbency testing) or, for research purposes, calf or horse serum. Alternatively, it is possible to make an extract of the dressing sample using an appropriate solution and place this into the well. A further test involves the incubation of a piece of dressing with a suitable volume of a bacterial suspension containing a known number of micro-organims. Following incubation, the dressing sample is extracted with an appropriate recovery medium and a total viable count performed on the extractant to determine the decrease in the number of viable organisms present. This test has the advantages that it can be conducted over various time intervals, and that it also provides a quantitative result. The tests have been described in detail previously in laboratory-based comparisons of silver containing dressings. 26,27 Unlike previous test systems, which gained fairly rapid acceptance by the industry enabling them to become adopted as official standards, it is

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more difficult to reach a consensus on tests for antimicrobial activity. Whilst there is a reasonable prospect of achieving agreement on the experimental techniques which can be used, there remains a problem in the interpretation of the results, the levels of activity that are required clinically, and, therefore, the limits which should be attached to each method. 28–31

2.7

Odour control tests

Certain types of wounds such as pressure ulcers, leg ulcers and fungating (cancerous) lesions produce noxious odours which, even in moderate cases, can cause significant distress or embarrassment to a patient and their relatives. 32

2.7.1

Causes of wound odour

The smell from a wound is caused by a cocktail of volatile agents that includes short-chain organic acids (n-butyric, n-valeric, n-caproic, nheptanoic and n-caprylic) produced by anaerobic bacteria, 33 together with a mixture of amines and diamines such as cadaverine and putrescine that are produced by the metabolic processes of other proteolytic bacteria. Organisms frequently isolated from malodorous wounds include anaerobes such as Bacteroides and Clostridium species, and numerous aerobic bacteria including Proteus, Klebsiella and Pseudomonas spp.

2.7.2 Management of wound odour The most effective way of dealing with malodorous wounds is to prevent or eradicate the infection responsible for the odour but, if for some reason this is not possible, it may be necessary to address the problem by some other means. In 1976, Butcher et al., 34 described the use of a charcoal cloth produced by carbonising a suitable cellulose fabric by heating it under carefully controlled conditions. The small pores formed in the surface of the fibres greatly increase their effective surface area and, hence, their ability to remove unpleasant smells, as it is believed that the molecules that are responsible for the production of the odour are attracted to the surface of the carbon and are held there (adsorbed) by electrical forces. Since 1976, a number of odour-absorbing dressings containing activated charcoal have been produced commercially, some of which are intended to be placed in direct contact with the wound whilst other products are designed as secondary dressings which are placed over a primary dressing, but beneath the retaining dressing or bandage.

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2.7.3 Testing odour absorbing dressings Despite the relatively widespread use of odour-absorbing dressings, however, little objective comparative data is available on their odour- and fluid-handling characteristics. A number of possible test systems have been described, 35–37 but some of these have only considered the efficacy of the dressing in the dry state, the fluid-handling properties of the dressing being considered separately. 38 This may be important because the presence of liquids, particularly those containing organic solutes, may have implications for the performance of the activated charcoal, competing for active sites with the molecules responsible for the odour and thus reducing its effectiveness. Previous studies have used both chemical, 35–37 and biological materials39,40 to test the efficacy of odour-adsorbing dressings. The former technique is often favoured as the efficiency of the dressing can be determined using standard analytical techniques such as gas–liquid chromatography. Determination of dressing performance using biological materials is currently restricted to more subjective methods of assessment such as the use of a human test panel. Lawrence et al.,40 adopted this second approach when they compared the odour-absorbing properties of five dressings containing activated charcoal with that of a cotton gauze swab, acting as a control. A more objective test system that could be used to compare the ability of different dressings to prevent the passage of a volatile amine when applied to a wound model under simulated ‘in-use’ conditions was devised by SMTL. This apparatus consists of a stainless-steel plate bearing a central recess (50 mm diameter × 3 mm deep) into which is inset a removable perforated stainless-steel disc and a disposable Millipore pre-fi lter. Fitted to the stainless-steel plate is an airtight Perspex chamber with inlet and outlet ports (Fig. 2.4). The dressing under examination is placed over the recess and sealed around the edges with impermeable plastic adhesive tape.

2.4 Apparatus for testing odour-absorbing properties of wound dressings.

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The test solution, consisting of Solution A to which is added 2% diethylamine and 10% newborn bovine serum, is applied to the dressing through the perforated plate at a rate of 30 ml h−1 by means of a syringe pump. The concentration of diethylamine in the air in the perspex chamber is constantly monitored using a Miran 1B2 portable ambient analyser (Quantitech Ltd, Milton Keynes) and the measured values recorded electronically using a datalogger. The test is continued until the concentration of diethylamine present in the air above the dressing has risen to approximately 15 ppm. By relating the flow rate of test solution to the rate at which wounds normally exude, it is possible to use the apparatus to estimate the useful life of a dressing in the clinical environment. The test system was evaluated in an independent study which compared the odour-absorbing properties of eight different dressings.41 The authors concluded that although there were still shortcomings associated with the use of the technique related to the application and orientation of the test sample, it appears to be the best way of objectively ascertaining quantitative comparable data on the odour-absorbing properties of different dressing products.

2.8

Biological tests

Because dressings come into intimate contact with damaged tissue, blood or body fluids, it is important to ensure that they are free from any agents that can adversely effect wound healing or otherwise cause an adverse reaction within the wound. The standard approach to testing medical devices is described in BS EN ISO 10993. This standard is divided into 18 parts, each of which describes a particular type of test or procedure that may be relevant to specific types of medical devices. For topical wound dressings the most relevant parts are as follows.

2.8.1 Part 5: Tests for in vitro cytotoxicity This part of the standard42 describes test methods to assess the in vitro cytotoxicity of materials using techniques in which cultured cells (typically L-929 mouse fibroblasts) are either exposed to an extract of the test sample, or brought into intimate contact with the sample itself using an agar diffusion or fi lter diffusion method. Cytotoxicity is graded on a fourpoint scale from non-toxic to severely cytotoxic according to the damage occasioned to the cell system used.

2.8.2 Part 10: Tests for irritation and sensitisation This part of the standard43 describes a technique in which extracts of the dressing are injected subcutaneously into multiple sites on the backs of

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rabbits following which the injection sites are examined visually for evidence of irritation (erythema and oedema) immediately and after 24, 48 and 72 h. The sensitisation potential is determined by intradermally injecting and occlusively patch testing multiple sites on 10 guinea pigs. The treated sites are examined visually for evidence of a skin reaction after 24, 48 and 72 h.

2.9

References

1. thomas s. Wound management and dressings. London: Pharmaceutical Press, 1990. 2. thomas s. Fluid handling properties of Allevyn Dressing. Wound management communications 2007; http://www.medetec.co.uk/Documents/ Fluid%20handling%20properties%20of%20Allevyn%20foam%20dressing 24-4-07.pdf. 3. BS EN 13726-1:2002 Test methods for primary wound dressings. Part 1: Aspects of absorbency. London: BSI, 2002. 4. thomas s. Observations on the fluid handling properties of alginate dressings. Pharm. J 1992; 248:850–851. 5. thomas s, loveless p. A comparative study of the properties of twelve hydrocolloid dressings. World Wide Wounds 1997; http://www.worldwidewounds. com/1997/july/Thomas-Hydronet/hydronet.html. 6. BS EN 13726-2:2002 Test methods for primary wound dressings. Part 2: Moisture vapour transmission rate of permeable fi lm dressings. London: BSI, 2002. 7. thomas s, loveless p. Moisture vapour permeability of hydrocolloid dressings. Pharm J 1988; 241:806. 8. williams aa. Proficiency of contemporary wound dressings. In: Turner TD, Brain KR, eds. Surgical dressings in the hospital environment. Cardiff: Surgical Dressings Research Unit, UWIST, Cardiff, 1975; 163–179. 9. harrison g, d’silva ap, horrocks ar, rhodes d. An apparatus to measure the water absorption properties of fabrics and fibre assemblies. Med Text 1997; 96:134–140. 10. thomas s, dawes c, hay np. Wound dressing materials – testing and control. Pharm J 1982; 228:576–578. 11. thomas s, fram p. The development of a novel technique for predicting the exudate handling properties of modern wound dressings, 2001. 12. thomas s, fram p, phillips p. The importance of compression on dressing performance. World Wide Wounds 2007; http://www.worldwidewounds.com/2007/ November/Thomas-Fram-Phillips /Thomas-Fram-Phillips-CompressionWRAP.html. 13. lamke lo, nilsson ge, reithner hl. The evaporative water loss from burns and water vapour permeability of grafts and artificial membranes used in the treatment of burns. Burns 1977; 3:159–165. 14. thomas s, fear m, humphreys j, disley l, waring mj. The effect of dressings on the production of exudate from venous leg ulcers. Wounds 1996;8(5): 145–149. 15. thomas s, hay np. Assessing the hydro-affi nity of hydrogel dressings. J Wound Care 1994; 3(2):89–92.

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16. thomas s, hay p. Fluid handling properties of hydrogel dressings. Ostomy Wound Manage 1995; 41(3):54–56, 58–59. 17. thomas s, hay np. In vitro investigations of a new hydrogel dressing. J Wound Care 1996; 5(3):130–131. 18. moffatt c. The principles of assessment prior to compression therapy. J Wound Care 1998; 7(7):suppl 6–9. 19. thomas s. Low-adherence dressings. J Wound Care 1994; 3(1):27–30. 20. ravenscroft mj, harker j, buch ka. A prospective, randomised, controlled trial comparing wound dressings used in hip and knee surgery: Aquacel and Tegaderm versus Cutiplast. Ann R Coll Surg Engl 2006; 88(1):18–22. 21. ASTM E 2149-101 Standard Test Method for determining the antimicrobial activity of immobilised antimicrobial agents under dynamic contact conditions. Pennsylvania: ASTM International, 2001. 22. AATCC TEST METHOD 147-1998 Antibacterial Assessment of Textile Materials: Parallel Streak Method. North Carolina: American Association of Textile Chemists and Colorists, 1999. 23. thomas s, russell ad. An in vitro evaluation of Bactigras, a tulle dressing containing chlorhexidine. Microbios Lett 1976; 2:169–177. 24. thomas s. An experimental evaluation of a chlorhexidine medicated tulle gras dressing (letter). J Hosp Infect 1982; 3:399–400. 25. thomas s, dawes c, hay np. Improvements in medicated tulle dressings. J Hosp Infect 1983; 4:391–398. 26. thomas s, mccubbin p. A comparison of the antimicrobial effects of four silver-containing dressings on three organisms. J Wound Care 2003; 12(3): 101–107. 27. thomas s, mccubbin p. An in vitro analysis of the antimicrobial properties of 10 silver-containing dressings. J Wound Care 2003; 12(8):305–308. 28. lansdown ab, jensen k, jensen mq. Contreet Foam and Contreet Hydrocolloid: an insight into two new silver-containing dressings. J Wound Care 2003; 12(6):205–210. 29. lansdown ab. Silver-containing dressings: have we got the full picture? J Wound Care 2003; 12(8):317; author reply 317–318. 30. thomas s, mccubbin p. Silver dressings: the debate continues. J Wound Care 2003; 12(10):420. 31. thomas s, ashman P. In vitro testing of silver containing dressings. J Wound Care 2004; 13(9):392–393. 32. van toller s. Psychological consquences arising from the malodours produced by skin ulcers. Proceedings of 2nd European Conference on Advances in Wound Management 1992, Harrogate: 70–71. 33. moss cw, dees sb, guerrant go. Gas chromatography of bacterial fatty acids with a fused silica capillary column. J Clin Microbiol 1974; 28:80–85. 34. butcher g, butcher ja, maggs fap. The treatment of malodorous wounds. Nurs Mirror 1976; 142:76. 35. schmidt rj, shrestha t, turner td. An assay procedure to compare sorptive capacities of activated carbon dressings: the detection of impregnation with silver. J Pharm Pharmacol 1988; 40:662–664. 36. shaw rj, maher ga. A test method for quantifying absorptive capacities of intact charcoal-containing wound management products. Proceedings of the

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37.

38.

39.

40.

41. 42.

43

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7th European Conference on Advances in Wound Management, Harrogate 1977. griffi ths b, jacques ej, jones sa. Determination of malodour reduction performance in various charcoal containing dressings. Proceedings of the 7th European Conference on Advances in Wound Management, Harrogate, UK 1997, Harrogate, UK. griffi ths b, jacques ej, waring mj, bowler p, bishop s. Investigation into the fluid-handling characteristics of various charcoal containing dressings. Proceedings of the 7th European Conference on Advances in Wound Management, Harrogate, UK 1997, Harrogate, UK. myles vm, griffi ths b, bishop s. An investigation into the selective adsorption of malodour molecules onto charcoal containing dressings. Proceedings of the 7th European Conference on Advances in Wound Management, Harrogate, UK 1997, Harrogate, UK. lawrence c, lilly ha, kidson a. Malodour and dressings containing active charcoal. Proceedings of the 2nd European Conference on Advances in Wound Management 1992, Harrogate, UK: 70–71. lee g, anand sc, rajendran s, walker i. Efficacy of commercial dressings in managing malodorous wounds. Br J Nurs 2007; 16(6):S14, S16, S18–20. bs en iso 10993-5:2003 Biological evaluation of medical devices. Test methods for primary wound dressings. Part 5: Tests for in vitro cytotoxicity. London: BSI, 1999. bs en iso 10993-5:2003 Biological evaluation of medical devices. Part 10: Tests for irritation and sensitization. London: BSI, 1999.

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3 Textile materials and structures for wound care products B. S. GU P TA, North Carolina State University, USA, and J. V. E DWA R D S, United States Department of Agriculture – Agricultural Research Service, USA

Abstract: A thorough understanding of the healing mechanism and dressing requirements for different types of wound repair is necessary before optimum products based on textiles could be engineered. In this chapter, fi rst a general overview of the wounds and their healing, and of the available dressings and bandages, is presented. This is followed by a detailed discussion of the polymer and fiber materials of which the dressings are composed and of the textile processes that are used in forming the wound care products. Key words: wounds, wound healing strategies, dressings, bandages, dressing polymers and fibers, textile processes.

3.1

Introduction

In a human’s fast-paced life, characterized by external hazards and physiological neglects, physical injury of one or the other form is a commonly encountered event. It must be attended to in order to protect body health, function and appearance. The primary procedure used is the application of a dressing, which, in the main, protects the site against external assaults and aids in generating the needed physiological environment for efficient repair. The dressing can be as simple as a strip of plain textile, or as complex as an engineered composite that contains layers of different geometries and reactive materials, including medicines. The type of dressing depends on the type and the condition of the wound. Wound repair may be simple and inconsequential and performed by the patient itself or it may be complex enough to warrant surgery and hospitalization. An effective treatment requires a thorough understanding of wound types and healing mechanisms and knowledge of the interventions that are available and would ideally assist in the repair process. A major increase in the understanding of the requirements for a dressing emerged in the 1970s when the pioneering work of Winter1 showed that the wounds healed faster and more satisfactorily if the environment at the site was kept moist. Until then, the primary function of a dressing was 48

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considered as one or more of absorbing the exudate, keeping the wound dry, and protecting it against external pathogens as well as further injury. The structure was also required to be comfortable. With the progress already made in terms of the understanding of the healing steps and requirements for different types of wounds, a wide variety of dressings are now available. A minor wound may be defi ned as one that is not chronic and also not seriously acute. However, if not attended to properly, the same wound could become infected, enlarged and acute enough to require advanced dressing and medical procedure. The fi rst line of treatment of a minor wound is a passive dressing, which is product that is textile in origin and may be made by a weaving, knitting or non-woven process. The dressing can also be a solid fi lm, cast directly from a polymer. If there is bleeding and the potential for swelling, a bandage may be required in conjunction with absorbent gauze in order to exert transverse pressure and control both hemorrhage and edema. Like the passive dressings, the bandages are also primarily textile structures that are made by one of the fabric-forming technologies. In this chapter, after a general review of wounds, healing, and dressing requirements, a brief description of the various types of dressings and the bandages available to choose from is given. A more in-depth coverage of some of the advanced dressings, touched on in the chapter, can, however, be found in other chapters of the book. In the second half of this chapter, a detailed discussion of the fiber materials and the textile structures used in producing the dressing and bandage products is presented.

3.2

The role of wound dressings

Skin is the largest organ of the body and has multiple components and, therefore, functions: the epidermis, which is the outer layer and composed of dead cells, is hydrophobic and responsible for protecting against the environment; 2 the dermis, or the middle layer, which is made up of living cells with a network of blood vessels and nerves, is responsible for registering external stimulus, i.e. touch/feel, and thermal regulation of the enclosed body; and the subcutaneous layer, which is mainly made up of fat, is responsible for insulating the body against shock. The cells on the surface are constantly replaced by those below, causing the top layer to slough off. The repair of an epithelial wound then is essentially a scaling up of this process by the use of interventions. Much has been learnt during the past half a century about wounds, the healing process and the nature of the products required to successfully treat the lesion. A wet environment, composed of isotonic saline and wound fluids, has been shown experimentally to be most favorable for rapid healing of wounds. The inflammatory and proliferative phases of dermal repair in healing are also accelerated. 3

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It was realized that bacteria did not generate in the wound but were acquired from an external source; thus simply washing with soap and water alleviated much of the risk of infection. Use of a protective covering formulated the simple but effective aseptic means for the treatment. An essential part of any wound management is wound dressing, important considerations for which are the extent to which it restricts evaporation of water from the wound surface, buffers pain and trauma, manages exudates and protects against bacterial invasion. Although wound healing which is the stated part of a wound management protocol has been described in recorded history, our understanding of its basic principles has grown more in the past half century than in the preceding two millennia.4 The recent outstanding growth in our knowledge about healing is highly promising and has already led to introduction of new and exciting concepts, novel therapeutic modalities, and innovative wound management products. As new materials are discovered, new dressings emerge which promise to play an active role in modifying healing of all types of wounds. 5,6 As the products become more sophisticated, they also tend to become more ‘wound-specific’. In order to select an optimum treatment for a wound and for different stages during healing, it is important that we understand the types of wounds we encounter, the sequence of events that take place during repair, and the treatment options we have available to choose from.

3.3

Categorization of wounds

Wounds have been categorized in many different ways, but they all reflect commonly the differences in the required treatment, and the expected time and prospects of healing. The classification of wounds recognizes the type of injury (blunt contusion, sharp laceration, thermal, chemical, etc.), the extent of tissue loss, and the presence of infection, foreign bodies, and underlying structural injuries (fracture of bone, exposure of vital parts such as tendons and blood vessels). A general classification of wounds is as follows: 1. 2.

Wounds with no tissue loss. Wounds with tissue loss. This generally includes three types of wounds; those that are (a) caused by burning, trauma or abrasion; (b) the result of secondary events involving chronic ailments, as, for example, venous statis, diabetic ulcers, and pressure sores; or (c) induced as a part of the treatment of the wound itself, as, for example, the wound arising at the donor site for skin grafting, or the wound due to derma-abrasion.

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From the standpoint of the extent of injury, a wound may also be classified in terms of the layers involved: 1. 2. 3.

The superficial wounds, involving only the epidermis. The partial thickness wounds, involving also the dermis. The full thickness wounds, involving, additionally, the subcutaneous fat or deeper tissue.

Most wounds can also be broadly characterized as acute and chronic. In the former type, that may or may not have tissue loss, healing tends to proceed through a timely and orderly reparative process. In the chronic wounds, on the other hand, healing has failed to proceed through this process or it has proceeded without establishing a sustainable anatomical and functional result. The chronic wounds are classically subdivided into venous statis ulcers, pressure ulcers, and diabetic ulcers. To a lesser extent, the traumatic wound with extensive cutaneous loss that has not been replaced for some reasons also may fall in the category of chronic wounds.4,7

3.4

Minor wounds

A wound that has no tissue loss and is not chronic can be classified as minor with high prospects of healing with minimum scarring. Minor wounds often occur as the result of unanticipated trauma and may include injuries, such as lacerations, abrasions and blisters, and more serious wounds such as skin tears and bites. In many instances, such as superficial wounds, the skin may only require protection from further injury and can be treated at home with due regard given to the possibility that infection may be present or could arise. Infection is usually one of the biggest risks for minor traumatic wounds. A visual check for the presence of foreign material, its removal and careful cleansing may precede the application of a wound dressing. If, on the other hand, the wound is deep, as for example caused by penetration, then the possibility that an underlying structure may have been damaged needs to be considered. Some of the causes of minor wounds are: 8 •

•

Lacerations. This wound occurs when soft body tissue has become torn and it is often irregularly shaped and jagged. It is highly common for this type of wound to be contaminated with debris and or bacteria by the object that caused it. Abrasions or grazes. These are more exactly superficial wounds in which the top layer of the skin is damaged or removed, e.g. by the skin sliding across a rough surface. Small blood vessels may become visible and bleed. These injuries often contain dirt and gravel. Abrasions are

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•

•

•

• •

Advanced textiles for wound care considered the most common type of wound, and perhaps the least dangerous.9 Blisters. These are usually the result of friction between the top two layers of the skin. Puncturing the blister, draining the fluid and removing the top layer often allow the area to heal more quickly. In many cases, the blister will burst of its own accord. In both instances, a protective dressing is required. Cut (incision). Such wounds usually have clean edges which are the result of surgery, or injury caused by a sharp-edged object. Since blood vessels are cut straight across, there can be profuse bleeding. Among all types of wounds, incisions are the least likely to become infected, because the abundance of flowing blood serves to protect against pathogens fi nding their way in. Puncture. A puncture wound typically occurs when the skin is pierced by a cylindrical object such as a needle or a nail. These wounds can be dangerous as one cannot easily identify the depth to which the puncture has reached; they can be particularly dangerous if the wound is located on the abdomen or thorax.9 With this type of wound, bleeding will occur, in a similar way to the wound caused by a knife. Figure 3.1 depicts the difference between a laceration and a puncture wound.10 Penetration. A penetration is a type of puncture but the damage is deeper such as it happens when a knife or bullet enters the body. Bites. These may be human or animal and are of special concern, especially if caused by an animal, as bacteria from the mouth can enter and

(a)

3.1 Wound types: a) laceration, b) puncture. 9

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result in an increased risk of tetanus and infection. Most animal bites are sustained from pets, usually dogs, and can cause abrasions, deep scratches, and lacerations as well as puncture wounds. Cat bites are considered more serious due to the high incidence of infection.

3.4.1 General treatment strategy for minor wounds Cleaning the wound and the surrounding skin is usually the fi rst stage in treating a minor wound. This step removes debris and other foreign material which, if left, could cause infection. Abrasions require thorough irrigation as dirt is frequently embedded in the ruptured skin. An antiseptic solution may be used to cleanse the wound. Clean surgical wounds that have been sutured simply require the cleaning of old blood before the application of a dry dressing. In some cases it may be necessary to debride the wound before proceeding; in others, repair to underlying structures may need to be addressed before applying a dressing. Wounds greater than 6–8 h old have an increased risk of infection. In all cases of traumatic injuries, the patient’s tetanus status needs to be assessed for coverage. Following this, an assessment of the wound in terms of the location, size and depth and any additional trauma to the underlying structures needs to be determined. Animal bites need to be monitored for 24–48 h for signs of infection. After thorough cleansing and assessment, a choice of dressing is then made, which may be a simple low-adherent or an advanced multi-layer composite to not only protect the wound but also to absorb blood or exudates and keep the wound moist. A detailed discussion of dressings is given later in this chapter.

3.5

Healing mechanisms

The various phases involved in wound healing are seen in all wounds irrespective of whether it is a carefully opposed, clean, incised, wound that is healed by primary intention or one that is not opposed, has tissue loss, or is infected and exuding and is healed by secondary intention. The length of each phase varies with wound type and extent, and can be manipulated to promote or delay healing. The body’s natural healing process can be broken down into several steps: hemostasis, inflammation, proliferation, and maturation or remodeling. Immediately after injury, the platelets from the severed blood vessels begin to aggregate and form a platelet plug. This reduces bleeding. A clot forms in the opening of the wound, which dehydrates in contact with the air and forms a scab. In the second phase, neutrophils, monocytes and macrophages emerge, which tend to demolish or debride any devitalized

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tissue and foreign bodies present, such as bacteria. The phagocytes act to clear debris and destroy the ingested material.11 In the third stage, new vessels are formed which carry the oxygenated blood to the site bed. The fibroblast cells lay down a network of collagen fibers surrounding the neo-vasculature of the wound. In the fi nal stage, the process of remodeling of the collagen fibers laid down in the proliferation phase occurs, and this may take a long time (Fig. 3.2).12 A problem arises in the last steps of the healing process for large or cavity wounds as the body is not able to completely seal the site with a scab-like formation. The cavity must be plugged with an appropriate dressing to assist in the process. Depending on the type of wound, healing treatment is considered to be by one of three processes: primary, secondary, or tertiary (often called delayed primary).6 Healing by primary intention occurs in most surgical

Skin surface

Red blood cell

Wound

Fibrin

Platelet

PMN

Epidermis and dermis of skin

Macrophage (a) Injury

(b) Coagulation

TGF-β PDGF

Macrophage (d) Late inflammation (48 h) Collagen

PMN (c) Early inflammation (24 h)

Fibroblast

(e) Proliferation (72 h)

(f) Remodelling (weeks to months)

3.2 Phases of cutaneous wound healing (a) injury, (b) coagulation, (c) early inflammation (24 h), (d) late inflammation (48 h), (e) proliferation (72 h), (f) remodelling (weeks to months).12

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wounds in which the edges have been adequately approximated. Such wounds are usually clean and heal rapidly. Large wounds with significant tissue loss are allowed to heal by secondary intention. Such wounds are often encountered following massive trauma, surgical ablation of large tumors, or deep burns. Tertiary or, more appropriately, delayed primary healing is induced by reconstruction using skin grafts or flaps. Tissue gaps and poorly approximated edges will ultimately heal by secondary intention accomplished by re-epithelialization from the wound edges and mostly by wound contraction. Clearly, primary or delayed primary wound healings are by far preferable and superior to secondary healing.

3.6

Wound dressings

3.6.1 Historical The history of surgical wound management indicates how, with research and understanding of wounds and their healing, dressings have evolved over time and set the criteria for the design of new and better dressings and effective wound management. Until the research by Winter1 which illustrated the benefits of a moist environment for healing in the second half of the twentieth century, relatively few advances had taken place in wound care management. Since the early nineteenth century, advances in wound treatment occurred largely due to experience gained in military surgery. These observations brought out the benefits of a sterile environment in healing and led to clean and sterile gauze replacing the nonsterile products. In 1880, Joseph Gamgee developed the famous composite dressing consisting of absorbent cotton or rayon fiber enclosed in a retaining sleeve.13 The dressings used were sometimes medicated with iodine or phenol. Gauzes impregnated with paraffi n were introduced as non-adherent dressings for the treatment of burns and other similar wounds. Medicated versions of these, the so-called ‘tulle gras’ were subsequently introduced and some of these are still being used. The work of Winter led to the development of a whole range of new dressings: films, gels, foams, polysaccharide materials and chitosan. These have revolutionized the treatment of wounds of all types. Some of the requirements for ideal wound dressing mentioned are:14–17 1. 2. 3. 4. 5. 6. 7.

Absorbing exudates and toxic components from the wounds surface Maintaining a high humidity at the wound/dressing interface Allowing gaseous exchange Providing thermal insulation Protecting the wound from bacterial penetration Being non-toxic Easily removable without causing trauma to the wound.

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Properties that were added later include (1) having acceptable handling qualities, and (2) being sterilizable and comfortable.9 Having acceptable handling qualities means that product will not tear easily and disintegrate into wound.

3.6.2 Case for moist environment The most significant advance in wound care resulted from the work of Winter1 which showed that the occluded wounds, i.e. those in a moist environment, healed faster than the dry wound. An open wound, which is exposed to air, dehydrates and results in the formation of a scab or a scar. The latter forms a mechanical barrier against migrating epidermal cells, causing them to move through a deeper level of tissue, retarding healing (Fig. 3.318). A moist environment prevents the formation of scab and allows the cells to move unhampered.19 If exudate is present, such as from an ulcer, it should be absorbed by the dressing, so that it does not solidify in the wound.

3.6.3 Dynamic nature and requirements Each wound is different from any other even on the same individual, occurring because of the same reason, and in about the same region. Although it may fall in a given category, it still itself remains unique. This is because a wound is influenced by so many variables within the host and the environment that each will act independent of all others. 20 This is exacerbated by the facts that both the wounds and the hosts are dynamic and constantly change. Thus, there is the ongoing challenge faced in selecting the wound care dressing at each stage for each different person, and this requires a frequent reassessment of the lesion. Surgical wound assessment is an ongoing nursing responsibility that should be conducted every time a

Occlusive dressing

No dressing Normal scab

Moist exudate

Epidermis

Wound surface

3.3 Healing under a moist environment.18

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Dry exudate Wound surface Dry dermis

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dressing is changed, until the healing is complete. Assessment tools are available that determine the following aspects: 21,22 • Type of wound – superficial or cavity. • Age of wound – fresh, days, weeks, dehisced (split along a natural line). • Stage of healing – granulating, epithelializing. • Progress of wound – healing, deteriorating, become necrotic, infected or static.

3.6.4 General classification Broadly, dressings may be classified as (1) passive, (2) interactive, and (3) bioactive, based on the nature of dressing action required. However, as illustrated above, the concept of wound occlusion to promote moist healing has probably impacted dressing design as much as any other development over the last thirty years. Wound occlusion does require careful regulation of the moisture balance at the site with vapor permeability helping the dressing to stay within its absorption limit. Thus, occlusive dressing types have been developed depending on the nature of the wound and the accompanying exudate. The theory of moist wound healing has led to approximately eight or nine separate types of materials and devices (Table 3.1), useful for different treatment indications. Each material type that represents these distinct groups has molecular and mechanical characteristics that confer properties to promote healing under specifically defi ned clinical indications. For example, it has been recommended that wounds with minimal to mild exudate be dressed with hydrocolloid, polyurethan, and saline gauze, and wounds with moderate to heavy exudate be dressed with alginate dressings. Dressings may also be selected based on wound tissue color, infection, and pressure ulcer grade. 23 When taken together, the combined properties of the dressing materials given in Table 3.1 would constitute an ideal dressing. Improvements in dressings that function at the molecular or cellular level to accelerate healing or monitor wound function are included among the ideal characteristics and may be termed interactive and intelligent materials, respectively. For example, a dressing that removes harmful proteases from the wound to enhance cell proliferation is an example of an interactive product. A dressing having a detection device in the material signaling ‘timeto-change,’ because the material has reached its capacity for deleterious protein levels, or reached a pH or temperature imbalance, may be termed ‘intelligent’. Currently, there is not a universal dressing that will work for all wound types. Therefore, a dressing for a wound should be chosen on a case by case basis. When choosing a product, there are several factors to

© 2009 Woodhead Publishing Limited

Table 3.1 Classes of occlusive wound dressings with a description of their properties, clinical indications, and contraindications Dressing and fiber type

Description

Properties

Indications

Thin films

Semipermeable, polyurethane membrane with acrylic adhesive

Permeable to water and oxygen providing a moist environment

Sheet hydrogels

Solid, non-adhesive gel sheets that consist of a network of crosslinked, hydrophilic polymers which can absorb large amounts of water without dissolving or losing structural integrity. Thus, they have a fixed shape. Semipermeable polyurethane film in the form of solid wafers; contain hydroactive particles as sodium carboxymethyl cellulose which swells with exudate or forms a gel. Soft, open cell, hydrophobic, polyurethane foam sheet 6–8 mm thick. Cells of the foam are designed to absorb liquid by capillary action.

Carrier for topical medications. Absorbs its own weight of wound exudate. Permeable to water vapor, and oxygen, but not to water and bacteria. Wound visualization

Minor burns, pressure areas, donor sites, post-operative wounds Light to moderately exudative wounds. Autolytic debridement of wounds. Stage II and III pressure sores.

Hydrocolloids

Semipermeable foam

Amorphous hydrogel

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Similar in composition to sheet hydrogels in their polymer and water make-up. Amorphous gels are not crosslinked. They usually contain small quantities of added ingredients such as collagen, alginate, copper ions, peptides, and polysaccharides

Impermeable to exudate, microorganisms, and oxygen. Moist conditions produced promote epithelialization

Shallow or superficial wound with minimal to moderate exudate.

Permeable to gases and water vapor, but not to aqueous solutions and exudate. Absorbs blood and tissue fluids while the aqueous component evaporates through the dressing. Cellular debris and proteinaceous material is trapped. Gels clear, yellowish, or blue from copper ions. Viscosity of the gel varies with body temperature. Available as tubes, foil packets, and impregnated gauze sponges

Used for leg and decubitus ulcers, sutured wounds, burns and donor sites.

Used for full-thickness wounds to maintain hydration. It may be used on infected wound or as wound filler

Fillers

Contact layer dressings (tulle gauze with petroleum jelly)

Gauze packing

Wound vacuum assisted closure

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Calcium alginate which consists of an absorbent fibrous fleece with sodium and calcium salts of alginic acid (ratio 80 : 20). Dextranomer beads consist of circular beads, 0.1 to 0.3 mm in diameter, when dry. The bead is a three-dimensional crosslinked dextran, and long-chain polysaccharide Greasy gauzes consisting of tulle gauze and petroleum jelly. Silicone-impregnated dressing sheet consists of an elastic transparent polyamide net impregnated with a medicalgrade crosslinked silicone Cotton gauze used both as a primary and secondary wound dressing. Gauze is manufactured as bandages, sponges, tubular bandages and stockings. Improvement in low-linting and absorbent properties. Gauze is still a standard of care for chronic wounds Polyurethane foam accompanied by vacuum negative pressure in the wound bed

Heavily exudating wounds, including chronic wounds as leg ulcers, pressure sores, fungating carcinomas. Wounds containing soft yellow slough, including infected surgical or post-traumatic wounds

Heavily exudating wounds

The dressing which is porous nonabsorbent and inert is designed to allow the passage of wound exudate for absorption by a secondary dressing

Shallow or superficial wounds with minimal to moderate exudate

Cotton gauze may be wetted with saline solution to confer moist properties. Possesses a slight negative charge, which facilitates uptake of cationic proteases. Absorbent and elastic for mobile body surfaces

For chronic wounds it fills deep wound defects and is useful over wound gel to maintain moist wound; needs to be packed lightly. May traumatize wound if allowed to dry

Wound filled with foam and sealed with a film. Vacuum is obtained over wound

Deep wound to stimulate the growth of granulation tissue

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consider, such as: (1) location, (2) size, (3) wound depth, (4) exudates amount, (5) infection, (6) frequency and difficulty of dressing change, (7) cost, and (8) comfort. Traditional products like gauze and tulle that account for the largest market segment are passive products. Interactive materials composed of polymeric fi lm products are mostly transparent, permeable to water vapor and oxygen but impermeable to bacteria. These film products are recommended for low exuding wounds. Bioactive dressings are ones that deliver substances active for wound healing; either by delivery of bioactive compounds or the dressing is constructed from a material having endogenous activity. These materials include proteoglycans, collagen, noncollagenous proteins, alginates or chitosan.

3.7

Types of dressings available

The range of dressing products is so large that there is potential for confusion when deciding which one to use. No single product is suitable for all types of wound and, when deciding which dressing to use, it is important to assess the wound and the stage of healing. Specific objectives must be identified; for example, if a wound is sloughy, the prime objective will be to de-slough by absorbing exudate; if the wound is clean and granulating, the aim will be to provide a moist environment to aid in healing. If the wound has a large cavity, it must be plugged. Based on considerations such as these, the available range of wound care materials can be described as below. 24–28

3.7.1

Gauze dressings

A gauze is a traditional dressing and is still one of the most widely used product. In general, it is used for many purposes: skin preparation, cleansing, wiping, absorption, and protection. It can be either woven or nonwoven. Cellulose fibers (cotton and rayon) are the typical materials used in making gauze. Synthetic fibers, in particular polyester, are also employed to modify properties and reduce cost. If woven, the pattern used is plain but it can vary from loose to tight. The non-woven dressings are highly homogeneous and soft. Figure 3.4 shows a comparison between a woven gauze and a non-woven sponge. Gauze comes in pad, strip, roll, and ribbon form and is easy to handle; it packs easily which makes it a good choice when the wound is located in hard to reach areas. Gauze can be dry, moist, or impregnated. There are some disadvantages associated with the use of gauze: it is not a good thermal insulator and, when removed, it can cause damage to the wound. The damage occurs because the fibers of the gauze get embedded into the wound exudates and when removed it often peels off some of the newly

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3.4 Woven and non-woven gauze. 29

formed epithelium. Impregnation of the fabric in a suitable compound alleviates this difficulty. Dry gauze Dry gauze, which is perhaps the most widely used material in home care, is used as a cover, as a means to prevent contamination, or to trap and lessen exudate. It is used as a primary absorbent dressing on a wound with a high amount of exudate. It is also used on closed wounds to prevent infection or additional trauma. The main problem encountered with gauze is that it tends to adhere to the wound and when removed from a large lesion may pull some of the newly formed tissues with it. If not being used for mechanical debridement as described below, it should be moistened before removal if it appears to be dry and adherent to the wound. Moist gauze This type of product is used to help maintain a moist environment and most often to promote granulation or protect a granulating wound, which is one of the fi rst visual signs of healing. 30 It has been noted that ‘wet-to-dry’ and ‘wet-to-moist’ gauze dressings are often used in practice in a way that makes them indistinguishable. 31 In fact, it should be noted, they have two different end purposes. Wet-to-dry dressings have been traditionally used as a means of mechanical debridement. The Agency for Healthcare Research and Quality has promoted the use of these for the debridement function. However, there are a variety of alternative methods for debridement, for example surgical debridement (when such is possible) and debridement using proteases, including collagenase-based and papain/ urea-based formulations. The wet-to-dry gauze method for mechanical debridement is a controversial method as it is known to cause pain to the patient on removal. On the other hand, the wet-to-moist gauze is used for creating moist wound healing. For treatment of open ulcerating wounds,

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gauze is made moist by soaking in normal saline. Normal saline dressings, which are still a standard of in-home and nursing home care, appear to act as an osmotic dressing. It has been shown that the osmolarity, sodium and chloride concentrations in dressings, placed on chronic wounds, remain relatively isotonic with time. The reason for this is that the dressing as a result of evaporation increases its tonicity. This draws fluid from the wound into the product so that a dynamic equilibrium occurs and the dressing regains isotonicity. Thus, the dressing remains functional for as long as it removes fluid from the wound. Impregnated gauze Further work has been done to fi x the limitations of gauze by impregnating it with substances that promote wound healing. Substances currently used include; hydrogels, saline, and antimicrobial agents, as well as a wide variety of other materials, including paraffi n wax. One such gauze, known for its vast improvement, is referred to as ‘Smart Gauze’, and has been found to be both super-absorbent as well as non-adherent to the tissue. Both the moist and the impregnated gauzes fall into the category of advanced occlusive dressings.

3.7.2 Impregnated dressings With the work of Lister in 1867, in which bandages were impregnated with carbolic acid, the use of antiseptic treatment arose, and, shortly thereafter, Joseph Gamgee produced the fi rst composite product containing cotton or viscose fiber medicated with iodine. 32 Some of these dressings are still in use. These materials include gauzes and non-woven sponges, ropes and strips saturated with either saline, hydrogel, or other wound-healing promoting compounds, including peptides, polysaccharides, alginate, copper ions, and collagen. They are non-adherent and require a secondary dressing.

3.7.3 Transparent film dressings Films are homogeneous materials, which come in different thicknesses and consist of a polymer sheet that has one adhesive side. Film dressings are acceptable coverings for superficial wounds; being impermeable to liquids, water and bacteria, but permeable to moisture vapor and atmospheric gases, makes them suitable for use as occlusive structures. Because of their transparent nature, the fi lms facilitate visual inspection without having to remove the dressing. They are applied to partial thickness wounds with very little or no exudate. They are also used to manage intravenous (IV) sites, lacerations, abrasions and second-degree burns.

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3.7.4 Composite dressings These dressings combine physically different components into a single product and provide multiple functions, such as bacterial barrier, absorption, and adhesion. The dressings, comprising multiple layers, have a semiadherent or non-adherent contact layer that covers the wound and may include an adhesive border. The inner is the contact layer that is designed to accept the fluid and allow it to pass into the layer above where it is absorbed and held. The outer most layer is designed for protection and to secure the dressing to the skin. They are used as primary or secondary dressing; the latter, for example, for daily applications of creams, ointments etc. An example of how different types of carbohydrate combinations, involving cellulose, alginate and other components, can be designed into composite dressings is shown in Fig. 3.5.

3.7.5 Biological dressings In 1975, Rheinwald and Green33 developed a method that made it possible to cultivate human keratinocytes so that a 1–2 cm 2 keratinocyte cultured graft could be generated in about 3 weeks. This work paved the way for the eventual development of skin substitutes and biomaterials with wound interactive properties and biological activity, which have progressed

lloi

and s ug dress ar-based ings

co ds

Fillers

dro

hy

nd dre con ssi tact ng lay

nd

uz ea

ls a

ge

dro

ings dress

Ga

Hy

rbing

Crosslinking chemistry

r-abso

Cotton dressing

Odou

er

Carbohydrate-based dressing

Carbohydrate-based Alginates and Charcoal cloth hydrogels and dextranomer beads/ dressing carboxymethyl cellulose sucrose and honey

Composite dressings that enhance the properties of both alginate and cotton while incorporating proteasesequestering properties

3.5 Various materials from carbohydrate sources present in wound dressings may be combined to form composite dressings with enhanced properties.

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from the mid-1990s through the present. Biological dressings are derived from a natural source. Collagen dressings, derived from bovine, porcine, or avian sources, fall in this group. All these products are meant to accelerate healing. The biological dressings are available in many forms, including gels, solutions or semi-permeable sheets. While gels and solutions can be applied directly to the wound surface and covered with a secondary dressing, the sheet form can be simply used as a membrane and left in place for undisturbed healing. Biological dressings are indicated to be used for partial thickness wounds such as burns, abrasions, donor sites, skin tears, etc. Skin substitutes that also fall under this category are being increasingly used. These contain both cellular and acellular components that appear to release or stimulate important cytokines and growth factors that have been shown to be associated with accelerated healing. 34 Some basic materials may also play a role in up-regulating growth factor and cytokine production and blocking destructive proteolysis. In this regard, the biochemical and cellular interactions that greatly promote healing have only recently been elucidated for some of the occlusive dressings described in Table 3.1. Some carbohydrate-based dressings stimulate growth factors and cytokine production. For example, certain types of alginate dressings have been shown to activate human macrophages to secrete pro-inflammatory cytokines. 35 Interactive dressing materials may also be designed with the purpose of either entrapping or sequestering molecules from the wound bed and removing the components responsible for deleterious activity from it as the product is removed, or stimulating the production of beneficial growth factors and cytokines through unique material properties. They may also be employed to improve recombinant growth factor applications. The impetus for material design of these dressings derives from advances in the understanding of the cellular and biochemical mechanisms underlying healing. With the knowledge of the interaction of cytokines, growth factors and proteases in acute and chronic wounds, 35–38 the molecular modes of action have been elucidated for dressing designs as balancing the biochemical events of inflammation. The use of polysaccharides, collagen, and synthetic polymers in the design of new fibrous materials that optimize wound healing at the molecular level has stimulated research on dressing material interaction with wound cytokines, 34 growth factors, 39–41 proteases,42–45 reactive oxygen species,46 and extracellular matrix proteins.45

3.7.6 Absorptive dressings Absorptive dressings are usually multilayer wound dressings which provide either a semi-adherent quality or a non-adherent layer. They are combined with highly absorptive layers of fibers such as cotton, rayon, etc. These

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dressings are designed in a way so as to minimize its adherence to the wound so that the secondary trauma is as less as possible. These dressings are generally used as primary or secondary dressings for surgical incisions, lacerations, abrasions, burns, skin grafts or any draining wound.

3.7.7 Alginate dressings These advanced absorbent dressings are non-woven, non-adherent, pads and ribbons composed of natural polymers derived from brown seaweed. Alginates provide many benefits for use as dressings: they swell and retain large amounts of water (100 to over 1000% of their dry mass), thus providing an optimal moist environment; the act of swelling and diffusion throughout the gel allows the wound exudates to be absorbed, which, in turn, speeds up healing; and, because of the wet structure, the dressing does not stick to the wound bed and cause secondary trauma upon removal. The alginate dressing can be applied either pre-wetted, to supply a desiccated wound with moisture, or dry, to aid in the absorption of exudates. They must, however, be used with a secondary dressing. As for the mechanism, when a dry mass of the material is applied to the site, it begins to absorb exudates during which a reversal in the ionexchange process (from calcium ion in the dressing to sodium ions in the blood and exudates) occurs. This transforms the water-insoluble calcium alginate into water-soluble sodium alginate, thus absorbing a large amount of fluid.47 The moist gel formed fi lls and covers the wound. The process is also said to make the dressing an excellent hemostatic agent, thus promoting clotting.48 For dressings, alginates are made as ropes for packing deep wounds and as sheets for treating shallow wounds. Alginate dressings act as a antimicrobial by absorbing micro-organism-infected exudates, which are then removed when the dressing is changed.47

3.7.8 Chitosan dressings Chitosan is well known for its haemostatic properties and its bacteriostatic and fungistatic behaviors, all of which are particularly useful for wound treatment. As a haemostat, chitosan helps in natural blood clotting and in blocking of nerve endings, thereby reducing pain. The polymer gradually depolymerizes to release N-acetyl-β-d-glucosamine, which initiates fibroblast proliferation, helps in ordered collagen deposition, and stimulates an increased level of natural hyaluronic acid synthesis at the wound site. These processes aid in increased wound healing and decreased scar formation. Figure 3.6 gives a schematic representation of the mechanism by which chitosan works. It shows that chitosan, which is a polymeric amine, becomes

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3.6 Haemostatic properties of chitosan.49

positively charged when wet and attracts the negatively charged ions in blood and exudates.49 Such attraction allows the material to clot blood quickly and also to act as an antibacterial agent on account of it attracting the negatively charged particles, including bacteria (Fig. 3.6), which are then removed at the dressing change.47 An increase in healing rate of as much as 75% has been reported.48 Because of the similarities in the chemical structures between chitosan and cellulose, the two are frequently mixed at both the polymer and the fiber levels. Such blending allows a manufacturer to engineer products with desired properties at lower cost. An example of a commercial product is 25% chitosan and 75% rayon. The improved fiber properties obtained allow the material to be converted into dressing by knitting, weaving or one of the available non-woven processes or by casting the polymer into a fi lm. The functionality of the polymer also allows it to have built-in compounds that provide additional antimicrobial, and even deodorizing, characteristics. 50 One of the heaviest uses of chitosan is in making dressings for use by military in the combat zone. The claim of a product is that it will bond with the blood in 1 to 5 min and will also form an adhesive-type structure to protect the wound until access to a medical facility becomes available. Such quick response is needed in managing combat related injuries, as nearly 80% of all battlefield deaths result from bleeding in less than 10 min.49 More specifically, chitosan has been developed as a sponge for use in controlling lethal extremity arterial hemorrhages in arteries. 51

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Chitosan is among a number of currently deployed haemostatic agents used within the armed services and has recently been contrasted with other materials for its efficacy in this application. 52,53 Chitosan-based haemostatic products have also been compared with the more highly ordered crystalline structures of glycosaminoglycan materials54 to learn more about the relative roles that carbohydrate structure and charge play in eliciting haemostatic activity. In addition to its use in fabric or fi lm form, the material may also be incorporated into dressings in the form of powder and beads, and it has been grafted onto cotton to study its antimicrobial and haemostatic activities.

3.7.9 Chitosan/alginate bicomponent fiber dressings Some wound products even combine chitosan and alginate to form a fiber. 55 With these bicomponent fibers (Fig. 3.756), the positively charged chitosan on the outside attracts the negatively charged microbes on the skin, promoting antimicrobial activity. The alginate polymer inside is still able to absorb the exudates. Thus, a non-toxic, biocompatible, absorbent and antimicrobial wound dressing could be made that combined the best attributes from both polymers to generate a faster healing product for large exuding wounds.

3.7.10 Hydrocolloid dressings Hydrocolloid dressings can have various compositions, but the most common composition has a backing (outer layer) of either a vaporpermeable fi lm or thin sheet of foam on which a mixture of sodium carboxymethyl cellulose, elastomers, adhesives and gelling agents are coated. Once the dressing is fi xed on the wound, the warmth softens the lining of the dressing providing a gel cover for the wound bed. Hydrocolloid dressings are able to absorb a minimal amount of wound exudate and once its capacity is reached the remainder may leak out from under the dressing, termed ‘strike-through’. The strike-through can be fast and, Chitosan Alginate

3.7 Core-sheath alginate/chitosan.56

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therefore, these dressings are best suited for rehydrating dry black/ brown necrotic tissues and wounds containing dry yellow slough. The hydrocolloid dressings are available in many shapes and some also have an additional adhesive border to prevent leakage or sliding of the dressing over the wound.

3.7.11 Hydrogel dressings There are two types of hydrogel dressings. Amorphous gels Amorphous gels donate moisture to a dry wound and are, therefore, used for rehydrating dry necrotic or sloughy tissues and keeping granulation tissues moist – in much the same way as do the hydrocolloids. If the wound is sloughy and wet, this dressing will not be suited for the application. The amorphous gels come in a variety of forms and some have hydrocolloid or alginate added in an attempt to make them better at debriding or coping with wet wounds. The amorphous gels require a secondary dressing, usually a vapor-permeable fi lm. The viscosity of amorphous hydrogels contributes to its function, and its ability to maintain integrity after absorbing wound fluid determines its role in moist wound healing. Less viscous types liquify after absorbing small amounts of exudate, and thereby add fluid to the wound. The more viscous types, on the other hand, maintain their structure and form a protective barrier over the site, thereby sequestering wound fluid and increasing the bioavailability of the exudate constituents, including proteases, for autolytic debridement and wound repair. Non-amorphous gels The non-amorphous gels provide a moist interface at the wound bed but do not donate as much water as do the amorphous gels and are, therefore, not the fi rst choice for rehydrating a wound. However, they do provide a moist cover for granulating wounds. They are very soothing to wounds, making the dressings particularly suitable for use on superficial burns, including those caused by radiotherapy reactions. As they are gentle on removal, they are also suitable for use on easily damaged skin. The sheet gels come in adhesive and non-adhesive versions. Foam dressings Foam dressings usually consist of coatings of foamed solutions of polymers on sheets. The foam has small and open cells capable of holding fluids. Their absorption capacity depends on the thickness of the layer, and the material. Foams are permeable to gases and water vapor, but not to aqueous

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solutions and exudate. Foams absorb blood and tissue fluids while the aqueous component evaporates through the dressing. Cellular debris and proteinaceous material are trapped in the material. These dressings are generally used on partial and full thickness wounds.

3.7.12 Antimicrobial dressings Almost any type of dressing, i.e. sponge, gauze, fi lm, or absorptive, can be made to have antimicrobial properties by incorporating agents such as silver and iodine. Silver is easily incorporated into chitosan and alginate products, thus greatly enhances their antimicrobial protection for the wound. A unique benefit of using silver in dressing is that it is highly effective in minute amounts (∼1 ppm).47

3.7.13 Silicone dressing These are atraumatic dressings (they do not cause trauma to newly formed tissue or tissue in the peri-wound area) based on soft silicones, which are a particular family of solid silicones, that are soft and tacky, and which, therefore, tend to adhere to dry surfaces. A silicone dressing consists of a contact layer that is coated with silicone. These materials are inert and their main attribute is that they can be removed from a sensitive wound without causing trauma. The exudates can also be absorbed but this is accomplished by using an absorbent dressing that is given a coating of silicone. These dressing are particularly recommended for use as the fi rst-line prophylactic treatment against development of hypertrophic scar and keloid after surgery. 57

3.7.14 Categories based on the management of moisture The dressings discussed above can be further grouped into three main types:16 Dressings that absorb exudates Absorbent dressings have a very high capacity for holding fluid. Hence, for a wound generating high levels of exudate, absorbent dressings will require fewer changes within a set period of time. Two of the materials that can support this function are the alginate and the foam products. Dressings that maintain hydration As a wound heals more, its exudate generation becomes less. This is when the wound starts to granulate or fi ll in with new connective tissue. When exudate levels decrease, it is not advisable to use absorbent dressings as

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they may result in the dehydration of the tissues. In such a situation, all that is required is to maintain the hydration level. The hydrocolloid and the fi lm products are suited for this application. Dressings that donate moisture When wounds are completely dry, they become covered by a layer of dead tissue, which needs to be removed to allow the wound to heal optimally. Often such tissues are removed by autolysis debridement which is slow digestion of the dead cells by enzymes. In such cases, maintaining a moist environment helps the process. The dressing should actively add moisture to the wound, and this is best performed by a hydrogel material.

3.8

Bandages

The functions of bandages are to (1) hold a dressing in place, (2) apply compression in some applications, such as to arrest bleeding in heavily hemorrhaging wounds or to treat varicose vein or leg ulcers, (3) immobilize fractures, (4) tie anesthetic tubes, and (5) hold cuffs, masks and other parts of textiles worn by a medical person for personal protection, safety or ease of mobility. Commonly, bandages performing a load-bearing function are made up of knitted or woven textiles, some containing elastomeric threads for required stretch and recovery force. Many types of products are available, including relatively inextensible, highly extensible, adhesive/cohesive, tubular, and medicated paste bandages. 58 The non-extensible bandages, essentially woven with open weave for breathability and low weight, are used for holding an absorbent pad or dressing in place at sites where stretch is not required, for example finger, arm or lower leg, tying anesthetic tubes and drains in position, and holding up a surgeon’s trousers. The extensible bandages are used for retaining a dressing and applying compression for control of edema and swelling in the treatment of venous disorders of the lower limb. The bandage should keep the dressing in close contact with the wound, and not inhibit movement or exert significant pressure that causes pain or restricts blood flow. The compression dressing falls in a class by itself and is used primarily for treatment of varicose vein ailment. The optimum pressure needed varies with condition and place on the leg. The highest pressure is required at the ankle and the lowest on the upper thigh. Stockings in different sizes and having various mechanical properties are now available to fit a range of patients and provide gradient pressures of magnitudes suited for different specific categories of venous disorders. The pressures used are as low

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as 14 and as high as 40 mm Hg. Mathematical analysis gives the bandage pressure P (Pa) on the surface as a function of the bandage tension T (N) – itself a function of the extension and the elastic modulus–, the radius of curvature of the limb R (m) and the width of the bandage W (m) as: P=

T RW

[3.1]

As the effects of superimposed layers are additive, a configuration involving two turns of a bandage will essentially double the pressure. Because the bandage pressure is inversely proportional to R, wrapping a bandage at a given tension T will give the highest pressure at the ankle, where R is lowest, medium pressure at the calf, and the lowest pressure at the thigh. Adhesive bandages are made of woven cotton or rayon fabric that is coated with a suitable adhesive. Highly twisted or crepe yarns in warp provide a degree of stretch and elasticity to the bandage that can serve as a structure for treatment of varicose veins and for immobilizing orthopedic fractures resulting from sport and other injuries. Cohesive bandages combine some of the characteristics of ordinary stretch bandage with those of adhesive products. Whilst they do not adhere to the skin, a special coating on the surface enables layers to adhere to each other, thus preventing slippage and untying during use, including sports activity. The simplest form of a tubular bandage consists of a knitted tube of a lightweight fabric. These are used under orthopedic casts, or placed over arms or legs that are covered with a medication. In summary, it is clear that bandages are more directly textile structures that supplement dressings in treatment of wounds, both external and internal.

3.9

Materials used in dressings and bandages

A number of polymeric materials are used as fi lms, fibers and other structures for developing wound-dressing products. Some of the primary materials employed are cotton, rayon, polyester, nylon, polyolefins, acrylic, polyurethan, chitosan and alginate. No doubt some other materials have been considered, for example recombinant silk, but for economic or technical reasons, they have either not passed beyond the experimental stage or are used in a limited way. A brief introduction to the chemical nature, the physical structure and the properties of the materials used in wound management products follows. An understanding of these can provide the manufacturer with a means of selecting the most appropriate material for a dressing for each different application.

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3.9.1 Cotton The fiber that has been historically the most highly used in construction of dressings, absorbent pads, and bandages, is cotton, which still accounts for a significant volume of wound-care products in the world. The chemical structure of one repeat unit of the cellulose chain is shown in Fig. 3.8. Each repeat has three hydroxyl groups that are capable of linking with neighboring chains by hydrogen bonds. These groups, when free or weakly bonded, also attract and bond with water. The oxygen bridges between the repeat units allow chains to bend and twist, making the polymer flexible. The chains are quite long, and the fiber has over 60% crystalline structure. The most commonly used cotton in wound products is short (<2.5 cm). The cross-section is kidney bean shaped, i.e. relatively flat, but it becomes round when swollen with aqueous fluids. Once the waxes and impurities, normally present on raw fiber, are removed by a chemical scouring/ bleaching step, the fiber surface becomes greatly hydrophilic and instantly wettable. Under ambient conditions, the material has a moisture regain (mass of water absorbed per dry mass of fiber, expressed as percentage) of about 8%, but when soaked can take up to about 30% water and swell significantly. One unique characteristic of cotton that separates it from other fibers is that it becomes stronger when wet. This makes the fiber preferred for use in towels, pads, sponges, swabs and many other absorbent wound care and surgical products, where mechanical integrity along with absorption are important. With an abundance of functional groups on the chains, the structure can be chemically modified to incorporate additional hydrophilic groups to enhance the fiber’s absorptive properties, or therapeutic agents for imparting antibacterial or healing characteristics. The highly absorbent carboxymethyl cellulose (CMC) is a cellulosic material (usually based on wood fibers) that has been grafted with groups such as acrylic acid and which allows the structure to swell enormously and absorb many times the fiber’s weight in water.

3.9.2 Rayon The fiber, although chemically similar to cotton (Fig. 3.8), differs from it in physical structure: rayon’s molecular weight is about one-fi fth and crystallinity about one-half of that of cotton. These differences make rayon relatively weaker and more extensible, but more absorbent (about two times) than cotton. Thus, under ambient conditions, the fiber absorbs about 14% moisture, and when soaked, can swell and absorb almost 70% by weight water. The fiber, however, becomes significantly weaker when wet and, therefore, requires care when used directly on open wounds. One of the major applications of the fiber has been in disposable absorbent

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Textile materials and structures for wound care products

Cellulose (cotton, rayon, lyocell)

CH2OH HH O O OH H

H OH OHH HH O CH2OH

H OH

Elastomer

73

O H O C N R' N C O ( R O )n C N R' N C O H

O

RO – aliphatic structure (n ~ 10–30) R' – ring structure CH2OH HH O O OH H

Chitosan

H

Polyester (PET)

NH2

H

OHH HH O CH2OH

NH2

O CH2 CH2 O

O

O

C

C n

O

Polyamide Nylon 6

O

C (CH2 )5 NH

NH O C

Nylon 66

O

(CH2 )4

Polyolefin UHMWHD polyethylene

Polypropylene (iPP)

H

H

C

C

H

CN

H

H

C

C

H

H

n

n

CH3

CH3

C

C

CH2

O HO O

3.8 Molecular structures of a fiber.

CH2

H

H

© 2009 Woodhead Publishing Limited

NH (CH2 )6 NH

C

n

Polyacrylonitrile

Alginic acid

C n

OH O OH

O O HO m

n

OH OH O

O

n

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pads, sponges, and sanitary napkins. For use in absorbent dressings, usually a multilayer structure with rayon sandwiched between a permeable wound contact layer and an outer fi lm layer is preferred. Being endowed by even more free functional groups than cotton, desirable compounds can be grafted readily to the material for specific uses.

3.9.3 Polyester Polyester is one of the most versatile of the manufactured fibers that fi nds applications in many categories of textile products and is one of the widely used synthetic fibers in medical products. It is also the fiber frequently selected for combining with cotton and rayon in developing needled and spunlaced non-wovens for dressings. The chemical constitution of the commonly used material, poly(ethylene terephthalate) or PET, is shown in Fig. 3.8. The fiber has an aromatic component and an aliphatic sequence. Although the polymer lacks strong functional groups, the molecules, when drawn, pack closely and lead to a semi-crystalline mechanically strong and thermally stable fiber. Because of the lack of polar groups, the fiber has a low attraction for water (moisture regain ∼0.4% under normal conditions); this makes the material largely hydrophobic. A number of variations of the basic repeat are available but they vary primarily in terms of the proportion of the aromatic and the aliphatic components and, as a result, lead to fibers with different physical and mechanical properties. Some low molecular weight aliphatic polyesters are used as low melt adhesives for binder applications. Aliphatic polyesters capable of hydrolytic degradation are also used in the manufacture of bioabsorbable products, in particular surgical sutures. The polymer can be melt-extruded both as a fi lm and a fiber, the latter in different cross-sectional shapes and sizes to provide materials with various surface, physical, and mechanical properties.

3.9.4 Nylon Although many different types of nylons can be produced, the two widely used are nylon 66 and nylon 6 (Fig. 3.8). The chains, being void of aromatic compounds, lead to fibers that have low modulus and high extensibility. The presence of amide groups in the chains, however, allows hydrogen bonding between NH and CO groups of adjacent chains; this gives the fiber excellent mechanical and thermal stability. The amide groups in the chains also attract water, thus making the fiber reasonably hydrophilic (moisture regain 4%) and wettable. Being one of the most stretchable and elastic of the common textile materials, in addition to being acceptably hydrophilic, nylon is a preferred material for the manufacture of tubular bandages and stretchable pressure hosiery for treatment of venous leg ulcers.

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3.9.5 Polyolefins The two materials of interest are polyethylene and polypropylene (Fig. 3.8). The one based on the simplest of the hydrocarbon polymers, polyethylene, can be produced in the extended form using the gel spinning process. This leads to the extended chain structures with ultra high modulus and tenacity (HMPE) suitable for use in many high-performance technical textiles. In the non-extended folded chain form, the polymer does not have adequate mechanical properties to lead to fibers, but the material can be made into flexible fi lm or low melt adhesive or wax. The second material is polypropylene which is also made into fiber and fi lm. For making fibers, the chains must be in a stereo regular form. The olefi n fibers have the lowest density (0.91–0.96 g cm−3) of all fibrous materials. Both materials being strictly hydrocarbons are truly hydrophobic and, therefore, do not wet. They also have very low surface energy (∼24 mN m−1), which, among textile polymers, is only higher than that for polytetrafluoroethylene (∼12 mN m−1). Accordingly, olefi ns generally lead to lowadhesion fi lm products, which are used for developing low-adhesion contact layers for dressings. The fibers also have low melting points (<175 °C), which vary with chain length and, in the case of polypropylene, with tacticity. Accordingly, olefi ns are frequently used as low-melt coatings on regular fibers or as binder fibers for making fabrics by the non-woven methods. In dressings, the polymer fi nds extensive use in the development of contact layer fi lms.

3.9.6 Acrylic The chemical structure of the basic polymer is illustrated in Fig. 3.8. The pendant acrylonitrile groups (C≡N) are highly polar and lead to extensive bonding between chains. Because of this, a second component, up to about 15% by weight, which is another vinyl monomer, e.g. methyl acrylate or vinyl acetate, is inserted into chains to improve polymer solubility for extrusion into fiber. The fiber, with only about 2% moisture regain, has limited interaction with aqueous fluids. A major attribute of the fiber that particularly suits its use in dressings is its naturally high resistance to colonization of micro-organisms.

3.9.7 Elastomeric fibers The unique characteristic of elastomeric materials, whether used as shaped fibers or fi lms, is that they are soft and highly stretchable and elastic. The synthetic elastomers are linear block copolymers containing soft amorphous sections that provide stretch and hard crystalline components that

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3.9 Illustration of fine structure in elastomeric fibers, composed of blocks of crystallizable hard segments and non-crystallizable coiled soft segments.

act as tie points and hold the structure together in a memory-endowed mechanically stable material. These polymers are usually known as the segmented polyurethanes, whose general chemical structure is given in Fig. 3.8. The hard segments of neighboring chains tend to associate with each other and crystallize, while the soft segments remain largely coiled and unassociated (Fig. 3.9). Stretch of the order of 100% or more is common. The material being elastic and having the ability to return back to its original shape and size, its major application is in developing products that are required to exert transverse pressure of the required level for treatment of skin disorders. Thus, using elastomeric fibers in a bandage, one can keep an absorbent dressing pressed on a puncture wound to stop bleeding, or in hosiery one can apply desired pressures on different parts of leg to treat venous disorders.

3.9.8 Chitosan Chitosan is a natural biopolymer and is derived from chitin. The latter is the second most abundant natural polysaccharide on earth, with cellulose being the fi rst. It is found in the shells of crabs, shrimps, prawns and other crustaceans. While chitin itself can be used in dressings, it is its deacetylated derivative chitosan that is used extensively in this application. Figure 3.10 shows the difference between chitin and chitosan, where the acetyl group is eliminated and replaced with an amino group. 59 The degree of substitution varies from product to product but is typically about 80%.60 The modification makes the material a poly(β-(1-4)-2amino-2-deoxy-d-glucopyranose), which is a polycationic biopolymer that is also found in some insects and species of fungi.48 The deacetylation process provides open groups that cause the chemical and biochemical reactivity of chitosan to be relatively much greater and is one reason why

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Textile materials and structures for wound care products OH

OH O

OH O

O O HO

HO

77

O

O HO

NH

NH

NH

C=O

C=O

C=O

CH3

CH3

CH3

Chitin

OH

OH O

OH

HO

O

O O HO

O

O HO

NH2

NH2

NH2

Chitosan

OH

OH O

OH

O HO

HO

O

O

O

O HO

OH

OH

OH

Cellulose

3.10 Chitin, chitosan and cellulose.

this form is used more frequently. Another reason is that chitosan is more soluble than chitin. Chitosan-based composite fi lms are gaining attention for their ability to stop bleeding in wounds and promote healing. Chitosan is biodegradable, biocompatible, non-toxic, and has great antibacterial properties. Its properties make it an excellent choice for many medical applications. As a fiber or fi lm it is used for wound care, and, in microcapsule or bead form, it is utilized for drug delivery.61 For use as a fi lm, that has some mechanical integrity, chitosan is mixed with another polymer.62

3.9.9 Alginate Alginate is a natural polysaccharide which is derived from brown seaweeds.63–65 It has been used for a variety of purposes, ranging from thickening agents in food, to pharmaceutical additives. It is a block copolymer made up of 1,4-linked b -d-mannuronic acid (M) and a-l-guluronic acid

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Advanced textiles for wound care COO– O

COO–

OH O

OH

OH O

–OOC

OH

O HO

OH

COO– G

G

–OOC

O

OH M

O O

M

O M

–OOC

O O HO

O

HO

OH HO O

OH

O

HO O

–OOC

COO– G

G –OOC

O

M

O

O

OH O

OH

O

OH

O

O

OH

HO O

O

HO

OH COO– G

M

3.11 Mannuronic (M) and guluronic (G) block structures in alginate polymers.65

(G) residues (see Fig. 3.11 for stereochemical structures). There are three block structures present: M/M blocks, G/G blocks and M/G blocks. There are a variety of seaweeds that alginate is derived from and each species has a different composition of the acids. These result in a range of properties found in the material. Those containing a higher percentage of gluronic acid tend to be stronger and stiffer than the ones containing a higher percentage of the mannuronic acid. The latter, however, tend to have better swelling properties. In order to achieve alginate fibers from seaweeds, sodium alginate must be extracted from crushed and washed raw material. The sodium alginate is soaked in water where a viscous solution is formed which is then extruded into a calcium chloride bath. In the process, the sodium ions are replaced by the calcium ions. After washing and drying of the gel, the insoluble calcium alginate fibers remain.66 Webs containing the fibers may be composed by fi rst airlaying or carding-cum-crosslapping and then needle punching, to make the dressing. Fibers may also be converted into knitted or woven fabrics or assembled in a rope form. When the calcium alginate dressing is used on a wound, a reverse ion-exchange process takes place. The sodium ions in the blood and wound exudates are exchanged with the calcium ions in the alginates.66 Moisture is necessary for the alginate dressings to work properly, which is why they will not be beneficial on dry wounds and are used mainly on heavily exuding wounds.

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During production, other desired molecules can be introduced resulting in altered physical and chemical properties. For instance, silver, chitosan, and other antimicrobial molecules can be integrated either physically during fiber formation or chemically by grafting them onto the alginate chains.67 Molecules are also frequently added to improve the mechanical properties of the dressing. The fibers produced can be processed to form a non-woven mesh by one of the methods available.

3.10

Textile processes involved in formation of dressings and bandages

3.10.1 Introduction Dressings are made from polymers and fibers in a variety of types. The form in which these materials are used may be film, rope, ribbon or fabric. The latter are made by a weaving, knitting, braiding or a number of non-woven processes. Unless the product required is primarily load bearing, the fabric used is most likely the non-woven. The latter is usually soft and bulky and is porous and absorbent. Non-wovens are also homogeneous and most economical to produce. Films used as dressings are also non-wovens, but they are cast or extruded directly from polymer. These are thin and flexible but usually not as three-dimensionally drapeable and conformable as are the woven and the knitted fabrics. The same limitation also applies to the regular non-woven fabrics, i.e. they lack drape and conformability. A description of the methods of forming fabrics for dressings is given below. Since the non-woven fabrics are the largest used in forming dressing products and there are several technologies involved in making these fabrics, a more detailed description is presented of these processes and the structures made from them.

3.10.2 Yarns Fibers or fi laments obtained from extrusion of polymers are twisted (for short fibers) or entangled (for continuous fi laments) to form a continuous thread that has mechanical integrity enough to support stresses imposed on them during their weaving, knitting, or braiding into fabrics. A typical short fiber or staple yarn will contain about 100 individual fibers in the cross-section and have a diameter of the order of 0.2 mm. These onedimensional structures are therefore quite strong and flexible.

3.10.3 Woven fabrics A significant fraction of gauze fabrics are based on woven structures. These fabrics are manufactured on a loom that has a running sheet of yarns,

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Filling cross-section

Warp cross-section

3.12 Plain weave and leno weave.

known as warp, within which are inserted cross-threads, known as weft, at right angles. The woven fabrics used in wound management applications have the simplest structure called plain weave, shown in Fig. 3.12. Woven fabrics are relatively inextensible but dimensionally very stable structures with porosity that can be varied from nearly zero value to very high value (gauze, cheese cloth). A major problem with the woven fabric is the tendency of threads to unravel at the cut edge. A special weave know as ‘Leno’ in which two warp threads twist around a weft reduces this tendency.68

3.10.4 Knitted fabrics Knitted fabrics are categorized as either ‘weft’ or ‘warp’ constructed. Of the two, the faster and the more economical to produce is the weft knitted fabric that can be accomplished with a single package of yarn. The warp knitting process, on the other hand, requires a warp beam, i.e. a running sheet of yarns as does the weaving process. Loops are formed transversely in the case of the weft knitting and essentially vertically in the case of the warp knitting (Fig. 3.13). Simplest or plain weft knits tend to be very extensible and dimensionally unstable. One could improve on these properties by using additional yarns that interlock the loops. In contrast, the warp knitted structures are basically more interlocked and dimensionally stable. The knitted fabrics are more flexible, compliant and conformable than the woven fabrics, and one of them, the warp, also does not unravel as easily when cut to fit an application. A major limitation of knitted fabrics in some applications is porosity which, owing to the nature of the loop structure, tends to be high. The knitted nets and bandages can be draped more effectively than woven materials over areas that require three-dimensional conformability. One of the primary applications of knitted structures in wound care is in compression hosiery used for treatment of venous stasis.

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Textile materials and structures for wound care products Face wale

81

Back wale

1 х 1 rib

Half-tricot structure

3.13 Weft knit and warp knit structures.

3.10.5 Braided fabrics Although not used as extensively as the other two types in wound care, the braided fabrics are unique structures that are particularly suited for producing small diameter tubular and mechanically stable rope structures, the latter suitable for packing cavity wounds. The braids (Fig. 3.14) resemble woven fabrics except that the crisscrossing is not at right angle. One can have flat braids and tubular braids, the latter with and without a core. The braids are mechanically stable structures like the woven, but they are more flexible and conformable than the woven. The criss-crossing pattern in braids also leads to porosity.

3.10.6 Non-woven fabrics As a major function of dressings is to provide a soft and resilient hand, absorb and retain exudates, if present, and serve as a protective covering, non-woven structures suit the application and fi nd extensive utilization in the products. Such structures have been used as the facing, as well as the entire absorbent pad of a wide variety of dressings. These fabrics (Fig. 3.15) differ from woven and knitted in that the former are more homogeneous, softer, and more resilient, than the latter. The processes involved are also faster and more economical. A reason for the latter is that the fabric is made directly from the fibers, without the intermediate step involving the yarns, or even from the polymer itself. Many different types of processes are involved in the manufacture of non-wovens used in wound care products. These lead to different structures

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(a)

(b)

3.14 Braided structures a) without and b) with core.

3.15 Non-woven fabric.69

and properties and, therefore, suit different functions of a dressing. Accordingly, it will be useful to include here an introduction to the different processes involved and the structures produced by them. Considering that there is a high similarity between the design of an advanced multi-layer composite dressing and an engineered absorbent sanitary product (napkin, diaper, or an incontinence pad), a highly relevant but detailed discussion of non-woven processes, structures produced by them, materials used in producing them, and the properties obtained, can be found in a chapter, titled ‘non-wovens in absorbent materials,’ by Gupta and Smith.70

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A non-woven fabric consists of a web based on fibers or fibrils. A binder may be incorporated to hold fibers more fi rmly and provide mechanical integrity and strength as required. The manner in which the fibers are assembled into a web and bonded has a profound effect on the web properties. A web structure can range from the extremes of a highly oriented fiber configuration produced by the carding process to one of completely random arrangement obtained from the air laying or spunbonding process. An intermediate arrangement obtained by cross-lapping can also be developed. The bonding of fibers is accomplished either mechanically through entanglements, chemically through use of a binder, or thermally through melting and fusing, or using a combination of these methods. A non-woven web is generally considered ‘fi nished’ as soon as the fibers are assembled into an appropriate structure and bonded by one of the methods mentioned. It is possible, however, to give additional chemical or mechanical treatment to the bonded web, which can have an important influence on web characteristics. These include, as examples, a chemical repellent, wetting or antimicrobial treatment, and mechanical embossing, aperturing or glazing treatment. Uni-directional dry form process This is a carding process in which fibers are teased, combed and oriented by wires and formed into a web a few fibers thick, with the fibers predominantly oriented along the longitudinal direction. A structure based on such a web will usually be characterized by good tensile properties in the longitudinal or the machine direction, but poor properties in the transverse direction. Cross-lapping of the web is done to alleviate this deficiency and also to increase its weight. The cross-laying (Fig. 3.16) is done in a continuous manner, often onto another carded uni-directional web. The result is a fiber web with one layer having a uni-directional orientation in the machine direction and the other succeeding layers having a unidirectional web oriented at an angle close to but less than 90° to the machine direction. By proper selection and juxtaposition of the layers of different webs, it is possible to control the orientation in the fi nal web. Random laid or air laid process In this process, individualized fibers are suspended into an air stream, and allowed to be deposited on a moving perforated belt or drum (Fig. 3.17). The web obtained has fibers distributed randomly. In addition to the typical textile length fibers (0.9–2 in.), very short wood pulp fibers (∼0.3 in.) can also be used in this method. The process of deposition prompts some fibers

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Advanced textiles for wound care Carded web Feed conveyor

Upper conveyor belt Web Lower conveyor belt Delivery conveyor

3.16 Carding cross-lapping process.71

Air Suspended fibers

Random web

Suction

Apron

3.17 Random air laying process.72

to be lifted out of the X–Y plane and become partially oriented in the Z direction. This results in a web having higher bulk and larger void volume, which enhances the web’s fluid absorbing and holding capability. Chemical and thermal bonding of webs A bonding method frequently employed for the dry form web is chemical, involving an acrylic or a latex binder.73 The proprietary formulation will include other ingredients as well, which are a catalyst (for cross-linking), a viscosity modifier, a defoaming agent, and a surfactant. The resin add-on

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can vary over a wide range, but the typical value will lie in the 10–25% range. The binder can be applied by a variety of procedures, including saturation of fabric, spraying the web, or printing binder on the web with a roll. The saturation method is normally not considered for absorbent materials, as the binder covers essentially all fiber surfaces. Spray bonding with careful adjustment of parameters can provide bonding at just the cross-over points, leaving the rest of the web material largely binder free. The placement of the binder resin can be even more fi nely controlled by print bonding, in which the binder is positioned on the web in a discrete predetermined pattern utilizing engraved rolls74 or a rotary screen. More recently, the use of binder in the form of foam has been utilized.75 This leads to a reduction in the drying cost of the printed web, as the binder is diluted with air rather than water. A modification of the bonding process has also been used, which is suited in particular for the contact layer of the dressing. This involves the use of thermal techniques for bonding.76,77 The fabric contains a blend of low melt fibers (polyethylene and polypropylene) and other fibers, natural or man-made, and is bonded with heat using engraved hot rolls. Another version of the thermal method involves the use of bicomponent fibers that have a higher melting core with a lower melting sheath. When heat is employed by embossed calendar rolls or by hot air, the sheath layers bond. Spunbond process A polymer melt is extruded through a large number of spinnerets to form numerous continuous fi laments. These fall onto a moving conveyer and form a web by overlapping with each other. Fibers are oriented randomly, which is achieved by oscillating spinnerets, field-induced by electrical charges, and/or the controlled flow of air. Webs may be bonded by thermal or chemical means over their entire area to produce a thin, smooth, fabric. Such a structure is stiff, but bonding at strategic points can be used to produce a softer and more flexible fabric. The polymers used in spunbonding are mainly polyester, nylon and polypropylene. Although made from a hydrophobic polymer, the web having a high porosity lends itself to use as a wound contact layer. Print bonding used for dry form non-wovens can also be utilized in bonding these webs.78 The amount of bonding area for a typical spunbond fabric ranges from about 10 to 35%. Needlepunch process In the needlepunch process, in which primarily the cardedcum-crosslapped or random laid webs are used, the bonding is achieved by the penetration of a set of barbed needles through the structure (Fig. 3.18). The barbs are designed such that, as a needle penetrates, groups

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Stripper plate Fibers

Bed plate

3.18 Needlepunch process with magnified view of the needling action.71,72

of fibers from the top layer of the web are engaged and driven through the thickness of the web. As the needle retracts, the fibers are released from the one-way barbs. This results in mechanical entrapment and orientation of the portions of fibers in the thickness direction. By control of the needle penetration and the repetition of the needling action from the opposite side of the fabric, a three-dimensional, mechanically entangled network can be achieved.79 The process tends to consolidate the web but creates oriented capillaries or channels along the thickness. This imparts resiliency to the web and the capability to efficiently imbibe and hold large volume of fluid. There is a minimum amount of fiber that is required for effective mechanical engagement. Consequently, most needle-felt structures have a weight of 60 g m−2 or more. Wet laid process The wet laid non-woven process bears a considerable resemblance to the paper manufacturing process. Short fibers (generally one-quarter inch or less) are suspended in an aqueous slurry along with minor amounts of other constituents. The slurry is subjected to strong agitation in order to cause the fibers to be uniformly distributed. The slurry is conveyed to a moving wire belt, where the liquid drains through and the fibers are left in the form of a mat in largely random configuration. The web is then removed from the conveyor, taken through a bonding process, dried and then wound up onto a roll. In paper manufacturing usually 100% pulp (∼3 mm) is used and bonding by hydrogen linkages is extensive, which leads to the typical thin and stiff structure. In the wet laid non-woven process, on the other hand, compositions can range from sizeable wood pulp content to a completely synthetic

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fiber furnish. Also, in these structures, usually the fibers used are longer and crimped or convoluted, and the frequency of bonding is lower. This leads to a fabric that is relatively bulkier and softer. If pulp is used as one of the constituents, its fraction and, therefore, the resulting hydrogen bonding, are small. An external binder is often employed to increase strength while maintaining bulk. Bonding is usually achieved by either the chemical or the thermal methods described earlier. Spunlace process This process, which also leads to mechanical bonding, utilizes high-energy, closely spaced, water jets that emerge from an injector and impinge on a web substrate and entangle loose arrays of fibers (Fig. 3.19).80,81 The process is claimed to have the capability of producing a variety of surface and fabric patterns from many different precursor webs made from essentially any fiber that is not too stiff or brittle to bend or move. Figure 3.20 shows a spunlaced web made from a blend of polyester and rayon fibers. The injectors are positioned above the moving backing belt or rotating drums, which are perforated and carry the unbonded web through the unit.82,83 The impaction of water jets forces fibers onto and into the backing belt, giving the fiber web surface the texture of the surface of the belt. If the backing belt has large holes, an apertured web is obtained; if it has very fine holes, a web approaching a non-apertured structure is obtained. This versatility associated with the configuration of the supporting belt provides the capability to produce a wide range of surface and structural features in a spunlace fabric. Wood pulp/polyester fiber blended spunlace fabrics were originally the largest volume of products produced by the process; however, other

High water pressure Water jet head Base web Entangled web Web support Drum Air and water return

3.19 Spunlace process.71

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3.20 Spunlace web from rayon and polyester.

spunlace fabric types have become significant commercial successes, including those based on 100% bleached cotton and its blend with synthetic fibers. In addition to drylaid and wetlaid precursors, a direct-laid web from the spunbonding or meltblowing process has also been used, but usually as part of a multilayer construction. Composite fabrics have been produced by hydroentangling a drylaid or a wetlaid staple fiber web superimposed on a direct-laid fabric that serves as a reinforcing scrim.84 This variant is especially useful in producing a composite of a lightweight spunbound fabric of olefi n or polyester around whose fi laments a wood pulp layer has been entangled. This can provide a strong yet absorbent fabric from relatively low-cost raw materials. Modifications of the hydroentangling system have also been used. One such process involves fiber entanglement at a relatively low level, which is still sufficient to convey some mechanical integrity; this is then supplemented by a limited amount (1–5%) of external latex binder, which conveys additional strength and integrity to the structure. 85 In another modification, the low level of fiber entanglement is supplemented by adding a small amount (∼15%) of thermoplastic binder fiber. After drying the fabric, additional heat is applied to melt and thus activate the latter. A polyolefi n bicomponent fiber is used for this process, although other binder fibers can also be employed. This same technique, involving addition of a low melt fiber, is now used at times to enhance the physical properties of needle punched fabrics as well.

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A vast majority of spunlace fabrics are produced in basic weights ranging from about 20 g m−2 to about 100 g m−2 . A web of weight less than 20 g m−2 does not develop enough integrity unless an auxiliary means of bonding or very low denier fibers providing high number of fibers are used. Webs weighing more than about 100 g m−2 are usually too heavy to be penetrated by water jets, unless very high energy levels are used. Meltblown process Meltblowing is a unique, one-step process in which the melt of a polymer emerging from orifices is blown into super fi ne fibers by hot, high-velocity air. A molten polymer is blown into ultrafine fibers and collected on a rotary drum or a forming belt with a vacuum underneath the surface to form a nonwoven web. Two hot air streams at near sonic velocity at the polymer exit attenuate the extruded stream of polymer (Fig. 3.21). A typical meltblown web contains fibers of a range of sizes (Fig. 3.22); however, typically, the fibers are 1–10 μm in diameter. The fibers are tacky and tend to stick to each other and take the shape of the apron or object on which they are collected. It is recognized that the fibers are weak Heated air

Polymer

Screw extruder Collecor

Gear Die body

3.21 Schematic of a meltblowing process.

3.22 Micrograph of a meltblown fabric showing variable fiber size. 86

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and the web lacks uniformity. This currently restricts the application of meltblown structures to non-load-bearing products. However, a meltblown web may be combined with a web made by another method and form a composite that not only has improved mechanical properties but also other desirable physical properties. Such products contain fibers of different types and sizes, which can lead to novel structures with properties not possible from a single material or process.87 Although polypropylene has been the material used most widely, other polymers have also been used successfully, these being polyethylene, polyester, and nylon. Essentially, any thermoplastic polymer, including biodegradable, can be used. Polymer web process These processes essentially lead to sheet materials such as thin foams, plastic nets,82,88 perforated fi lms,83,89 and similar materials. The methods of manufacturing these miscellaneous materials are as diverse as their natures. They frequently arise from modified plastic processing techniques and often represent the combination of technologies. In general, the products are not hydrophilic and, hence, not inherently absorbent. Because of their structure and characteristics, however, these materials can often substitute for a component of an absorbent product, including non-adherent contact layer and protective outer layer of a dressing. Advanced composites from combination of technologies Attractive composites can be made by a combination of airlaid and spunlace processes. One example is infusing pulp by airlaying onto a regular cotton or rayon web during hydroentangling. Such a product has similar or superior absorbency of 100% cotton or rayon fabric but at a fraction of the cost. A typical blend for pulp and fiber will be 50/50. Such a structure can be used as the absorbent layer in a dressing. Another structure that has received great emphasis during the past two decades is one that combines spunbond and meltblown processes in producing a composite fabric. Examples of these are the spunbond (SB)/meltblown (MB), known as SM, and the SB/MB/SB or SMS composites. Often two layers of meltblown are sandwiched between two of spunbond to lead to SMMS. The production and properties of these are particularly enhanced by the use of polypropylene/polyethylene bicomponent materials in the preparation of MB webs.90,91 The spunbond fabric, combined with ultralightweight meltblown fabric, is suited for use as facing for absorbent products (Fig. 3.23). Most interesting of the composite structures, however, that can lend to direct use as dressings, are the cellulose-centered non-wovens that are capable of being produced on an integrated line.70,92 These are laminates

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that have cotton, or another cellulosic fiber web, sandwiched as a core between two layers of meltblown and/or spunbond webs, with the size and the characteristics of each of the three adjusted to suit the application. For developing such products, the absorbent material used could be cotton or rayon of regular length, fed from a pre-formed roll, or pulp of short length, deposited directly from an airlaying system on the site in coordination with the formation of the spunbond/meltblown webs (Fig. 3.24).

3.23 Micrograph of a polypropylene SMMS fabric. 91

Cotton centered spunbonded/meltblown composite

Spunbond extrusion system

Cotton nonwoven

Heated calender rollers Melt blown fabric

3.24 Preparation of cotton-centered composite with spunbond and meltblown webs forming the outer surfaces.

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3.11

Acknowledgement

The figures included in this chapter were put together by Mr Venugopal Boppa, a graduate student in Textile Engineering at the North Carolina State University, Raleigh, NC 27695-8301. The authors express their thanks to Mr Boppa for this valuable assistance.

3.12

References

1. winter g, ‘Formation of a scab and the rate of epithialization of superficial wounds in the skin of the young domestic pig’, Nature, 193, 293–294, 1962. 2. paul w, sharma cp, ‘Chitosan and alginate wound dressings: A short review’, Trends Biomater Artif Organs, 18(1), 18–23, 2004. 3. dyson m, young s, pendle l, webster df, lang sm, ‘Comparison of the effects of moist and dry conditions on dermal repair’, J Invest Dermatol, 91, 434–439, 1988. 4. atiyeh bs, ioannovich j, al-amm ca, el-musa ka, ‘Management of acute and chronic open wounds: the importance of moist environment in optimal wound healing’, Curr Pharm Biotechnol, 3, 179–195, 2002. 5. cohen ki, ‘The biology of wound healing’, Contemp Surg Suppl, 4, 2–3, 2000. 6. cohen ki, diegelmann rf, yager dr, womum iii il, graham mf, crossland mc, ‘Wound care and wound healing’, in Principles of Surgery, Schwartz International edition, Spencer S and Galloway DF, eds, McGraw–Hill Book Company, New York, 269–290, 1999. 7. cohen ki, ‘Wound healing: Key advances in research and clinical care’, Contemp Surg Suppl, 4, 4–8, 2000. 8. smith and nephew, Wound Management Website, http://www.smith-nephew. com/ 9. stashak ts, farstvedt e, othic a, ‘Update on wound dressings: indications and best use’, Clinical Techniques in Equine Practice, 3, 148–163, 2004. 10. adam medical illustration team, US National Library of Medicine. Laceration versus puncture wound, 2004. Retrieved from http://www.nlm.nih. gov/medlineplus/ency/imagepages/19616.htm 11. boateng js, matthews kh, stevens hn, eccleston gm, ‘Wound healing dressings and drug delivery systems: A review’, J Pharm Sci, Oct 26, 2007. 12. steven rb, catherine d, chia s, kang t, ‘Skin repair and scar formation: the central role of TGF-β’, Expert Rev Mol Med, 5(8), 1–22, March 2003. 13. gamgee s, ‘A new sponge,’ Lancet, 1, 795–796, 1884. 14. turner t, 1985, ‘Which dressing and why’, in Wound Care, S. Westaby, ed., Heinman Medical Books, London, 1985. 15. morgan d, ‘The application of the “ideal dressing” theory to practice’, Nurs Scot, 16–18, July, 1998. 16. thomas s, (2003) ‘Atraumatic Dressings’, Worldwide Wounds (online), available: http://www.worldwidewounds.com/2003/january/Thomas/AtraumaticDressings.html

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17. shwartz r, (2007) ‘Surgical Dressings’, eMedicine (online), available: http:// www.emedicine.com/derm/topic826.htm 18. winter gd, ‘Epidermal wound healing’, in Maibach HI and Rovee DT, Ed., Surgical dressings in the hospital environment, Chicago, Year Book Medical publishers, 1972, 71–112. 19. balakrishnan b, mohanty m, umashankar pr, jayakrishnan a, ‘Evaluation of an in situ forming hydrogel wound dressing based on oxidized alginate and gelatin’, Biomaterials, 26(32), 335–342, 2005. 20. mendez-eastman s, ‘Wound Dressing Categories’, Plast Surg Nurs, 25(2), 95–99, 2005. 21. thomas s, ‘Assessment and management of wound exudate’, J Wound Care, 6(7), 327–330, 1997. 22. worley c, ‘So, what do I put on this wound? Making sense of the wound dressing puzzle part II’, MEDSURG Nursing, 15, 182–183, 2006. 23. bello ym, phillips tj, ‘Recent advance in wound healing’, JAMA, 283(6), 716–718, 2000. 24. ovington l, ‘Advances in wound dressings’, Clin Dermatol, 25, 33–38, 2007. 25. worley c, ‘Clinical ‘How To’-1’, MEDSURG Nurs, 15, 106–107. 2006. 26. worley c, ‘Clinical ‘How To’-3’, MEDSURG Nurs, 15(4), 251–254, 2006. 27. eastman s, ‘Wound dressing categories’, Plast Surg Nurs, 25(2), 95–100, 2005. 28. yudanova t, reshetov i, ‘Modern wound dressings: manufacturing and properties’, Pharm Chem J, 40(2), 24–31, 2006. 29. Retrieved from http://www1.istockphoto.com/fi le_thumbview_approve/ 788040/2/istockphoto_788040_white_guaze_on_dark_background.jpg 30. thomas bc, Advances in skin and wound care, Springhouse Corporation, PA, USA, 2000. 31. armstrong mh, price p, ‘Wounds wet-to-dry gauze dressings: fact and fiction’. Volume 16(2), 56–62, February 2004. 32. elliot imz, A short history of surgical dressings, London, Pharmaceutical Press, 1964. 33. rheinwald jg, green h, ‘Formation of a keratinizing epithelium in culture by a cloned cell line teratoma’, Cell, 6, 317–330, 1975. 34. falling v, isaacs c, packet d, downing g, kowtow n, butter eb, hardenyoung j, ‘Wounding of bioengineer skin: cellular and molecular aspects after injury’, J Invest Dermatol, 119, 653–660, 2002. 35. thomas a, harding kg, moore k, ‘Alginates from wound dressings activate human macrophages to secrete tumor necrosis factor-α, Biomaterials, 21, 1797–1802, 2000. 36. schultz gs, sibbald rg, falanga v, ayello ea, dowsett c, harding k, romanelli m, stacey mc, teot l, vanscheidt w, ‘Wound bed preparation: a systematic approach to wound management’, Wound Rep Reg 11, 1–28, 2003. 37. mast ba, schultz gs, Interactions of ctyokines, growth factors and proteases in acute and chronic wounds, Wound Rep Reg, 4, 411–420, 1996. 38. baker ea, leaper dj, ‘Proteinases, their inhibitors, and cytokine profi les in acute wound fluid’, Wound Rep Reg, 8, 392–398, 2000. 39. trengove nj, bielefeldt-ohmann h, stacey mc, ‘Mitogenic activity and cytokine levels in non-healing and healing chronic leg ulcers’, Wound Rep Reg, 4, 234–239, 1996.

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40. christoforou c, lin x, bennett s, connors d, skalla w, mustoe t, linehan j, arnold f, guskin e, ‘Biodegradable positively charged ion exchange beads: a novel biomaterial for enhancing soft tissue repair’, J Biomed Mater Res, 42, 376–386, 1998. 41. connors d, gies d, lin h, gruskin e, mustoe ta, tawil nj, ‘Increase in wound breaking strength in rats in the presence of positively charged dextran beads correlates with an increase in endogenous transforming growth factor-β1 and its receptor TGF βR1 in close proximity to the wound’, Wound Rep Reg, 8, 292–303, 2000. 42. cullen b, smith r, mcculloch e, silcock d, morrison l, ‘Mechanism of action of PROMOGRAN, a protease modulating matrix, for the treatment of diabetic foot ulcers’, Wound Reg Rep, 10, 16–25, 2002. 43. edwards jv, yager dr, cohen ik, diegelmann rf, montante s, bertoniere n, bopp af, ‘Modified cotton gauze dressings that selectively absorb neutrophil elastase activity in solution’, Wound Rep Reg, 9, 50–58, 2001. 44. edwards jv, batiste sl, gibbins em, goheen sc, ‘Synthesis and activity of NH 2- and COOH-terminal elastase recognition sequences on cotton, J Peptide Res, 54, 536–543, 1999. 45. wright jb, lam k, buret ag, olson me, burrell re, Early healing events in a porcine model of contaminated wounds: effects of nanocrystalline silver on matrix metalloproteinases, cell apoptosis, and healing, Wound Reg Rep, 10, 141–151, 2002. 46. moseley r, leaver m, walker m, waddington rj, parsons d, chen wyi, embery g, ‘Comparison of the antioxidant properties of HYAFF- 11p75, AQUACEL and hyaluronan towards reactive oxygen species in vitro’, Biomaterials, 23, 2255–2264, 2002. 47. qin y, ‘Novel antimicrobial fibres (Chitosan and alginates)’, Text Mag, 31(2), 14–17, 2004. 48. ghosh s, jassal m, ‘Use of polysaccharide fibres for modern wound dressings’, Indian J Fibre Text Res, 27(4), 434, 2002. 49. hemcon incorporated, ‘How HemCon Dressings Work’, retrieved from http:// www.hemcon.com/EducationCenter/HowHemConDressingsWork.aspx 50. yoshikawa m, midorikawa t, otsuki t, terashi t, ‘Process for producing articles of regenerated chitin–chitosan containing material and the resulting articles’, In Omikenshi Company Limited (Osaka, JP), Koyo Chemical Company Limited (Tokyo, JP) (Eds.), (424/402, 424/443, 424/445, 424/446, 424/447, 604/289, 604/304 ed.). Japan: A01N 025/34; A61L 015/16, 1998. 51. gustafson sb, fulkerson p, bildfell r, aguilera l, hazzard tm, ‘Chitsosan dressing provides hemostasis in swine femoral arterial injury model’, Prehosp Emerg Care, 11(2), 172–178, 2007. 52. pusateri ae, holcomb jb, kheirabadi bs, alam hb, wade ce, ryan kl, ‘Making sense of the preclinical literature on advanced haemostatic products’, J Trauma, Injury, Infect, Crit Care, J Trauma, 60, 674–682, 2006. 53. ward kr, tiba mh, holbert wh, blocher cr, draucker gt, proffi tt ek, bowlin gl, ivatury rr, diegelmann rf, ‘Comparison of a new haemostatic agent to current combat haemostatic agents in a swine model of lethal extremity arterial hemorrhage’, J Trauma, 276–284, 2007. 54. favuzza j, hechman hb, ‘Hemostasis in the absence of clotting factors’, J Trauma, 57, S42–S44, 2004.

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55. holme i, ‘Smart surgery’, Nonwovens Rep Int, (February): 40–41, 2004. 56. hiroshi tamura, yukihiko tsuruta, seiichi tokura, ‘Preparation of chitosancoated alginate fi lament’, Mater Sci Eng C, 20, 143–147, 2002. 57. thomas s, ‘Soft silicone dressings: Frequently asked questions’, World Wide Wounds, Oct 2003, http://www.worldwidewounds.com/2003/october/Thomas/ Soft-Silicone-FAQ.html 58. thomas s, ‘Bandages and Bandaging’, in Wound management and dressings, The Pharmaceutical Press, London’, 88–98, 1990. 59. dalwoo, ‘Structure of chitin / chitosan and cellulose’, 2002. http://members. tripod.com/∼Dalwoo/structure.htm 60. meron biopolymers: a division of marine chemicals, ‘Applications of chitin’. http://www.meronbiopolymers.com/html/mbio2apln.htm 61. smart g, miraftab m, kennedy j, groocock m, ‘Chitosan: crawling from crab shells to wound dressings’, Medical textiles and biomaterials for healthcare, Woodhead Publishing, 2005. 62. wittaya-areekul s, prahsarn c, ‘Development and in vitro evaluation of chitosan-polysaccharides composite wound dressings’, Int J Pharm, 313, 123–128, 2006. 63. qin y, ‘Absorption characteristics of alginate wound dressings’, J Appl Polym Sci, 91(2), 953, 2004. 64. qin y, ‘Gel swelling properties of alginate fibers’, J Appl Polym Sci, 91(3), 1641. 2004. 65. qin y, ‘Alginate fibres: An overview of the production processes and applications in wound management’, Polym Int, 57(2), 171–180, 2008. 66. schenck k, ‘Wound dressings (1), Calcium alginates for moist wound treatment’, http://www.hartmannonline.de/english/produkte/wundbehandlung/ wundforum/default.htm. 67. wang l, khor e, wee a, lim ly, ‘Chitosan–alginate PEC membrane as a wound dressing: assessment of incisional wound healing’, J Biomed Mater Res, 63(5), 610–618, 2002. 68. kapadia i, ibrahim im, ‘Woven vascular grafts’, US Pat. 4,816,028, 1989. 69. wei q, liu y, wang x, huanga f, ‘Dynamic studies of polypropylene nonwovens in environmental scanning electron microscope’, Polym Test, 26(2–8), 2007. 70. gupta bs, smith dk, ‘Nonwovens in absorbent materials’, in Absorbent Technology, Chatterjee and Gupta eds., Elsevier 349–388, 2002. 71. albrecht w, fuchs h, kittelmann w, Nonwoven fabrics, Wiley-VCH, 2003. 72. russell sj, Handbook of nonwovens, Cambridge, Woodhead Publishing, 2007. 73. dewitt wg, brodnyan jg, ‘The development of a soft latex binder for durable nonwovens’ 8th INDA Technical Symposium, 1980. p. 12. 74. drelich ah, in Modern Non-wovens Technology, edited by D. T. Ward, Texpress, Manchester’, 1977. p. 61. 75. jarvis cw, danforth pa, ko1inofsky ba, vaughn ea, ‘A comparison of foam and saturate banded nonwovens: effects of fiber and binder blends’, 8th INDA Technical Symposium, New York, March 1979, p. 175. 76. mansfi eld rg, Advanced Forming/Bonding Conference, INSIGHT 82, Marketing/Technology Service, Kalamazoo, Michigan’, 1982. Section II.

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77. drelich ah, Advanced Forming/Bonding Conference, INSIGHT 81, Marketing/Technology Service, Kalamazoo, Michigan (September 1981), Section VI. 78. debrunner re, 5th Annual TANDEC, Knoxville, TN p 5.6–1, 1995. 79. hearle jws, purdy at, jones jj, ‘A study of needle action during needle punching’, J Text Inst, 64, 617, 1973. 80. evans fj (to DuPont), US Patent, 3,485,706 (December 23, 1969). 81. bolton a (to Johnson & Johnson), US Patent 4,144,370 (March 13, 1979). 82. lloyd r (to Smith & Nephew Research Ltd.), UK Patent 1,496,786 (January 5, 1978). 83. raley ge, adams jm (to Ethyl Corporation), US Patent 4,252,516 (February 24, 1981). 84. medeiros fj, Proc. INDA-TEC 96, International Nonwovens Conference, Crystal City, VA p 5.1, 1996. 85. brooks ba (to Johnson & Johnson), US Patent 2,045,825 (November 5, 1980). 86. bodaghi h, ‘Melt Blown Microfiber Characterization’, INDA JNR, 1(1), 14–27, 1989. 87. wadsworth lc, Proc. 2001 Beltwide Cotton Conference, National Cotton Council, January 9–13, Anaheim, CA, 1, 629, 2001. 88. madsen wb, jensen fh, rasmussen gb, goldstein g, roussin-moynier y (to Beghin-Say), UK Patent 1,455,981 and 1,455,982 (August 11, 1976). 89. thompson ha (to Procter & Gamble Co.), US Patent 3,929,135 (December 30, 1975). 90. berger rm, US Patent 5,633,082, May 27, 1997. 91. madsen jb, ‘New generation of hydrophilic spunmelt composites’, Nonwovens World, August–September’, 69–75, 2001. 92. sun c, zhang d, wadsworth lc, mclean m, ‘Processing and property study of cotton-surfaced non-wovens’, Textile Res J, 70(5), 449–453, 2000.

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4 Interactive dressings and their role in moist wound management C. W E L L E R, Monash University, Australia

Abstract: Technological advances in the development of interactive wound dressings are reviewed. An important original work was that of George Winter, who demonstrated the value of a moist wound environment in wound healing. Recent advances in wound management incorporate new technologies that interact with the wound at a cellular level rather than simply reducing moisture loss. The balance of moisture is critical to healing and this principle has been the driving force in the development of products that are currently available such as hydrogels, hydrocolloids, alginates, and foams and fi lms. Many interactive dressings are able to work actively with wound properties such as wound exudate, tissues, cells and some growth factors to enhance healing. Key words: moist wound healing, tissue repair, interactive dressings, hydrogels, hydrocolloids, alginates.

4.1

Introduction

As with many aspects of medicine, the field of wound management has had an interesting journey. We have come a long way since the 16th century when Ambroise Pare travelled with the French army as a barber–surgeon. To counteract the purported poisonous effects of gunpowder, the wounds of injured soldiers were scalded with boiling oil. A shortage of boiling oil at the Battle of Turin forced Pare to concoct another therapeutic intervention for the doomed soldiers. He mixed a portion of egg yolks, turpentine, and oil of roses to help heal gun power wounds (an ancient roman turpentine remedy) and found, to his surprise, that the soldiers deprived of boiling oil not only survived but their wounds healed more quickly and with less pain. Pare had created the fi rst clinical trial in wound care (Baxter 2002). Pare may have, unknowingly, also concocted one of the fi rst interactive moist wound dressings. Since the 16th century, there have been many periods of enlightenment in the area of wound management. Through World War I, the task of changing dressings was the realm of physicians and medical students. In the 1930s, the dressing changes were performed by nurses. For the next 40 97

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years, the mainstay dressings were gauze, cotton wool pads, paraffi n impregnated gauze and absorbent cotton. A major development in moist wound healing was the original work by George Winter which demonstrated the value of a moist wound environment in wound healing, although the concept of moist wound healing did not begin to receive serious consideration until the 1970s and 1980s. Our understanding of the function of wound healing has increased remarkably since Winter’s work ‘Formation of a scab and the rate of epithelialisation of superficial wounds in the skin of young domestic pigs’ was published in Nature (Winter 1962). This work was the foundation of the concept of moist wound management as it showed that wounds that heal under moist conditions healed 50% faster than those wounds that healed in dry, open to air, conditions. Moist wound healing not only facilitates fragile epithelial cells to migrate more freely it also enhances viability of the epithelial cells as the cells are protected from dehydration and scab formation. Epithelialisation of the wound therefore occurs more quickly if a moist wound environment is maintained (Weller 2005). Before the work of Winter and the human validation of Winter’s research (Hinman and Maibach 1963), practitioners commonly accepted the notion that wound healing depended on maintaining a dry wound bed, The scab has, in the past, been described as ‘nature’s dressing’. Today, most clinicians are more likely to accept that a moist wound environment facilitates the healing of wounds and promotes the growth of new tissue. Recent advances in wound management incorporate new technologies that interact with the wound at a cellular level rather than simply reducing moisture loss (Leaper et al. 2002). A balanced moist wound environment aids cellular growth and collagen proliferation within a non-cellular matrix. The balance of moisture is critical to healing and this principle has been the driving force in the development of products that are currently available. These are hydrogels, hydrocolloids, alginates, and foams and fi lms. Nowadays, many of these dressings also incorporate antibacterials in their delivery systems (Leaper et al. 2002).

4.2

Normal wound healing

The healing of a wound requires a well-orchestrated integration of complex biological and molecular events of cell migration, cell proliferation and extracellular matrix (ECM) deposition. In cutaneous injuries that heal readily and do not have an underlying pathophysiological defect (acute wounds), the main aim of the body is to achieve a quick repair expending the least amount of energy. This often means such wounds will heal with a scar and no regeneration (Falanga 2005). In wounds with underlying

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pathophysiological abnormalities such as venous leg ulcers, diabetic foot ulcers and full thickness burn injury evolutionary adaptations may not have occurred and impaired healing is the result.

4.2.1 Phases of wound healing The basic elements of wound healing, with information mainly derived from experimental wounds in animals, cannot be separated and categorised in a clear defi nitive way. It is useful to divide the repair process into four overlapping phases of coagulation, inflammation, migration– proliferation (including matrix deposition) and remodelling (Falanga 2005), each phase being modulated by different cytokines and growth factors (Leaper et al. 2002). The inflammatory phase of wound repair starts almost immediately after wounding and lasts for up to several days when symptoms such as oedema, erythema, heat and pain are well known. The initial response to injury is vasoconstriction which stops blood loss and platelet activation promotes fibrin clot formation. The fibrin plug consists of platelets enmeshed in fibrinogen, fibronectin, vitronectin and thrombospondin which not only forms a temporary wound cover but also protects against bacteria. Substances released by platelets include a wide range of growth factors including platelet-derived growth factor (PDGF) and transforming growth factor. These, as well as other growth factors have an early role in cell recruitment and ECM formation. Injury to the wound creates a hypoxic episode owing to blood vessel damage. Hypoxia increases keratinocytes migration, early angiogenesis, proliferation of fibroblasts and the synthesis of crucial growth factors and cytokines including PDGF and vascular endothelial growth factor. Once the inflammatory phase is almost complete, wound contraction begins. Formation of ECM, proteins, angiogenesis, contraction and keratinocytes migration are important elements of these phases. The balance between contraction and wound closure depends on the depth and location of the wound and the presence of complications such as infection which could impair healing (Falanga 2005). Acute wounds progress through the linear process of overlapping biological and molecular events, whereas chronic wounds are often in different phases at the same time and progression may not occur in synchrony (Falanga 2005). This ‘normal’ wound healing model has helped us understand the basic biology of tissue repair and use that knowledge when the healing process is impaired. We now know that chronic wounds contain decreased levels of some intrinsic growth factors, including PDGF, basic fibroblast factor, extracellular glycoprotein (ECG) and Transforming Growth Factor beta (TGFβ), compared with acute wounds (Harding et al. 2002).

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4.3

Wound characteristics

The type, size, and depth of wound will all have important implications for healing events at the cellular and molecular level. In acute wounds and surgical wounds, there is usually less tissue damage and the wound will close by primary intention. Wounds that are restricted to the superficial layer of the dermis still have some keratinocytes in the hair follicles in the wound bed and therefore can heal from the edges as well as from within the wound bed (Enoch et al. 2006b). Determining wound duration, size and depth and wound bed condition are important aspects to consider in wound assessment. Specific wound characteristics correlate with healing. Patients with a large wound area (>2 cm 2), an ulcer of long duration (>2 months), and ulcer depth (exposed tendon, ligament or bone) were three important factors that would delay healing (Margolis et al. 1999; Margolis et al. 2002; Margolis et al. 2004). As research and understanding improves at a cellular level, we are better able to assist the body not only by covering the wound to protect it but also by providing wound dressings to aid the healing process. Normal wound healing processes require restoration of epithelisation and collagen formation. The fi rst occurs by migration and proliferation of keratinocytes from the wound edges and by differentiation of stem cells from remaining hair follicle bulbs. The second occurs by influx of growth factors secreted by macrophages, platelets and fibroblasts, by fibroblast proliferation and subsequent synthesis and remodelling of collagenous dermal matrix. However, for full thickness burn injuries and chronic wounds such as pressure ulcers, venous ulcers and diabetic foot ulcers, these processes are damaged. Interactive wound dressings have been developed to improve healing in these chronic conditions (Sibbald et al. 2003). The time it takes for a chronic wound to heal will vary due to the idiosyncratic nature of each wound and inherent complex factors, which may impede healing. If a wound is slow to heal, there may be an underlying reason for non-healing. This may because of vascular disease or mechanical injury such as trauma or pressure. The cause will need to be identified and addressed if the wound is to be healed. For venous ulcers, we would not only consider the dressing choice but we would also need to use compression bandaging in order for the wound to heal. Controlling factors affecting healing requires an understanding of both intrinsic and extrinsic factors and addressing these where possible to improve healing. Physical factors such as diabetes mellitus, obesity, venous insufficiency, decreased perfusion, malnutrition, old age, organ failure, sepsis, and restrictions on mobility have an impact on healing (Phillips et al. 2000). Correcting underlying pathology and any co-morbidities is

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central to managing the wound. The inflammatory process is important in acute wound healing and if disturbed will affect healing and increase the risk of wound chronicity. Immunosuppressive states and the use of immunosuppressive drugs such as corticosteroids or methotrexate that are known to affect the immuno-inflammatory response all adversely affect wound healing and increase the risk of sepsis. (Burns and Pieper 2000, Troppmann et al. 2003). Tissue repair research and advances in moist wound healing pharmaceuticals have been pivotal in improving wound dressing technology and facilitating the moist wound healing principles (Schonfeld et al. 2000). Different products are able to simplify debridement by aiding autolysis and wound hydration, facilitate the wound cleansing process, aid in the granulation and epithelialisation process and in some instances allow growth factors, cells and enzymes to be activated to an optimal level for healing to take place. Wound bed preparation is paramount to improved healing. An important factor in wound bed preparation is the maintenance of moisture balance, which often involves exudate management. Failure to manage exudate adequately can expose the peri wound skin to toxic wound exudate that may impede the healing process. The TIME (Table 4.1) principle of wound bed preparation was developed by an International Advisory Board on wound bed preparation (Schultz et al. 2004; Schultz et al. 2003). The TIME principle is based on four factors: wound factors, clinical action factors, suggested product selection and the healing outcome.

Table 4.1 TIME wound bed preparation Description

Factors

Clinical action

Tissue non-viable

Slough or necrotic tissue present

Inflammation and/or infection

Increased exudate, surface discoloration or increased odour

Moisture imbalance

Heavy exudate, risk of maceration or dry wound bed – risk of desiccation Chronic wound with prolonged inflammation

Remove defective tissue (surgical or autolytic debridement) Remove or reduce bacterial load (antimicrobials, debridement of devitalised tissue) Restore moisture balance (absorb exudate or add moisture to dry wounds)

Edge of wound not advancing

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Moist wound healing processes that have been researched and determined to be significantly more effective than the dry healing of the past have improved healing outcomes. However, it has become evident that moist wound healing alone may not be sufficient to improve healing outcomes. Equally as important is a holistic approach to wound care. A holistic approach addresses the whole patient in a medical, environmental and social context. Four simple actions underlie moist wound management practice: 1. 2. 3. 4.

Determine aetiology of the wound; Identify any co-morbidities or complications that may contribute to wound recurrence or delay healing; Assess the status of the wound and select dressing product; and Review management plan with patient.

4.4

Dressings

An ideal dressing not only maintains a moist environment but also: • absorbs excess exudate and prevent maceration of surrounding skin and prevent the wound from desiccation; • allows gaseous exchange so that oxygen, water vapour and CO2 may pass in and out of the dressing; • provides thermal insulation to maintain the optimum wound core temperature, and • provides a barrier to bacteria to minimise contamination of the wound. The interactive ideal dressing should also be: • free of toxic or particulate components, • atraumatic on removal, • comfortable and conformable, and • cost effective. (adapted from Ovington and Pierce 2001)

4.4.1 Choosing the appropriate dressing product As wounds are dynamic and undergo different phases of healing, the choice of dressing will change with each phase (Cutting and White 2002). Dressing choice is based on three simple criteria: the colour of wound bed tissue, the depth of the wound and the level of exudate. Dressing choice can be based on the colour, depth and exudate (CDE) rule as shown in Table 4.2.

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Table 4.2 Wound assessment and dressing selection Colour

Exudate

Aim and dressing selection

Pink

Nil

Maintain moist environment, protect and insulate. Foams, thin hydrocolloids, thin hydroactives, film dressings and simple non-adherent dressing such as the modern tulles will provide the necessary cover.

Red unbroken

Low

Prevent skin breakdown. Thin hydrocolloids or film dressings provide protection.

Red

High

Maintain moist environment, absorb exudate and promote granulation and epithelialisation. Foams, alginates and hydroactive dressings help control exudate. Hydrocolloids as paste or powder for deeper areas.

Red

Low

Maintain moist environment and promote granulation and epithelialisation. Hydrocolloid, foams, sheet hydrogels and film dressings will maintain a moist environment. It is possible to use a combination of amorphous hydrogels with a foam cavity dressing in deeper wounds.

Yellow

Low

Remove slough absorbs exudate and maintain a moist environment. Hydrogel in particular will re-hydrate the slough. Hydrocolloids will also aid in autolysis.

Yellow

High

Remove slough and absorb exudate Hydrocolloids as paste or powder for the deeper wounds. Alginates will aid in the removal of the slough and absorb the exudate.

Black

Low

Rehydrate and loosen eschar. Surgical debridement is the most effective method of removal of necrotic material; Dressings can enhance autolytic debridement of the eschar. Amorphous hydrogels, hydrocolloid sheet.

Green

High

Absorb infected exudate. Hypertonic saline, silver products, cadexamer iodine.

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4.4.2 Colour The Red wound is a granulating wound with new tissue fi lling the deficit and possibly with some islets of epithelium present. The aim is to absorb any excess exudate, maintain a moist environment and protect the wound. The Yellow wound contains a level of slough. This is non-viable tissue that must be removed or healing will not take place. The methods of removal are surgical, re-hydration with dressings such as hydrogels or hydrocolloids. The aim is slough removal by re-hydration and absorption of exudate. The Pink wound is in the fi nal stages of healing with new epithelium covering the wound. The aim is to protect this very delicate tissue, prevent the wound from drying out so as to maintain a moist environment, and insulate the wound. The Black wound has an outer layer of thick hard eschar; this must be removed to commence the healing process. The fastest and most effective method is by surgical removal. The use of dressings such as hydrogels to aid autolytic debridement will at best be slow. The Green wound term is often used to describe an infected wound. The use of topical antibiotics is generally discouraged. The most appropriate treatment is to control high exudate levels, protect surrounding skin from toxic wound exudate, identify micro-organisms by wound biopsy and treat the client with systemic antibiotics.

4.4.3 Depth The wound may be superficial, partial thickness, deep or a cavity. The product choice will depend on the shape, location and type of wound. The shape and depth of the wound will vary depending on underlying aetiology. For example, venous ulcers are often superficial and highly exudating whereas arterial ulcers are deeper and have a ‘punched out’ appearance with little exudate. In some instances, the wound may have undermined edges and a careful assessment is paramount to ensure that the dressing product chosen will be easily removed and prevent residual product from being left in the cavity.

4.4.4 Exudate Exudate is produced from fluid that has leaked out of blood vessels and closely resembles blood plasma. Fluid leaks from capillaries into tissue at a rate that is determined by the permeability of the capillaries

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and the hydrostatic and osmotic pressures across the capillary walls. Most wounds will contain some exudate; this will vary from very little to copious levels. In a healing wound, exudate production generally reduces over time. In a chronic wound that is not healing, exudate production may continue and be excessive due to ongoing inflammatory processes (WUWHS). Studies suggest that wound fluid from acute wounds may have a beneficial effect on wound healing, whereas that of chronic wounds may inhibit healing. Any unexpected change in exudate characteristics may indicate a change in wound status and may indicate the presence of infection. Careful monitoring of the exudate can provide information for the application of systemic and local therapies. Individual wound care products have specific functions which relate to the volume, viscosity and nature of the exudate and these should guide skin care and dressing selection (Vowden and Vowden, 2003). The choice of both primary and secondary dressing will depend on the exudate level and the depth of the wound (White and Cutting 2004). The balance of moisture in the wound environment can be maintained primarily by applying newer generation interactive wound dressings.

4.5

Interactive wound dressings

Modern interactive dressings facilitate wound healing by altering the environment and interacting with the wound surface to optimise the healing process. Many interactive dressings have the ability to work actively with wound properties such as wound exudate, tissues, cells and some growth factors to enhance healing. Interactive dressings have different properties and vary in the ability to absorb exudate (Bale et al. 2001). Selecting the most appropriate dressing to treat the wound can be complicated and understanding form and function is often a challenge for busy clinicians (Carville 2006). Effective wound management requires knowledge of the process of tissue repair and the knowledge of the properties of the dressings available. Dressing selection is only one part of a holistic wound management plan, it is necessary to assess the patient’s concerns before assessing the wound and choosing the dressing (Schultz et al. 2003). Interactive dressings alter the wound environment and interact with the wound surface to optimise healing. Interactive dressings use the environment provided by the body to encourage normal healing. Bioactive dressings stimulate the healing cascade. Interactive dressing form, function, properties and some of the indications of the commonly used dressing groups in clinical practice are outlined in Table 4.3.

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Table 4.3 Interactive dressings: form, properties and indications Dressing form

Brand names

Properties and indications

Semi-permeable films

Opsite (Flexigrid, Flexifix, Post-op), Tegaderm, Bioclusive, Cutifilm, Polyskin, Hydrofilm and Aqua Protect Film

Non-absorbent, semi-permeable, waterproof, allow wound visualisation. Superficial burns, grazes, closed surgical incisions, small skin tears and IV sites. May be used as a secondary dressing. Contraindications: Known infection or fragile skin.

Foams

Allevyn (adhesive, cavity), Lyofoam (Flat, Extra, C, T, A), Curafoam, Hydrosorb, Tegafoam, Permafoam, Truefoam and Cavicare

Protects wound and periwound. Thermal insulation. Useful for moderately to heavily exudating wounds. Not effective for wounds with dry eschar. Superficial and cavity wounds, Venous ulcers (with compression), pretibial lacerations, infected ulcers, skin tears, pressure ulcers, skin grafts or donor sites and pilonidal sinuses. May require secondary dressing.

Alginates

Kaltostat, Sorbsan, Algoderm, Curasorb, Comfeel Seasorb and Algisite M. Melgisorb

Need wound exudate to function. Most suitable for heavily exudating wounds such as venous ulcers, pressure ulcers and dehisced abdominal wounds. Forms moist gel in wound. Highly absorptive. Fills dead space.

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Hydrocolloids

Duoderm (Extra thin, CGF, paste), Comfeel (ulcer dressing, transparent, contour dressing), Tegasorb, Replicare, Combiderm and Hydrocoll

Useful for light to moderately exudating wounds that would benefit from autolytic debridement. Leg ulcers, pressure ulcers, burns and donor sites. Thin sheets are useful over suture lines and IV sites. Do not use occlusive sheets on infected wounds. Reduces pain.

Hydrogels

Intrasite Gel (amorphous unpreserved). Intrasite Conformable (gauze impregnated). Solosite Gel (amorphous preserved). Solugel (amorphous preserved and unpreserved). Duoderm Gel (amorphous unpreserved). Nu-gel (sheet hydrogel). Comfeel Purilon Gel (amorphous). Curafil (amorphous). Curagel (sheet hydrogel). Aquaclear (sheet hydrogel). Hypergel (hypertonic saline) (amorphous). Steri Gel (amorphous). Second skin (sheet hydrogel)

Absorbency of hydrogels is limited and best used in minimally exudating wounds or dehydrated wounds such as minor burns, grazes/lacerations, donor sites and pressure ulcers. Soothing and reduces pain. Rehydrates dry wound. Comes in amorphous gel, sheets, and freeze dry forms. Indications for the thicker gel products include protection of exposed tendon and/or bone from dehydrating and rehydrating eschar before debridement. The thinner gel products are useful for soothing burns and acute chickenpox lesions.

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4.5.1 Semi-permeable film dressings Film dressings are adhesive, thin transparent polyurethane, which are permeable to gas but impermeable to liquid and bacteria. Films are elastic, conformable and transparent allowing inspection of wound. As fi lms are non-absorbent, they are not suitable for exudating wounds, although island dressings with a central non-stick pad are available and can absorb slightly more exudate that the simple films. The three factors that most drastically affect the pattern, speed and quality of healing are dehydration of exposed tissues, the status of the blood supply bringing oxygen and nutrients to the area, and sepsis. Wounds exposed to the air lose water vapour, the upper dermis dries and healing takes place beneath a dry scab. Covering a wound with an occlusive dressing prevents scab formation and radically alters the pattern of epidermal wound healing (Winter 2006). Film dressings are indicated as primary dressings in minor burns, simple abrasions and lacerations. It is also common to use fi lms as a post-operative layer over dry sutured wounds. Films can also be used as secondary dressings to waterproof a primary dressing such as foam. Films can be used as a protective layer on skin that is prone to superficial pressure ulcers, although incorrect removal of fi lm dressings when applied to fragile skin may cause trauma to surrounding skin so they should be used with care. Films should be discontinued if the level of exudate results in pooling under the dressing as not only is the dressing choice incorrect but it may also cause maceration to the surrounding skin and increase the risk of infection. Films may stay in place for up to one week and frequency of change may be dependent on position of wound, type and size of wound.

4.5.2 Foam dressings Foam dressings are made from polyurethane, which may in some cases have been heat-treated on one side to create a semi-permeable membrane. This allows the passage of exudate through the non-adherent, semi-permeable surface into the insulating foam. These open-cell sheets with varying cell sizes come in single, double or multilayer products. Foams have several advantages; they are highly absorbent, cushioning and protective, and insulate and conform well to body surfaces. Foams facilitate a moist wound environment and absorb excess exudate to decrease the risk of maceration. Foam dressings are also available with charcoal impregnation for malodorous wounds. Foam wound cavity dressings reduce dead space in the wound, conform to wound shape and absorb large amounts of exudate therefore reducing the need for frequent dressing changes, although cavity foam dressings

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require secondary dressings that adds to cost. Foams are generally nonadhesive and require a secondary dressing or tape/bandage to keep in place. Depending on the level of exudate, foams can be left in place for up to 7 days (Carville 2006). A prospective open-label study to assess the clinical performance of foam dressings in chronic wounds found a significant decrease in the level of exudate from the wound bed, the proportion of patients with peri-wound skin problems and the percentage of patients with wound pain. Foam dressings are indicated in venous ulcers with high exudate levels (Zoellner et al. 2006).

4.5.3 Alginate dressings Alginate may be either calcium or calcium/sodium salts of alginic acid. These products are highly absorbent, biodegradable dressings derived from seaweed. An active ion exchange of calcium ions for sodium ions at the wound surface forms soluble sodium alginate gel that provides a moist wound environment. The polysaccharides are made up as textile fibre or as freeze-dried sheets. Calcium dressings need exudate from the wound to function and therefore are not suitable for dry wounds or wounds with hardened eschar. When placed into an exudating wound, the sodium ions present in the wound fluid displace the calcium and forms sodium alginate. The fibrous nature of most alginates can leave residual fibres in the wound if there is insufficient wound exudate to gel the fibres. This may precipitate an inflammatory reaction as it stimulates a foreign body response. Caution is also needed when using alginate rope dressings into very deep or narrow sinuses, as complete removal can be difficult. Studies have shown that some calcium alginate products promote haemostasis in bleeding wounds owing to the active release of calcium ions that aids the clotting mechanism (Segal et al. 1998). The calcium ions released by this type of dressing are a natural co-factor in the coagulation therapy. Alginate dressings are available in sheet, ribbon or rope form in various sizes and require a secondary dressing. Alginates are used for wounds with moderate to heavy exudate, haemostasis post-debridement or biopsy.

4.5.4 Hydrocolloid dressings Hydrocolloids are moisture-retentive dressings, which contain gel-forming agents such as sodium carboxymethylcellulose and gelatin. Many products combine the gel-forming properties with elastomers and adhesives are applied to a carrier such as foam or fi lm to form an absorbent, selfadhesive, waterproof wafer. In the presence of wound exudate hydrocolloids absorb liquid and form a gel, the properties of which are determined

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by the nature of the formulation (Heenan 2007). In sheet form, the polymer outer layer can be either semi-occlusive or occlusive. Hydrocolloid interaction debrides by autolysis and can reduce dressing frequency by up to 7 days’ wear time depending on amount of exudate and the type of the hydrocolloid product (Segal et al. 1998). The product is also available in paste and powders for increased absorption and to decrease dead space in the wound cavity. Generally, hydrocolloids are not recommended on clinically infected wounds due to the semi-occlusive nature of the dressing. There have been reports of hypergranulation with prolonged use of hydrocolloids in moderate to highly exudating wounds, so wound tissue assessment is paramount when applying hydrocolloids over a period of months so that the product can be discontinued before hypergranulation occurs. Hydrocolloid dressings are indicated for chronic venous ulcers, pressure ulcers, burns, partial thickness wounds, diabetic foot ulcers.

4.5.5 Hydrogel dressings Hydrogel dressings are semi-occlusive and composed of complex hydrophyllic polymers with a high (90%) water content. As the name implies, hydrogels are designed to hydrate wounds, re-hydrate eschar and aid in autolytic debridement. Hydrogels are insoluble polymers that expand in water and are available in sheet, amorphous gel or sheet hydrogelimpregnated dressings. Hydrogels provide a moist environment for cell migration and absorb some exudate. Autolytic debridement without harm to granulation or epithelial cells is another advantage of hydrogel dressings. Hydrogels are recommended for wounds that range from dry to mildly exudating and can be used to degrade slough on the wound surface. Hydrogels have a marked cooling and soothing effect on the skin, which is valuable in burns and painful wounds. In addition to their use in wounds, the thin hydrogels are helpful in the management of chicken pox and shingles. The viscosity varies between products, Purilon and IntraSite gel are two of the thickest gels available to help the product stay in the cavity of the wound and Solugel and Solosite are two of the thinnest for easy spread over a larger area (Carville 2006). Some amorphous gels contain propylene glycol that can cause allergic reactions in elderly skin. Amorphous hydrogels are applied liberally onto or into a wound and covered with a secondary dressing such as foam or fi lm. Hydrogels can remain in situ for up to 3 days. Hydrogels are indicated in dry, sloughy wounds with mild exudate, partial thickness wounds.

4.6

Future trends

Novel techniques are being developed to improve healing in difficultto-treat wounds. Emerging dressing types include bioactive dressings and

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tissue engineered skin substitutes. Randomised controlled clinical trials to examine safety and efficacy of many of the new materials are lacking and clinical uptake has been slow (Begg et al. 1996; Enoch et al. 2006b). When choosing the optimum treatment for patients, it is important to take into account ease of use, patient satisfaction and cost effectiveness (Carville 2006). Research into genetic coding mechanisms to identify factors influencing wound healing will be an area to monitor. Several markers that could form the basis of new diagnostic tools for use in wound care are currently under investigation, ongoing research is likely to discover others. Some markers under current investigation are: platelet-derived growth factor, sex steroids, thyroid hormones, immunohistochemical markers, inflammatory mediators such as cytokines and interleukins to monitor healing status. Nitric oxide could be clinically useful in predicting wound outcomes and interventions to alter wound nitric oxide levels may be of benefit. These markers may be able to aid the clinician in choosing appropriate dressing products depending on the phase of the wound, tissue colour, depth of wound and exudate level (Enoch et al. 2006a). Current areas of research include regulation of target genes of cells involved in wound healing. New methods of delivery of cell products to the wound bed include stem cells that are capable of differentiating into essential cells involved in wound healing. To date, there is only experimental evidence for gene and stem cell therapy in the treatment of chronic wounds (Enoch et al. 2006b). The cost-effectiveness of new treatments compared with standard care must also be considered, not only in terms of direct treatment costs, but in terms of length of initial hospital stay, requirements for home and community care, secondary dressing needs, and the quality of the overall outcome.

4.7

Conclusions

Technological advancement in interactive dressing development has grown since Winter’s research. Availability of different types of wound products has increased remarkably in the last decade. New wound dressing technologies continue to be developed to improve healing in difficult to treat wounds (Embil et al. 2000). Wound care practitioners have at their disposal an extensive range of interactive dressings. Emerging dressing types include bioactive dressings and tissue-engineered skin substitutes. Wound dressings have come a long way since Pare’s effort in the battle of Turin. Tissue repair research and advances in moist wound healing pharmaceuticals has been pivotal in the improvement of wound product technology. This review has characterised the different types of established interactive dressings. For new dressing types, ‘bioactivity’ appears to be the way forward in maintaining a moist healing environment, offering antimicrobial properties and cellular interactions.

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4.8

Sources of further information and advice

European Wound Management Association (EWMA) World Union of Wound Healing Societies (WUWHS) WUWHS Principles of best practice: wound exudate and the role of dressings. A consensus document EWMA position document 2005: Identifying criteria for wound infection. EWMA position document 2004: Wound bed preparation in practice. EWMA position document 2002: Pain at wound dressing changes Cochrane wound group www.cochranewounds.org

4.9

References

bale, s., baker, n., crook, h., rayman, a., rayman, g. and harding, k. g. (2001). Exploring the use of an alginate dressing for diabetic foot ulcers. J Wound Care, 10(3), 81–84. baxter, h. (2002). How a discipline came of age: a history of wound care. J Wound Care, 11(10), 383–386, 388, 390. begg, c., cho, m., eastwood, s., horton, r., moher, d., olkin, i., et al. (1996). Improving the quality of reporting of randomized controlled trials. The CONSORT statement. JAMA, 276(8), 637–639. burns, j. and pieper, b. (2000). HIV/AIDS: impact on healing. Ostomy Wound Manage, 46(3), 30–40, 42, 44; quiz 48–39. carville, k. (2006). Which dressing should I use? It all depends on the ‘TIMEING’. Aust Fam Physician, 35(7), 486–489. cutting, k. f. and white, r. j. (2002). Maceration of the skin and wound bed. 1: Its nature and causes. J Wound Care, 11(7), 275–278. embil, j. m., papp, k., sibbald, g., tousignant, j., smiell, j. m., wong, b., et al. (2000). Recombinant human platelet-derived growth factor-BB (becaplermin) for healing chronic lower extremity diabetic ulcers: an open-label clinical evaluation of efficacy. Wound Repair Regen, 8(3), 162–168. enoch, s., grey, j. e. and harding, k. g. (2006a). ABC of wound healing. Non-surgical and drug treatments. BMJ, 332(7546), 900–903. enoch, s., grey, j. e. and harding, k. g. (2006b). Recent advances and emerging treatments. BMJ, 332(7547), 962–965. falanga, v. (2005). Wound healing and its impairment in the diabetic foot. Lancet, 366(9498), 1736–1743. harding, k. g., morris, h. l. and patel, g. k. (2002). Science, medicine and the future: healing chronic wounds. BMJ, 324(7330), 160–163. heenan, a. (2007). Alginates: an effective primary dressing for exuding wounds. Nurs Stand, 22(7), 53–54, 56, 58. hinman, c. d. and maibach, h. (1963). Effect of air exposure and occlusion on experimental human skin wounds. Nature, 200, 377–378. leaper, et al. (2002). Growth factors and interactive dressings in wound repair, EWMA Journal, 2(2), 17–23.

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margolis, d. j., berlin, j. a. and strom, b. l. (1999). Risk factors associated with the failure of a venous leg ulcer to heal. Arch Dermatol, 135(8), 920–926. margolis, d. j., bilker, w., santanna, j. and baumgarten, m. (2002). Venous leg ulcer: incidence and prevalence in the elderly. J Am Acad Dermatol, 46(3), 381–386. margolis, d. j., knauss, j. and bilker, w. (2004). Medical conditions associated with venous leg ulcers. Br J Dermatol, 150(2), 267–273. ovington, l. g., pierce, b. (2001). Wound dressings: form, function, feasibility and facts. In: Krasner, D, Rodeheaver G, Sibbald G (Eds). Chronic wound care: a clinical sourcebook for healthcare professionals. Wayne, PA: Management Publications Inc., 311–319. phillips, t. j., machado, f., trout, r., porter, j., olin, j. and falanga, v. (2000). Prognostic indicators in venous ulcers. J Am Acad Dermatol, 43(4), 627–630. schonfeld, w. h., villa, k. f., fastenau, j. m., mazonson, p. d. and falanga, v. (2000). An economic assessment of Apligraf (Graftskin) for the treatment of hard-to-heal venous leg ulcers. Wound Repair Regen, 8(4), 251–257. schultz, g. s., barillo, d. j., mozingo, d. w. and chin, g. a. (2004). Wound bed preparation and a brief history of TIME. Int Wound J, 1(1), 19–32. schultz, g. s., sibbald, r. g., falanga, v., ayello, e. a., dowsett, c., harding, k., et al. (2003). Wound bed preparation: a systematic approach to wound management. Wound Repair Regen, 11 Suppl 1, S1–28. segal, h. c., hunt, b. j. and gilding, k. (1998). The effects of alginate and non-alginate wound dressings on blood coagulation and platelet activation. J Biomater Appl, 12(3), 249–257. sibbald, r. g., orsted, h., schultz, g. s., coutts, p. and keast, d. (2003). Preparing the wound bed 2003: focus on infection and inflammation. Ostomy Wound Manage, 49(11), 23–51. troppmann, c., pierce, j. l., gandhi, m. m., gallay, b. j., mcvicar, j. p. and perez, r. v. (2003). Higher surgical wound complication rates with sirolimus immunosuppression after kidney transplantation: a matched-pair pilot study. Transplantation, 76(2), 426–429. vowden, k. and vowden, p. (2003). Understanding exudate management and the role of exudate in the healing process. Br J Community Nurs, 8(11 Suppl), 4–13. weller, c. d., sussman, g. (2006). Wound dressings update. Journal of Pharmacy Practice and Research, 36(4), 318–324. white, r. j., cutting, k. f. (2004). Maceration of the skin and wound bed by indication. In: White, R. J. (Ed), Trends in wound care III, Quay Books, 23–29. winter, g. d. (1962). Formation of the scab and the rate of epithelization of superficial wounds in the skin of the young domestic pig. Nature, 193, 293–294. winter, g. d. (2006). Some factors affecting skin and wound healing. J Tissue Viability, 16(2), 20–23. zoellner, p., kapp, h. and smola, h. (2006). A prospective, open-label study to assess the clinical performance of a foam dressing in the management of chronic wounds. Ostomy Wound Manage, 52(5), 34–36, 38, 40-32.

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5 Bioactive dressings to promote wound healing G. S C HOU K E N S, Ghent University, Belgium

Abstract: The role of bioactive dressings derived from natural resources in managing both acute and chronic wounds is discussed. Bioactive dressings deliver substances active in wound healing either by delivery of bioactive compounds or by being constructed from materials having endogenous activity. These materials include hydrocolloids, hydrogels, alginates, collagens, honey dressings, chitosan, chitin, derivatives from chitosan or chitin and biotextiles. The application of dibutyrylchitin (DBC) derived from chitin is extensively reviewed. The O-butyrylation of chitin or chitosan is an important modification of chitin which increases the biochemical activity of chitin or chitosan. Future developments in bioactive wound dressing materials based on chitin, chitosan and their derivatives are indicated using the increased knowledge and understanding of the action of these dressings in wound healing. Key words: bioactive dressing, wound healing, alginate, hydrocolloids, chitin.

5.1

Introduction

Bioactive dressings are dressings which deliver substances active in wound healing; either by delivery of bioactive compounds or constructed from materials having endogenous activity. These materials include hydrocolloids, alginates, collagens, chitosan, chitin, derivatives from chitosan or chitin and biotextiles. These bioactive dressings belong normally to the FDA dressing category of interactive wound and burn dressings. Wound healing is a natural restorative response to tissue injury. Healing is the interaction of a complex cascade of cellular events that generates resurfacing, reconstitution, and restoration of the tensile strength of injured skin. Healing is a systematic process, traditionally explained in terms of three classic phases: inflammation, proliferation, and maturation or remodelling. In another scheme, the wound healing process can be divided into four continuous phases, namely haemostasis, inflammation, proliferation and remodelling. A clot forms and inflammatory cells debride injured tissue during the inflammatory phase. Epithelialisation, fibroplasia, and angiogenesis occur during the proliferative phase. Meanwhile, granulation tissue forms and the wound begins to contract. Finally, during the maturation phase, collagen forms tight cross-links to other collagen and, with 114

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protein molecules, increases the tensile strength of the scar. The role of bioactive dressings derived from natural resources in managing both acute and chronic wounds is discussed in this chapter and the application of dibutyrylchitin (DBC) derived from chitin is extensively reviewed.

5.2

Physiology of wound healing

5.2.1 Inflammatory phase The early events of wound healing are characterised by the inflammatory phase, a vascular and cellular response to injury. An incision made through a full thickness of skin causes a disruption of the microvasculature and immediate hemorrhage. Following incision of the skin, a 5- to 10-min period of vasoconstriction ensues, mediated by epinephrine, norepinephrine, prostaglandins, serotonin, and thromboxane. Vasoconstriction causes temporary blanching of the wound and functions to reduce hemorrhage immediately following tissue injury, aids in platelet aggregation, and keeps healing factors within the wound.

5.2.2 Proliferative phase Formation of granulation tissue is a central event during the proliferative phase. Inflammatory cells, fibroblasts, and neovasculature in a matrix of fibronectin, collagen, glycosaminoglycans, and proteoglycans comprise the granulation tissue. Granulation tissue formation occurs 3–5 days following injury and overlaps with the preceding inflammatory phase.

5.2.3 Epithelialisation Epithelialisation is the formation of epithelium over a denuded surface. Epithelialisation of an incisional wound involves the migration of cells at the wound edges over a distance of less than 1 mm, from one side of the incision to the other. Incisional wounds are epithelialised within 24 to 48 h after injury. This epithelial layer provides a seal between the underlying wound and the environment. The process begins within hours of tissue injury. Epidermal cells at the wound edges undergo structural changes, allowing them to detach from their connections to other epidermal cells and to their basement membrane.

5.2.4 Collagen The synthesis and deposition of collagen is a critical event in the proliferative phase and to wound healing in general. Collagen consists of three

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polypeptide chains, each twisted into a left-handed helix. Three chains of collagen aggregate by covalent bonds and twist into a right-handed superhelix, forming the basic collagen unit. A striking structural feature of collagen is that every third amino acid is glycine. This repeating structural feature is an absolute requirement for triple-helix formation. Collagen is rich in hydroxylysine and hydroxyproline moieties, which enable it to form strong cross-links. Deficiencies of oxygen and vitamin C, in particular, result in underhydroxylated collagen that is less capable of forming strong cross-links and, therefore, are more vulnerable to breakdown. Approximately 80% of the collagen in normal skin is type I collagen; the remaining is mostly type III. In contrast, type III collagen is the primary component of early granulation tissue and is abundant in embryonic tissue. Collagen fibres are deposited in a framework of fibronectin. Collagen remodelling during the maturation phase depends on continued collagen synthesis in the presence of collagen destruction. During remodelling, collagen becomes increasingly organised. Fibronectin gradually disappears, and hyaluronic acid and glycosaminoglycans are replaced by proteoglycans. Type III collagen is replaced by type I collagen. Water is resorbed from the scar. These events allow collagen fibres to lie closer together, facilitating collagen cross-linking and ultimately decreasing scar thickness.

5.2.5 pH of wounds Surface wounds develop, according to Leveen and others, a respiratory alkalosis owing to escape of CO2 from the wound surface into the air. Therefore, the pH of surface wounds is in the region of pH 8. This alkalinity produces an inappropriate shift of the oxyhemoglobin–hemoglobin dissociation curve and reduces the available oxygen supply to the tissues. In contrast to alkalinisation of the wound, acidification was found to increase the partial pressure of oxygen (pO2) of surface wounds by appropriate shift in the oxyhemoglobin–hemoglobin dissociation curve (Bohr effect). In addition, significant quantities of ammonia were found on most surface wounds further contributing to the alkalinity of the wound. The concentrations of ammonia found in surface wounds were histotoxic. This histotoxicity is pH dependent. Ammonia is non-toxic in acid medium because of neutralisation. A number of chemicals suitable for clinical acidification of wounds have already been investigated. A prerequisite is the prolonged chemical acidification of clinical wounds. Acetic acid solutions do not maintain acidity for periods longer than one hour. The histotoxicity of ammonia provokes the slough found in infections caused by some potent urease-producing organisms. Chemical acidification of wounds is most effective in minimising the toxicity of the ammonia formed by ureaseproducing organisms.

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117

Principles and roles of bioactive dressings

From 1946, after the Second World War, experiments were carried out with a number of dressings based on products derived from polyamide or polyethylene, and, later on, polyurethane fi lm dressings. Later on, other interactive and bioactive dressings were developed such as impregnated gauzes, foam dressings, hydrogels, alginates, hydrocolloids, hydrofibres, odour-absorbing dressings and, more recently, bioactive dressings based on chitin or chitosan and their derivatives. The most significant advance in wound care came from Winter’s study1,2 in the 1960s, which showed that occluded wounds healed much faster than dry wounds and a moist wound healing environment optimised the healing rates. He demonstrated that, when wounds on pigs are kept moist, epithelialisation is twice as rapid as on wounds allowed to dry by exposure to air. Later Hinman and Maibach3 confi rmed his work on human beings in 1963. An open wound that is directly exposed to air will hydrate and a scar is formed. This forms a mechanical barrier to migrating epidermal cells, which are then forced to move into a deeper level of tissue, thus, prolonging the healing process. Moist healing prevents the formation of scar as the dressing absorbs wound exudate secreted from the ulcer. The ability of bioactive dressings to absorb exudates and provide a moist environment is a very important characteristic of these dressings. Another important aspect of these bioactive dressings is their ability to neutralise the wound alkalinity and to restore the natural pH of the wound or the skin. This requires the presence of an acidic carboxylic group (—COOH) in these bioactive dressings or the formation of acidic compounds owing to the hydrolysis of the applied dressings. These bioactive dressings are also affected by classical hydrolysis or are degraded by the action of enzymes, like hydrolases, lysozymes and/or matrix metalloproteinases. Non-healing chronic wounds differ from acute wounds significantly. Whereas healing acute wounds have low levels of protein-degrading enzymes, exudates from non-healing chronic wounds contain elevated levels of proteases, like matrix metalloproteinases and elastase.4–6 Moreover, the concentrations of pro-inflammatory cytokines,7 as well as reactive oxygen species8 are significantly higher, compared with the concentrations in acute wounds. Reactive oxygen species, such as superoxide radicals (O2⋅ −) and hydroxyl radicals (OH⋅), as well as reactive nitrogen species, such as nitric oxide (NO⋅) arise from inflammatory cells.9–11 An imbalance between reactive oxygen and nitrogen species and the antioxidant defence mechanism of a cell, leading to an excessive production of oxygen metabolites, leads to condition of ‘oxidative stress’. Overproduction of reactive oxygen and nitrogen species results in an imbalanced oxidant/antioxidant static in wounds and especially in chronic wounds.8,11,12 Owing to the resulting

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disproportion between the degradation and remodelling processes, chronic wounds persist in the inflammatory phase of the normal healing process for months or even years. The reduction in reactive oxygen and reactive nitrogen species in the wound fluid seems to be a suitable way to stop the inflammation process and diminished epithelisation and to support the normal healing process. The antioxidant capacity of bioactive dressing materials may also be an important characteristic for wound healing. The chemical structure of the bioactive dressing materials is important for this antioxidant capacity. Some bioactive dressing materials contain a large number of functional groups, such as —OH, —COOH, and others, which allow various interactions with other molecules via hydrogen bonds and electrostatic interactions. As studies with oxidised, phosphorylated, carboxymethylated and sulphonated cotton gauze have shown, the chemical modification of the wound dressing leads to a decreased activity of proteases, such as matrix metalloproteinases and elastase, in chronic wound fluids.13 A possible explanation is that the negatively charged groups of the gauze interact with arginine side chains on the surface of elastase. Studies of the topical application of compounds with free radical scavenging properties on patients have shown to significantly improve healing and protect tissue from oxidative damage. However, a too high concentrated application of antioxidants may result in toxic response in the wound. To obtain good results on wound healing, a slow release of the antioxidant is required. Current concepts of modern wound management are focused on a moist wound environment. This is beneficial for tissue remodelling (re-epithelialisation) owing to a good control of the humidity of the wounds, together with a better control of the pH of the wounds and the oxygen permeability and concentration in the wounds. In addition to these aspects and others, such as biocompatibility, biodegradability, and fluid absorption, the understanding of the antioxidant capacity of the bioactive dressing materials is important for improved wound healing.

5.4

Types and structures of bioactive dressings

5.4.1 Alginates Wound dressing based on alginic material is well known, in the literature as well as from a commercial point of view, in wound management.14 Alginates are linear copolymers of β-(1-4)-linked d-mannuronic acid and α-(1-4)-linked l-guluronic acid units, which exist widely in many species of brown seaweeds. Alginate fibres can be prepared by extruding solutions of sodium alginate into a calcium salt solution bath or an acidic solution to produce the corresponding calcium alginate or alginic fibres, respectively.

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Typically, the degree of crystallinity of the alginate fibres is of the order of 30% with a degree of water absorption of 90% after immersion in water. Fibres of this type have been used extensively in wound dressing applications owing to their excellent biocompatibility, non-toxicity, and potential bioactivity. Alginate fibres, typically as a calcium salt, interact with the wound exudates to form a moist gel, as a result of the ion exchange between the calcium ions in the fibre and the sodium ions in the exudates.15 The gel-forming property of alginate eliminates fibre entrapment in the wound and helps in removing the dressing without much trauma, thus, reducing the pain experienced by the patient during dressing changes.16 Such gelation provides the wound with a moist healing environment, which promotes healing and leads to better cosmetic repair of the wound. The gel-forming property provides a moist environment that leads to rapid granulation and re-epithelialisation.1 In a controlled clinical trial, a significant number of patients dressed with calcium alginate was completely healed at day 10. In another study with burn patients, calcium alginate significantly reduced the pain severity and was favoured by the nursing personnel because of its ease of care. This in situ generation of a moist healing environment and the consequent high absorbency of the alginate dressings are two of the outstanding properties, which make the alginate dressing one of the most versatile wound dressings available today. In addition, alginate-containing dressings have been demonstrated to activate macrophages within the chronic wound bed and generate a pro-inflammatory signal which may initiate a resolving inflammation characteristic of healing wounds.17 Therefore, many commercially available wound dressings used in wound management contain calcium alginate fibres. The alginate dressings currently available on the market have mainly been manufactured from fibres of calcium alginate or sodium–calcium alginate. Depending on the quantity of the mannuronic or guluronic acid derivatives in the fibre-forming material, the fibres change into gel form to varying degrees.18,19 Modern active dressings, besides their function of providing a moist wound environment, should also be adapted to the stage of wound healing and, on this basis, capable of stimulating the granulating process or protecting against the damage of a newly formed tissue. 20 A possible advantage of alginate fibres is that they are relatively easy to modify by incorporating appropriate metal ions, microelements or other biologically active substances that accelerate the healing process or have bacteriostatic properties. 21 As an alternative to standard alginate dressing, new alginate dressings that have been trialled are said to have superior properties, e.g., zinc alginate fibres. The replacement of sodium ions with zinc ions during solidification allows zinc alginate fibres with suitable properties for medical

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applications to be prepared. Zinc alginate fibres show high moisture absorption, an acceleration of the wound-healing process and antibacterial character resulting from the presence of zinc ions. These fibres can be used for the manufacture of dressings to be used for wounds in subsequent healing stages. The bacteriostatic effects of zinc can be increased or extended by incorporating typical bactericidal or fungicidal agents into fibres during the spinning stage. In addition to zinc ions, silver ions have been found to have antibacterial effects on some microbes. The silver salt is normally seen as the most effective antimicrobial agent in the treatment of burn patients. 22 The so-called antibacterial fibres can be obtained by treatment with an aqueous solution of silver nitrate. The calcium alginate fibres were converted into calcium/ silver alginate fibres by the treatment with silver nitrate. The calcium alginate fibres have little antibacterial activity, but the calcium/silver alginate fibres have good antibacterial activity toward Staphylococcus aureus. 23 Various alginate wound dressing materials have been commercially utilised and reviewed in the literature. Some commercial alginate wound dressing materials include: Algisite® (Smith & Nephew), Kaltostat® (ConvaTec), Tegagen® HG or HI (3M Health Care), Comfeel SeaSorb ® (Coloplast AS), AlgiDERM (Bard), Algosteril® (Johnson & Johnson), CarraSorb H® (Carrington), CURASORB® (Kendall), Dermacea® (Sherwood-Davis & Geck), Fybron® (B. Braun), Gentell® (Gentell), Hyperion Advanced Alginate Dressing® (Hyperion Medical Inc.), Kalginate® (DeRoyal), and Maxorb ® (Medline).

5.4.2 Hydrocolloids Hydrocolloids, fi rst patented in 1967, 24 were originally used in stoma care. Later on, hydrocolloids were also used in practice for both acute and chronic wounds. 25 According to Cockbill and Turner, 26 classical hydrocolloids are supposed to consist of 40% polyisobutylene, 20% sodium carboxymethylcellulose, 20% gelatine and 20% pectin. The hydrocolloid dressing absorbs the wound fluid and as a result changes into a jelly-like mass. The outside of the dressing is covered with a polyurethane foam or fi lm which enables the exchange of water vapour and protects the wound against contamination from the outside. In addition to this sheet form, hydrocolloids are also available as a paste or granules which are used to fi ll up the deep wounds. 26 Hydrocolloids are said to aid the healing by creating a moist environment and, through an intensification of the autolysis process, advance debridement.26 They are supposed to be comfortable, and time- and money-saving because dressing changes are less frequently required. The reasons for these frequently cited characteristics are not always based on research evidence.

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Amorphous hydrogels are a category of products used for debridement. These gels function by keeping the wound moist and thereby enhancing autolytic debridement of necrotic tissue by enzymes generated in the body by inflammatory cells. A too aggressive debridement can impair the healing as some of the active components may be cytotoxic. 27 Often polyols are used for amorphous hydrogels as bacteriostatic agents, but are known for being potential allergenic. Some of the amorphous hydrogels may contain from 15 to 20 wt% of propylene glycol and from 2 to 4.5 wt% of sodium carboxymethylcellulose. The more recently developed amorphous hydrocolloids are based on water-insoluble, water-swellable cross-linked cellulose derivatives, an alginate and distilled water. These amorphous hydrocolloids contain between 3.3 and 4.8 wt% of cross-linked carboxymethylcellulose, between 0.3 and 0.53 wt% of alginate and the rest distilled water. 28 These hydrocolloids show excellent debriding and good absorption properties, they speed up debridement of necrotic tissue in chronic wounds, and they speed up the healing of the wound without the use of propylene glycol. In experiments on wound healing, the amorphous hydrocolloids accelerate epithelialisation of clean superficial wounds by more than 20% compared with the control. Hydrocolloids are frequently used in the treatment of pressure ulcers. For this application, hydrocolloids are more effective than gauze dressings with regard to the number of healed wounds, 29 the reduction of the pressure ulcer dimensions, 30 the time needed for dressing changes, 30–32 the absorption capacity, the pain during dressing changes33 and the side-effects. 31 Compared with other bioactive dressings, such as alginate dressings or biosynthetic dressings, hydrocolloids are significantly less effective. 34 Commercial hydrocolloid dressings include Comfeel Contour® (Coloplast AS), Granuflex® (ConvaTec), Tegasorb ® (3M Health Care), and Duoderm® (ConvaTec).

5.4.3 Hydrogel Traditionally, wounded tissues have been covered with various ointments and gauzes. However, these treatments do not shield the wound from external contamination and do not sufficiently retain moisture. The gauzes often become embedded in the wound tissue causing damage and pain when wound dressings are changed. A more recent approach has been to use various forms of hydrogels as wound dressings. The term hydrogel refers to water-absorbing gel substances of varying rigidity. Hydrogels of least rigidity are often administrated by syringe while more rigid hydrogels are packed in sterile sachets opened immediately before applying the hydrogel to the wound.

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Most of the hydrogel wound dressings are hydrogels based on alginates35–38 and alginate hydrogels can be obtained by cross-linking the alginate polymers. Such hydrogels contain large amounts of water without dissolution. Applications with the hydrogels of alginates include cell or tissue encapsulation, tissue engineering, drug delivery and hydrogel wound dressings. Most frequently, the basic structure of the hydrogel wound dressing is a matrix composed of either sodium or calcium alginate or a combination of both. Upon treating alginate with sodium or calcium ions, insoluble fibres are formed. This alginate matrix imparts a cohesive structure to the dressing and gives the hydrogels mechanical properties suitable for protecting a wound while remaining flexible. The amount of alginate incorporated in the hydrogels varies from 1 to 4 wt% according to the type used. The hydrogels are loaded with salt components, obtained by absorbing salts from sodium, magnesium, silver or other therapeutically acceptable salts into the hydrogel. These salts have advantageous disinfectant properties and various wound healing properties. For example, a 4 wt% sodium chloride solution consisting of sterilised sea salt is loaded in the hydrogel. 39 This gives the hydrogel anti-bacterial properties and makes use of the known therapeutic value of sterilised seawater solutions on open wounds.40 Some commercial hydrogel dressing materials are Granugel® (ConvaTec), Intrasite Gel® (Smith & Nephew), Nu-Gel® (Johnson & Johnson) and Sterigel® (Seton).

5.4.4 Collagen Among the bioactive and biocompatible wound-dressing materials, collagen is probably the most promising skin substitute or wound-dressing biomaterial, owing to minimal inflammation, cytotoxicity and its property to promote cellular growth.41 Collagen is the predominant extracellular protein in the granulation tissue of healing wound and a rapid increase in the synthesis of this protein in the wound area occurs soon after an injury.42 In addition to providing strength and integrity to a tissue matrix, collagen also plays a dual role in haemostasis.43 Collagen has characteristics suitable for medical application, such as biodegradability and weak antigenicity, and has been used over the years in the preparation of resorbable surgical sutures and wound-dressing materials.44 The role of collagen at each phase of wound healing is well understood and appreciated. The major applications of collagen-based dressings introduced to date include, collagen fi lms, collagen gels and collagen sponges45. Most of the commercially available skin substitutes are collagen based, ranging from the acellular dressings like BioBrane ®

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(Smith & Nephew) 46 or Integra® (IntegraTM) 46,47 to the autologous keratinocyte-loaded counterparts Apligraf® (Novartis) 45,48 or OrCell® (Ortec International Inc.).48 However, all suffer from relative rapid biodegradation in vivo, frequently with a non-synchronised dermal regeneration rate.49 Maintenance of structural and functional properties of the bioactive dressing material whilst maintaining cell compatibility until the healing has been completed is a necessary and challenging task to be addressed. Chemical collagen cross-linking agents have negatively affected cell viability and physical methods of cross-linking have proved insufficient 50,51 to maintain structural integrity in vivo.51

5.4.5 Honey dressings For centuries, honey has been used as an effective remedy for wounds, burns and ulcers. In recent years, there has been renewed interest in the medicinal properties of honey. Honey is most commonly used as a topical antibacterial agent to treat infections in a wide range of wound types. These include leg ulcers, pressure ulcers, diabetic foot ulcers, infected wounds resulting from injury or surgery and burns. Honey is used when conventional antibacterial treatment with antibiotics and antiseptics is ineffective. Honey promotes rapid healing with minimal scarring. Honey can be used as a fi rst aid treatment for burns as it has antiinflammatory activity. Honey is composed primarily of sugars and water, on average, 80 wt% sugar and 17 wt% water. The primary sugars are fructose (38%) and glucose (31%). Honey also contains acids, on average 0.57 wt%. The high acidity of honey owing to the presence of acids plays an important role in the system which prevents bacterial growth. The pH of honeys may vary from approximately 3.2 to 4.5, with an average value of 3.9, making it inhospitable for attack by most bacteria. The high acidity of honey neutralises also the high pH value of wounds, especially of burned wounds, and stimulates the rapid healing of these wounds. It has long been known that honey possesses antimicrobial properties that make it suitable for use in treating a range of infections and skin disorders. This antimicrobial activity can be attributed to a number of factors such as the natural presence in honey of hydrogen peroxide, its high saccharide content which tends to dehydrate bacteria by osmosis and its high acidity. Honey can also contain an enzyme, glucose oxidase, which reacts with glucose to produce hydrogen peroxide and gluconic acid, both of which have an antibacterial effect. In recent years, a lot of research was published about the clinical effects of topical honey in superficial burns and wounds. 52 Important results from this research were the measures of wound-healing time and

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of infection rates. Generally, a positive effect was observed on these two parameters. If the mean time to wound healing was 13.5 days in conventionally treated patients, the wound healing occurred in 9 days for honeytreated patients. Also, the number of infected wounds decreased from 12 to 5.5%. In another study, a comparison was made between honey and silver sulfadiazine on burn wound healing. Healing was faster with honey, 90% were healed after 14 days, than with silver sulfadiazine where only 52% were healed after 14 days. These results render honey suitable for use in dressing of wounds. However, an obvious problem associated with the use of honey in such circumstances is that it is a rather runny substance. On an exuding wound, it rapidly becomes unevenly liquefied and runs off the wound. Attempts have been made to overcome this problem by combining honey with other materials like viscosity-enhancing additives or the use of absorbent material such as existing bandages or gauzes. New solutions are proposed such as the use of a three-layer structure. 53 A possible dressing is composed of non-woven calcium alginate fabric impregnated with a mixture of sodium alginate and honey, so as to form a wound-contacting layer of the sodium alginate/honey mixture, an intermediate layer of the fabric impregnated with the sodium alginate/honey mixture and a backing layer of the fabric.

5.4.6 Chitin, chitosan and derivatives Chitin, a naturally abundant mucopolysaccharide, and the supporting material of crustaceans, insects, etc., is well known to consist of 2-acetamido-2-deoxy-β-d-glucose through a β (1→4) linkage. Chitin is the second most abundant organic compound in nature after cellulose. Chitin is widely distributed in marine invertebrates, insects, fungi and yeast. However, chitin is not present in higher plants and higher animals. Generally, the shell of selected crustacean was reported to consist of 30–40% protein, 30–50% calcium carbonate and calcium phosphate, and 20–30% chitin. Chitin is widely available from a variety of sources, among which the principal one is waste from shellfish such as shrimps, crabs and crawfish. It also exists naturally in a few species of fungi. In terms of its structure, chitin is associated with proteins and, therefore, is high in protein content. Chitin fibrils are embedded in a matrix of calcium carbonate and phosphate that also contains protein. The matrix is proteinaceous, where the protein is hardened by a tanning process. Studies demonstrated that chitin represents 14–27% and 13–15% of the dry weight of shrimp and crab processing wastes, respectively. Its immunogenicity is exceptionally low, in spite of the presence of nitrogen. It is a highly insoluble material resembling cellulose in its solubility and low

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chemical reactivity. It may be regarded as cellulose with hydroxyl at position C-2 replaced by an acetamido group. Like cellulose, it functions naturally as a structural polysaccharide. Chitin is a white, hard, inelastic, nitrogenous polysaccharide and the major source of surface pollution in coastal areas. Chitin is made up of a linear chain of acetylglucosamine groups, while chitosan is obtained by removing sufficient acetyl groups (—COCH 3) from the molecule to make it soluble in most dilute acids. Chitosan is the N-deacetylated derivative of chitin, although this Ndeacetylation is almost never complete. A clear nomenclature with respect to the degree of N-deacetylation has not been defined between chitin and chitosan. 54,55 The structures of cellulose, chitin and chitosan are shown in Fig. 5.1.

CH2OH H

CH2OH O

OH

H

O

H

OH

H H

O

H

H

O H H

OH

H

n

OH

Cellulose CH2OH H

CH2OH O

OH

H

O

H

OH

H H

O

H

H

O H H

NHCOCH3

H

NHCOCH3

n

Chitin

CH2OH H

CH2OH O

OH

H

O

H

OH

H H

O

H

H

H

NH2

H Chitosan

5.1 Structures of cellulose, chitin and chitosan.

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O H

NH2

n

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As seen in Fig. 5.1, the only difference between chitosan and cellulose is the amine (—NH 2) group in the position C-2 of chitosan instead of the hydroxyl (—OH) group in cellulose. However, unlike plant fibre, chitosan possesses ionic charges, which gives it the ability to chemically bind with negatively charged fats, lipids, cholesterol, metal ions, proteins and macromolecules. In this respect, chitin and chitosan have attained increasing commercial interest as suitable resource materials owing to their excellent properties including biocompatibility, biodegradability, adsorption, and ability to form fi lms, and to chelate metal ions. Chitin and chitosan are of commercial interest due to their high percentage of nitrogen (6.89%) compared with synthetically substituted cellulose (1.25%). This makes chitin a useful chelating agent. 54 As most modern polymers are synthetic materials, their biocompatibility and biodegradability are much more limited than those of natural polymers such as cellulose, chitin, chitosan and their derivatives. However, these naturally abundant materials also exhibit a limitation in their reactivity and processability. 56,57 In this respect, chitin and chitosan are recommended as suitable functional materials, because these natural polymers have excellent properties such as biocompatibility, biodegradability, non-toxicity and adsorption properties. Recently, much attention has been paid to chitosan as a potential polysaccharide resource. 58 Although several efforts have been reported to prepare functional derivatives of chitosan by chemical modifications, 59–61 very few attained solubility in general organic solvents62,63 and some binary solvent systems.64–66 Chemically modified chitin and chitosan structures resulting in improved solubility in general organic solvents have been reported by many workers.67–76 Most of the naturally occurring polysaccharides, e.g. cellulose, dextran, pectin, alginic acid, agar, agarose and carragenan, are neutral or acidic in nature, whereas chitin and chitosan are examples of highly basic polysaccharides. Their unique properties include polyoxy salt formation, ability to form fi lms, chelate metal ions and optical structural characteristics.62 Like cellulose, chitin functions naturally as a structural polysaccharide, but differs from cellulose in its properties. Chitin is highly hydrophobic and is insoluble in water and most organic solvents. It is soluble in hexafluoroisopropanol, hexafluoroacetone, and chloroalcohols in conjugation with aqueous solutions of mineral acids67 and dimethylacetamide containing 5% lithium chloride. Chitosan, the deacetylated product of chitin, is soluble in dilute acids such as acetic acid and formic acid. Recently, the gel-forming ability of chitosan in N-methylmorpholine N-oxide and its application in controlled drug release formulations has been reported.73–75 The hydrolysis of chitin with concentrated acids under drastic conditions produces relatively pure d-glucosamine. Unlike most polysaccharides, chitosan possesses charge because of deacetylation and makes the polymer soluble in water. However, the degree of solubility depends on the extent of acetylation.76

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The nitrogen content of chitin varies from 5 to 8% depending on the extent of deacetylation, whereas the nitrogen in chitosan is mostly in the form of primary aliphatic amino groups. Chitosan, therefore, undergoes reactions typical of amines, of which N-acylation and the Schiff reaction are the most important. Chitosan derivatives are easily obtained under mild conditions and can be considered as substituted glucans. N-Acylation with acid anhydrides or acyl halides introduces amido groups at the chitosan nitrogen. Acetic anhydride affords fully acetylated chitins. Linear aliphatic N-acyl groups above propionyl permit rapid acetylation of hydroxyl groups. Higher benzoylated chitin is soluble in benzyl alcohol, dimethylsulfoxide, formic acid and dichloroacetic acid. The N-hexanoyl, N-decanoyl and N-dodecanoyl derivatives have been obtained in methanesulphonic acid.77,78 The presence of the more or less bulky substituent weakens the hydrogen bonds of chitosan; therefore N-alkyl chitosans swell in water in spite of the hydrophobicity of the alkyl chains, but they retain the fi lm-forming property of chitosan. 54 The basic structural element of chitin is N-acetylglucosamine, which initiates fibroblast proliferation, helps in ordered collagen deposition, and stimulates an increased level of natural hyaluronic acid synthesis at the wound site. It helps in faster wound healing and scar prevention. Chitosan is known in the wound-management field for its haemostatic properties. Further, it also possesses other biological activities and affects macrophage function to result in faster wound healing. It also has an aptitude to stimulate cell proliferation and histoarchitectural tissue organisation. The biological properties including bacteriostatic and fungistatic properties are particularly useful for wound treatment. Like alginate material, there is also number of references on chitosan in wound treatment. They showed that chitosan facilitated rapid wound re-epithelialisation and the regeneration of nerves within a vascular dermis. Early returns to normal skin colour at chitosan-treated areas were also demonstrated. Treatment with chitin and chitosan demonstrated a substantial decrease in treatment time with minimum scar formation on various animals. The preparation of water-soluble chitosan for delivering an anticancer agent has been patented.79

5.5

Example of bioactive dressing: di-O-butyrylchitin (DBC)

5.5.1 General description of DBC An original method of synthesis of di-O-butyrylchitin (DBC), the soluble derivative of chitin, was worked out at the Technical University of Łódz´, Poland.65,66 The proposed method applied to chitin of different origin (crab, shrimp and krill shells, and insect chitin) gave products of definite chemical

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Advanced textiles for wound care O O

O O

C O

C3H7

C O

C3H7

O NH

O C

O

C3H7

C CH3

C O

C3H7

O NH

O O

O O

C

O

C3H7

C CH3

O NH

O O

C

O

C3H7

C

O

CH3

5.2 Chemical structure of dibutyrylchitin (DBC) after complete O-butyrylation (degree of substitution = 2).

structure with a degree of esterification very close to two (Fig. 5.2). DBC is readily soluble in common organic solvents and has both fi lm and fibre-forming properties.67–72 Such properties of DBC created the possibility of manufacturing a wide assortment of DBC materials suitable for medical applications in the form of fi lms, fibres, non-woven, knitted materials, and woven fabrics. It was also stated that the treatment of fi nished materials made from DBC, carried out under mild alkaline conditions, led to chitin regeneration without destroying their macrostructure.72 Moreover, the regeneration of DBC to chitin resulted in improving the mechanical properties of the newly obtained materials containing regenerated chitin (RC).74,75 Thus, O-butyrylation of chitin, preparation of several forms of dressings from DBC, and then returning to pure chitin in the process of alkaline hydrolysis of DBC materials, gives the possibility of practically unlimited manufacturing of DBC and chitin-based dressing materials, which are comfortable and easy in use. The fi rst investigations of biological properties of DBC and RC materials, carried out in vitro and in vivo in accordance with the European standards EN ISO 10993 (‘Biological evaluation of medical devices’), showed good biocompatibility of both polymers75,77,78,80,81 and their ability to accelerate wound healing.74,82 Recent investigations published by Muzzarelli et al.83 confi rms the biocompatibility of DBC. The presented results indicated that DBC is not cytotoxic for fibroblasts and keratinocytes. The fi rst clinical investigations into medical properties of DBC have been carried out at the Polish Mother’s Health Institute in Łódz´ , Poland. DBC samples under investigation have been used in the form of non-woven materials made at Technical University of Łódz´ using krill chitin as a source of DBC. Results of their clinical investigations were presented at the 6th International Conference of the European Chitin Society84 and published.85 Further results have been received using non-woven dressing

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materials with DBC that was obtained from shrimp shell chitin.86-91 Combined results of clinical investigations of DBC non-woven dressing materials are used and explained in this chapter.

5.5.2 Biological properties of DBC: in vitro and in vivo assays The realisation of clinical investigations was preceded by the determination of biological properties of DBC fibres and wound dressings in the form of neutral polypropylene sheets covered bilaterally by DBC fi lms. The investigations were carried out in accordance with the requirements of the standard EN ISO 10993 (‘Biological evaluation of medical devices’). They included investigation of cytotoxic effects of aqueous extracts of DBC fibres and wound dressings coated with DBC, investigation of haemolytic effects of aqueous extracts of DBC fibres, fulfi lment of intracutaneous reactivity tests of aqueous extracts, evaluation of local tissue reactions after implantation of DBC fibres into the gluteal muscles of the Wistar rats and peritoneal cavity of mice BALB/C. Moreover, the investigation of the tissue regeneration process after coverage of damaged rabbit skin with DBC type wound dressings was completed. In order to define the inflammatory and immunomodulation effects of DBC-containing wound dressings, an assessment of their influence on the induction of cytokines and on the synthesis of nitrogen oxides of human leukocytes was conducted. Evaluation of the influence of DBC for activation of the blood coagulation system was completed in the latter research. Fibres and wound dressings were sterilised by ethylene oxide before investigation. From the results of biological investigation, the following conclusions were drawn: • Tests of aqueous DBC extracts from fibres performed in vitro proved that cytotoxicity and haemolytic effects were not found.77,81 • After animal tests conducted in vivo on rabbits, no reaction resulted from intradermal application of DBC fibres.77,81 • No intensification of the tissue reaction was found after implantation of DBC fibres into the gluteal muscles of the Wistar rats83 or into the peritoneal cavity of mice BALB/C.77 The results of microscopic observation were the same as those obtained in investigation of the reactions in the surrounding of the Maxon surgical threads.77 • Tests of IL1β and IL6 interleukin levels in the peritoneal fluids of the experimental mice BALB/C have not proved the existence of statistically essential differences when comparing two animal groups: the group represented by animals with DBC fibres inserted into the peritoneal cavity and those with peritoneal-implanted Maxon surgical threads.77

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• It was confi rmed that the polypropylene nonwoven materials coated with DBC do not demonstrate cytotoxicity and primary irritation effects, do not cause an increase of the activities of TNF-α, IFNs or the nitrogen oxide level, and have an active positive influence on the wound healing process.74,81 • DBC materials showed the activity of blood procoagulation and have no influence on the activity of the plasma protein coagulation system.92 Based on these results, the Ethics Committee of the Polish Mother’s Health Institute has given approval for a project on the application of DBC in surgical paediatric patients.

5.5.3 Rationale for the provision of butyrate Short-chain fatty acids, especially butyrate, play a central metabolic role in maintaining the mucosal barrier in the gut. A lack of butyrate, leading to endogenous starvation of enterocytes, may be the cause of ulcerative colitis and other inflammatory conditions. The main source of butyrate is dietary fibre, but it can also be derived from structured biopolymers like DBC. Butyrate has been shown to increase wound healing and to reduce inflammation in the small intestine.93 In the colon, butyrate is the dominant energy source for epithelial cells and affects cellular proliferation and differentiation by as yet unknown mechanisms. Recent results suggest that the luminal provision of butyrate may be an appropriate means to improve wound healing in intestinal surgery and to ameliorate symptoms of inflammatory diseases. It was also suggested that butyrate may inhibit the development of colon cancer.94,95 Butyrate has a relatively short metabolic half life. The half-life of butyrate in plasma is extremely short, as concentrations of butyrate in plasma peaked between 0.25 and 3 h after application and had disappeared by 5 h after the application.

5.5.4 Interaction between DBC and enzymes The enzymic susceptibility of DBC and RC and the consequences on their polymer structure is an important factor in its use as a bioactive wound dressing material. When dealing with DBC, the chemical nature of the modified chitin, an ester, suggests that it would be susceptible to enzymic attack by lipases insofar as the removal of butyryl groups is concerned. Characteristics of used DBC fibres Average results of elemental analysis of DBC gave: C 55.80% (calculated 55.98%), H 7.51% (calculated 7.29%) and N 4.10% (calculated 4.08%) and

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suggested that the degree of esterification was very close to 2; intrinsic viscosity 1.41 dL g−1 in acetone at 25 °C; intrinsic viscosity 2.17 in dimethylacetamide at 25 °C; weight average molecular weight c. 170 kDa; degree of crystallinity (when in form of flakes) 47.2%. The fibres were prepared by wet spinning, by using a 16% solution of DBC in dimethylformamide; the nonwovens were prepared from 6-cm fibres by the needle-punching technique. The 1H NMR spectrum of DBC was recorded using a Brucker AM 400 spectrometer. Deuterated chloroform, CDCl3 was used as a solvent. In the 1H spectrum both substituted hydroxyl groups in the secondary position 3, at 5.0 ppm, and in the primary position 6, at 4.3 ppm, gave well separated signals. This applies to both protons in CH 3 and CH 2 groups. The proton signals of the N-acetyl group of the original chitin are present in the spectrum as a singlet placed at 1.9 ppm. The intensity ratio of signals of the CH 3 group, coming from the butyryl substituent, to the signal intensity of N-acetyl group, derived from the spectra, amounts to 1 : 2. According to NMR investigation, the reaction product is dibutyrylchitin. Both signals of amide group: CH 3 —CO at 2.0 ppm and NH at 6.1 ppm indicate that more than 90% of N-acetyl groups of the original chitin are present in DBC. Preparation of regenerated chitin fibres (RC) The DBC fibres were immersed in 1.25 m aqueous NaOH solution at 50 °C and allowed to be hydrolysed for defi nite periods of time up to 150 min; then the samples were washed several times with water to remove alkali, dried and weighed; then they were treated with acetone to extract unreacted DBC and dried and weighed again. Treatment with lipases Lipase solutions were prepared by dissolving the desired lipase (100 mg) in 100 ml of a 0.5 g l−1 NaN3 aqueous solution, fi nal pH 6.0. The samples (c. 200 mg) were introduced in 40 ml of enzyme solution and kept on a rolling bar machine for 4 weeks. The lipases (EC 3.1.1.3) were crude porcine pancreas lipase L-3126 (PPL), and wheat germ lipase L-3001 (WGL). The results showed that DBC is not degraded by lipases. Susceptibility of dibutyrylchitin to enzymic hydrolysis DBC does not seem particularly prone to enzymic hydrolysis; in fact it is not hydrolysed by lysozyme and it is not degraded by lipases. Lysozyme and lipase being the main enzymes that could release oligomers of

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N-acetylglucosamine from chitin-based textiles and non-wovens used in wound management, it seems that the biochemical significance of DBC is low. Collagenase and amylase do not appear to be able to remove any significant portion from the fibres, but it should be said that collagenase has a certain tendency to adhere to the fibres while exerting poor activity on them. Even crude cellulase and pectinase preparations exerted very little hydrolytic activity on dibutyrylchitin over the extended period of 48 days at 25 °C. It can thus be added that dibutyrylchitin seems to be relatively resistant to biodegradation. This resistance to biodegradation will be further discussed in the chapter describing the clinical experiments. These clinical experiments indicate a complete biodegradation of DBC when applied as bioactive material in wound dressings.

5.5.5 Live/dead assays The live/dead assays were indicative of full biocompatibility of fibroblasts with the DBC fi lm: the viability values for the cells grown in regular multiwell plates ranged from 95.5 to 75.6%, close to those for DBC-lined plates (93.0–72.8%) in the 24–72 h period. For the cell proliferation assay, the percentages of cells positive to fluorescein over the 24–72 h period were similar in the two cases: regular multiwell plates (20.6–53.3%) and DBC-coated multiwell plates (22.7–60.0%). The Neutral Red Retention and the Lactate Dehydrogenase spectrophotometric assays provided results in line with those already illustrated: there was no significant difference between the Neutral Red release rate for reference fibroblasts and DBC-exposed fibroblasts.

5.5.6 Haemocompatibility The contact angle value for untreated human blood decreased with time from the initial value of 60° to 42° in 21 min. The contact angle values for heparinised blood were slightly but significantly lower, owing to addition of heparin, and decreased with time at a similar rate, from 53° to 42°. The relatively modest values for the angles observed indicated that DBC is wettable by human untreated and heparinised blood. However, DBC is less wettable than glass. On glass slides, the contact angle decreased from 23° to 16° for heparinised blood in 17 min. The fact that the drops of untreated blood deposited on DBC film maintained their shape after 21 min is indicative of the absence of thrombogenic or coagulation-enhancing capacity in DBC. The values for saline (9 g l−1 NaCl) were the following: DBC 75°, chitin 56°, and chitosan 64°.

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5.5.7 Radical scavenging activity of DBC DBC was submitted to the action of free radicals in order to detect its scavenging activity. The radicals were benzyl radical C6H 5CH 2⋅ and adamantyl radical C9H13⋅, both generated in situ by photoactivation from stable precursors. Owing to their very short life, the radicals were stabilised with the spin trap dimethylpyrroline N-oxide (DMPO). DBC solutions in dichloromethane containing a precursor of benzyl radicals were exposed to sunlight or UV under inert atmosphere. The spectra were recorded with a Bruker EPR spectrometer in aqueous acetonitrile–DMPO solution. The NMR spectra obtained on the chromatographic fractions from a silica gel column showed the formation of adducts of DBC and benzyl group. Similar preliminary results were obtained with the adamantyl radical. The EPR spectra recorded in aqueous acetonitrile–DMPO solution for adamantyl radicals, the same with added DBC and for irradiated DBC in the absence of radical precursors, show that: • DBC alone does not produce radicals upon irradiation. • DBC is a free radical scavenger because it modifies the radical species of the adamantane type. • DBC forms adduct with the benzyl radicals. These results are in agreement with published results that fi nd that oligomeric species of chitosan exhibit radical scavenging activity towards a number of radicals (other than those used here). Normally, the radical scavenging activities of chitin or chitosan are strongly dependent on the degree of acetylation. Chitosan with the highest degree of deacetylation is characterised by the highest radical scavenging properties, owing to the high number of free amino groups. The scavenging mechanism of chitosan on free radicals may be related to the fact that free radicals can react with the residual amino groups (NH 2) to form stable macromolecule radicals and the NH 2 groups can form ammonium groups (NH 3 +) by absorbing hydrogen ions from the solution. The positive results of DBC as a free radical scavenger and antioxidant is the result of a totally different mechanism because most (89%) of the NH 2 groups are acetylated in the used DBC. It is likely that the free radicals are reacting with the CH 2 groups of the O-substituted butyryl groups. These radical-containing CH2 groups are stable for a long time and are consequently neutralised by reaction with other compounds containing radicals. The free radical scavenger action and antioxidant capacity of DBC is related to the presence of the butyryl groups and their stable radical substances. This antioxidant capacity of DBC can be an important factor for nonhealing acute wounds. Whereas healing acute wounds have low levels of

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protein-degrading enzymes, exudates from non-healing chronic wounds contain elevated levels of proteases, like matrix metalloproteinases and elastase.4–6 Moreover, the concentrations of pro-inflammatory cytokines,7 as well as reactive oxygen species, 8 are significantly higher, compared with the concentrations in acute wounds. Reactive oxygen species, such as superoxide radicals (O2⋅ −) and hydroxyl radicals (OH⋅), as well as reactive nitrogen species, such as nitric oxide (NO⋅) arise from inflammatory cells.9–11 Overproduction of reactive oxygen and nitrogen species results in an imbalanced oxidant/antioxidant static in wounds and especially in chronic wounds.8,11,12 Owing to the resulting disproportion between degradation and remodelling processes, chronic wounds persist in the inflammatory phase of the normal healing process for months or even years. The reduction in reactive oxygen and reactive nitrogen species in the wound fluid by the free radical scavenger action of DBC seems to be a logical way to stop the inflammation process and diminished epithelialisation and to start the normal healing process.

5.5.8 Conclusions of the biochemical tests All biochemical tests described indicated that DBC is biocompatible for human fibroblasts and keratinocytes. The SEM data on the colonisation of non-woven DBC by rat fibroblast-like cells confi rmed the biocompatibility of DBC that seems also endowed with radical scavenging properties. These results are in line with those already published on other chitins and chitosans: for instance, keratinocytes were co-cultured with fibroblasts in chitosan–gelatin scaffolds to construct an artificial bilayer skin in vitro. The haemocompatibility assessment based on contact angle analysis indicated that DBC does not promote coagulation or thrombus formation when in contact with human blood.

5.5.9 In vitro cytotoxicity tests The objectives of the in vitro cytotoxicity tests were: 1. 2.

To evaluate the cytotoxic effect of materials involved in the production of DBC. To evaluate the fi nal products (non-wovens or knitted materials).

The cell cultures used were: primary obtained fibroblasts, human 3T3 cells, and human lymphocytes. In conclusion, the fi nal non-woven materials obtained from dibutyrylchitin showed that cells grown in contact with the material showed good cell viability. It seemed that they were not adhesive for the cells. Based on

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the cytotoxicity tests and on the physical properties of the materials, a selection of non-wovens was prepared in order to perform in vivo animal experiments: DBC and cellulosic fibers containing 4 wt% DBC.

5.5.10 In vitro and in vivo investigations The main aim of research on wound-dressing material made from DBC is to understand the mechanism of wound healing by DBC-based material. The in vitro and in vivo investigations were carried out in co-operation with the Medical Academy in Wroclaw, Poland. The experiments conducted investigated main biomedical characteristics like cytotoxicity, intradermal reactivity and immunological response, as well as biodegradability. Results showed that dibutyrylchitin has similar properties to chitin or RC, and all requirements described by European Standards are fulfi lled. Clinical investigation conducted in the Polish Mother Memorial Hospital shows a positive influence of DBC fabric on wound healing. The main aim of this research was to determine the mechanism of wound healing under DBC application and to compare it with the mechanism of wound healing using RC and chitosan products. The influence of DBC implants on the formation of the intercellular matrix of connecting tissue (collagen and glycosaminoglycans) and granular tissue in wound model was investigated. In addition, the reaction of the whole organism and thermoregulation of the body was examined. Investigations were carried out on 42 male Wistar rats, with mass 250 g ± 30 g. Animals were divided into six groups (of seven animals each): 1. 2.

3.

4.

5.

Control: polypropylene mesh implanted subcutaneously. Size of implant 2 × 3 cm; DBC A9: polypropylene meshes connected with DBC nonwovens were implanted. The surface density of the non-woven was 40 g m−2 ; fibres were formed from DBC polymer with an intrinsic viscosity of 1.75 dl g−1; DBC A8: polypropylene meshes connected with DBC non-wovens were implanted. The surface density of non-woven was 40 g m−2 ; fibres were formed from DBC polymer with an intrinsic viscosity of 2.08 dl g−1; Copolymer: polypropylene meshes connected with DBC/RC nonwovens were implanted. The surface density of non-woven was 40 g m−2 ; fibres were formed from DBC polymer with intrinsic viscosity 1.75 dl g−1 and hydrolysed to 50% of RC; RC: polypropylene meshes connected with RC non-wovens were implanted. The surface density of non-woven was 40 g m−2 ; fibres were

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3000 2500 2000 1500 1000 500

n sa

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D

BC

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GAG in µg mg–1 dry tissue

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5.3 Concentration of glycosaminoglycans (GAG) in granular dry tissue.

6.

formed from DBC polymer with intrinsic viscosity 1.75 dl g−1 and regenerated to chitin (RC); and Chitosan: polypropylene meshes connected with chitosan non-wovens were implanted. The surface density of nonwoven was 40 g m−2 .

The most important results are hereby summarised. The content of glycosaminoglycans in granular tissue was significantly higher in wounds with DBC. In addition, an increase in the content of glycosaminoglycans was observed for RC and copolymer. For wounds with implanted chitosan, the content of glycosaminoglycans was significantly lower (Fig. 5.3). The polymers examined did not influence the total collagen in the wound but DBC A9, copolymer and chitosan did reduce the soluble collagen. In addition, the tendency for reducing content of soluble collagen in the wound is observed with DBC A8 and RC groups (Fig. 5.4). The amount of total collagen is not reduced, therefore we can conclude that the examined polymers significantly improve the quality of collagen in the wounds. The following conclusions were obtained from these experiments: 1. 2.

3.

Dibutyrylchitin (DBC) exerts not only local but also general effects on the animal organism (influence on thermoregulation); Similar phenomena were seen in animals treated with RC. In the wounds, several beneficial effects of implanted inserts containing DBC dressings were seen: increase of granulation tissue weight, antiedematic properties, elevation of the glycosaminoglycans content and improvement of collagen quality in the wounds; and The results of the present experiments and clinical studies strongly support the suggestion that DBC is a good dressing material that improves the healing process.

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p<0.05

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p<0.05 p<0.05

400 350 300 250 200 150 100 50

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C

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Soluble collagen µg 100 mg wet tissue

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5.4 Concentration of soluble collagen.

5.5.11 In vivo animal experiments The healing of surgical wounds after DBC implants in rats followed the regular course; thus, the presence of DBC did not delay the early stages of the healing process. Clear indications of resorption were obtained. The role of DBC is essentially confi ned to imparting better handling and mechanical resistance; it does not seem that DBC has any relevant role in promoting the ordered regeneration of the wounded tissues, because it is hardly susceptibile to enzymic hydrolysis by lysozyme, lipase, collagenase and amylase. The information that DBC is also poorly degraded by other enzymes, such as raw cellulase and pectinase might be important in other fields: DBC appears to be particularly resistant in the environment, taking into account that chitin and chitosan were recognised as promptly degradable by both enzyme preparations, and in particular by Aspergillus niger pectinase. Additional experiments indicated that when DBC is put into an alkaline medium, a slow hydrolysis of the DBC took place until the medium is returned to a neutral pH. DBC may be an important material to control and regulate the pH of the wound during the healing process. As already mentioned, pH is an important parameter for wound healing and the reduction of pH to neutral constitutes an important positive effect of DBC on wound healing. The objectives of the in vivo animal experiments were to evaluate the in vivo behaviour of the material with regard to:

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• anti-inflammatory properties, • their wound healing properties, • their biodegradation. To investigate the wound healing efficiency of DBC dressing materials, the dressings were placed on the wound bed of critical size skin defects. Twelve Wistar Han rats (six male, six female, 60 days old) were used. A histological evaluation of the wound area and surrounding healthy tissue at different time points post-injury was performed and the results for the various potential bioactive dressing materials are presented. Cellulose fibres containing 4 wt% DBC Day 4 post-injury: A thick crust, composed of fibres and blood, covered the wound area. In two rats, the epithelium started to re-grow from the wound edges, in the third, there was no formation of new epithelium. Many neutrophils were present underneath the scab and between the fibres. There was no formation of new connective tissue. Day 7 post-injury: A thick scab was present. The epithelium started to renew in two out of the three rats. There were still inflammatory cells present, but no formation of connective tissue. Day 14 post-injury: Almost the same as at day 7. Day 35 post-injury: A thin scab covered the wound. No (complete) reepithelialisation and practically no new connective tissue formation was noticed. The material was still present in the wound site. Many inflammatory cells were observed. Non-woven DBC Day 4 post-injury: The epithelium was starting to renew and was covered with scab. The formation of connective tissue had not started yet, and some neutrophils were present underneath the scab and between the dressings. Day 7 post-injury: The epithelium was restoring. Scab stayed present. The connective tissue was starting to be formed and some of the DBC was reabsorbing. Day 14 post-injury: A thin scab covered the newly formed epithelium. The connective tissue is composed of dense collagen bundles, with a lot of blood vessels. The DBC material was being reabsorbed. Day 35 post-injury: All scab had disappeared. The epithelium showed invaginations in the underlying connective tissue. Dense collagen bundles, a lot of blood vessels and some skin appendages appeared in the connective tissue. There were no signs of inflammation and the DBC seemed completely reabsorbed.

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SeaSorb alginate dressing Day 4 post-injury: A thick scab was present at the wound site. In one out of the three rats, the epithelium started to re-grow. There was no formation of connective tissue. Neutrophils were observed around the alginate material. Day 7 post-injury: A thin scab covered the newly forming epithelium. Some inflammatory cells could be seen around the alginate. At the wound site of two rats, new connective tissue started to be formed. Day 14 post-injury: Re-epithelialisation was completed and a thin scab rested on it. In two rats, dense collagen and blood vessels appeared in the connective tissue above the alginate layer. Day 35 post-injury: A thin and flat epithelium covered the former wound area. All scab was removed, and there were no signs of inflammation. The connective tissue was dense, with some blood vessels and skin appendages appeared at the former wound edges. The alginate layer was not reabsorbed during these 35 days. Open wound Day 4 post-injury: The epithelium was starting to re-grow at the wound edges. A thick layer of scab spanned the wound site. Underneath the scab, neutrophils were present. There was no formation of new connective tissue. Day 7 post-injury: The epithelium was restored, but scab remained. New connective tissue was forming. Day 14 post-injury: No scab was noticed on the thin and flat epithelium. The connective tissue was dense with some blood vessels. No indications of inflammation. Day 35 post-injury: Same observations as at day 14 post-injury. The connective tissue is dense, with not a lot of blood vessels and no skin appendages: presence of scar tissue.

5.5.12 Conclusions of the in vivo experiments The wounds covered with the DBC dressing and the SeaSorb alginate showed the best wound healing: dense collagen in the connective tissue with a lot of blood vessels and some skin appendages at day 35 post-injury. The main difference was that the DBC material was degraded (complete absorption of the material was noticed after 35 days). The DBC-material could stay on the wound during the healing process, while this alginate should be removed after a couple of days. Owing to this biodegradable property, DBC-based dressing has advantages compared with other

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Time (day)

100

10

1 0

20

40

60

80

100

Absorption (%)

5.5 Time for complete absorption of chitin fibres into wounds.

available wound-dressing materials. In contrast with the laboratory tests of DBC with different enzymes to study the enzymatic hydrolysis of DBC, DBC is completely degraded in this application of wound dressing material. This difference will be discussed later on, after the description of the clinical experiments. The best choice for solubility and bioactive dressing materials based on acetylated chitosan seems to be around 50% substitution. This follows also from the absorption of chitin or chitosan fibres into wounds as function of the degree of substitution as represented in Fig. 5.5. The fast absorption, in vivo, of chitin fibres into treated wounds is obtained with chitin containing 50% acetylglucosamine. These fibres are completely absorbed in 1 week against 4 weeks for the used chitin fibres with 90 to 100% acetyl groups. The complete absorption of the chitin fibres into the wounds is a result of the combined action of two enzymes, lipases for the hydrolysis and lysozymes for the breakdown of the hydrolysed chitins into their basic monomers or oligomers. This time for complete absorption of the chitin fibres corresponds with the time necessary for the complete absorption of the DBC-based fibres.

5.5.13 Results of clinical investigations The surgical staff of the Department of Paediatric Surgery was provided with a number of DBC petals for medical application. It has been planned to apply DBC in the group of 29 children with following indications: • burns, • wounds of various aetiology, • bed sores – in patients immobilised for long periods regardless of reason, • lesion of parietes as a result of multifactorial processes (e.g. sepsis).

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(b)

5.6 Lower limb burn injury (a) before treatment and (b) healing nearly completed.

The fi rst group of patients comprised 10 persons suffering from burns. Nine of them were aged 7–40 months and the mean age in this group was 16 months. The total area of thermal burns of patients range from 5 to 20%. The depth of burns was classified in each case as 2a. All the burns healed up within 1–2 weeks after DBC petal application. The healing processes are documented in Fig. 5.6a and b. One patient who was a 17-year-old boy suffered from electric burn of class 3, locally to the left forearm. After removal of necrotic tissue, a DBC petal was applied as a pre-treatment before surgery – split-thickness skin transplantation. The result of the healing process was very good. The second group of patients suffered from wounds other than burns with various aetiology such as: post-operative, post-traumatic and posttraumatic/post-operative. Five patients complained of post-operative wounds. In the post-traumatic group, there were five patients. Three of them sustained injury to the digits with partial necrosis of soft tissues. After removal of necrotic tissue, the DBC petal was applied and there was no need of further surgical interference. The other two children had extensive wounds to the limbs and skin loss owing to necrosis. The petals of DBC were applied on the raw surface as a pre-treatment before surgery. In one patient, the wound healed up spontaneously and rapidly and he avoided surgery. In the other, the split-thickness skin transplant was performed. The healing processes of these groups were very good. Four patients from the post-traumatic/post-operative group sustained severe injuries to the lower limbs resulting in open fractures of the tibia with loss of soft tissue. All were repeatedly operated by orthopaedic surgeons. As a consequence, residual chronic ulcers with tibial bone exposed were seen in all cases. The application of DBC petals resulted in the healing of wounds in two cases.

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The third group of patients is related to various entities leading to skin/ epidermis loss. The local treatment with the use of DBC petals was introduced in a 1.5-year-old child with foci of necrosis of the skin in the course of general sepsis. As a result of removal of the necrotic tissue and application of DBC petals, healing of the wound was achieved. The last group of patients suffered from bedsores. Extensive chronic bedsores were infected and covered with pus. The pieces of DBC did not stick to the bedsore and were flowing freely on its surface, making no contact with the tissue. The conservative treatment was discontinued. DBC-supported wound dressings for pre-clinical studies were prepared by using chitosan, chitin and chlorhexidine together with DBC non-wovens. A total of 80 pieces (10 × 10 cm) of DBC non-wovens were treated with chlorhexidine, forwarded for gamma-ray sterilisation and then tested in the Clinics of Surgery in Rome, Italy. These new dressings were found most useful in all cases treated, leading to healing of a variety of wounds.

5.5.14 Discussion and conclusions of the clinical trials As far as thermal burn patients are concerned, the depth of the wound was evaluated as 2a in all cases. This means there was no necrotic tissue and no indication for operative treatment. In all cases, healing was quick and uneventful, and in no case did infection develop. Regarding the only child with an electric burn, the fi rst step in the procedure was the removal of necrotic tissue. The application of DBC, as preparation for surgery, and the operation itself followed. The non-septic wounds are by defi nition an indication for surgical treatment. As a matter of fact, all patients presented were primarily treated this way. In three of them, after plastic operation, small unhealed patches with granulation were found. No signs of infection and no necrotic tissue were indicated. All these places healed up soon after the application of DBC. Another four children suffered mechanical injury, and the wounds were complicated by the presence of necrotic tissue. The fi rst stop in all cases was the removal of necrosis followed by the use of DBC. Two of them were considered as candidates for further surgery, but this was the case only in one patient. Surprisingly, the other one healed up soon enough to avoid surgery. The greatest surprise was the uneventful progress, which took place by two children repeatedly operated for open, complicated leg fracture. The wounds were clean, without necrosis but with exposed bone in the centre. In spite of this, they healed up quickly. The third such patient hopefully will be going the same way. DBC was also applied in three other children with various entities. They all have two things in common: the lesion of the skin/epidermis and the absence of necrosis and infection.

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In all cases, DBC dressings have been applied to the clean wound, and not removed until the end of the healing process, while DBC has been disintegrated in the area of the wound. No other medical products have been applied for the wound healing. The results were at least promising but too few cases have been observed until now, and the aetiology was diverse. It turned out that, in another suggested indication for DBC application, in the cases of bedsore, no benefit was seen. However, extensive bedsores are always connected with infections; suppuration, non-viable tissue, and indications arise for surgery rather than for conservative treatment. The observations presented are preliminary and further evaluation is necessary. Summarising, it is possible to conclude: • Preliminary results of DBC application are highly promising: DBC seems to promote the healing of wounds. • Selection of patients for this treatment has to be meticulous: the tissues to be covered with DBC should be viable, possible without infection. Otherwise, the results are doubtful as in the case with bedsores. • Further randomised trials with referential groups should be completed to obtain evidence-based proofs of beneficial effects of DBC wound dressings.

5.5.15 Biodegradation of DBC in wound dressings Research results show that matrix metalloproteinases are present at elevated levels during early wound healing and suggest that matrix metalloproteinases may play a significant role in wound healing. The matrix metalloproteinases are a family of zinc metalloendopeptidases that can collectively cleave all components of the extracellular matrix. Early research work on the porcine skin model96,97 identified changes in matrix metalloproteinases during wound healing. Collagenase activity was high early after wounding and declined with post-operative time, returning to baseline levels when epithelialisation was complete. Gelatinase activity followed a similar pattern. The activity of matrix metalloproteinases returns to normal as healing progresses.98 A known enzyme that catalyses the deacetylation of N-acetylglucosamine to form glucosamine and acetate is a zinc-dependent enzyme,99 UDP-3-O(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC). LpxC functions via a metalloprotease-like mechanism by using zinc-bound water as nucleophile. In clinical experiments with DBC-based wound dressings, matrix metalloproteinases probably catalyse the deacetylation of DBC in the presence

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of zinc-bound water. The fi nal result of this deacetylation reaction is the formation of O-butyrylated chitosan. As it is known from other research results that O-butyrylated chitosan is soluble in water,100 a possible explanation for the complete resorption of DBC during the wound-healing experiments is the deacetylation of DBC by the action of matrix metalloproteinases in combination with zinc-bound water and the formation of a complete water-soluble derivative, O-butyrylated chitosan. This watersoluble derivate is completely absorbed in the wound and probably hydrolysed afterwards by other enzymes. The clinical experiments with DBC-based bioactive wound-dressing materials elucidate a totally different action of wound healing and possible other approaches for bioactive wound-dressing materials.

5.6

Future trends

The role of bioactive dressing materials is to deliver substances active in wound healing. Most of the commercial available so-called bioactive wound dressings are based on the principle of occluding the wounds, usually by preventing the formation of a scab by the action of absorbing the wound exudate secreted from the ulcer. These dressings maintain a moist environment on the wound, and prevent exposure to air and dehydration. In addition, they make it possibile to control the pH of wounds, mostly owing to their intrinsic acid nature, and the partial pressure of oxygen. Some of the commercially available bioactive wound-dressing materials contain bioactive substances such as calcium, zinc or silver ions. Increasingly common is the use of silver-based antiseptics. The new, advanced dressings are impregnated with silver-based antiseptics linked to their broad-spectrum activity and their lower propensity to induce bacterial resistance than antibiotics. Chitosan, chitin and their derivatives have been studied widely as bioactive wound-dressing materials, but wound-dressing materials based on these products are still not as fully commercially available as other bioactive dressing materials, such as alginates. It is likely that the future trends in bioactive wound dressing materials will be the use of materials based on chitin, chitosan and their derivatives. A better knowledge and understanding of the action of these dressings in wound healing will be the basis for future developments of more bioactive dressing materials. As described, some of these materials are completely absorbed in the healing wound, must not be changed during the healing process, are characterised by an excellent antioxidant activity and, some of them, have a good anti-bacterial activity. So, there are many possibilities for future developments of effective bioactive dressing materials. Owing to their complete resorption into the healing wounds, the use of powder instead of fibres or fi lms is possible

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and this can be an important factor for the price of the bioactive dressing materials and their fi nal cost in the treatment of wounds. In addition, the use of these materials can be expanded to use by private individuals in addition to the classical clinical use. Examples of such bioactive dressing materials are dressings made from blends of chitosan and alginate,101 blends of alginate and water-soluble chitin. 23 Flexible, thin, transparent, novel chitosan-alginate polyelectrolyte complex membranes caused an accelerated healing of incision wounds in a rat model compared with conventional gauze dressing. Water-soluble chitin, or half-deacetylated chitin, can be prepared from chitosan by N-acetylation with acetic anhydride. Alginate and water-soluble chitin blend fibres can be obtained by solution spinning into a coagulation bath. There is good miscibility between alginate and water-soluble chitin. The introduction of water-soluble chitin into the fibres improves water-retention properties of the blend fibres compared with pure alginate fibre. The use of these blends based on alginate and chitin or chitin derivatives may be a further and next step in the development of new bioactive dressing materials. Another type of experimental bioactive dressing material is based on a blend of collagen and chitosan.102 Wound dressing materials were obtained from these blends by electrospinning by using poly(ethylene oxide) as a third component. Poly(ethylene oxide) was necessary to improve the processability of the blends and to obtain fibres by electrospinning. Electrospinning is a simple and effective method for preparing nanofibres with diameters ranging from 5 to 500 nm. Wound dressings from electrospun fibres potentially offer many advantages over conventional processes. With its huge surface area and microporous structure, the electrospun fibres could quickly interact with the enzymes present in the wound exudate. From animal studies, the membrane produced from the electrospun collagen/chitosan/poly(ethylene oxide) fibres was better than gauze and commercial sponge in wound healing. The future development will be the production of nanofibres from chitin derivatives, by electrospinning of its aqueous solutions or ethanol solutions, or by the direct production of nanoparticles from those derivatives. This will probably increase the biochemical activity of those derivatives. As also demonstrated by the example, the O-butyrylation of chitin or chitosan is an important modification of chitin and increases the biochemical activity of chitin or chitosan. Even water-soluble derivatives of chitin or chitosan can be obtained by O-butyrylation. Probably, an optimum choice of the acetylation degree of the starting chitin for O-butyrylation is still necessary to increase the bioactive action of those compounds. The increased biochemical activity of chitin derivatives by O-butyrylation is also supported by the wound-healing activity of an ointment containing dibutyryl cyclic adenosine monophosphate (DBcAMP).103 Not only the

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degree of O-butyrylation, but also the degree of N-acetylation or Nbutyrylation and the porosity of the materials may be very important in order to obtain bioactive dressing materials with still better wound-healing properties.104–106

5.7

Acknowledgements

The study on DBC has been supported by the European Commission under the Project CHITOMED, QLK5-CT-2002–01330. My thanks go to all companies, universities and collaborators incorporated in that research project and their references are cited in the publications and references concerning DBC.

5.8

References

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33. chang, k.w., alsagoff, s., ong, k.t., sim, p.h., ‘Pressure ulcers – randomised controlled trial comparing hydrocolloid and saline gauze dressings’, Med J Malaysia, 53 (1998) 428–431. 34. heyneman, a., beele, h., vanderwee, k., defloor, t., ‘A systematic review of the use of hydrocolloids in the treatment of pressure ulcers’, J Clin Nurs, 17 (2008) 1164–1173. 35. sagar, b., hamlyn, p., ‘Wound dressing’, Patent US4960413 to Shirley Inst, October 2, 1990. 36. cole, s.m., garbe, j., ‘Alginate hydrogel foam wound dressing’, Patent US4948575 to Minnesota Mining & MFG, August 14, 1990. 37. wren, d., ‘Wound dressing’, Patent US5238685 to Britcair LTD, August 24, 1993. 38. gilding, d.k., ‘Wound dressing’, Patent US5998692 to Innovative Tech Ltd, December 7, 1999. 39. hazzi, n., ‘Wound dressing’, Patent US6706279 to Pharma Mag Inc., March 16, 2004. 40. dillon, r.s., ‘Method and solution for treating tissue wounds’, Patent US5084281 to Dillon R.S., January 28, 1992. 41. kane, j.b., tompkins, r.g., yarmush, m.l., burk, j.f., ‘Burn dressings’ in Ratner, B.D., Hoffman, A.S., Schoen, F.J., Lemens, J.E., (Eds.), Biomaterial science, Academic Press, San Diego, (1996) 360–370. 42. nwomeh, b.c., liang, h.x., cohen, i.k., yager, d.r., ‘MMp-8 is the predominant collagenase in healing wounds and nonhealing ulcers’, J Surg Res, 81(2) (1999) 189–195. 43. lockhart, l.k., pampolina, c., nickolaychuk, b.r., mcnicol, a., ‘Evidence for a role for phospholipase C, but not phospholipase A2, in platelet activation in response to low concentrations of collagen’, J Thromb Haemost, 85(2) (2001) 882–889. 44. tolstykh, p.i., gostishchev, v.k., virnik, a.d., arutiuniuan, b.n., ‘Biologically active dressings and surgical suture materials’, Khirurg (Mosk), 4 (1988) 3–8. 45. balasubramani, m., kumar, t.r., babu, m., ‘Skin substitutes: a review’ Burns, 27 (2001) 534–544. 46. supp, d.m., boyce, s.t., ‘Engineered skin substitutes: practices and potentials’, Clin Dermatol, 23 (2005) 403–412. 47. enoch, s., grey, j.e., harding, k.g., ‘Recent advances and emerging treatments’, Br Med J Clin Res Ed, 332 (2006) 962–965. 48. ehrenreich, m., ruszczak, z., ‘Uptake on tissue-engineered biological dressings’ Tissue Eng, 12 (2006) 2407–2424. 49. eisenbud, d., huang, n.f., luke, s., silberklang, m., ‘Skin substitutes and wound healing: current status and challenges’, Wounds, 16 (2004) 2–17. 50. angele, p., abke, j., kujat, r., faltermeier, h., schuman, d., nerlich, m., ‘Influence of different collagen species on physico-chemical properties of crosslinked collagen matrices’, Biomaterials, 25 (2004) 2831–2841. 51. orban, j.m., wilson, l.b., kofroth, j.a., el-kurdi, m.s., maul, t.m., vrop, d.a., ‘Crosslinking of collagen gels by transglutaminase’, J Biomed Mater Res, 68 (2004) 756–762.

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52. subrahmanyam, m., ‘A prospective randomised clinical and histological study of superficial burn wound healing with honey and silver sulfadiazine’, Burns, 24 (1998) 157–161. 53. bray, r., champa, p., philip, r.c., ‘Wound dressings’, Patent application US 2005/0033213, Feb. 10, 2005. 54. muzzarelli, r.a.a., pasiser, e.r (eds), Chitin/chitosan, 1977, MIT Sea Grant, Program 78–7, 1978, p.108. 55. hirano, s., tokura s. (eds), Chitin and chitosan. 1982, Japanese Chitin Soc., Tottori. 56. Chitin, chitosan and related enzymes. 1984. Zikakis J.P. (ed.), Academic Press, NY. 57. Chitin in nature and technology. 1986. Muzzarelli R.A.A, Jeuniaux C., Gooday W. (eds), Plenum Press, NY. 58. oshimoma, y., nishino, k., yonekura, y., kishimoto, s., wakabayashi, s., ‘Clinical application of chitin non-woven fabric as wound dressings’, Eur J Plast Surg 10 (1987) 66–69. 59. Chitin and chitosan: sources, chemistry, biochemistry, physical properties and applications, 1989. Skjak-Braek G., Sandford P. (eds.), Elsvier, NY. 60. Advances in chitin and chitosan. 1992. Brine C., Sandford P., Zikakis J.P. (eds), Elsvier Applied Science, NY. 61. Chitin derivatives in life science. 1992. Tokura S., Azuma I. (eds), Japanese Chitin Soc., Sapporo. 62. roberts, g.a.f., Chitin chemistry, 1992. Macmillan, London. 63. muzzarelli, r.a.a., In vivo biochemical significance of chitin-based medical items in Polymeric biomaterials, 1993. S. Dimitriu (ed.), Marcel Dekker, Inc., NY., 179–197. 64. muzzarelli, r.a.a, Chitin in polymeric materials encyclopedia. 1996. Salamone J.C. (ed.), CRC Press, Boca Raton, USA. 65. szosland, l., janowska, g. Patent PL 169077 (1996). 66. szosland, l., ‘Synthesis of highly substituted butyrylchitin in the presence of perchloric acid’ J. Bioactive and Compatible Polymer, 11 (1996) 61–71. 67. Chitin Handbook. 1997. Muzzarelli R.A.A., Peter M.G. (eds), European Chitin Society, Ancona, Potsdam. 68. szosland, l., east, g.c., ‘The dry spinning of dibutyrylchitin fibres’ J Appl Pol Sci, 58 (1995) 2459–2466. 69. szosland, l., ‘A simple method for the production of chitin materials from the chitin ester derivatives’, 1996. Advances in chitin science, Muzzarelli R.A.A., Peter M.G. (eds.), 1 (1996) 297–302. 70. szosland, l., ‘Di-O-butyrylchitin’ Chitin handbook, Muzzarelli R.A.A., Peter M.G. (eds.), Germany, (1997) 53–60. 71. szosland, l., ste plewski, w., ‘Rheological characteristic of dibutyrylchitin semi-concentrated solutions and wet spinning of dibutyrylchitin fibre’ Advances in chitin science, Domard A., Roberts G.A.F, Varum K.M. (eds.), II (1998) 531–536. 72. szosland, l., ‘Alkaline hydrolysis of dibutyrylchityn: kinetics and selected properties of hydrolysis products’, Fibres Text East Eur, 4 (1996) 76–79.

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73. struszczyk, h., ciechan´ ska, d., wawro, d., ste˛ plewski, w., krucin´ska, i., szosland, l., van de velde, k., kiekens, p., ‘Some properties of dibutyrylchitin fibres’. (2004) Proceedings of 6th International Conference of the European Chitin Society, EUCHIS’04, Poznan´, Poland. 74. szosland, l., cisło, r., krucin´ ska, i., paluch, d., staniszewska-kus´ , j., pielka, s., solski, l., z˙ywicka, b., ‘Dressings made from dibutyrylchitin and chitin accelerating wound healing’, (2002), Proceedings of International Conference MEDTEX’2002, Łódz´, Poland. 75. włochwicz, a., szosland, l., binias, d., szumilewicz, j., ‘Crystalline structure and mechanical properties of wet-spun dibutyrylchitin fibres and products of their alkaline treatment’, J Appl Pol Sci, 94 (2004) 1861–1868. 76. rajendran, s., anand, s.c., ‘Developments in medical textiles’, Text Prog, 32 (2002) 1–37. 77. staniszewska-kus´ , j., paluch, d., szosland, l., kołodziej, j., staniszewskakus´ , j., szymonowicz, m., solski, l., ‘A biological investigation of dibutyrylchitin fibres’, Eng Biomater, II(7–8) (1999) 52–60. 78. paluch, d., pielka, s., szosland, l., staniszewska-kus´ , j., szymonowicz, m., solski, l., z˙ywicka, b., ‘Biological investigation of the regenerated chitin fibres’, Eng Biomater, 12 (2000) 17–22. 79. nah, j.w., jung, t.r., jang, m., jeong, y., ‘Water soluble chitosan nanoparticles for delivering an anticancer agent and preparing method thereof’, Patent application US2006/0013885, January 2006. 80. paluch, d., szosland, l., staniszewska-kus´ , j., solski, l., szymonowicz, m., ge˛ barowska, e., ‘The biological assessment of chitin fibres’, (2000), Polym Med, 30(3–4), 3–31 (Source: Scopus database). 81. szosland, l., krucin´ ska, i., cisło, r., paluch, d., staniszewska-kus´ , j., solski, l., szymonowicz, m., ‘Synthesis of dibutyrylchitin and preparation of new textiles made from dibutyrylchitin and chitin for medical applications’, 2001. Fibres Text East Eur, 9(34) (2001) 54–57. 82. pelka, s., paluch, d., staniszewska-kus´ , j., zywicka, b., solski, l., szosland, l., czarny, a., zaczyn´ ska, e., ‘Wound healing accelerating by a textile dressing containing dibutyrylchitin and chitin’, Fibres Text East Eur, 11 (2003) 79–84. 83. muzzarelli, r.a.a., guerrieri, m., goteri, g., muzzarelli, c., armeni, t., ghiselli, r., cornellisen, m., ‘The biocompatibility of dibutyryl chitin in the context of wound dressings’ Biomaterials, 26 (2005) 5844–5854. 84. chilarski, a., szosland, l., krucin´ ska, i., błasin´ ska, a., cisło, r., ‘Nonwovens made from dibutyrylchitin as novel dressing materials accelerating wound healing’ (2004) Proceedings of 6th International Conference of the European Chitin Society, EUCHIS’04, Poznan´, Poland. 85. chilarski, a., szosland, l., krucinska, i., błasinska, a., cisło, r., ‘The application of chitin derivatives as biological dressing in treatment of thermal and mechanical skin injuries’, Annual Pediatr Traum Surg, Div Pediatr Traum Surg, 8(XXXII) (2004) 58–61. 86. terbojevich, m., cosani, a., ‘Molecular weight determination of chitin and chitosan’, (1997), Chitin handbook 87–101, Muzzarelli R.A.A., Peter M.G. (eds.), European Chitin Society, Ancona, Potsdam. 87. szumilewicz, j., szosland, l., ‘Determination of the absolute molar mass of chitin and dibutyrylchitin by means of size exclusion chromatography coupled

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with light scattering and viscometry’ (2000) Chitin and chitosan, Uragami T., Kurita K. and Fukamizo T. (eds). Kodansha Scientific Ltd., Tokyo, 99–102. Polish Patent P 370755 (2004). krucin´ ska, i., błasin´ ska, a., komisarczyk, a., chrzanowski, m., szosland, l., ‘Nowe materiały włókninowe wytwarzane bezpos´ rednio z roztworu dibutyrylochityny’. Przegla˛ d Włókienniczy, 11 (2003) 3–5. błasin´ ska, a., krucin´ ska, i., chrzanowski, m., ‘Dibutyrylchitin nonwoven biomaterials manufactured using electrospinning method’ (2004) Proceedings of World Textile Conference – 4th AUTEX Conference Roubaix, France. komisarczyk, a., krucin´ ska, i., szosland, l., strzembosz, w., ‘Influence of the rate of air flow onto the structure of nonwovens made from dibutyrylchitin solution’ (2004) Proceedings of International Conference on ‘Magic World of Textiles’, Dubrovnik, Croatia. szymonowicz, m., paluch, d., solski, l., pielka, s., błasin´ ska, a., krucin´ ska, i., szosland, l., ‘Evaluation of the influence of dibutyrylchitin materials for activation of blood coagulation system’, Eng Biomater, 7 (2004) 123–125. wächtershäuser, a., stein, j., ‘Rationale for the luminal provision of butyrate in intestinal diseases’, Eur J Nutr, 39 (200) 164–171. hinnebusch, b.f., meng, s., wu, j.t., archer, s.y, hodin, r.a., ‘The effects of short-chain fatty acids on human colon cancer phenotype are associated with histone hyperacetylation’, J Nutr, 132 (2002) 1012–1017. emenaker, n.j., calaf, g.m., cox, d., basson, m.d., qureshi, n., ‘Short-chain fatty acids inhibit invasive human colon cancer by modulating uPA, TIMP-1, TIMP-2, Bcl-2, Bax, p21 and PCNa protein expression in an in vitro cell culture model’, J Nutr, 131(suppl. 11) (2001) 3041S–3046S. agren, m.s., taplin, c.j., woessner, j.f. jr, eaglestein, w.h., mertz, p.m., ‘Collagenase in wound healing: effect of wound age and type’, J Invest Dermatol, 99 (1992) 709–714. agren, m.s., ‘Gelatinase activity during wound healing’, Br J Dermatol, 131 (1994) 634–640. trengrove, n.j., stacey, m.c., macauley, s., bennett, n., gibson, j., burslem, f., murphy, g., schultz, g., ‘Analysis of the acute and chronic wound environments: the role of proteases and their inhibitors’, Wound Rep Reg, 7 (1999) 442–452. hernick, m., genndios, a., whittington, d.a., rusche, k.m., christanson, d.w., fi erke, c.a., ‘UDP-3-O-R-3-hydroxymyristoyl)-N-acetylglucosamine Deacetylase functions through a general acid-base catalyst pair mechanism’, J Biol Chem, 280(17) (2005) 16969–16978. grant h.s., blair, g., mckay, g., ‘Water-soluble derivatives of chitosan’, Polym Commun, 29 (1988) 342–344. knill, c.j., kennedy, j.f., mistry, j., miraftab, m., smart, g., groocock, m.r., williams, h.j., ‘Alginate fibres modified with unhydrolyzed and hydrolyzed chitosans for wound dressings’, Carbohydr Polym, 55 (2004) 65–76. chen, j.p., chang, g.y., chen, j.k., ‘Electrospun collagen/chitosan nanofibrous membrane as wound dressing’, Colloids Surf A: Physicochem Eng Aspects, 313–314 (2008) 183–188.

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103. zhou, l.j., ono, i., ‘Stimulatory effects of dibutyryl cyclic adenosine monophosphate on cytokine production by keratinocytes and fibroblasts’ Br J Dermatol, 143 (2000) 506–512. 104. schoukens, g., krucinska, i., blasinska, a., chrzanowski, m., szosland, l., kiekens, p., ‘Review of techniques for manufacturing dibutyrylchitin nonwoven biomaterials’ General lecture, 2nd International technical Textiles Congress, Instanbul/Turkey, (2005) July 13–15. 105. schoukens, g., ‘Bioactive materials from butyrylated chitosan’ 11th Annual Seminar and Meeting Ceramics, Cells and Tissues, October 2–5 (2007), Faenza (Italy). 106. schoukens, g., kiekens, p., krucinska, i., ‘New bioactive textile dressing materials from dibutyrylchitin’ 3rd International Technical Textiles Congress, December 1–2 (2007), Istanbul (Turkey).

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6 Advanced textiles for wound compression S. R A J E N DR A N and S. C. A NA N D, University of Bolton, UK

Abstract: The application of compression textiles in managing venous leg ulcers is discussed. The classification of compression bandages, merits and limitations of the current compression therapy regimen, and the research into the development of novel orthopaedic padding and compression bandages are highlighted. The role of compression therapy in the treatment of oedema, varicose veins and deep vein thrombosis (DVT) is outlined. Research and development of a novel single-layer 3D spacer bandage, which replaces the existing multilayer bandage regime, is discussed. Key words: wound, venous leg ulcer, padding bandage, compression bandage, 3D spacer bandage.

6.1

Introduction

It has been predicted that there is a substantial market potential for advanced wound dressings. The woundcare industry generated between US$3.5 and 4.5 billion for the period from 2003 to 2006, mostly from the US and Europe. The European advanced wound management market was valued at US$544.4 million in 2004 and is expected to grow by an average of 12.4% a year to US$1.23 billion in 2010. The forecast for annual growth is between 10 and 15% in 2012. An ageing population creates an increased demand for ulcer treatment. The pressure ulcer treatment accounts for 4% of the National Health Service (NHS) annual budget. The annual cost of treating diabetic foot ulceration accounts for 5% of the total NHS budget. The treatment of venous leg ulcers creates considerable demands upon healthcare professionals throughout the world. The total cost to the NHS for venous leg ulcers treatment is about £650 million per annum, which is 1–2% of the total healthcare expenditure. Costs per patient have recently been estimated to be between £1200 and £1400. In the US, venous leg ulcers affect 3.5% of people over the age of 65 and the estimated annual cost is from $1.9 to $2.5 billion. In the EU, the annual cost for treating patients with venous leg ulcers accounts for 1–2% of the overall healthcare expenditure. In Australia, around 1% of the adult population suffer from venous ulceration. 153

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Venous ulcers are the most common type of chronic leg ulceration. Chronic ulcers are defi ned as those lasting six weeks or more.1 In the UK alone, about 1% of the adult population suffers from active ulceration during their life time.2 Approximately 400 000 patients have the initial symptoms of leg ulcers and 100 000 have open leg ulcers that require treatment. 3 About 80% of patients who have leg ulceration suffer with a venous ulcer. Some patients may have more than one episode of venous ulceration with estimated recurrence rates ranging from 6 to 15%.4 The prevalence of leg ulcers increases with age affecting 1.69% of patients aged between 65 and 95 years. The incidence rate for patients in this age group is estimated at 0.76% for men and 1.42% for women. 5 It has been established that compression therapy, by making use of compression bandages, is an efficient treatment for healing various leg ulcers, despite surgical strategies, electromagnetic therapy and intermittent pneumatic compression.

6.2

Elastic compression bandages

Bandages can be used for many purposes and include retention, support and compression: • Retention bandages are used to retain dressings in the correct position. • Support bandages provide retention and prevent the development of a deformity or change in shape of a mass of tissue due to swelling or sagging. • Compression bandages are employed mainly for the treatment of leg ulcers and varicose veins. Elastomeric compression bandages made with rubber were fi rst used in the late 19th century. However, these have now been replaced by lighter, stronger, more comfortable and washable bandages made from Lycra or other elastane fibres. Modern bandages are either woven or knitted and are designed to provide prescribed levels of compression in accordance with specified performance-based standards (Table 6.1).

Table 6.1 Types of bandages Bandage

Commercial name

Remark

Retention bandage

Slinky®, Stayform ®, K-Band ®, Easifix®, Slinky®, Crinx®, Tensofix® Crepe BP®, Elastocrepe ®

Exerts very little pressure on a limb

Support bandage

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Prevents formation of oedema and supports joints

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155

Table 6.1 Continued Bandage

Commercial name

Compression bandages Light compression (3a)

J-Plus ®, K-Crepe ®

Moderate compression (3b)

Veinopress ®, Granuflex adhesive Compression ® Setopress ®, Tensopress ® Surepress ® Bilastic Forte ®, Blue line webbing ® Zincaband ®, Tarband ®, Quinaband ®, Icthaband ®

High compression (3c) Extra high compression (3d) Paste bandages

Tubular bandages Elasticated Foam padded

6.3

Tubifast®, Tubigrip ® Netelast® Tubipad ®

Remark Exert various pressure, according to the type on a limb Gives sub-bandage pressures of 14– 17 mm Hg at the ankle Sub-bandage pressures 18–24 mm Hg 25–35 mm Hg

Up to 60 mm Hg Woven cotton fabric impregnated with a medicated cream or paste. Used for the treatment of eczema and dermatitis Dressing on awkward sites Provides padding and protection against physical damage

Venous leg ulcers

6.3.1 Venous leg ulcers: problem It is important that the arterial and venous systems should work properly without causing problems to blood circulation around the body. Pure blood flows from the heart to the legs through arteries taking oxygen and food to the muscles, skin and other tissues. Blood then flows back to the heart carrying away waste products through veins. The valves in the veins are unidirectional which means that they allow the venous blood to flow in an upward direction only. If the valves do not work properly or there is not enough pressure in the veins to push back the venous blood towards the heart (chronic venous insufficiency, CVI), the pooling of blood in the veins takes place and this leads to higher pressure on the skin. Because of high pressure and lack of availability of oxygen and food, the skin deteriorates and eventually the ulcer occurs. The high venous pressure causes oedema followed by tissue breakdown. The initial indications of venous leg ulcers

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are oedema, swollen veins (varicose veins), stasis eczema, fibrosis, lipodermatosclerosis, atrophie blanche, ankle flare and blood clots in veins (deep vein thrombosis, DVT). DVT is a growing problem for passengers on longhaul fl ights. DVT blocks blood from flowing towards the heart. Venous ulcers appear in the gaiter area of the lower limb between the ankle and mid-calf. They can vary in size ranging from very small to large ulcers that extend beyond the gaiter area. The wound is characteristically shallow, irregular in shape, and has sloping well-defi ned borders. Typically, the skin surrounding the wound is thickened and hyperpigmented indicating lipodermatosclerosis.6 With chronic ulcers a yellow– white exudate is observed signifying the presence of slough. A shiny appearance indicates a fibrinous base, which inhibits new tissue formation and wound healing. Varicose veins and ankle oedema often accompany a venous ulcer.7 Approximately 80% of patients who have a venous leg ulcer suffer from some form of discomfort, while 20% experience severe or unremitting pain. 8

6.3.2 Diagnosis of venous leg ulcers The diagnosis of lower limb ulceration must start by determining the patient’s full clinical history together with a physical examination of the condition. It is essential to identify possible risk factors that could cause ulceration or impact on the treatment of the ulcer. These risk factors could include arterial disease, trauma and malignancy.9 A number of non-invasive test methods are available to the clinician for investigating the cause of leg ulceration and venous insufficiency. These test methods help to assess the arterial and venous circulation of the patient and can provide information on the location of blood reflux or an obstruction within the veins. Doppler ultrasonography Doppler ultrasonography is used to measure the ankle-to-brachial blood pressure index (ABPI) of the patient. The ultrasound technique produces a signal that identifies the presence of blood flow within the arteries. The ABPI is obtained by measuring the systolic blood pressure within the dorsalis pedis or posterior tibial artery of the lower limb and the ipsilateral brachial artery of the arm.10 The ratio between the ankle systolic pressure and the brachial systolic pressure provides the ABPI value. Measurement of the ABPI is important in order to exclude arterial disease as the cause of ulceration or as a possible risk factor that might inhibit treatment. An ABPI of >0.80 leads to diagnosis of a venous leg ulcer, whereas patients with the ABPI of <0.92 indicates the presence of arterial disease.11 An

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index of about 0.8 or below is generally considered indicative of significant arterial disease. These patients should be excluded from high-compression bandage therapy since its use could lead to further ulcer complications or even limb amputation.12 The Doppler ultrasonic measurement technique produces elevated readings when diagnosing patients that may have diabetes and other conditions with calcified arteries.13 Ultrasound scanning Colour duplex ultrasound scanning is currently the technique of choice in order to assess the venous system of the lower limb. The technique combines ultrasound imaging with pulsated Doppler ultrasound and provides detailed anatomic information of the superficial, deep, and perforating venous systems. It can identify specific veins in which blood reflux occurs or obstructions which may be contributing to venous hypertension. Photoplethysmography and air plethysmography Photoplethysmography and air plethysmography are simple tests designed to evaluate calf muscle dysfunction and degree of venous reflux. The techniques are used to observe the change in blood volume within the lower limb before and after exercise. Application of a tourniquet to restrict blood flow within the superficial system allows the deep venous system to be assessed for a potential obstruction. Invasive venous tests such as ascending and descending phlebography are also used to assess venous insufficiency. Phlebography combines electromagnetic radiation (X-rays) and fluorescent materials to provide a technique that allows the veins to be clearly visualised. These immunofluorescence methods can detect venous outflow obstructions, provide information of valvular incompetence, and also highlight the presence of pericapillary fibrin.14 Phlebography is usually used before a patient undergoes valvular surgery.

6.4

Venous leg ulcer treatment

It should be stated that venous leg ulcers are chronic and there is no medication to cure the disease other than the compression therapy. A sustained graduated compression mainly enhances the flow of blood back to the heart, improves the functioning of valves and calf muscle pumps, reduces oedema and prevents the swelling of veins. Mostly elderly people are prone to develop DVT, varicose veins and venous leg ulcers. Venous leg ulcers are the most frequently occurring type of chronic wound accounting for 80 to 90% of all lower extremity ulceration and compression remains the

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mainstay of treatment.15 Compression treatment has been extensively covered in a Cochrane review.16

6.4.1 Compression bandages Compression bandaging is the ‘Gold standard’ for managing venous leg ulceration and treating the underlying venous insufficiency.17 The main function of a compression bandage is to exert external pressure onto the leg, and this is determined by its elastic properties. A recent study investigated the degree of pressure required to narrow and occlude the superficial and deep veins of the calf when a subject is in different body positions. For compression therapy to be effective, it has to exceed the hydrostatic pressure within the veins in order to narrow the vessels and achieve a subsequent increase in blood flow. Initial narrowing of the veins occurred at a pressure of 30–40 mm Hg in both the sitting and standing positions and complete occlusion occurred at 20–25 mm Hg (supine position), 50–60 mm Hg (sitting position), and at 70 mm Hg (standing position).18 In a further study, Partsch19 compared the different haemodynamic effects that are achieved when using compression stockings and compression bandages. The study concluded that compression stockings which exert external pressures of up to 40 mm Hg are effective in increasing blood flow velocity (supine position), and reducing oedema after extended periods of sitting and standing. In addition, short-stretch and multi-layered compression bandages which exert pressures of over 40 mm Hg reduce venous hypertension during walking and improve the venous pumping function. Classification Compression bandages are mainly classified as elastic and non-elastic. Elastic compression bandages (Table 6.2) are categorised according to the level of pressure generated on the angle of an average leg. Class 3a bandages provide light compression of 14–17 mm Hg, moderate compression (18–24 mm Hg) is imparted by class 3b bandages, and 3c type bandages impart high compression between 25 and 35 mm Hg.20 The 3d type extrahigh-compression bandages (up to 60 mm Hg) are not often used because the very high pressure generated will reduce the blood supply to the skin. It must be stated that approximately 30–40 mm Hg at the ankle which reduces to 15–20 mm Hg at the calf is generally adequate for healing most types of venous leg ulcers. 21 Compression stockings provide support to treat DVT and varicose veins, and to prevent venous leg ulcers. They are classified as light support (Class 1), medium support (Class 2) and strong support (Class 3). 22

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Table 6.2 Elastic Bandage Classification Class

Bandage type

Bandage function

1

Lightweight conforming

2

Light support

3a

Light compression

3b

Moderate compression

3c

High compression

3d

Extra high compression

Apply very low levels of sub-bandage pressure and are used to hold dressings in place Apply moderate sub-bandage pressure and are used to prevent oedema or for the treatment of mixed aetiology ulcers Exert a pressure range of 14–17 mm Hg at the ankle Exert a pressure range of 18–24 mm Hg at the ankle Exert a pressure range of 25–35 mm Hg at the ankle Exert a pressure of up to 60 mm Hg at the ankle

Compression hosiery Elastic stockings are used for the treatment of DVT which is associated with a risk of pulmonary embolism and post thrombotic syndrome (PTS). 23 The recent introduction of two-layered high-compression hosiery kits may have provided an alternative solution for the treatment of venous ulceration since they are easier and safer to apply than traditional compression bandages and improve patient concordance. 24 The hosiery kits consist of two knee-high garments; a light compression (10 mm Hg) understocking and a Class 3 compression-hosiery overstocking providing 25–35 mm Hg. The understocking is applied on to the leg fi rst and owing to its smooth surface allows the overstocking to slip over it for ease of application. Compression stockings (antiembolism stockings) are the most commonly available and accepted methods for DVT treatment. Compression hosiery contains elastomeric yarns that are capable of recovering their size and shape after extension giving similar performance properties to long-stretch compression bandages. There are three classification Standards for graduated compression hosiery: the British Standard, 25 French Standard, 26 and German Standard. 27 Attempts were made to produce a European Standard (draft ENV 12718:2001) but consensus could not be achieved and consequently the Standard was cancelled. 28 The above Standards generally classify compression hosiery according to the level of pressure exerted around the ankle (Table 6.3).25–27 Patients are advised to wear elastic stockings every day after the ulcer has healed in order to prevent recurrence. 29 However, in everyday practice

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Table 6.3 European Classification of Compression Hosiery Class

Support

British Standard BS 6612:1985

French Standard ASQUAL

German Standard RAL-GZ 387:2000

1 2 3 4

Light Medium Strong Heavy

14–17 mm Hg 18–24 mm Hg 25–35 mm Hg Not reported

10–15 mm Hg 15–20 mm Hg 20–36 mm Hg >36 mm Hg

18–21 mm Hg 23–32 mm Hg 34–46 mm Hg >49 mm Hg

patients are reluctant to wear compression hosiery on a long-term basis. 30 A systematic review concluded that there is circumstantial evidence to suggest that compression hosiery does reduce ulcer recurrence but there is no strong evidence to support this. In addition, high-compression stockings may be more effective than moderate compression in preventing ulcer recurrence. 31 Compression system Compression can be exerted to the leg either by a single-layer bandage or multilayer bandages. In the UK, a four-layer bandaging system is widely used whilst in Europe and Australia the non-elastic two-layer short stretch bandage regime is the standard treatment. A typical four-layer compression bandage system comprises of padding bandage, crepe bandage, highcompression bandage and cohesive bandage. Both the two layer and four layer systems require padding bandage (wadding or orthopaedic wool) that is applied next to the skin and underneath the short stretch or compression bandages. A plaster type non-elastic bandage, Unna’s boot is favoured in the USA. However, compression would be achieved by three-layer dressing that consists of Unna’s boot, continuous gauze dressing, followed by an outer layer of elastic wrap. It should be realised that Unna’s boot, being rigid, is uncomfortable to wear and medical professionals are unable to monitor the ulcer after the boot is applied. Unna’s Boot provides a high working pressure when the calf muscle contracts, but very little pressure while the patient is at rest. 32 The high working pressure serves to increase blood flow, while the low resting pressure facilitates deep venous fi lling. The Unna’s Boot is only effective in ambulatory patients and requires constant re-application as leg volume decreases owing to a reduction in oedema. Used widely in the USA, the Unna’s Boot system is uncomfortable to wear because of its rigidity and is both expensive and difficult to apply.

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A multi-centre study compared the venous ulcer healing rates between Unna’s Boot and CircAid® in 38 patients. 33 The time to heal for the Unna’s Boot group of patients was 9.69 ± 3.28 weeks in comparison to the CircAid® device group which was 7.98 ± 4.41 weeks. The study data supported a trend towards more rapid ulcer healing in the CircAid® device group but the results did not reach statistical significance owing to the small number of patients studied. Short-stretch bandages function in a similar manner to the rigid/inelastic Unna’s Boot. They consist of 100% high twisted cotton yarns and are applied onto the limb at full extension. Unlike elastic bandages, short-stretch bandages fi rmly hold the calf thereby providing a high working pressure when the patient walks. 34

6.4.2 Padding bandages (orthopaedic wool or wadding) Padding bandages play a significant role in the successful treatment of venous leg ulcers. A variety of padding bandages are used beneath the compression bandage system as padding layers in order to evenly distribute pressure and give protection. They absorb high pressure created at the tibia and fibula regions. It will be noticed that the structure of a padding bandage is regarded as an important factor in producing a uniform pressure distribution. Research has shown that the majority of the commercially available bandages do not provide uniform pressure distribution. 35,36 A padding at least 2.5 cm thick is placed between the limb and the compression bandage to distribute the pressure evenly at the ankle as well as the calf region. Wadding helps to protect the vulnerable areas of the leg from the high compression levels required along the rest of the leg. 37 Padding can also be used to reshape legs which are not narrower at the ankle than the calf. It makes the limb more like a cone-shape so that the pressure is distributed over a pressure gradient with more pressure at the foot and less at the leg. Generally, the longer a compression bandage system is to remain in place, the greater is the amount of padding needed. An ideal padding bandage should be: • lightweight and easy to handle; • soft and impart cushioning effect to the limb; • capable of preventing tissue damage; • capable of distributing pressure evenly around the leg; • a good absorbent and have good wicking properties; • comfortable and should not produce irritation or any allergic reaction to the skin on prolonged contact; • easily tearable by hand; and • cheap.

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6.4.3 Ideal compression bandages It should be noted that compression bandages may be harmful if not applied properly. They provide high tension as well as high pressure. A thorough assessment involving several criteria is therefore essential before applying a compression bandage on a limb. For example, it is important to consider the magnitude of the pressure, the distribution of the pressure, the duration of the pressure, the radius of the limb and the number of bandage layers. The ability of a bandage to provide compression is determined by its construction and the tensile force generated in the elastomeric fibres when extended. Compression can be calculated by Laplace’s Law, which states that the sub-bandage pressure is directly proportional to the bandage tension during application and the number of layers applied but inversely proportional to limb radius. 38 Sub-bandage pressure is a function of the tension induced into the compression bandage during application. Applying the bandage with a 50% overlap effectively produces two layers, which generates twice the pressure. When a compression bandage is applied at a constant tension on a limb of increasing circumference, it will produce a sub-bandage pressure gradient with the highest pressure exerted on the ankle. The sub-bandage pressure will increase for people with smaller ankles. The ability of a bandage to maintain sub-bandage pressure is determined by the elastomeric properties of the yarns, the fabric structure, as well as the fi nishing treatments applied to the fabric. The structure of a compression bandage is regarded as an important factor in producing a uniform pressure distribution. An ideal compression bandage should: • provide compression appropriate for the individual; • provide pressure evenly distributed over the anatomical contours; • provide a gradient pressure diminishing from the angle to the upper calf; • maintain pressure and remain in position until the next change of dressing; • extend from the base of the toes to the tibial tuberosity without gap; • function in a complimentary way with the dressing; and • possess non-irritant and non-allergenic properties.

6.4.4 Ideal bandage pressure Compression bandages are mostly used during the initial therapy phase where the aim of treatment is to reduce oedema and overcome venous insufficiency. A number of different types of compression bandage systems are commercially available and, as discussed, the bandages are classified as either rigid/inelastic, short-stretch, long-stretch, or multilayered. The type of fabric construction influences the degree of extensibility that the bandage

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will have. At some point, the bandage will not be able to extend or stretch any further (lock-out) under a predetermined tension. Evidence suggests that a sub-bandage pressure of 35–40 mm Hg at the ankle, which gradually reduces to 17–20 mm Hg at the knee, is required to overcome venous hypertension and successfully treat venous leg ulcers. 39 A recent study investigated the degree of pressure that is required to narrow and occlude leg veins when a subject is in different body positions. The authors found that initial narrowing of the veins occurred at a pressure of 30–40 mm Hg in both the sitting and standing positions. Complete occlusion of the superficial and deep leg veins occurred at 20–25 mm Hg (supine position), 50–60 mm Hg (sitting position), and at 70 mm Hg (standing position).18

6.5

Applications of bandages

The elastic properties of the bandages help to provide a high recoiling force, which serves to increase venous flow and reduce venous hypertension. In addition, they conform easily around the lower limb and allow for frequent dressing changes. Skill is required to apply compression bandages at the correct tension and to avoid excessive sub-bandage pressures.40 Application of high sub-bandage pressure on patients with any type of micro-vascular disease can lead to further occlusion and pressure necrosis of these vessels.41 Some manufacturers supply compression bandages with a series of geometric markers printed onto the bandage surface. The markers assist in the application of a predetermined level of compression by visually distorting when the bandage is stretched to a specific tension. For example, printed rectangles become squares when the correct bandage tension is reached. In a multilayer bandaging system, three or four layers of different types of bandage are used to provide external compression. A multilayer system may include a combination of nonwoven padding bandage, inelastic creep bandage, elastic compression bandages and cohesive (adhesive) bandage. The different properties of each bandage type contribute to the overall effectiveness of the bandage system. The elastic bandage component provides sustained compression while the cohesive bandage offers rigidity thereby enhancing calf muscle pump function. The four-layer high compression system developed by a clinical group at Charing Cross Hospital (London) has gained wide acceptance for use in UK hospitals. The fourlayer system was developed specifically to incorporate different bandage types and properties in order to overcome the clinical issues of exudate, protection of bony prominences, and the ability to sustain sub-bandage pressure over a period of time.42 In addition, the system was designed to apply the required 40 mm Hg of pressure at the ankle, overcome disproportionate limb size and shape, and to remain in position on the leg without

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slippage. Application of the four-layer system involves fi rst applying a padding bandage layer from the base of the toes to just below the knee. A crepe bandage is applied next followed by an elastic compression bandage. Finally, a cohesive layer is applied in order to add durability and to complete the overall pressure profi le. Examples of different types of compression bandages, cohesive bandages, padding bandages, and multilayer compression systems are shown in Table 6.4. A multilayer high compression bandage system has been shown to provide a safe and effective treatment option for uncomplicated venous leg ulcers. Ulcer healing rates of up to 70% at twelve weeks have been obtained.43 The four-layer bandaging technique has been shown to heal chronic ulcers that have failed to respond with traditional adhesive plaster bandage systems.44 A recent review on compression therapy for venous leg ulcers concluded that a multilayer compression system is more effective than low compression or single-layer compression.45 Table 6.4 Illustration of bandages used in compression therapy Bandage name

Function

Manufacturer

Tensopress Setopress SurePress Adva-co Dauerbinde K Silkolan Tensolan Comprilan Actiban Actico (Cohesive) Rosidal K Co-Plus Tensoplus Coban Surepress Soffban K-soft Softexe Advasoft Flexi-ban Cellona Ultra-soft Ortho-band Formflex Profore Proguide Ultra Four System 4 K-four

Type 3c long stretch bandage Type 3c long stretch bandage Type 3c long stretch bandage Type 3c long stretch bandage Long stretch bandage Type 2 short stretch bandage Type 2 short stretch bandage Type 2 short stretch bandage Type 2 short stretch bandage Type 2 short stretch bandage Type 2 short stretch bandage Cohesive bandage Cohesive bandage Cohesive bandage Padding bandage Padding bandage Padding bandage Padding bandage Padding bandage Padding bandage Padding bandage Padding bandage Padding bandage Padding bandage Multilayer compression system Multilayer compression system Multilayer compression system Multilayer compression system Multilayer compression system

Smith + Nephew Medlock Medical ConvaTec Advancis Medical Lohmann + Rauscher Urgo Limited Smith + Nephew Smith + Nephew Activa Healthcare Activa Healthcare Lohmann + Rauscher Smith + Nephew Smith + Nephew 3M ConvaTec Smith + Nephew Urgo Limited Medlock Medical Advancis Medical Activa Healthcare Lohmann + Rauscher Robinsons Healthcare Millpledge Healthcare Lantor (UK) Limited Smith + Nephew Smith + Nephew Robinsons Healthcare Medlock Medical Urgo Limited

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6.6

165

Present problems and novel bandages

During the past few years, there have been increasing concerns relating to the performance of bandages especially pressure distribution properties for the treatment of venous leg ulcers. This is because compression therapy is a complex system and requires two or multilayer bandages, and the performance properties of each layer differ from those of other layers. The widely accepted sustained graduated compression mainly depends on the uniform pressure distribution of different layers of bandages in which textile fibres and bandage structure play a major role. The padding bandages commercially available are nonwovens that are mainly used to distribute the pressure, exerted by the short stretch or compression bandages, evenly around the leg. Otherwise higher pressure at any one point not only damages the venous system but also promotes arterial disease. Therefore, there is a need to distribute the pressure equally and uniformly at all points of the lower limb and this can be achieved by applying an effective padding layer around the leg beneath the compression bandage. In addition, padding bandages should be capable of absorbing the high pressure created at the tibia and fibula regions. Wadding also helps to protect the vulnerable areas of the leg from generating extremely high pressure levels as compared with those required along the rest of the leg. The research carried out at the University of Bolton involving 10 most commonly used commercial padding bandages produced by major medical companies showed that there are significant variations in properties of commercial padding bandages, 35,36 more importantly the commercial bandages do not distribute the pressure evenly at the ankle as well as the calf region (Fig. 6.1). In addition, the integrity of the non-woven bandages is also of great concern. When pres60.00

Measured pressure (mm Hg)

50.00

PB1 PB2 PB3 PB4 PB5 PB6 PB7 PB8 PB9 PB10

40.00

30.00

20.00

10.00

0.00

2.93 5.86 8.79 11.72 14.6517.58 20.5123.4426.3729.22 32.1535.08 38.0140.9443.8746.8049.73 52.6655.6658.5259.99

Applied pressure (mm Hg)

6.1 Pressure distribution of commercial padding bandages.

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sure is applied using compression bandages, the structure of the non-woven bandages may collapse and the bandage would not impart a cushioning effect to the limb. Comfort and a cushioning effect are considered to be essential properties for padding bandages because they stay on the limb for several days. Twelve padding bandages, which consisted of single-component fibres, binary blends and tertiary blends incorporating polyester, bicomponent fibres and natural fibres such as cotton and viscose, have been designed and developed at the University of Bolton (Table 6.5). The salient properties of the developed bandages are: • all the developed padding bandages possess suitable bulkiness; • none of the bandages has lower tensile strength or breaking extension that hinders its performance characteristics as an ideal padding bandage; • the tear resistance of bandages, except 100% hollow viscose (NPB5) is high and this means that the bandage cannot be easily torn by hand after wrapping around the leg. However, making perforations at regular intervals across the bandage facilitates easy tearing; • the absorption of solution containing Na + and Ca2+ ions (artificial blood) is significantly high, irrespective of fibre type and structure; • the rate of absorption of all the developed bandages is also high; and • the pressure distribution of all the novel bandages is good up to 60 mm Hg (Fig. 6.2). In the UK, multilayer compression systems are recommended for the treatment of venous leg ulcers.46 Although multilayer compression bandages are more effective than single-layer bandages in healing venous leg ulcers,45 it is generally agreed by clinicians that multilayer bandages are too bulky for patients and the cost involved is high. A wide range of compression bandages is available for the treatment of leg ulcers but each of them has a different structure and properties and this influences the variation in performance properties of bandages. In addition, long stretch compression bandages tend to expand when the calf muscle pump is exercised, and the beneficial effect of the calf muscle pump is dissipated. It is a wellestablished practice that elastic compression bandages that extend up to 200% are applied at 50% extension and at 50% overlap to achieve the desired pressure on the limb. It has always been a problem for nurses to exactly stretch the bandages at 50% and apply without losing the stretch from ankle to calf, although there are indicators for the desired stretch (rectangles become squares) in the bandages. Elastic compression bandages are classified into four groups (Table 6.3) according to their ability to produce predetermined levels of compression and it has always been a problem to select the right compression bandage for the treatment. The

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Table 6.5 Novel padding bandages Identification code

Product

Fibre type

Fibre dtex; length (mm)

Blend ratio (%)

Structure

NPB1 NPB2 NPB3 NPB4 NPB5 NPB6 NPB7 NPB8 NPB9 NPB10

Single component Single component Single component Single component Single component Single component Binary blends Binary blends Binary blends Binary blends

Polyester Polyester (bleached) Hollow polyester Viscose Hollow viscose Lyocell Polyester/viscose Polyester/viscose Polyester/viscose Polyolefin/viscose

3.3;40 5.3;60 3.3;50 3.3;40 3.3;40 3.3;38 3.3;40/3.3;40 3.3;40/3.3;40 3.3;40/3.3;40 2.2;40/3.3;40

100 100 100 100 100 100 75 : 25 50 : 50 25 : 75 20 : 80

NPB11

Tertiary blends

3.3;40/3.3;40/1.8;22

33 : 33 : 33

NPB12

Tertiary blends

Polyester/viscose/cotton (bleached) Polyester/viscose/polyolefin

Needlepunched (both sides) Needlepunched (both sides) Needlepunched (both sides) Needlepunched (both sides) Needlepunched (both sides) Needlepunched (both sides) Needlepunched (both sides) Needlepunched (both sides) Needlepunched (both sides) Needlepunched (both sides) and thermal bonded Needlepunched (both sides)

3.3;40/3.3;40/2.2;40

60 : 25 : 15

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Measured pressure (mm Hg)

60.00

50.00

NPB1 NPB2 NPB3

40.00

NPB4 NPB5 NPB6

30.00

NPB7 NPB8 NPB9

20.00

NPB10 NPB11 NPB12

10.00

0.00 2.93 5.86 8.79 11.72 14.6517.58 20.5123.44 26.37 29.2232.1535.08 38.0140.9443.8746.8049.7352.6655.6658.5259.99

Applied pressure (mm Hg)

6.2 Pressure distribution of novel padding bandages.

inelastic short stretch bandage (Type 2) system, which has started to appear in the UK market, has the advantage of applying at full stretch (up to 90% extension) around the limb. Short stretch bandages do not expand when the calf muscle pump is exercised and the force of the muscle is directed back into the leg which promotes venous return. The limitations of short stretch bandages are that a small increase in the volume of the leg will result in a large increase in compression and this means the bandage provides high compression in the upright position and little or no compression in the recumbent position when it is not required. During walking and other exercises the sub-bandage pressure rises steeply and while at rest the pressure comparatively drops. Therefore, patients must be mobile to achieve effective compression and exercise is a vital part of this form of compression. Moreover, the compression bandage is not in contact with the skin when there is a reduction in limb swelling because the short stretch bandage is inelastic, and it has already been stretched to its full. The application of a multilayer bandage system requires expertise and knowledge. Nurses must undergo significant practice-based training in order to develop appropriate bandage application skills needed for multilayer compression system. Successful bandaging relies upon adopting good technique in both stretching the bandage to the correct tension and ensuring proper overlap between layers. In addition, nurses need to have knowledge of the different performance properties of each bandage within the multilayer system, and how the performance each bandage combines is to achieve safe and adequate compression. The ability of multilayer bandage systems to maintain adequate compression levels for up to one week has

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reduced the necessity for frequent dressing changes and has therefore, decreased treatment costs. However, the cost of a multilayer compression system is still relatively high owing to the requirement for a specific bandage for each layer. Tolerance to multilayer compression system is generally good but non-compliance in some patients often results in prolonged or ineffective treatment. Some patients are unable to wear footwear due to the bulkiness of multilayer compression regime. These patients often refuse treatment since the requirement to remain house-bound is totally unacceptable. At night patients fi nd compression bandages too uncomfortable and often remove them in order to sleep. Since the application of multilayer compression systems is complex most patients are unable to re-apply the bandages themselves. In order to address some of the problems mentioned above, a novel nonwoven vari-stretch compression bandages (NVCB) has been designed and developed at the University of Bolton. The principal features of the NVCB are: 47,48 • novel non-woven technology was used to develop the variable compression bandages. It should be mentioned that no non-woven compression bandages are listed in Drug Tariff. In the UK, the availability of wound dressings and bandages for use in patients’ homes is dictated by the Drug Tariff; • the performance and properties of the novel bandages are superior to existing multilayer commercial compression bandages. This fulfi ls the requirement of ideal variable pressure from ankle to below knee positions of the limb for the treatment of venous leg ulcers; and • vari-stretch non-woven bandages also meet the standards and the tolerances stipulated by BS 7505.

6.7

Three-dimensional spacer compression bandages

Recently, spacer technology has been increasingly used to produce threedimensional materials for technical textiles sectors such as the automotive, medical, sports and industrial market. The spacer technology is flexible, versatile, cost effective and an ideal route to produce 3D materials for medical use. It is identified that spacer is the right technology to produce novel compression bandages that meet the prerequisites of both ideal padding and compression bandages. The main reasons for the current interest in 3D spacer fabrics for producing novel compression bandages are several-fold. In 3D spacer fabrics, two separate fabric layers are combined with an inner spacer yarn or yarns using either the warp knitting or weft knitting route (Fig. 6.3). The two layers can be produced from different fibre types such as polyester, polyamide, polypropylene, cotton, viscose,

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6.3 A spacer structure.

lyocell and wool and can have completely different structures.49 It is also possible to produce low modulus spacer fabrics by making use of elastic yarns. Elastic compression could be achieved by altering the fabric structure. It should be mentioned that 3D structure allows greater control over elasticity and these structures can be engineered to be uni-directional, bi-directional and multi-directional. Uni-directional elasticity is one of the desired properties for compression bandages. The three-dimensional nature of spacer fabrics makes them ideal for application next to the skin because they have desirable properties that are ideal for the human body. 50 The 3D fabrics are soft, have good resilience that provides a cushioning effect to the body, are breathable, and are able to control heat and moisture transfer.49 For venous leg ulcer applications, such attributes, together with improved elasticity and recovery, promote faster healing. It must be stated that 3D spacer fabrics can also be produced using double-jersey weft knitting machines.49 The main advantages of weft-knitted spacer fabrics over warp-knitted fabrics include cost effectiveness because there is no need to prepare a number of warp beams and spun yarns, and coarser count hairy yarns can be used on weft-knitting machines. Because of the problems associated with the currently available bandages for the treatment of venous leg ulcers as discussed in section 6.6, it is vital to research and develop an alternative bandaging regime that meets all the requirements of an ideal compression system. The research and development programme currently in progress at the University of Bolton has the ultimate aim of developing a single-layer compression-therapy regime for the treatment of venous leg ulcers. The research programme imposes significant challenge in developing 3D spacer

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bandages for compression therapy. There is no doubt that there would be substantial savings for the NHS in the UK and other health services in the world because the ultimate goal of the research programme is to replace the multilayer bandages with a single-layer bandage. A single-layer system simplifies and standardises the application of compression, is more patient friendly, reduces the nursing time, and significantly decreases the treatment cost.

6.7.1

Effect of pressure transference of spacer bandages

Four spacer fabrics identified as black (1), white (2), white (3) and blue (4) were used to study the pressure transference at various pressure ranges. Four padding bandages (PB1a to PB4a) recently available at Drug Tariff were also used for comparison. Pressure transference apparatus and an extension test rig were used to study the pressure transference of spacer bandages both at unrestrained and stretch conditions. It can be observed in Fig. 6.4 that the pressure transference of different spacer bandages at any one point varies, and it mainly depends on the structure and fibre content of the material. It is interesting to note that spacer bandages distributed the applied pressure more uniformly around the leg than did commercial padding bandages (Fig. 6.5). For instance, the white (2) spacer bandage absorbed an applied pressure of 43.9 mm Hg and a pressure of transfer 2 mm Hg at one point. In other words, the absorbed pressure of 41.9 mm Hg is uniformly

Measured pressure (mm Hg)

12.00 10.00 8.00 Black (1) White (2) White (3) Blue (4)

6.00 4.00 2.00 0.00

7.3

14.6

21.9 29.3 36.6 43.9 Applied pressure (mm Hg)

51.2

58.6

6.4 Pressure transference of spacer bandages (relaxed).

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60

Measured pressure (mm Hg)

50

40

30

PB1a PB2a PB3a PB4a

20

10

0

0 2.94 5.9 8.81 11.8 14.7 17.6 20.6 23.5 26.4 29.3 32.2 35.2 38.1 41.1 44 46.9 49.9 52.8 55.7 58.6 60.1

Applied pressure (mm Hg)

6.5 Pressure transference of commercial padding bandages.

distributed inside the fabric structure which is one of the essential requirements for venous leg ulcer treatment. On the other hand, the commercial padding bandage (PB4a) absorbed 43.9 mm Hg and transferred 35 mm Hg at one point (Fig. 6.5) and this means the bandage distributed only 8.9 mm Hg uniformly inside the structure. The higher output pressure from the bandage at one point is undesirable and may slow down and/or block the blood flow in arteries. Figures 6.6 to 6.9 represent the pressure transference of spacer bandages at known pressures under extension up to 120%. It is noticed that an increase in applied pressure does not influence the pressure transference at any one point and the variation is marginal in all the samples. This affi rms that these spacer fabrics can be used as ideal padding bandages and, by controlling the tension, it will be possible to generate the required pressure for the treatment of venous leg ulcers. As discussed in section 6.4.3, the pressure generated on the limb by a bandage is directly proportional to the tension of the bandage and the number of layers but inversely proportional to the width of the bandage and the circumference of the limb. This Laplace’s concept is being applied in the research and development programme into the mathematical modelling of spacer bandages to achieve the required pressure mapping for the treatment of venous leg ulcers at the University of Bolton.

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7.00

Pressure transference (mm Hg)

6.00 5.00 4.00 7.3 (mm Hg) 14.6 (mm Hg) 21.9 (mm Hg) 29.3 (mm Hg) 36.6 (mm Hg) 43.9 (mm Hg) 51.2 (mm Hg) 58.6 (mm Hg)

3.00 2.00 1.00 0.00

0

10

20

30

40

50

60

70

80

90

100

110 120

Fabric extension (%)

6.6 Effect of extension on pressure transference of spacer bandages – black (1).

4.50

Pressure transference (mm Hg)

4.00 3.50 3.00 2.50

7.3 (mm Hg) 14.6 (mm Hg) 21.9 (mm Hg) 29.3 (mm Hg) 36.6 (mm Hg) 43.9 (mm Hg) 51.2 (mm Hg) 58.6 (mm Hg)

2.00 1.50 1.00 0.50 0.00

0

10

20

30

40

50

60

70

80

90

100

Fabric extension (%)

6.7 Effect of extension on pressure transference of spacer bandages – white (2).

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Pressure transference (mm Hg)

6.00 5.00 7.3 (mm Hg) 14.6 (mm Hg) 21.9 (mm Hg) 29.3 (mm Hg) 36.6 (mm Hg) 43.9 (mm Hg) 51.2 (mm Hg) 58.6 (mm Hg)

4.00 3.00 2.00 1.00 0.00

0

10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 Fabric extension (%)

6.8 Effect of extension on pressure transference of spacer bandages – white (3).

10.00

Pressure transference (mm Hg)

9.00 8.00 7.00 6.00 7.3 (mm Hg) 14.6 (mm Hg) 21.9 (mm Hg) 29.3 (mm Hg) 36.6 (mm Hg) 43.9 (mm Hg) 51.2 (mm Hg) 58.6 (mm Hg)

5.00 4.00 3.00 2.00 1.00 0.00

0

10

20

30

40

50

60

70

80

90

Fabric extension (%)

6.9 Effect of extension on pressure transference of spacer bandages – blue (4).

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175

Conclusions

Compression-delivery systems have an important role in the treatment of venous leg ulceration since they can reduce venous reflux, increase venous and arterial blood flow, improve microcirculation, and reduce ankle oedema. There is a variety of compression bandaging systems available, the advantages and disadvantages of each are constantly reviewed and debated. In the UK, for example, a four-layer bandaging system is popular and has been shown to provide a safe and effective treatment option. Other countries, such as the USA, prefer the rigid characteristics of the Unna’s Boot. The success of any compression bandage system relies upon the skill and expertise of the clinician applying it. Moreover, the effective management of venous leg ulcer involves careful selection of bandages to reverse the venous blood flow back to the heart. The contribution of padding as well as compression bandages in healing the ulcer is significant. The advantages and limitations of the existing two-layer and four-layer bandaging regimens have been discussed. It is obvious that the pressure transference of commercial padding bandages varied and none of the padding bandages investigated satisfied the requirements of an ideal padding bandage. On the other hand, the novel padding bandages exhibited a uniform pressure distribution around the leg. The paper also demonstrated the need for developing a single-layer bandaging regime for the benefit of the elderly and to cut the cost of treatment. The use of 3D spacer technology has been investigated and the results affirmed that spacer bandages would be utilised to design and develop a single-layer system that could replace the currently used cumbersome four-layer system. A suitable spacer structure can combine the desirable attributes of both the padding and two-dimensional compression bandages into one composite three-dimensional structure.

6.9

References

1. reichenburg, j., davis, m. Venous Ulcers. Semin Cutan Med Surg 2005; 24(4): 216–226. 2. martson, w.a., carlin, r.e., passman, m.a., farber, m.a., keagy, b.a., parent iii, f.n. Healing rates and cost efficacy of outpatient compression treatment for leg ulcers associated with venous insufficiency. J Vasc Surg 1999; 30(3): 491–498. 3. sarkar, p.k., ballentyne, s. Management of leg ulcers. Postgrad Med J 2000; 76: 674–682. 4. nicholaides, a.n. Investigation of chronic venous insufficiency: a consensus statement (France, March 5–9, 1997). Circulation 2000; 102(20): E126– E163.

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5. margolis, d.j., bilker, w., santanna, j., baumgarten, m. Venous leg ulcer: incidence and prevalence in the elderly. J Am Acad Dermatol 2002; 46(3): 381–386. 6. naschitz, j.e., yeshurun, d., misselevich i., boss j.h. The pathogenesis of lipodermatosclerosis: facts, uncertainties and theories. J Eur Acad Dermatol Venereol 1997; 9(3): 209–214. 7. zimmet, s.e. Venous leg ulcers: modern evaluation and management. Dermatol Surg 1999; 25(3): 236–241. 8. franks, p.j., moffatt, c.j., bosanquet, n., oldroyd, m., greenhalgh, r.m., mccollum, c.n. connolly, m. Community leg ulcer clinics: effect on quality of life. Phlebology 1994; 9(2): 83–86. 9. london, n.j.l., donnelly, r. Ulcerated lower limb. BMJ 2000; 320: 1589–1591. 10. sibbald, r.g. Venous leg ulcers. Ostomy Wound Manage 1998; 44(9): 52–64. 11. sumner, d.s. Non-invasive assessment of peripheral arterial occlusive disease. In: Rutherford, K.S, editor. Vascular Surgery (3rd edition) Philadelphia: WB Saunders, 1998; 41–60. 12. callam, m.j., ruckley, c.v., harper. dale, j.j. Chronic ulceration of the leg: extent of the problem and provision of care. Br Med J (Clin Res Ed) 1985; 290(6485): 1855–1856. 13. mcguckin, m., stineman, m., goin, j., williams, s. Draft guideline: diagnosis and treatment of venous leg ulcers. Ostomy Wound Manage 1996; 42(4): 48–54. 14. valencia, i.c., falabella, a., kirsner, r.s. eaglstein, w.h. Chronic venous insufficiency and venous leg ulceration. J Am Acad Dermatol 2001; 44(3): 401–424. 15. blair, s.d., wright, d.d.i., backhouse, c.m., riddle, e., mccollum, c.n. Sustained compression and the healing of chronic ulcers. BMJ 1988; 297: 1159–1161. 16. cullum, n., nelson, e.a., fletcher, a.w., sheldon, t.a. Compression for venous leg ulcers. Cochrane Database Syst Rev 2004; (2): CD000265. 17. choucair, m., phillips, t.j. Compression therapy. Dermatol Surg 1998; 24(1): 141–148. 18. partsch, b., partsch, h. Calf compression pressure required to achieve venous closure from supine to standing positions. J Vasc Surg 2005; 42(4): 734–738. 19. partsch, h. Do we still need compression bandages? Haemodynamic effects of compression stockings and bandages. Phlebology 2006; 21(3): 132–138. 20. thomas, s. Bandages and bandaging: the science behind the art. Care Sci Pract 1990; 8(2): 56–60. 21. simon, d. Approaches to venous leg ulcer care within the community: compression, pinch skin grafts and simple venous surgery. Ostomy Wound Manage 1996; 42(2): 34–40. 22. anon. The complete Scholl guide to health care for legs. Luton: Scholl, 1996. 23. hach-wunderle, v. düx, m., hoffmann, a., präve, f., zegelman, m., hach, w. Treatment of deep vein thrombosis in the pelvis and leg. Deutsch Ärztebl 2008; 105: 23–34.

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24. polignano, r., guarnera, g., bonadeo, p. Evaluation of SurePress comfort: a new compression system for the management of venous leg ulcers. J Wound Care 2004; 13(9): 387–391. 25. british standards institution. Specification for graduated compression hosiery. BS 6612:1985; London: BSI, 1985. 26. certificat de qualite-produits. Referentiel technique prescrit pourles ortheses elastiques de contention des membres. 1999; Paris: ASQUAL. 27. deutsches institut für gütesicherung und kennzeichnung. Medizinische Kompressionsstrümpfe RAL-GZ 387. 2000; Berlin: Beuth. 28. clark, m., krimmel, g. Lymphoedema and the construction and classification of compression hosiery. Lymphoedema Framework. Template for Practice: compression hosiery in lymphoedema. 2006; London: MEP Ltd. 29. williams, c. Leg ulcer after care: the role of compression hosiery. Br J Nurs 2000; 9(13): 822–828. 30. vowden, k.r., vowder, p. Preventing venous ulcer recurrence: a review. Int Wound J 2006; 3(1): 11–21. 31. nelson, e.a., bell-syer, s.e.m., cullum, n.a. Compression for preventing recurrence of venous ulcers. Cochrane Database System Rev 2000; (4): CD002303. DOI: 10.1002/14651858.CD002303. 32. partsch, h. Compression therapy of the legs: a review. J Dermatol Surg Oncol 1991; 17(10): 799–805. 33. depalma, r.g., kowallek, d., spence, r.k. Comparison of costs and healing rates of two forms of compression in treating venous ulcers. Vasc Surg 1999; 33(6): 683–690. 34. hampton, l. Venous leg ulcers: short stretch bandages for compression therapy. Br J Nurs 1997; 6(17): 990–998. 35. rajendran, s., anand, s.c. Design and development of novel bandages for compression therapy. Br J Nurs (Tissue Viability Supplement) 2003; 12(17): S20–S29. 36. rajendran, s., anand, s.c. Development of novel bandages for compression therapy, Wounds UK 2002, Harrogate, 19–20 November 2002. 37. gibson, b., duncan, v., armstrong, s. Know how: ischaemic leg ulcer. Nurs Times 1997; 93(36): 34–36. 38. moffat, c., harper, p. Leg ulcers. Churchill Livingstone, Edinburgh, 1997. 39. stemmer, r. Ambulatory-elasto-compressive treatment of the lower extremities particularly with elastic stockings. Derm Kassenarzt 1969; 9: 1–8. 40. logan, r.a., thomas, s., harding, e.f., collyer, g. A comparison of sub-bandage pressures produced by experienced and inexperienced bandagers. J Wound Care 1992; 1(3): 23–26. 41. simon, d.a., freak, l., williams, i.m. et al. Progression of arterial disease in patients with healed venous ulcers. J Wound Care 1994; 3(4): 179–180. 42. moffatt, c.j., dickson, d. The Charing Cross high compression four-layer bandaging system. J Wound Care 1993; 2(2): 91–94. 43. nelzen, o., bergqvist, d., lindhagen, a. Leg ulcer etiology – a cross sectional population study. J Vasc Surg 1991; 14(4): 557–564.

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44. buchbinder, d., mccullough, g.m., melick, c.f. Patients evaluated for venous disease may have other pathological considerations contributing to symptomatology. Am J Surg 1993; 166: 211–215. 45. cullum, n., nelson, e.a., fletcher, a.w. sheldon, t.a. Compression for venous leg ulcers. Cochrane Database System Rev 2001; (2): CD000265. DOI:10.1002/ 14651858.CD000265. 46. nhs centre for review and dissemination. University of York. Compression therapy for venous leg ulcers. Effect Healthcare 1997; 3(4): 1–12. 47. rajendran, s., anand, s.c. The contribution of textiles to medical and healthcare products and developing innovative medical devices. Indian J Fibre Text Res 2006; 31: 215–229. 48. rajendran, s., anand, s.c. Challenges in development of woundcare medical devices, FiberMed 06, Tampere, Finland, 7–9 June, 2006. 49. anand, s.c. Spacers – at the technical frontier. Knit Int 2003; 110: 38–41. 50. anon. Spacer fabric focus. Knit Int 2002; 109: 20–22.

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7 Antimicrobial textile dressings in managing wound infection Y. QI N, Jiaxing College, China

Abstract: The causes and consequences of clinical wound infection are reviewed and the various types of antimicrobial materials that have been used to manage wound infection are summarised. Methods of incorporating antimicrobial materials into textile dressings are discussed and the applications of modern silver-containing antimicrobial wound dressings are highlighted. Key words: wound care, silver, antimicrobial materials, textile dressings, infection.

7.1

Introduction

Wounds are defi ned as skin defects caused by mechanical, thermal, electrical or chemical injuries, or by the presence of an underlying medical or physiological disorder. A wounded skin is typically associated with the loss of the normal skin function, such as its ability to serve as a barrier to invasion by bacteria. Many types of wounds also exude a large amount of fluid, which together with the warm body temperature and rich nutritional components, serve as the ideal place for bacterial growth, leading eventually to wound infection and cross-infection in hospital wards. These infections complicate patient illness, cause anxiety, increase patient discomfort and, in the worst cases, can lead to death of the patient. Depending on the level of bacteria colonisation, wound infection can be classified into the following stages:1–3 • wound contamination: the presence of bacteria within a wound without any host reaction; • wound colonization: the presence of bacteria within the wound which multiply or initiate a host reaction; • critical colonization: multiplication of bacteria causing a delay in wound healing, usually associated with an exacerbation of pain but with no overt host reaction; • wound infection: the deposition and multiplication of bacteria in tissue with an associated host reaction. 179

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Of the various types of bacteria that can cause wound infection, Staphylococcus aureus is a Gram-positive bacterium that exists as a skin commensal, with the ability to cause a wide range of infections from localised skin eruptions to life-threatening conditions such as bacteraemia, endocarditis and pneumonia. S. aureus is one of the most common causes of hospital-acquired infections and its pathogenicity is caused by the production by the organism of coagulase, an enzyme that clots plasma and thus inhibits host defence mechanisms. In recent years, methicillinresistant S. aureus (MRSA) has attracted much attention in the medical field because of its deadly nature. Since it was fi rst reported in the UK in the 1980s, many different strains of MRSA have been found, affecting a large number of individuals in many different healthcare settings. The degree to which people are affected ranges in severity from simple wound colonisation, which does not need to be treated aggressively, to systemic infection such as bronchopneumonia, which may be fatal. The cost of managing the problems associated with infection is considerable. According to a report by the National Audit Office, at any given time, about 9% of hospital patients have a nosocomial infection, i.e. a hospitalacquired infection, costing the National Health Service as much as £1bn per annum and contributing to the death of an estimated 5000 people each year.4 In 1995, the US Office of Technology Assessment reported that antibiotic-resistant infections caused by six species of bacteria in US hospitals cost the country at least $1.3bn (£709m) a year. The report of the UK working party on hospital infection, 5 and, more recently, the report by the National Audit Office,6 recommended that, despite practical problems, where infection control facilities may be inadequate or in situations where MRSA has become endemic, active intervention to prevent the further spread of the organism is of benefit and should be encouraged. Wound dressings that readily permit strikethrough or shed fibres on removal should be avoided as they may transmit contaminated particles that could easily be carried around the room on air currents, contaminating adjacent surfaces. The use of irrigant solutions to remove adherent dressings may also increase the potential for infected material to be transferred from the wound to the surrounding area, either in droplets that bounce off the wound surface when a jet of solution is applied with force by means of a syringe or even in a gentle trickle that runs down the patient’s leg. Semi-permeable dressings such as fi lms, fi lm-foam combinations and hydrocolloids, which effectively seal off the peri-wound area, may help to prevent the passage of contaminating organisms both into and out of a wound.7 However, the use of these products depends on whether their fluid-handling characteristics and performance are appropriate to the condition of the wound and the amount of exudate produced.

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The most effective way to control the spreading of bacteria from wound sites is to incorporate antimicrobial agents in wound dressings. Over the years, many antimicrobial materials have been used in wound management. These include chlorhexidine, honey, hydrogen peroxide, iodine, proflavine, silver and many other novel materials.

7.2

Topical antimicrobial agents in wound care

For patients with infected wounds, two basic treatment protocols are available for medical practioners, viz, systemic administration of antibiotics and topical application of antimicrobial agents on the wounded area directly. Whilst systemic antibiotics is outside the scope of the present review, over the years, many topical antimicrobial agents have been used to treat wound infection. These are briefly summarised below.

7.2.1 Chlorhexidine Chlorhexidine is available as the diacetate, digluconate or dihydrochloride, with the digluconate form most frequently used in wound management. Chlorhexidine was discovered in 1946 and introduced into clinical practice in 1954.8 It has rapid, bactericidal activity against a wide spectrum of nonsporing bacteria by damaging outer cell layers and the semi-permeable cytoplasmic membrane to allow leakage of cellular components. It also causes coagulation of intracellular constituents, depending on concentration.9 It is widely used as an antiseptic in handwashing and as a surgical scrub, but, in wounds, its application has been limited largely to irrigation.

7.2.2 Honey Honey has been used in the wound management practice for a long time and many therapeutic properties have been attributed to honey, including antibacterial activity and the ability to promote healing.10 Evidence of antibacterial activity is extensive, with more than 70 microbial species reported to be susceptible.11 The use of honey for infected wounds is increasing in popularity and a number of dressings or preparations containing it are now available; some of these have been shown to possess good antimicrobial activity against a wide range of pathogenic organisms, including resistant strains.10,12

7.2.3 Hydrogen peroxide Hydrogen peroxide has been widely used as an antiseptic and disinfectant. A 3% solution has most often been used to clean wounds. It is a clear,

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colourless liquid that decomposes in contact with organic matter. It has a broad spectrum of activity against bacteria, with greater effect on Grampositive species than Gram-negatives. Hydrogen peroxide functions as an oxidising agent by producing free radicals that react with lipids, proteins and nucleic acids to affect cellular constituents.

7.2.4 Iodine Iodine is an element that was discovered in 1811. It is a dark violet solid that dissolves in alcohol and potassium iodide. Its fi rst reported use in treating wounds was by Davies in 1839,13 and later it was used in the American Civil War. Early products caused pain, irritation and skin discolouration, but the development of iodophores (povidone iodine and cadexomer iodine) since 1949 yielded safer, less painful formulations. Povidone iodine is a polyvinylpyrrolidone surfactant/iodine complex (PVP-I); cadexomer iodine is composed of beads of dextrin and epichlorhydrin that carry iodine. Both release sustained low concentrations of free iodine whose exact mode of action is not known, but involves multiple cellular effects by binding to proteins, nucleotides and fatty acids. Iodine is thought to affect protein structure by oxidising S–H bonds of cysteine and methionine, reacting with the phenolic groups of tyrosine and reacting with N–H groups in amino acids, such as arginine, histidine and lysine, to block hydrogen bonding. It reacts with bases of nucleotides to prevent hydrogen bonding, and it alters the membrane structure by reacting with C=C bonds in fatty acids.14 Iodine has a broad spectrum of activity against bacteria, mycobacteria, fungi, protozoa and viruses.

7.2.5 Proflavine Proflavine is a brightly coloured acridine derivative that was extensively used during the Second World War in the treatment of wounds.15 Modern use is as a prophylactic agent in surgical wounds packed with gauze soaked in proflavine hemisulfate solution. It is an intercalating agent that inhibits bacteria by binding to DNA and prevents unwinding before DNA synthesis.

7.2.6 Silver Silver has a long history as an antimicrobial agent,16 especially in the treatment of burns. Metallic silver is relatively unreactive, but in aqueous environments silver ions are released and antimicrobial activity depends on the intracellular accumulation of low concentrations of silver ions. These avidly

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bind to negatively charged components in proteins and nucleic acids, thereby effecting structural changes in bacterial cell walls, membranes and nucleic acids that affect viability. In particular, silver ions are thought to interact with thiol groups, carboxylates, phosphates, hydroxyls, imidazoles, indoles and amines either singly or in combination, so that multiple deleterious events rather than specific lesions simultaneously interfere with microbial processes. Hence, silver ions that bind to DNA block transcription, and those that bind to cell surface components interrupt bacterial respiration and adenosine triphosphate (ATP) synthesis.17 In wound care, silver has been utilised in several formulations such as silver nitrate, silver sulfadiazine (SSD) and other types of silver-containing compounds. Silver nitrate is no longer widely used, but SSD and silverreleasing dressings remain popular. When introduced in 1968,18 SSD was recommended as a topical treatment for the prevention of pseudomonad infections in burns, but it has since been demonstrated to possess broadspectrum antibacterial, antifungal, and antiviral activity.19–21 Other agents that have been recommended for the treatment of MRSA infections include tea tree oil 22 and gentian violet ointment.23 Extracts of tea are also said to have inhibitory effects on MRSA. 24

7.3

Main types of antimicrobial wound dressings

In developing wound dressings with antimicrobial function, it is important to note that, in addition to its antimicrobial functions, wound dressings have many other performance criteria, such as the need to protect the wound surface, the ability to absorb wound exudates, and the ease of application and removal. Traditionally, wound dressings are made from textile materials since they share the same functional requirement of being able to protect the underlying object. Over the years, various methods have been used to combine antimicrobial agents with base materials. These methods are described below.

7.3.1 Antimicrobial creams and ointment Antimicrobial agents can be combined with a suitable thickening and gelling agent to prepare creams and ointment with antimicrobial properties. For example, Betadine Solution and Betadine Cream contain 10 and 5% povidone iodine, respectively. It has been shown that these products are effective against MRSA. 25 In another example, antimicrobial silver ions can be combined with a hydrogel. SilvaSorb Silver Antimicrobial Wound Gel is an amorphous gel wound dressing for use in moist wound care management. Its SilvaSorb

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MicroLattice® technology maintains an optimally moist wound environment by either absorbing slight drainage or donating moisture while it delivers antimicrobial ionic silver. SilvaSorb Silver Antimicrobial Wound Gel can act as an effective antimicrobial barrier.

7.3.2 Textile fabric soaked with antimicrobial agents A simple way to prepare an antimicrobial wound dressing is to soak a traditional dressing in a hydrogel containing antimicrobial agents. For example, some paraffin gauze dressings are available medicated with antibiotics or antimicrobial agents for the treatment or prevention of infection: Sofra-Tulle from Hoechst contains framycetin, Bactigras from Smith and Nephew Medical Ltd and Serotulle from Seton Healthcare contain 0.5% chlorhexidine acetate, and Inadine (Johnson and Johnson Medical Ltd), which is similar in appearance to the other medicated tulle products contains povidone iodine in a polyethylene glycol base on a knitted viscose fabric. Urgotul SSD dressing comprises a polyester mesh impregnated with carboxymethylcellulose, vaseline and silver sulfadiazine (3.75%). Silver sulfadiazine is composed of sulfonamide, which is bacteriostatic, and silver, which is bactericidal. Its mechanism of action results from the synergetic activity of the sulfonamide and silver components, which inhibit the replication of bacterial DNA. 26

7.3.3 Antimicrobial-coated textile substrate Antimicrobial agents can be coated onto the surface of a textile substrate to produce antimicrobial wound dressings. For example, Acticoat consists of two layers of a silver-coated, high-density polyethylene mesh, enclosing a single layer of an apertured nonwoven rayon and polyester fabric. These three components are ultrasonically welded together to maintain the integrity of the dressing while in use. Silver is applied to the polyethylene mesh by a vapour deposition process which results in the formation of microscopic crystals of metallic silver. Upon activation with water, Acticoat provides a rapid and sustained release of silver ions within the dressing and to the wound bed for three or seven days. Silverlon is a knitted fabric dressing that has been silver-plated by means of a proprietary autocatalytic electroless chemical (reduction–oxidation) plating technique. This technique coats the entire surface of each individual fibre from which the dressing is made, resulting in a very large surface area for the release of ionic silver.

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7.3.4 Textile fibres containing antimicrobial agents Antimicrobial compounds can be mixed with the spinning solution during the spinning process to produce fibres with antimicrobial properties. For example, AlphaSan RC5000 is a silver sodium hydrogen zirconium phosphate with an average particle size of about 1 μm. It consists of a three-dimensional, repeating framework of sodium hydrogen zirconium phosphate, with many equally spaced cavities containing silver. Silver (at 3.8% by weight) provides the main antimicrobial properties, while the framework matrix acts to distribute silver evenly (without clumping or pooling) throughout the individual fibres where the AlphaSan particles are added. When AlphaSan RC5000 is mixed with sodium alginate solution, the fi ne particles can be evenly distributed in the spinning solution under a high rate of shearing. Because the particles are very fi ne, they can be suspended uniformly while the solution is extruded to form fibres. Since the sodium hydrogen zirconium phosphate framework prevents the silver ions from oxidising the alginate, this type of silvercontaining alginate fibre remains white even after sterilisation through irradiation. 27 Figure 7.1 shows the photomicrograph of alginate fibre with the Alphasan RC5000 particles uniformly distributed inside the fibre structure.

Silver-containing particles

7.1 Photomicrograph of alginate fibre with the Alphasan RC5000 particles uniformly distributed inside the fibre structure.

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7.3.5 Textile composite containing antimicrobial fibres Antimicrobial fibres can be mixed with traditional textile materials to produce antimicrobial wound dressings. For example, Silvercel combines the potent broad-spectrum antimicrobial action of a silver-coated nylon fibre with the enhanced exudates-management properties of alginate fibres. Because of the sustained release of silver ions, the dressing acts as an effective barrier and helps reduce infection. As is shown in Fig. 7.2, the antimicrobial properties are built-in through the use of X-STATIC silver-coated fibres blended into the nonwoven structure. Silvercel dressing has been proven effective in vitro against 150 clinically isolated micro-organisms, including antibiotic-resistant strains.

7.3.6 Other novel methods Actisorb Silver 220 consists principally of activated carbon impregnated with metallic silver, produced by heating a specially treated fi ne viscose fabric under carefully controlled conditions. The carbonised fabric is enclosed in a sleeve of spun-bonded nonwoven nylon, sealed along all four edges, to facilitate handling and reduce particle and fibre loss. When applied to a wound, the dressing adsorbs toxins and wound degradation products as well as volatile amines and fatty acids responsible for the production of wound odour. Bacteria present in wound exudate are also attracted to the surface of the dressing where they are killed by the antimicrobial activity of the silver.

X-Static fibre

Alginate fibre

7.2 Photomicrograph of Silvercel wound dressing.

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Aquacel consists of a fleece of sodium carboxymethylcellulose fibres containing 1.2% ionic silver. In the presence of exudate, the dressing absorbs liquid to form a gel, binding sodium ions and releasing silver ions.

7.4

Wound dressings containing silver

7.4.1 Antimicrobial properties of silver Silver has broad-spectrum antimicrobial properties and has a low level of toxicity to human body. In recent years, as bacterial resistance to antibiotics becomes common and as more and more attention is being paid to cross-infection in hospital wards, wound dressings with antimicrobial properties are becoming increasingly popular. Silver is gaining importance as an effective antimicrobial component of advanced wound dressings. The antimicrobial action of silver products has been directly related to the amount and rate of silver released and its ability to inactivate target bacterial and fungal cells. In various laboratory and clinical studies, it has been found that metallic silver does not possess significant antimicrobial potency whilst silver ions are highly antimicrobial. 28 The oligodynamic microbiocidal action of silver compounds at low concentrations probably does not reflect any remarkable effect of a comparatively small number of ions on the cell, but rather the ability of bacteria, trypanosomes and yeasts to take up and concentrate silver from very dilute solutions. 29 Therefore, bacteria killed by silver may contain 105 –10 7 Ag + per cell, the same order of magnitude as the estimated number of enzyme-protein molecules per cell. 30 Chemically, metallic silver is relatively inert but its interaction with moisture on the skin surface and with wound fluids leads to the release of silver ion and its biocidal properties. Silver ion is a highly reactive moiety and avidly binds to tissue proteins, causing structural changes in bacterial cell walls and intracellular and nuclear membranes. 31 These lead to cellular distortion and loss of viability. Silver binds to and denatures bacterial DNA and RNA, thereby inhibiting replication. 32 A recent study demonstrated the inhibitory action of silver on two strains of Gram-negative Escherichia coli and Gram-positive S. aureus. It found that exposure to silver nitrate led to the formation of electron-light regions in their cytoplasm and condensation of DNA molecules. 33 Granules of silver were observed in the cytoplasm, but RNA and DNA damage and protein inactivation seemed to be the principal mechanisms for bacteriostasis. Silver-related degenerative changes in bacterial RNA and DNA, mitochondrial respiration and cytosolic protein led to cell death.

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The action of silver ion on cell walls is illustrated by reference to the yeast Candida albicans. Silver has been shown to inhibit the enzyme phosphomannose isomerase (PIM) by binding cysteine residues. 34 This enzyme plays an essential role in the synthesis of the yeast cell wall, and defects led to the release of phosphate, glutamine and other vital nutrients. Recent studies suggest that the microbicidal action of silver products is partly related to the inhibitory action of silver ion on cellular respiration and cellular function. 35 The exact nature of these silver radicals is not clear but Ovington36 noted that nanocrystalline silver products (Acticoat, Smith and Nephew) can release a cluster of highly reactive silver cations and radicals, which provide a high antibacterial potency on account of unpaired electrons in outer orbitals. Silver and silver radicals released from Acticoat also cause impaired electron transport, bacterial DNA inactivation, cell membrane damage, and binding and precipitation of insoluble complexes with cytosolic anions, proteins and sulfydryl moieties.

7.4.2 Types of silver compounds used in wound dressings Silver is a group 11 element (formerly group Ib) of the Periodic Table and exists as two isotopes, 107Ag and 109Ag, in approximately equal proportions. In solution, silver exhibits three oxidation states, viz, Ag + , Ag 2+ and Ag3+ , each capable of forming inorganic and organic compounds and chemical complexes. Compounds involving Ag2+ or Ag3+ are unstable or insoluble in water. The silver compounds used in wound dressings can be divided into three groups: • Elemental silver, e.g. nanocrystalline particles or foil. • Inorganic compounds/complexes, e.g. silver nitrate, silver sulfadiazine, silver oxide, silver phosphate, silver chloride or a silver zirconium compound. • Organic complexes, e.g. colloidal silver preparations, silver zinc allantoinate or silver proteins. Colloidal silver solutions were the most common delivery system before 1960. It is in the form of charged pure silver particles (3–5 ppm) held in suspension by a small electric current, where the positively charged ions repel each other, hence making it possible for the particles to remain in solution when applied topically to a wound. Although it is highly bacteriocidal with no resistance, since the solutions are unstable when exposed to light, colloidal silver offers little practical value. When the silver ions are complexed to small proteins to improve stability in solution, they become more stable. However, they are also much less antibacterial than pure ionic silver.

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Table 7.1 Silver compounds used in various wound dressings Manufacturer

Name of the product

Silver compound used

Argentum Smith and Nephew Medline Convatec Medline Coloplast Johnson and Johnson

Silverlon Acticoat SilvaSorb Aquacel Ag Arglaes Contreet Actisorb Silver 220

Metallic silver Metallic silver Silver chloride Silver chloride Silver calcium phosphate Silver ammonium complex Silver carbon

In the 1960s, various silver salts were developed. The salts AgCl, AgNO3, and Ag 2SO4 act as stable delivery systems for silver ions. Silver nitrate was the most widely used compound but it is dangerous to use in concentrations exceeding 2%. An aqueous 0.5% silver nitrate solution is the standard solution for treating burns and infected wounds. However, nitrate is toxic to wounds and cells and appears to decrease healing. It is also unstable in light. Various studies have shown that pure silver ions and radicals produce the best antimicrobial results as well as optimising the wound-healing environment. As a consequence, the silver salts and complexes used today were developed to maintain a sustained release of silver ions. A typical silver-containing compound is Alphasan RC5000 developed by Milliken. As a zirconium phosphate based ceramic ion-exchange resin containing silver, Alphasan is effective against a range of micro-organisms that can cause undesirable effects. The material is widely used in Europe, Japan, and the United States, and it has been approved by the US FDA for contact applications. Table 7.1 summarises the various silver compounds used in silver-containing wound dressings.

7.4.3 Methods of incorporating silver into wound dressings The silver-containing wound dressings currently available vary considerably in their overall structure, and in the concentration and formulation of the silver compounds used. Overall, silver ions can be attached to wound dressings by four basic methods: •

Physical treatment of the base material. In this method, the fibre or fabric can be coated with metallic silver; • Chemical treatment of the base material. In this method, the fibre or fabric can be treated with silver-containing solutions, whereby silver ions can be attached to the wound dressing through ion exchange;

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Advanced textiles for wound care Table 7.2 Typical silver contents of silver-containing wound dressings Proprietary name

Ag content (mg 100 cm−2)

Silverlon Calgitrol Ag Acticoat Contreet Foam Contreet Hydrocolloid Aquacel Ag SilvaSorb Actisorb Silver 220 Arglaes powder

546 141 105 85 32 8.3 5.3 2.7 6.87 mg g −1

• Blending. Fine particles of the silver compounds can be blended with the base material; • Blending of silver-containing fibres with other fibres. This method is used in the production of Silvercel where alginate fibres are blended with the silver coated X-static fibres. Because of the differences in the types of silver compounds and techniques in applying them to the wound dressings, different silver-containing wound dressings have considerably different silver contents. Table 7.2 shows the typical silver contents of the silver-containing wound dressings. 37–39

7.5

Applications of modern antimicrobial wound dressings containing silver

In the management of infected wounds, modern silver-containing wound dressings have become widely used. Depending on the characteristics of wounds, the profi les for silver-containing wound dressings can be divided into three main types: • Products having a high silver content that give a rapid release of silver ions and are designed for wounds with heavy exudate and bacterial colonisation; • Products that maintain a more modest silver-release pattern, where silver ion is released over several days. These are claimed to be sufficient for moderate to severe pathogenic bacterial populations. The non-silver components of these dressings are attuned to wound bed management, i.e., exudate control, debridement of wound debris and management of the wound environment; • Products with a low silver content, which may be sufficient for lowgrade infections in chronic wounds but are more appropriately used as a barrier to infection in acute wounds, burns and surgical injuries.

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Figure 7.3 shows the silver concentration in the contact solution after the silver-containing dressings are placed in contact with wound fluid over various periods of time. It can be seen that Silverlon and Acticoat release more silver ions than other types of products. Both the Silverlon and Acticoat products are coated with a high level of metallic silver. The high level of silver release is needed since both products are intended for burn wounds where the prevention of infection is an important consideration. In other types of dressings, the silver ions act as an antimicrobial agent to control bacteria growth and prevent cross-infection. As is shown in Fig. 7.4, with silver-containing alginate wound dressings, the dressing fi rst absorbs exudate from the wound bed into the dressing structure. As the dressing becomes wet, silver ions are activated and liberated into the contacting solution, exerting an antimicrobial effect on the bacteria. In these cases, the rate of silver release can be significantly lower than in burn wound management. Lansdown et al.40 made a sequential microbiological examination of wound swabs, wound exudate and wound scale from seven patients with chronic wounds. After determining the silver content using atomic absorption spectrometry, they found that: 80 70

Silver concentration, mg l−1

60 50

Silverlon Acticoat

40

SilvaSorb Arglaes

30

Aquacel Ag

20 10 0 0

20

40

60

80

Time (h)

7.3 Silver concentration in the contact solution after the silvercontaining dressings are placed in contact with wound fluid for various periods of time.

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Advanced textiles for wound care Wound exudate with bacteria Non-woven alginate with silver

Fibre swelling Bacteria trapped in non-woven alginate Release of silver ions

Ag

Ag Ag

Ag

Ag

Ag

Ag

Ag Ag

Ag

Ag

Bacteria killed with silver ions

7.4 Mechanism of action for silver-containing alginate wound dressings.

• All silver released into the wound bed was absorbed by wound exudate or debris (wound scale, etc); • Silver uptake by wound exudate is approximately proportional to its viscosity (protein content); • Silver absorbed into the wound bed may be released into the exudate for several weeks following the termination of silver therapy; • The amount of silver released from the dressings is closely related to the amount of moisture absorbed; • Wounds treated with silver do not attain a germ-free status, suggesting that silver-resistant organisms such as S. aureus and Pseudomonas aeruginosa may contribute to a delay in healing. In a detailed study of the performances of various silver-containing wound dressings, Thomas38 found that, when testing against S. aureus: • Acticoat exhibited a marked bactericidal effect within 2 h; • Contreet-H had an inhibitory effect; • Actisorb Silver 220 appeared to prevent the proliferation of the organism within the dressing after a minimum contact time of 4 h. Actisorb Silver 220 removed the organisms from the suspension and bound them to the surface of the charcoal fibres. These organisms remain viable for many hours until they are progressively inactivated by the silver ions in the dressing. The inner core, which contains the silver, forms an effective barrier, whereas the outer nylon sleeve does not.

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While total silver content is important, other factors also influence the ability of a dressing to kill micro-organisms. These include the distribution of the silver within the dressing (whether it is present as a surface coating or is dispersed through the structure), its chemical and physical form (whether it is present in a metallic, bound or ionic state) and the dressing’s affi nity for moisture – a prerequisite for the release of active agents in an aqueous environment. Products in which the silver content is concentrated on the dressing surface rather than ‘locked up’ within its structure performed well, as did those in which silver was present in the ionic form. An in vitro study41 compared the antimicrobial properties of Acticoat with a solution of silver nitrate and cream containing silver sulfadiazine against 11 antibiotic multi-resistant clinical isolates. Acticoat was the most effective at killing the organisms. A later study compared the activity of the same dressings against a spectrum of common burn wound fungal pathogens and showed that the silver-coated membrane provided the fastest and broadest-spectrum fungicidal activity.42 Yin et al.43 compared the antimicrobial activity of Acticoat with silver nitrate, silver sulfadiazine and mafenide acetate in order to determine their minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC) and zone of inhibition. Although mafenide acetate produced the greatest zone of inhibition, the MBC of the product was higher than its MIC, indicating that it had a bacteriostatic rather than a bactericidal action. In contrast, the MICs and MBCs of the silver-containing products were very similar, indicating that their activity is essentially bactericidal. The authors showed that, although the MIC values for the three silver preparations were very similar when calculated in terms of their silver content, Acticoat acted more rapidly than the other two products, perhaps because the metallic silver on the surface of the dressing forms a reservoir of silver ions, which are released continuously and are therefore always available for bacterial uptake.

7.6

Future trends

In developing antimicrobial textile dressings to manage wound infection, it should be noted that since wound dressings are directly in contact with broken skin, there are strict requirement for the type of applicable antimicrobial materials. These materials should meet the following requirements: • Be non-toxic and safe to use on broken skin; • Do not cause allergic reaction; • Do not develop bacteria resistance; • Have a broad-spectrum antimicrobial effect; • Have sustained antimicrobial effect during the useful lifetime of the material

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In this respect, organic antimicrobial compounds commonly used for antimicrobial textiles have limited use in wound management, since, in most cases, they are not suitable for use on broken skin. In recent years, two classes of materials have become increasingly used in the woundmanagement industry as novel materials for the manufacture of wound dressings with antimicrobial function. These are briefly discussed below.

7.6.1 Metal ions with antimicrobial properties In recent years, silver has been successfully used as an effective antimicrobial agent for wound management and silver-containing wound dressings are now widely used thoroughout the world. In addition to silver, other metal ions have also proven effective in preventing bacterial growth. In particular, zinc and copper ions, whilst being non-toxic to human, can be easily attached to wound dressings through chelation with fibres containing amine groups. In this respect, chitosan fibres treated with zinc and copper compounds have the combined antimicrobial properties of the chitosan as well as the metal ions. Experimental results have shown that the zinc and copper containing chitosan fibres have excellent antimicrobial efficacy. As can be seen in Table 7.3, when tested against C. albicans, the original chitosan produced a reduction in bacterial count of 78.6%, the respective figures for the copper and zinc containing fibres were 96.2 and 97.7%.44

7.6.2 Naturally occurring antimicrobial materials Melaleuca alternifolia oil, also called tea tree oil, has demonstrated promising efficacy in treating wound infections. Tea tree oil has been used for centuries as a botanical medicine, and has only in recent decades surfaced in the scientific literature as a promising adjunctive wound treatment. Tea tree oil is antimicrobial and anti-inflammatory, and has demonstrated its ability to activate monocytes. There are few apparent side effects to using tea tree oil topically in low concentrations, with contact dermatitis being the most common. Tea tree oil has been effective as an adjunctive therapy Table 7.3 The antimicrobial effect against Candida albicans by different types of chitosan fibres Samples

Bacteria count (cfu ml−1)

Reduction (%)

Control Chitosan fibre Cu(II) chitosan fibre Zn(II) chitosan fibre

5.4 × 103 1155 208 123

n/a 78.6 96.2 97.7

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in treating osteomyelitis and infected chronic wounds in case studies and small clinical trials.45 It is reported that, of the various naturally occurring antimicrobial compounds, tea tree oil is effective against skin infections; honey can be used for wound infections; mastic gum can be used for Helicobacter pylori gastric ulcers and cranberry juice for urinary tract infections. Many infections may prove amenable to safe and effective treatment with nonantibiotic naturally occurring compounds.46

7.7

Sources of further information and advice

For more information on wound care and wound management products, the readers should consult the following references. 1. A prescriber’s guide to dressings and wound management materials, VFM Unit, Welsh Office Health Department, 1997. 2. G. Bennett and M. Moody, Wound care for health professionals, Chapman and Hall, London, 1995. 3. C. Dealey, The care of wounds, Blackwell Science Ltd, Oxford, 1994. 4. D.J. Leaper and K.G. Harding (eds), Wounds: biology and management, Oxford University Press, 1998. 5. M. Morison, C. Moffatt, J. Bridel-Nixon and S. Bale (eds), Nursing management of chronic wounds, Mosby, London, 1997. 6. S. Thomas, Wound management and dressings, The Pharmaceutical Press, London, 1990. 7. J. Wardrope and J.A.R. Smith, The management of wounds and burns, Oxford University Press, Oxford, 1992.

7.8

References

1. ayton m. Wound care: wounds that won’t heal. Nurs Times, 1985, 81(46): suppl 16–19. 2. falanga v, grinnell f, gilchrest b, et al. Workshop on the pathogenesis of chronic wounds. J Invest Dermatol, 1994, 102(1): 125–27. 3. kingsley a. A proactive approach to wound infection. Nurs Stand, 2001, 15(30): 50–54. 4. national audit office. The management and control of hospital acquired infection in acute NHS trusts in England. London: Stationery Office, 2000; 121 (HC 230 Session 1999–2000). 5. duckworth g, cookson b, humphreys h, et al. Revised guidelines for the control of methicillin-resistant Staphylococcus aureus infection in hospitals. British Society for Antimicrobial Chemotherapy, Hospital Infection Society and the Infection Control Nurses Association. J Hosp Infect, 1998, 39(4): 253–290. 6. national audit office. Improving patient care by reducing the risk of hospital acquired infection: a progress report. London: Stationery Office, 2004; (HC 876 Session 2003–2004).

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7. hutchinson j j, lawrence j c. Wound infection under occlusive dressings. J Hosp Infect, 1991, 17(2): 83–94. 8. russell a d. Introduction of biocides into clinical practice and the impact on antibiotic-resistant bacteria. J Appl Microbiol, 2002, 92 Suppl: 121S–135S. 9. mcdonnell g, russell a d. Antiseptics and disinfectants: activity, action, and resistance. Clin Microbiol Rev, 1999, 12(1): 147–179. 10. molan p c. The role of honey in the management of wounds. J Wound Care, 1999, 8(8): 415–418. 11. molan p c. The antibacterial activity of honey. Part 1. Its use in modern medicine. Bee World, 1992, 80(2): 5–28. 12. moore o a, smith l a, campbell f, et al. Systematic review of the use of honey as a wound dressing. BMC Complement Altern Med, 2001, 1(1): 2. 13. davies j. Selections in pathology and surgery. Part II. London: Longman, Orme, Browne, Greene and Longmans, 1839. 14. gottardi w. Iodine and iodine compounds. In: Block S, editor. Disinfectants, sterilisation and preservations (3rd edition). Philadelphia, USA: Lea Febinger, 1983. 15. mitchell g a g, buttle g a h. Proflavine in closed wounds. Lancet, 1943, ii: 749. 16. klasen h j. Historical review of the use of silver in the treatment of burns. I. Early uses. Burns, 2000, 26(2): 117–130. 17. trevors j t. Silver resistance and accumulation in bacteria. Enzyme Microb Technol, 1987, 9: 331–333. 18. fox c. Topical therapy and the development of silver sulphadiazine. Surg Gynecol Obstet, 1968, 157: 82–88. 19. wlodkowski t j, rosenkranz h s. Antifungal activity of silver sulphadiazine. Lancet, 1973, 2(7831): 739–740. 20. speck w t, rosenkranz h s. Letter: Activity of silver sulphadiazine against dermatophytes. Lancet, 1974, 2(7885): 895–896. 21. rahn r o, setkiw j k, landry l c. Ultraviolet irradiation of nucleic acids complexed with heavy metals. III. Influence of Ag + and Hg + on the sensitivity of phage and of transforming DNA to ultraviolet radiation. Photochem Photobiol, 1973, 18: 39–41. 22. carson c f, cookson b d, farrelly h d, et al. Susceptibility of methicillinresistant Staphylococcus aureus to the essential oil of Melaleuca alternifolia. J Antimicrob Chemother, 1995, 35(3): 421–424. 23. saji m. Effect of gentian violet against methicillin-resistant Staphylococcus aureus (MRSA). Kansenshogaku Zasshi, 1992, 66(7): 914–922. 24. yam t s, hamilton-miller j m, shah s. The effect of a component of tea (Camellia sinensis) on methicillin resistance, PBP2’ synthesis, and betalactamase production in Staphylococcus aureus. J Antimicrob Chemother, 1998, 42(2): 211–216. 25. goldenheim p d. In vitro efficacy of povidone–iodine solution and cream against methicillin-resistant Staphylococcus aureus. Postgrad Med J, 1993, 69(Suppl 3): S62–65. 26. meaume s, senet p, dumas r. Urgotul: a novel non-adherent lipido-colloid dressing. Br J Nurs, 2002, 11: 42–50. 27. qin y, groocock, m r. PCT WO/02/36866A1, May 2002.

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28. lansdown a b g. Physiological and toxicological changes in the skin resulting from the action and interaction of metal ions. CRC Crit Rev Toxicol, 1995, 25: 397–462. 29. charley r c, bull a t. Bioaccumulation of silver by a multispecies population of bacteria. Arch Microbiol, 1979, 123: 239–244. 30. clarke a j. General pharmacology. In: Heffter, A. (ed.). Handbuch der experimentelle Pharmakologie. Ergänzung, Vol. 4. Berlin: Springer, 1937. 31. ovington l g. Nanocrystalline silver: where the old and familiar meets a new frontier. Wounds, 2001, 13: (suppl B), 5–10. 32. modak s m, fox c l. Binding of silver sulfadiazine to the cellular components of Pseudomonas aeruginosa. Biochem Pharmacol, 1973, 22: 2391–2404. 33. feng q l, wu j, chen g q, et al. A mechanistic study of the antibacterial effect of silver ions on Escherischia coli and Staphylococcus aureus. J Biomed Mat Res, 2000, 52: 662–668. 34. wells t n, scully p, paravicini g, et al. Mechanisms of irreversible inactivation of phosphomannose isomerases by silver ions and flamazine. Biochemistry, 1995, 34: 7896–7903. 35. demling r h, disanti l. Effects of silver on wound management. Wounds, 2001, 13: (Suppl A), 5–15. 36. ovington l g. Nanocrystalline silver: where the old and familiar meets a new frontier. Wounds, 2001, 13: (suppl B), 5–10. 37. thomas s, mccubbin p. A comparison of the antimicrobial effects of four silver-containing dressings on three organisms. J Wound Care, 2003; 12(3): 101–107. 38. thomas s, mccubbin p. An in vitro analysis of the antimicrobial properties of 10 silver-containing dressings. J Wound Care, 2003, 12(8): 305–308. 39. lansdown a b, williams a. How safe is silver in wound care? J Wound Care, 2004, 13(4): 131–136. 40. lansdown a b g, williams a, chandler s, et al. Silver absorption and antibacterial efficacy of silver dressings. J Wound Care, 2005, 14(4):155–160. 41. wright j b, lam k, burrell r e. Wound management in an era of increasing bacterial antibiotic resistance: a role for topical silver treatment. Am J Infect Control, 1998, 26: 572–577. 42. wright j b, lam k, hansen d, et al. Efficacy of topical silver against fungal burn wound pathogens. Am J Infect Control, 1999, 27: 344–350. 43. yin h q, langford r, burrell r e. Comparative evaluation of the antimicrobial activity of ACTICOAT antimicrobial barrier dressing. J Burn Care Rehabil, 1999, 20: 195–200. 44. qin y, zhu c, chen j, liang d, wo g. Absorption and release of zinc and copper ions by chitosan fibers. J Appl Polym Sci, 2007, 105(2): 527–532. 45. halcon l, milkus k. Staphylococcus aureus and wounds: a review of tea tree oil as a promising antimicrobial. Am J Infect Control, 2004, 32(7): 402–408. 46. carson c f, riley t v. Non-antibiotic therapies for infectious diseases. Commun Dis Intell, 2003, 27 Suppl: S143–146.

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8 Novel textiles in managing burns and other chronic wounds H. ON I SH I and Y. M AC H I DA, Hoshi University, Japan

Abstract: Recent developments in the theory of wound healing and in the use of wound dressings to manage skin wounds, including wounds caused by exogenous factors like skin defect and endogenous factors such as diabetes, are described. Results of recent studies on novel dressings based on the latest materials science and textiles technology are discussed with respect to their characteristics, usefulness and advantages. Key words: wound dressing, burn, pressure ulcer, skin defect, diabetes, textiles, wound healing, deep wound, chronic wound.

8.1

Introduction: current practice in the management of deep skin wounds or ulcers

8.1.1

Management of burns, pressure ulcers and skin defects

The concept of wound healing has changed recently. Before the concept of moist wound healing was generally accepted, disinfection, bandaging, leaving scar tissue and keeping a wound area dry were regarded as the best ways of promoting wound healing. However, it was then realized that drying the wound tended to delay its healing (Winter and Scales, 1963). Keeping wound areas moist, with a cover such as polyethylene fi lm, was found to be more effective for faster healing, and since then moist wound healing has been accepted as a general concept of wound healing (Horncastle, 1995; Bryan, 2004; Brett, 2006). Thus, firstly, wound washing or debridement is performed, and then treatment with sutures, dressings, etc. is started. Many dressings have been developed for the management of various skin wounds, such as burns, skin defects, and pressure ulcers (Kaya et al., 2005; Martineau and Shek, 2006). These have been used for the protection of wounds, removal of exudates, prevention of infection, promotion of the 198

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rate of healing, etc. (Seaman, 2002; Fletcher, 2003). In moist wound healing, the dressings have to keep the wound area under moist (not wet) conditions. Furthermore, they must protect the wound from contamination and infection, which are the greatest potential problems in moist wound healing. In particular, hematoma, excessive exudates and necrotic tissue often cause infection and delay wound healing in severe or chronic wounds (Caputo et al., 1994; Stotts and Hunt, 1997; Mi et al., 2002; Dowsett, 2004). The choice of dressing, therefore, is very important. Antimicrobial agents are generally useful to protect the wound from infection, although they must be used with care because their application may sometimes be unfavorable owing to toxic side effects (Simons and Morales, 1980; Lansdown, 2006; Aoyagi et al., 2007; Atiyeh et al., 2007). A combination of wound dressings and pharmaceutical agents is often utilized as a beneficial approach in the treatment of deep wounds. The process of wound healing is shown in Fig. 8.1. In severe or chronic wounds, the dermis and panniculus adiposus are damaged, and the muscle and bone sometimes invaded. Since deep dermal wounds and damage extending to the panniculus adiposus lack hair follicles, which are important for fast re-epithelialization, the healing proceeds gradually. Reepithelialization is initiated only from the edge of the wound. Wound healing is completed through a necrosis and infection stage, an agglutination period, a proliferation period of granulation and re-epithelialization, and a fi nal remodeling stage (Gabbiani et al., 1971; Rovee et al., 1972; Clark et al., 1995; Clark, 1996). Immediately after the production of the wound, a blood clot covers the damaged site, and leukocytes, macrophages, etc., associated with inflammation, gather there in the necrosis and infection stage. In severe and chronic wounds, hematoma, exudates and necrotic tissues are fairly

Epidermis

Dermis Panniculus adiposus Hair follicle

(a)

(b)

8.1 Wound healing process in (a) non-deep and (b) deep wounds (re-epithelialization → ; granulation Ö).

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extensive. These are often subject to infection, deteriorating the condition of the wound. At this stage, therefore, the removal of excessive exudates and necrotic tissue is important, and antimicrobial agents may be needed to prevent deterioration of the wound. Washing and debridement of the wound surface are important to promote the rate of healing. Keeping the wound moist is necessary in order not to inhibit the healing process in the wound. A few days after the production of the wound, fibroblast cells proliferate by responding to various cell growth factors excreted in the exudates. The cells produce extracellular matrices, such as collagen, which bury the wound area. This granulation step is a very important repairing process. Angiogenesis is also important because it plays an important role in the supply of oxygen and nutrients, which are necessary in the proliferation stage. At the same time, re-epithelialization is an essential step in the completion of wound healing. In severe or chronic wounds, which lack hair follicles, re-epithelialization starts at the edge of the epidermis. The wound is fi lled with granulation tissue, which shrinks gradually with healing, and is then covered by the process of re-epithelialization. The removal of contamination and infection, and the maintenance of moist conditions, are important to achieve efficient granulation and re-epithelialization (Rovee et al., 1972; Brett, 2006). Dressings specifically designed to create such conditions are chosen. Some growth factors or pharmaceutical agents can be utilized to promote granulation and re-epithelialization. Finally, remodeling continues after the wound has closed up. Dermal remodeling reduces the scar, which is very important for cosmetic reasons.

8.1.2 Management of chronic leg ulcers and diabetic foot wounds Burns or pressure ulcers are mainly produced by exogenous factors. Endogenous factors, on the other hand, are essentially associated with skin defects in leg ulcers and diabetic foot wounds. These are very complicated ulcers and wounds that are chronic in most cases and difficult to heal. Venous or arterial occlusion can cause ischemic defects in the related area, leading to poor blood circulation. This results in poor nutritional conditions in the periphery of the legs, including the skin, making these areas vulnerable to infections (Nelson et al., 2004). Poor healing may necessitate leg amputation. In the treatment of leg ulcers, it is very important to improve ischemic defects fi rst. This improvement, including elastic compression around the ulcer area, appears to be useful in the healing process for leg ulcers. The combination of dressing application and medical compression seems to be useful in the treatment of venous leg ulcers (Koksal and Bozkurt, 2003). Diabetic foot ulcers are also significantly related to ischemic defects (Jude et al., 2007). Diabetics can often develop foot ulcers owing to ischemic

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defects of the peripheral blood vessels, which, like leg ulcers, are often chronic and difficult to heal. These ulcers are often accompanied by infections and the ischemic defects delay healing of the diseased sites. In the treatment of diabetic foot ulcers, the most important factor is to improve the diabetic conditions. In addition, the application of dressings to the ulcers appears to be effective. The combination of dressings and antibacterial agents seems to be useful. For example, use of hyaluronate and an iodine complex produced significant improvement in ulcers of this type (Sobotka et al., 2006, 2007). Furthermore, topical treatment with dressings containing epidermal growth factor (EGF) showed positive effects in promoting the healing of chronic diabetic foot wounds (Hong et al., 2006). In the treatment of these chronic wounds, it seems necessary to keep the wound or ulcer in moderately moist conditions; extreme moist conditions can increase the infection. It is therefore suggested that wound dressings with or without bioactive agents are useful to enhance the healing of chronic leg ulcers or diabetic foot ulcers. For the treatment of the deep wounds or ulcers, this chapter examines wound dressings and composites containing pharmaceutical agents – some commercially available and some not – and compares them with common dressings.

8.2

Normal treatment options for deep skin wounds or ulcers

Moist wound healing is generally accepted today and the dressings used are based on this concept, although extreme moist conditions are not appropriate for healing chronic ulcers, such as leg or diabetic foot ulcers. The maintenance of wet conditions around the wound provides circumstances that allow biologically active agents, such as growth factors and cytokines, to be kept in the wound area (Cross and Mustoe, 2003; Akita et al., 2006). Cell migration is allowed in wet conditions, but not in dry conditions. Contamination with scar tissue, caused in dry conditions, can inhibit the process of proliferation, resulting in delayed healing. Dressings designed to fulfi ll these conditions have recently been developed. However, moist healing can also lead to a deterioration of wound conditions, such as infection, particularly in deep skin wounds. For the treatment of deep skin wounds, therefore, some pharmaceutical agents are often necessary in addition to dressings, in order to support wound healing.

8.2.1 Topical pharmaceutical agents Topical pharmaceutical agents used in deep skin wounds are shown in Table 8.1. In the infection and necrosis stage, contamination, infection and

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Table 8.1 Topical formulations for the treatment of severe skin wounds Classification

Formulation (commercial name)

Active ingredient

Debridement agents

Bromelain ointment Elase

Bromelain Fibrinolysin, deoxyribonuclease Trypsin, fradiomycin sulfate

Francetin.T.Powder Incarnant agent

Antibacterial agents

Fiblast spray Prostandin ointment Olcenon ointment Actosin ointment U-Pasta Kowa ointment Reflap Solcoseryl ointment Erythrocin Achromycin ointment Chloromycetin cream Gentacin Terramycin ointment with polymixin B Baramycin ointment Geben cream Fucidin leo ointment Cadex ointment

Trafermin Alprostadil–alfadex Tretinoin tocoferil Bucladesine sodium Sucrose, povidone iodine Lysozyme hydrochloride Solcoseryl Erythromycin Tetracycline hydrochloride Chloramphenicol Gentamicin sulfate Oxytetracycline hydrochloride, Polymixin B sulfate Bacitracin, fradiomycin sulfate Sulfadiazine silver Sodium fusidate Iodine, Cadexomer

scar tissue are obstacles to the subsequent healing process (Wysocki, 2002). Contamination must be removed by washing because foreign substances lead to foreign-body reactions. Drugs containing enzymes that hydrolyze biogenic substances are commercially available for this purpose. These allow the degradation of proteins and nucleic acids in the exudates and their easy removal, resulting in better conditions at the wound surface (Levine et al., 1973; Schwarz, 1981). Antimicrobial agents are necessary to suppress possible infection. Various kinds of antimicrobial agents are used, and dosage forms of ointment and cream are commercially available (Breloff and Caffesse, 1983; Lee et al., 1984; Yoshida et al., 1997). Silver sulfadiazine (Geben cream) is often used because it is widely effective against Gram positive and Gram negative bacteria and fungi. These agents are useful to treat the wound in the early stage. However, prolonged use may prevent the subsequent healing process, resulting in delayed healing. After cleaning the wound surface with debridement agents and antimicrobial drugs, the promotion of proliferation, granulation and reepithelialization are important in order to accelerate the rate of wound

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healing. Pharmaceutical agents and growth factors are included in the promoting agents, but caution should be exercised when using them (Kawabata et al., 2002; Kakigi et al., 2005; Asai et al., 2006). For example, excessive granulation caused by overuse can delay the completion of wound healing or produce an ugly scar. Although these agents are effective in improving the severe situation of wounds, caution has to be exercised in applying them, and overuse must be avoided in order to reduce side effects.

8.2.2 Currently used dressings As shown above, the misuse or overuse of pharmaceutical agents can become an obstacle to wound recovery. The concept of moist wound healing indicates that it is better to provide the conditions to help the wound tissue to recover naturally (Bryan, 2004). The use of dressings in the treatment of wounds is based on this concept. Dressings have therefore been developed to fulfi ll these conditions (Seaman, 2002). In fact, when there is infection or necrotic tissue in the wound, dressings are applied after cleaning the wound surface to remove these obstacles. It is possible to use a combination of dressings with pharmaceutical agents. Various commercially available dressings are shown in Table 8.2, and many are useful for deep skin wounds. A polyurethane (PU) fi lm is often used as a thin dressing (Holland et al., 1985; Cosker et al., 2005). Since gases such as oxygen, and water vapor can pass through a PU fi lm, but liquids such as water and exudates cannot, this fi lm allows wet conditions for wounds. Although a PU fi lm can be left covering a light wound for a long time, prolonged use is difficult owing to the generation of excessive exudates. Changing the fi lm is, therefore, required when wound conditions deteriorate. Chitin fi lms are used in the form of non-woven textile, cotton-like sheets or sponge forms, and are available for the treatment of various skin wounds, including deep skin ulcers (Su et al., 1997, 1999). As chitin fi lms allow liquids such as exudates to pass through them, some dressings are needed to keep the wound under wet conditions. Chitin fi lms are biocompatible and biodegradable, although the degradation process is lengthy. Beschitin W is a typical thin chitin fi lm that is very useful in the treatment of light or moderate burns. Beschitin W-A is a cotton-like sheet, thicker than Beschitin W, which can be applied to deep wounds, i.e. to wounds extending to the panniculus adiposus, such as pressure ulcers. Beschitin F is a sponge type of chitin, 2 mm thick, that is available for the treatment of deep skin wounds, especially wounds up to muscle or bone. These must be applied to the wound after cleaning by washing or debridement, since contamination, excessive exudates or scar tissue threaten to cause infection. Chitin

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Table 8.2 General wound dressings for the treatment of severe skin wounds Degree of wound severity

Material

Commercial name

Transparent occlusive cover Wound reaching into dermis

Polyurethane films

Opsite Tegaderm Beschitin W DuoActiveET Tegasorb light Absocure-surgical Viewgel NU-GEL Comfeel DuoActive DuoActiveCGF Absocure-wound Tegasorb Jelliperm Intrasite gel GranuGEL Beschitin W-A Kaltostat Sorbsan Algoderm Kurabio-AG Aquacel Tielle Hydrosite Hydrosite AD Hydrosite cavity Beschitin F

Chitin film Hydrocolloid dressing

Hydrogel Wound reaching into panniculus adiposus

Hydrocolloid dressing

Hydrogel

Chitin film Alginate

Hydrofiber Hydropolymer Polyurethane foam Wound reaching into muscle or bone

Polyurethane foam Chitin film

fi lms provide wet conditions to the wound and, furthermore, have the ability to promote the granulation process. Like PU fi lms, these dressings need to be changed when wound conditions deteriorate. Composite fi lms containing hydrocolloids are also used in the treatment of wounds of varying degrees. This type of fi lm is usually composed of a hydrocolloid-containing matrix and a waterproof sheet (Agren and Everland, 1997; Sugihara et al., 2000). Water is absorbed by the hydrocolloids and wet conditions are maintained around the wound. The ulcer dressing Comfeel is relatively thick (1.1 cm), and superior to the thin type of hydrocolloid-containing composite fi lm in the absorption of exudates. Hydrogels are usually used in combination with a non-woven sheet. Their function is the same as that of composite fi lms containing hydrocolloids.

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Textiles made from calcium sodium alginate perform the excellent function of significant absorption of exudates and hemostasis (Gilchrist and Martin, 1983; Vanstraelen, 1992). These can be applied to deep skin wounds, that is, to wounds extending to the panniculus adiposus. Both ribbon- and sheet-types of these textiles are available. The ribbon-type is suitable for the treatment of pockets in the wound. These dressings need to be changed before deterioration of the gel state. A textile of carboxymethylcellulose sodium (CMC) is used in a similar manner to calcium sodium alginate textiles (Piaggesi et al., 2001; Walker et al., 2003). The main characteristic of the CMC textile is its significant absorption of exudates. The CMC textile is changed before deterioration of the gel state by the absorption of exudates. Hydropolymers and PU foams are useful for the treatment of deep skin wounds (Rubin et al., 1990; Berry et al., 1996; Diehm and Lawall, 2005). Hydropolymers can be applied to deep skin wounds, that is, to wounds extending to the panniculus adiposus. With regard to PU foams, special forms are made for the wound cavity or sacral region. They can be used for deep wounds extending to the muscle and bone and need to be changed before they are completely fi lled with exudates.

8.3

Novel wound dressings for managing deep skin wounds or ulcers

Although the widely used dressings described above are useful in treating various wounds, it is difficult to remove completely the possibility of infection and delay of wound healing. These problems tend to occur in severe wounds accompanied by excessive exudates, infection and the contamination of necrotic tissues. Novel wound dressings have, therefore, been developed. This section examines some examples of novel wound dressings, including novel textiles and the combination of dressings and bioactive substances.

8.3.1 Novel wound dressings made only of polymers Nanofibrous polyurethane membrane As stated above, PU fi lms are a typical dressing used to protect wounds and keep moist conditions around the wound as an occlusive dressing (Martin et al., 1992; Cross and Mustoe, 2003). Although water vapor and oxygen can permeate PU fi lms, exudates can accumulate in severe wounds, leading to infection or delayed healing. In this case, wound dressings with higher permeability are desirable to give protection from infection and hydration. An electrospinning technique has recently been utilized,

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enabling the production of polymer nanofibers in order to manufacture nanofibrous textile (Khil et al., 2003). The nanofibrous PU fi lm consists of PU fiber a few hundred nanometers in diameter, and with ultra-fi ne porous structure. The nanofibrous PU fi lm was non-toxic, controlled water vapor well, exhibited excellent oxygen permeation and promoted drainage of fluids due to high porosity. Furthermore, the superfi ne structure allowed no invasion of exogenous bacteria. Comparison was made between the effects of the nanofibrous PU fi lm and the control PU fi lm (Tegaderm®) on a full-thickness wound in guinea pigs. The dermis of the wound covered with Tegaderm® showed a fairly long-lasting inflammatory state, while in the case of the nanofibrous PU fi lm, the re-epithelialization rate was increased and the dermis well organized. Histological studies confi rmed that the re-epithelialization rate was accelerated in the nanofibrous PU fi lm. This nanofibrous PU fi lm prepared by electrospinning can, therefore, be proposed as a valid wound dressing. Cross-linked alginate dressings Non-woven calcium alginate fiber dressings have been used on deep skin wounds. Kaltostat and Sorbsan are typical non-woven fiber alginate dressings and provide wounds with good absorption of the exudates and an occlusive environment. However, these dressings have been shown to cause cytotoxicity and foreign-body reaction owing to remaining dressing debris, leading to severe chronic inflammation (Matthew et al., 1995; Suzuki et al., 1998). Non-woven fiber alginate dressings are biodegraded, but the degradation rate is very slow. Suzuki et al. showed that calcium alginate fibers remained after implantation in the muscle of rabbits, and severe chronic inflammation continued (Suzuki et al., 1999). This was considered to be caused by foreign-body reaction to the debris of dressings. However, an alginate gel prepared by cross-linking with ethylenediamine, using the amide coupling reagent water-soluble carbodiimide, showed no cytotoxicity and reduced foreign-body reaction to a great extent (Suzuki et al., 1999). In experiments using pigs, cross-linked alginate gel showed a significantly higher wound closure rate in a full-thickness wound than Kaltostat and Sorbsan (Fig. 8.2). Furthermore, the biodegradation rate of crosslinked alginate gel was much faster than Kaltostat and Sorbsan, i.e. it was absorbed completely within a few months without inflammation. Since the crosslinked alginate gel has a non-fibrous structure, it is considered to be easily biodegraded because of its high-swelling with biological fluid. The crosslinked alginate gel appears to overcome the disadvantages of the conventional dressings Kalostat and Sorbsan. However, weakness of the gel strength may be a drawback of crosslinked alginate gel, and this needs to be improved.

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Wound closure after 15 days (%) 90

92

94

96

98

100

Crosslinked alginate gel

Kaltostat

Sorbsan

8.2 Wound closure rate after 15 days. Mean ± SD (n = 10) (Suzuki Y et al., 1999).

Fibroin/alginate sponge Much attention has recently been paid in material sciences to a protein: silk fibroin. In particular, it has been found that silk fibroin is an invaluable biosynthetic material in the field of biomedical engineering and wound healing (Yeo et al., 2000; Min et al., 2004a). Silk string has been used as a suture since ancient times, and silk is therefore widely known as a safe material. Silk fibroin is very biocompatible and its safety and usefulness have been demonstrated in various studies, showing that its fi lm is very effective in wound healing and exhibits high compatibility as a vascular graft, and its sheet and sponge forms can function as a good support for the proliferation of fibroblasts, epithelial cells, etc. Silk fibroin products act as a safe and strong support structure, and promote granulation tissue proliferation and re-epithelialization (Min et al., 2004b; Gobin, 2005). Alginate, on the other hand, has the ability to absorb wound exudates effectively, and alginate dressings provide an appropriately moist environment to the wound. Given the advantages of silk fibroin in the promotion of proliferation and alginate’s maintenance of a moist environment, it is suggested that their combined use is useful in wound healing. A sponge made by blending silk fibroin and alginate (SF/AA-S) was prepared by mixing the solution and subsequent lyophilization. SF/AA-S was compared with silk fibroin sponge (SF-S) and alginate sponge (AA-S) for wound closure rate, granulation and re-epithelialization following the treatment of full-thickness wounds in rats (Roh et al., 2006). The rate of wound size reduction was significantly faster in SF/AA-S than in the control (Nu Gauze), SF-S and AA-S. The area of new epithelialization tissue was the largest in SF/AA-S, which showed a significantly better effect on

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Epithelialization (mm2)

0.16 0.14 0.12 0.1 0.08 0.06 Control

AA-S

SF-S

SF/AA-S

8.3 Effect of wound dressings on re-epithelialization. Mean ± SE (n = 6) (Roh et al., 2006).

re-epithelialization than SF-S and AA-S (Fig. 8.3). The area of collagen deposition in the granulation tissue was significantly increased in SF-S, AA-S and SF/AA-S compared with the control, but no significant difference was observed between the treated groups. The acceleration of reepithelialization by SF/AA-S was also confi rmed by the increase in proliferating cell nuclear antigen expression. Thus, SF/AA-S showed significant synergic wound healing effects as compared with SF-S and AA-S, mainly associated with the promotion of re-epithelialization rather than collagen deposition. SF/AA-S may be useful clinically. Chitin/chitosan-blended fi lm Chitin is biocompatible and biodegradable and has the ability to promote wound healing (Ervin, 1976; Nishimura et al., 1984). Chitin is useful as an excellent biosynthetic material for the treatment of wounds of varying degrees of severity, and is used clinically in non-woven sheet and spongy forms, etc. These forms absorb exudates from the wound and provide a properly moist environment around the wound, but hardly exhibit any antimicrobial effects. Therefore, frequent changes of the forms are necessary when exudate accumulation or infectious states are observed. Chitosan, on the other hand, synthesized by the alkaline deacetylation of chitin, shows antimicrobial activity to various bacteria (Seo et al., 1992). Furthermore, chitosan exhibits good biocompatibility and appropriate moisturizing effects (Gobin et al., 2005). Chitosan is far superior to chitin in these areas. Biomaterials made of chitosan have recently been utilized as a good scaffold to facilitate tissue regeneration. Chitin/chitosan-blended preparations are, therefore, considered potentially useful in treating skin wounds. Chitin-, chitosan-, and chitin/chitosan fi lms, called CN-F, CA-F and CN/ CA-F, respectively, were prepared by casting techniques, using various

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kinds of chitin and chitosan. They were compared for in vitro characteristics such as swelling and strength, and their in vivo effects were examined for wound states and the rate of reduction of the wound area, using rats with full-thickness burn wounds (Tachihara et al., 1997a). CN-F exhibited a small absorption of water, but CA-F made of chitosan with a moderate degree of deacetylation showed a high absorption of water. CN/CS-F exhibited medium water absorption. CN-F was rigid in vitro and in vivo, and lacked the ability to absorb the exudates. CA-F made of chitosan with moderate deacetylation degrees showed good absorption of exudates, but their strength was not maintained in the in vitro swelling study. However, these disadvantages were improved in CN/CA-F. Although CA-F made of chitosan with a high deacetylation degree exhibited fairly good absorption of exudates, the rate of reduction of the wound area was not promoted. On the other hand, CN/CA-F made using chitosan with moderate deacetylation degrees was fairly flexible and adaptable to the wound surface, and showed a significantly faster rate of reduction of the wound area. In addition, the effect of CN/CA-F on wound states and reduction of the wound area was better than with Beschitin W. CN/CA-F showed fairly good absorption of exudates and fairly good maintenance of flexibility and structure strength, leading to a good environment for tissue recovery. Furthermore, improved wound states, such as a reduction of pus, were observed in CN/CA-F, which was considered to be associated with chitosan’s antimicrobial effects. The inhibition of infection resulted in better wound states and promotion of the rate of wound healing. CN/CA-F is considered to be an excellent dressing for the treatment of severe burn wounds.

8.3.2 Novel wound dressings loaded with bioactive substances PVA sponge containing chito-oligosaccharide Chito-oligosaccharides (COS), obtained by the hydrolysis of chitin and chitosan, exhibit biological functions such as immunostimulating action, and these biological properties are dependent on the number of sugars contained as well as N-acetyl-COS (Suzuki et al., 1986; Tokoro et al., 1988, 1989). COS consisting of 5–6 sugars shows high biological activity. COS is attracting attention as a new bioactive substance and is expected to exhibit effective and high interaction with tissue because it has a much lower molecular weight than chitosan. You et al. developed polyvinyl alcohol (PVA) sponge containing COS and examined its efficacy in wound healing (You et al., 2004). Sponges with various PVA/COS ratios, called PVA/ COS-S, were prepared by mixing in aqueous solution and subsequent lyophilization. PVA/COS-S inhibited the growth of bacteria, while simple

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PVA sponge (PVA-S) showed no antimicrobial activity. PVA/COS-S released COS gradually over several days. The rate of wound healing was examined, using rats with full-thickness wounds. When compared with cotton gauze (the control), PVA-S and PVA/COS-S showed faster closure of the wound. PVA/COS-S was more effective than PVA-S, and PVA/ COS-A with a higher ratio of COS showed a faster rate of reduction of the wound area. COS-loaded PVA sponge can easily be prepared and is considered a useful formulation for wound treatment because of its high degree of effectiveness. Poly(l-leucine) sponge loaded with silver sulfadiazine Various kinds of dressings or formulations have been developed for the treatment of wound healing, but infection is still a serious problem in clinical use. In particular, excessive exudates and the appearance of pus occur frequently in severe or chronic wounds. In these cases, quick drainage of the exudates and the supply of antimicrobial agents may be needed in addition to ensuring the moist environment. Poly(l-leucine) is insoluble in aqueous conditions, less toxic and slowly biodegradable. These characteristics may be appropriate for impregnating pharmaceutical agents and supplying them gradually to the wound. A poly(l-leucine) sponge containing silver sulfadiazine (AgSD), called PL/AgSD-S, was prepared by mixing and subsequent lyophilization (Kuroyanagi et al., 1991, 1992). The release of AgSD from the sponge was examined in vivo using mice with fullthickness dorsal skin wounds: that is, the remaining amount of AgSD was measured after application to the wound. The AgSD was gradually released over one week. Its in vivo antibacterial activity was examined using mice with full-thickness dorsal skin wounds, inoculated with bacteria such as Staphylococcus aureus or Pseudomonas aeruginosa. Twelve hours after inoculation, the formulation was applied to the wound and the number of bacteria was counted. Compared with the non-treated group, the sponge suppressed the growth of S. aureus or P. aeruginosa. This study demonstrated that the AgSD-loaded poly(l-leucine) sponge would be useful in the treatment of bacteria-infected wounds. When this sponge was clinically tested using patients with burn wounds or pressure ulcers, it showed excellent protection and suppression of infection. Ointments and creams are still used in the treatment of severe wounds such as serious burns and pressure ulcers, but they require frequent change of the formulation and gauze used as a cover, resulting in a burden for the patients. However, dressings such as PL/AgSD-S are easy to handle, provide wound protection and good suppression of infection, and result in an enhanced quality of life (QOL) for patients. Various other types of dressing containing AgSD were also

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reported to show these advantages (Tachihara et al., 1997b; Cho et al., 2002). These formulations are considered useful for the treatment of severe or chronic wounds. Chitosan/polyurethan films containing minocycline Chitin/chitosan-blended films have also been shown to be effective for the treatment of severe burn wounds (Tachihara et al., 1997a). In that study, the fi lms made of chitosan with a high degree of deacetylation were also found to be more effective than chitin film and gauze alone. However, these blended or chitosan fi lms did not necessarily demonstrate good wound states in terms of the elimination of pus, etc. Minocycline (MC) is widely and highly effective in the suppression of bacteria in skin ulcers (Shigeyama et al., 2001). In fact, attempts have also been made to develop topical formulations containing MC (Shigeyama et al., 1999, 2001). However, these semi-solid formulations require frequent changing and multiple washing of the wound, leading to pain or burden for the patients. Dressings are considered to be better for usability and QOL. Therefore, the combination of dressings and some antimicrobial agents was suggested to improve efficacy. Chitosan/PU fi lms were produced, called CA/MC-F, in which MC powder was sandwiched between chitosan fi lm, controlling the release of MC, and the PU fi lm (TegadermTM) acting as a backing fi lm, (Aoyagi et al., 2007). The CA/MC-F, composed of chitosan with an 83% deacetylation degree and a small amount of MC (2 mg), called CA83/MC-F, showed a gradual drug release over 2 days in vitro and in vivo. CA83/MCF, CA83 fi lm, MC ointment, Geben cream and Beschitin W were applied to full-thickness burn wounds in rats in the early stage (Days 2 and 4), and the reduction rate of the wound area and wound states were compared between the different formulations. CA83/MC-F and CA83 fi lm showed a faster reduction rate of the wound area than MC ointment, Geben cream and Beschitin W (Fig. 8.4). When the wound underwent complete occlusion, the wound states deteriorated owing to excessive exudates. Appropriate drainage seemed to be required to promote wound healing. When a greater amount of MC (10 mg) was contained, the sandwich fi lm showed a worse effect because MC remained too long on and in the wound. Prolonged use and overuse of MC appeared to worsen wound states and delay wound healing. CA83 fi lm and CA83/MC-F containing 2 mg of MC exhibited improved wound states and promoted wound closure rate when it was applied in conditions allowing appropriate drainage. Given the effect on wound states, CA83/MC-F may be more effective than CA83 fi lm. Chitosan/PU fi lm containing MC is suggested as a useful formulation for the treatment of severe burn wounds.

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Advanced textiles for wound care Control CA83/MC-F CA83 film Beschitin W MC ointment Geben cream

100

Wound area(%)

75

50

25

0 0

5

10

15

Time (days)

8.4 Change of wound area after application of preparations. Mean (n = 3) (Aoyagi et al., 2007).

8.4

Future trends

Many dressings other than the novel dressing formulations described above have also been developed recently. Materials which not only provide appropriate environments but also function well to promote wound healing will become important in obtaining more effective dressings or formulations. Technical innovation and the discovery of better functional substances are being actively progressed. Some interesting current studies in the development of novel dressings or formulations are described below.

8.4.1 Nanofibrous non-woven matrices In the field of textiles, an electrospinning method is one of the technical innovations for the production of nanofibers (Greiner and Wendorff, 2007). In addition to the nanofibrous PU membrane referred to above, nanofibrous non-woven textiles have been manufactured with chitin, collagen and silk fibroin (Min et al., 2004c; Noh et al., 2006; Roh et al., 2006). These biosynthetic polymers are considered invaluable owing to their promotion of tissue generation and wound healing. Chitin nanofibrous non-woven matrices (Ch-N) and conventional fibrous nonwoven membrane Beschitin W (Ch-M) were compared with respect to their scaffold characteristics for tissue regeneration and wound healing, that is, for cell attachment and the spreading of keratinocytes and fibroblasts (Noh et al., 2004). The Ch-N consisted of electrospun chitin fibers of a few hundred nanometers

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100 μm

(a)

(b)

213

100 μm

8.5 Structures of (a) chitin nanofiber (Ch-N) and (b) Beschitin W (Ch-M) (Noh et al., 2006).

diameter, while the Ch-M was composed of approximately 10-μm-thick chitin microfibers (Fig. 8.5). The Ch-N showed faster biodegradation than Ch-M, Ch-N promoted cell attachment and spreading of keratinocytes and fibroblasts, more than Ch-M did, and Ch-N coated with type I collagen promoted cellular response. These results suggest that Ch-N would be useful for wound healing. Collagen nanofibrous matrices were also fabricated by the electrospinning technique and found to be effective for wound healing. Furthermore, silk fibroin nanofibrous non-woven matrices, produced by the same technique, showed good cell attachment and spreading of keratinocytes and fibroblasts. Thus, nanofibrous non-woven matrices manufactured with these biocompatible biosynthetic polymers are considered a very effective candidate as a novel dressing for the treatment of severe wounds, because they can provide a similar structure and function to those of the natural extracellular matrix (ECM). They are now expected to offer very high potential as a technique for recovery from severe wounds, and will be examined actively in the future.

8.4.2 Bioactive dressings A further trend may consist of a combination of dressings and bioactive substances including pharmaceutical agents. N-(2,2,2-Trifluoroethyl)-8methoxy-4-methyl-2-benzazepin-3-one was found to promote the repair of skin wounds by facilitating epithelial cell migration, and this 2-benzazepine derivative is a potential new drug for the treatment of such wounds

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(Matsuura et al., 2007). Antibiotics are still useful in suppressing infection. Minocycline-based formulations or silver-based dressings have also been examined, as described above. Furthermore, composites made from a polymer matrix and a controlled release system, such as collagen sponges with gentamycin-loaded poly(dl-lactide-co-glycolide) (PLGA) microparticles, have been developed to achieve both promotion of wound healing and suppression of infection (Schlapp and Friess, 2003; Friess and Schlapp, 2006). Recently, bioactive peptides or proteins, importantly related to the promotion of wound healing, have shown a high potential for clinical use. For example, since the basic fibroblast growth factor (bFGF) promotes the proliferation and growth of fibroblast cells and vascular endothelial cells, it is useful to accelerate wound healing (Yamamoto et al., 2000; Huang et al., 2006). These functions can operate efficiently when used with dressings that provide appropriate environments for the wounds. A gelatin sponge dressing containing bFGF-loaded gelatin microspheres (GMbFGF) showed more sustained release of bFGF, as compared with a gelatin sponge containing free bFGF (GS-bFGF) (Fig. 8.6), and a greater degree of reduction in the wound area in pigs with full-thickness skin defects (Huang et al., 2006). The dressing was biocompatible and did not cause foreign-body reaction. The newly formed dermis exhibited almost the same structure as that of normal skin. Dressings loaded with bioactive proteins are suggested as useful and novel wound formulations. Although the use of bioactive proteins is difficult owing to problems such as the determination of optimal concentrations, they are certain to be useful for wound 5

bFGF released (μg)

4

3 GS-bFGF 2

GM-bFGF

1

0 0

1

2

3

4

5

6

7

Time (days)

8.6 Release of bFGF from GS-bFGF (sponge containing free bFGF) and GM-bFGF (sponge containing microspheres loaded with bFGF) (Huang et al., 2006).

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healing and will be examined actively in the future. In addition, pharmacologically active natural substances such as polysaccharides have received much attention due to their multi-functionality and low toxicity. Polysaccharides isolated from the fungus Phellinus gilvus were also found to be effective in promoting wound healing (Bae et al., 2005). Natural bioactive substances will be useful candidates for dressing/bioactive substance composites in the treatment of severe burn wounds.

8.5

Sources of further information and advice

Dressings and formulations relating to the healing of severe or chronic wounds cover various fields of science, such as medical science, biomedical engineering, biomaterials, cellular biology, microbiology, pharmacology and pharmaceuticals. Information on dressings and pharmaceutics that have already been officially approved can be obtained from package inserts, brochures, publications and websites made publicly available by administrative organisations. These provide information on their application and regulation of use. Practical guides, patents and papers issued by companies or manufacturers are also very useful for obtaining detailed information. News about medicines, industries and the development and research of companies also help us to obtain current or future information. Papers from universities and research institutes provide concepts, methodologies and the evaluation of individual research studies. Many books and reviews about wound healing have recently been published. Biomaterial science is probably at the center of this field, but various sciences are considered fundamentally or practically to promote the development of dressings and formulations for the treatment of severe wounds. Furthermore, it must not be forgotten that, along with the development of materials, dressings and formulations, the establishment of their proper use, depending on wound states and patient conditions, is also of great importance.

8.6

References

agren m s, everland h, ‘Two hydrocolloid dressings evaluated in experimental full-thickness wounds in the skin’, Acta Derm Venereol, 1997 77(2) 127–31. akita s, akino k, imaizumi t, tanaka k, anraku k, yano h, hirano a, ‘The quality of pediatric burn scars is improved by early administration of basic fibroblast growth factor’, J Burn Care Res, 2006 27(3) 333–8. aoyagi s, onishi h, machida y, ‘Novel chitosan wound dressing loaded with minocycline for the treatment of severe burn wounds’, Int J Pharm, 2007 330(1–2) 138–45. asai j, takenaka h, katoh n, kishimoto s, ‘Dibutyryl cAMP influences endothelial progenitor cell recruitment during wound neovascularization’, J Invest Dermatol, 2006 126(5) 1159–67.

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atiyeh b s, costagliola m, hayek s n, dibo s a, ‘Effect of silver on burn wound infection control and healing: review of the literature’, Burns, 2007 33(2) 139–48. bae j s, jang k h, park s c, jin h k, ‘Promotion of dermal wound healing by polysaccharides isolated from Phellinus gilvus in rats’, J Vet Med Sci, 2005 67(1) 111–4. berry d p, bale s, harding k g, ‘Dressings for treating cavity wounds’, J Wound Care, 1996 5(1) 10–7. breloff j p, caffesse r g, ‘Effect of Achromycin ointment on healing following periodontal surgery’, J Periodontol, 1983 54(6) 368–72. brett d w, ‘A review of moisture-control dressings in wound care’, J Wound Ostomy Continence Nurs, 2006 33(6 Suppl) S3–8. bryan j, ‘Moist wound healing: a concept that changed our practice’, J Wound Care, 2004, 13(6) 227–8. caputo g m, cavanagh p r, ulbrecht j s, gibbons g w, karchmer a w, ‘Assessment and management of foot disease in patients with diabetes’, N Engl J Med, 1994 331(13) 854–60. cho y s, lee j w, lee j s, lee j h, yoon t r, kuroyanagi y, park m h, pyun d g, kim h j, ‘Hyaluronic acid and silver sulfadiazine-impregnated polyurethane foams for wound dressing application’, J Mater Sci Mater Med, 2002 13(9) 861–5. clark r a, nielsen l d, welch m p, mcpherson j m, ‘Collagen matrices attenuate the collagen-synthetic response of cultured fibroblasts to TGF-beta’, J Cell Sci, 1995 108(Pt 3) 1251–61. clark r a (1996), ‘Wound repair – overview and general considerations’, in Clark R A, The molecular and cellular biology of wound repair (2nd ed.), New York, Plenum Press, 3–50. cosker t, elsayed s, gupta s, mendonca a d, tayton k j, ‘Choice of dressing has a major impact on blistering and healing outcomes in orthopaedic patients’, J Wound Care, 2005 14(1) 27–9. cross k j, mustoe t a, ‘Growth factors in wound healing’, Surg Clin North Am, 2003 83(3) 531–45. diehm c, lawall h, ‘Evaluation of Tielle hydropolymer dressings in the management of chronic exuding wounds in primary care’, Int Wound J, 2005 2(1) 26–35. dowsett c, ‘The use of silver-based dressings in wound care’, Nurs Stand, 2004 19(7) 56–60. ervin v, ‘The effect of chitin powder on the healing of skin wounds’, Magy Traumatol Orthop Helyreallito Seb, 1976 19(2) 108–14. fletcher j, ‘Managing wound exudate’, Nurs Times, 2003 99(5) 51–2. friess w, schlapp m, ‘Sterilization of gentamicin containing collagen/PLGA microparticle composites’, Eur J Pharm Biopharm, 2006 63(2) 176–87. gabbiani g, ryan g b, majne g, ‘Presence of modified fibroblasts in granulation tissue and their possible role in wound contraction’, Experientia, 1971 27(5) 549–50. gilchrist t, martin a m, ‘Wound treatment with Sorbsan – an alginate fibre dressing’, Biomaterials, 1983 4(4) 317–20. gobin a s, froude v e, mathur a b, ‘Structural and mechanical characteristics of silk fibroin and chitosan blend scaffolds for tissue regeneration’, J Biomed Mater Res A, 2005 74(3) 465–73.

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greiner a, wendorff j h, ‘Electrospinning: a fascinating method for the preparation of ultrathin fibers’, Angew Chem Int Ed Engl, 2007 46(30) 5670–703. holland k t, harnby d, peel b, ‘A comparison of the in vivo antibacterial effects of “OpSite”, “Tegaderm” and “Ensure” dressings’, J Hosp Infect, 1985 6(3) 299–303. hong j p, jung h d, kim y w, ‘Recombinant human epidermal growth factor (EGF) to enhance healing for diabetic foot ulcers’, Ann Plast Surg, 2006 56(4) 394–8; discussion 399–400. horncastle j, ‘Wound dressings. Past, present, and future’, Med Device Technol, 1995 6(1) 30–4, 36. huang s, deng t, wu h, chen f, jin y, ‘Wound dressings containing bFGFimpregnated microspheres’, J Microencapsul, 2006 23(3) 277–90. jude e b, apelqvist j, spraul m, martini j, silver dressing study group, ‘Prospective randomized controlled study of Hydrofiber dressing containing ionic silver or calcium alginate dressings in non-ischaemic diabetic foot ulcers’, Diabet Med, 2007 24(3) 280–8. kakigi a, sawada s, takeda t, ‘The effects of basic fibroblast growth factor on postoperative mastoid cavity problems’, Otol Neurotol, 2005 26(3) 333–6. kawabata h, kamada t, takatsuka y, takeuchi s, suzuki s, makino t, utsunomiya a, ‘Successful treatment for leg ulcers due to hydroxyurea in a patient with chronic myelogenous leukaemia’, Haematologia (Budap), 2002 31(4) 369–72. kaya a z, turani n, akyüz m, ‘The effectiveness of a hydrogel dressing compared with standard management of pressure ulcers’, J Wound Care, 2005 14(1) 42–4. khil m s, cha d i, kim h y, kim i s, bhattarai n, ‘Electrospun nanofibrous polyurethane membrane as wound dressing’, J Biomed Mater Res B Appl Biomater, 2003 67(2) 675–9. koksal c, bozkurt a k, ‘Combination of hydrocolloid dressing and medical compression stockings versus Unna’s boot for the treatment of venous leg ulcers’, Swiss Med Wkly, 2003 133(25–26) 364–8. kuroyanagi y, kim e, shioya n, ‘Evaluation of a synthetic wound dressing capable of releasing silver sulfadiazine’, J Burn Care Rehabil, 1991 12(2) 106–15. kuroyanagi y, kim e, kenmochi m, ui k, kageyama h, nakamura m, takeda a, shioya n, ‘A silver-sulfadiazine-impregnated synthetic wound dressing composed of poly-l-leucine spongy matrix: an evaluation of clinical cases’, J Appl Biomater, 1992 3(2) 153–61. lansdown a b, ‘Silver in health care: antimicrobial effects and safety in use’, Curr Probl Dermatol, 2006 33 17–34. lee a h, swaim s f, yang s t, wilken l o, ‘Effects of gentamicin solution and cream on the healing of open wounds’, Am J Vet Res, 1984 45(8) 1487–92. levine n, seifter e, connerton c, levenson s m, ‘Debridement of experimental skin burns of pigs with bromelain, a pineapple-stem enzyme’, Plast Reconstr Surg, 1973 52(4) 413–24. martin p, hopkinson-woolley j, mccluskey j, ‘Growth factors and cutaneous wound repair’, Prog Growth Factor Res, 1992 4(1) 25–44. martineau l, shek p n, ‘Evaluation of a bi-layer wound dressing for burn care. II. In vitro and in vivo bactericidal properties’, Burns, 2006 32(2) 172–9. matsuura k, kuratani t, gondo t, kamimura a, inui m, ‘Promotion of skin epithelial cell migration and wound healing by a 2-benzazepine derivative’, Eur J Pharmacol, 2007 563(1–3) 83–7.

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matthew i r, browne r m, frame j w, millar b g, ‘Subperiosteal behaviour of alginate and cellulose wound dressing materials’, Biomaterials, 1995 16(4) 275–8. mi f l, wu y b, shyu s s, schoung j y, huang y b, tsai y h, hao j y, ‘Control of wound infections using a bilayer chitosan wound dressing with sustainable antibiotic delivery’, J Biomed Mater Res, 2002 59(3) 438–49. min b m, lee g, kim s h, nam y s, lee t s, park w h, ‘Electrospinning of silk fibroin nanofibers and its effect on the adhesion and spreading of normal human keratinocytes and fibroblasts in vitro’, Biomaterials, 2004a 25(7–8) 1289–97. min b m, jeong l, nam y s, kim j m, kim j y, park w h, ‘Formation of silk fibroin matrices with different texture and its cellular response to normal human keratinocytes’, Int J Biol Macromol, 2004b 34(5) 281–8. min b m, lee g, kim s h, nam y s, lee t s, park w h, ‘Electrospinning of silk fibroin nanofibers and its effect on the adhesion and spreading of normal human keratinocytes and fibroblasts in vitro’, Biomaterials, 2004c 25(7–8) 1289–97. nelson e a, iglesias c p, cullum n, torgerson d j, venus i collaborators, ‘Randomized clinical trial of four-layer and short-stretch compression bandages for venous leg ulcers (VenUS I)’, Br J Surg, 2004 91(10) 1292–9. nishimura k, nishimura s, nishi n, saiki i, tokura s, azuma i, ‘Immunological activity of chitin and its derivatives’, Vaccine, 1984 2(1) 93–9. noh h k, lee s w, kim j m, oh j e, kim k h, chung c p, choi s c, park w h, min b m, ‘Electrospinning of chitin nanofibers: degradation behavior and cellular response to normal human keratinocytes and fibroblasts’, Biomaterials, 2006 27(21) 3934–44. piaggesi a, baccetti f, rizzo l, romanelli m, navalesi r, benzi l, ‘Sodium carboxyl-methyl-cellulose dressings in the management of deep ulcerations of diabetic foot’, Diabet Med, 2001 18(4) 320–4. roh d h, kang s y, kim j y, kwon y b, young kweon h, lee k g, park y h, baek r m, heo c y, choe j, lee j h, ‘Wound healing effect of silk fibroin/alginate-blended sponge in full thickness skin defect of rat’, J Mater Sci Mater Med, 2006 17(6) 547–52. rovee d t, kurowsky c a, labun j, downes a m (1972), ‘Effect of local wound environment on epidermal healing’, in Maibach H, Rovee D T, Epidermal wound healing, Chicago, Year Book Medical Publishers, 159–181. rubin j r, alexander j, plecha e j, marman c, ‘Unna’s boot vs polyurethane foam dressings for the treatment of venous ulceration. A randomized prospective study’, Arch Surg, 1990 125(4) 489–90. schlapp m, friess w, ‘Collagen/PLGA microparticle composites for local controlled delivery of gentamicin’, J Pharm Sci, 2003 92(11) 2145–51. schwarz n, ‘Wound cleansing with the enzyme combination fibrinolysin/deoxyribonuclease’, Fortschr Med, 1981 99(25) 978–80. seaman s, ‘Dressing selection in chronic wound management’, J Am Podiatr Med Assoc, 2002 92(1) 24–33. seo h, mitsuhashi k, tanibe h (1992), ‘Antibacterial and antifungal fiber blended by chitosan’, in Brine C J, Sandford P A, Zikakis J P, Advances in chitin and chitosan, London, Elsevier Applied Science, 34–40.

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shigeyama m, ohgaya t, kawashima y, takeuchi h, hino t, ‘Mixed base of hydrophilic ointment and purified lanolin to improve the drug release rate and absorption of water of minocycline hydrochloride ointment for treatment of bedsores’, Chem Pharm Bull, 1999 47(6) 744–8. shigeyama m, ohgaya o, takeuchi h, hino t, kawashima y, ‘Formulation design of ointment base suitable for healing of lesions in treatment of bedsores’, Chem Pharm Bull, 2001 49(2) 129–33. simons j j, morales a, ‘Minocycline and generalized cutaneous pigmentation’, J Am Acad Dermatol, 1980 3(3) 244–7. sobotka l, velebný v, smahelová a, kusalová m, ‘Sodium hyaluronate and an iodine complex – Hyiodine – new method of diabetic defects treatment’, Vnitr Lek, 2006 52(5) 417–22. sobotka l, smahelova a, pastorova j, kusalova m, ‘A case report of the treatment of diabetic foot ulcers using a sodium hyaluronate and iodine complex’, Int J Low Extrem Wounds, 2007 6(3) 143–7. stotts n a, hunt t k, ‘Pressure ulcers. Managing bacterial colonization and infection’, Clin Geriatr Med, 1997 13(3) 565–73. su c h, sun c s, juan s w, hu c h, ke w t, sheu m t, ‘Fungal mycelia as the source of chitin and polysaccharides and their applications as skin substitutes’, Biomaterials, 1997 18(17) 1169–74. su c h, sun c s, juan s w, ho h o, hu c h, sheu m t, ‘Development of fungal mycelia as skin substitutes: effects on wound healing and fibroblast’, Biomaterials, 1999 20(1) 61–8. sugihara a, sugiura k, morita h, ninagawa t, tubouchi k, tobe r, izumiya m, horio t, abraham n g, ikehara s, ‘Promotive effects of a silk fi lm on epidermal recovery from full-thickness skin wounds’, Proc Soc Exp Biol Med, 2000 225(1) 58–64. suzuki k, mikami t, okawa y, tokoro a, suzuki s, suzuki m, ‘Antitumor effect of hexa-N-acetylchitohexaose and chitohexaose’, Carbohydr Res, 1986 151 403–8. suzuki y, nishimura y, tanihara m, suzuki k, nakamura t, shimizu y, yamawaki y, kakimaru y, ‘Evaluation of a novel alginate gel dressing: cytotoxicity to fibroblasts in vitro and foreign-body reaction in pig skin in vivo’, J Biomed Mater Res, 1998 39(2) 317–22. suzuki y, tanihara m, nishimura y, suzuki k, yamawaki y, kudo h, kakimaru y, shimizu y, ‘In vivo evaluation of a novel alginate dressing’, J Biomed Mater Res, 1999 48(4) 522–7. tachihara k, onishi h, machida y, ‘Evaluation of fi lms of chitin, chitosan and chitin–chitosan mixture as dressings for dermal burn wounds’, Yakuzaigaku, 1997a 57(1) 40–49. tachihara k, onishi h, machida y, ‘Preparation of silver sulfadiazine-containing spongy membranes of chitosan and chitin–chitosan mixture and their evaluation as burn wound dressings’, Yakuzaigaku, 1997b 57(3) 159–167. tokoro a, tatewaki n, suzuki k, mikami t, suzuki s, suzuki m, ‘Growth-inhibitory effect of hexa-N-acetylchitohexaose and chitohexaose against Meth-A solid tumor’, Chem Pharm Bull, 1988 36(2) 784–90. tokoro a, kobayashi m, tatewaki n, suzuki k, okawa y, mikami t, suzuki s, suzuki m, ‘Protective effect of N-acetyl chitohexaose on Listeria monocytogenes infection in mice’, Microbiol Immunol, 1989 33(4) 357–67.

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vanstraelen p, ‘Comparison of calcium sodium alginate (KALTOSTAT) and porcine xenograft (E-Z DERM) in the healing of split-thickness skin graft donor sites’, Burns, 1992 18(2) 145–8. walker m, hobot j a, newman g r, bowler p g, ‘Scanning electron microscopic examination of bacterial immobilisation in a carboxymethyl cellulose (AQUACEL) and alginate dressings’, Biomaterials, 2003 24(5) 883–90. winter g d, scales j t, ‘Effect of air drying and dressings on the surface of a wound’, Nature, 1963 197 91–2. wysocki a b, ‘Evaluating and managing open skin wounds: colonization versus infection’, AACN Clin Issues, 2002 13(3) 382–97. yamamoto m, tabata y, kawasaki h, ikada y, ‘Promotion of fibrovascular tissue ingrowth into porous sponges by basic fibroblast growth factor’, J Mater Sci Mater Med, 2000 11(4) 213–8. yeo j h, lee k g, kim h c, oh h y l, kim a j, kim s y, ‘The effects of PVA/chitosan/ fibroin (PCF)-blended spongy sheets on wound healing in rats’, Biol Pharm Bull, 2000 23(10) 1220–3. yoshida t, ohura t, sugihara t, yoshida t, ishikawa t, homma k, kouraba s, kimura c, murazumi m, ‘Clinical efficacy of silver sulfadiazine (AgSD: Geben cream) for ulcerative skin lesions infected with MRSA’, Jpn J Antibiot, 1997 50(1) 39–44. you y, park w h, ko b m, min b m, ‘Effects of PVA sponge containing chitooligosaccharide in the early stage of wound healing’, J Mater Sci Mater Med, 2004 15(3) 297–301.

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9 Drug delivery dressings P. K. SE HGA L, R. SR I P R I YA and M. SE N T H I L K U M A R, Central Leather Research Institute, India

Abstract: A description of wound types is presented and the wounds that need drug delivery dressings are identified. Both acute and chronic wounds require drugs for controlling infection during healing. Healing of such wounds needs proper management mediated through the concept of delivering drug to the wound site. The properties of drug delivery dressings are described. Some dressings control the transport of biological fluids, whereas others offer haemostatic properties leading to control of infection and improved healing. With the advent of tissue engineering technology and advances in micro and nanotechnology, gene delivery and stem cell research, it is possible to design and construct an environment-sensitive dressing tailor-made to the specific wound type leading to its complete healing without any adverse reactions. Key words: acute wounds, chronic wounds, drug delivery dressings, infection control, healing.

9.1

Introduction

The administration of topical medications to wound sites is one of the most documented areas in medical history.1 Conventional wound therapy comprised primarily of various ointments, local antimicrobial agents, and sterile bandages. 2 In the early 1980s, very few dressing types were available; they comprised mainly traditional dressings, paste bandages and similar preparations. During the mid-1980s modern wound management products began to emerge and hospitals across the world started using them in a small way. Today, their uses have increased manifold. The principal function of a wound dressing is to protect the wound from infection and dehydration and to provide an optimum healing environment. The choice of a wound dressing is dependent on the cause, presence of infection, wound type and size, stage of wound healing, cost and patient acceptability. One dressing type may not be appropriate for all wounds. An ideal wound dressing should have a host of advantages which includes rapid and cosmetically acceptable healing to prevent or combat infection, inducing haemostasis, non-toxic, non-allergic and non-sensitizing nature of the material to absorb wound exudates and wound odour, to provide debridement action and thermal insulation and to allow gaseous and fluid exchange. 223

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In addition to this, it should be cost-effective with a long shelf-life and provide maximum comfort to the patients. 3 Wound dressings are mainly employed to prevent bulk loss of tissue and they are effective against trauma, chronic wounds such as chronic burn wounds, and diabetic, decubitus and venous stasis ulcers. Where there is infection, the dressings applied without the use of a drug may not be effective because the infectious organisms preferentially target the wound beneath the dressing materials and elicit serious infections requiring removal of the dressing for further treatment and healing.4–7 Treatment of these wounds requires the suppression and control of bacterial growth. Such wounds require topical antimicrobial treatment with a dressing for proper management and healing. Here, the role of drug delivery dressings can play an important role in the effective healing and proper management of wounds. Current efforts in the area of drug delivery in wound dressings include the development of targeted delivery in which the drug shows activity at the wound site. Sustained release formulations in which the drug is released over a period of time in a controlled manner are effective in such cases. Localized drug delivery technologies are emerging as a way to target an optimum dose of a bioactive substance precisely where it is needed, rather than distributing excessive and unnecessary drug over the wound and avoiding excessive drug spreading throughout the body via the systemic circulation. Targeting an optimum dose can be especially useful for drugs with a narrow therapeutic index, i.e. the difference between the dose at which the drug becomes therapeutically active and the dose at which undesired side effects can occur. Dressings can be significantly more effective and safer than their intravenous (IV) or orally administered counterparts, particularly with respect to unwanted side effects. The interest in formulated dosage forms, where the drug release can be controlled, has increased steadily during the last five decades. In most cases, the purpose is to make a product that maintains a prolonged therapeutic effect at a reduced dosing frequency.8 In addition to improved efficacy and safety, the frequency of administration can be decreased with sustained delivery, thereby improving patient compliance. Controlled release systems are particularly useful for drugs which have relatively short half-lives and require a high frequency of administration in conventional dosage forms.

9.2

Wounds: definition and types

A wound is a type of physical trauma wherein the skin is torn, cut or punctured to create an open wound or where blunt force trauma causes a contusion to create a closed wound. In pathology, a wound specifically refers to a sharp injury which damages the dermis of the skin.

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The types of open wound are incisions or incised wounds; incisions which involve only the epidermis are classified as cuts, rather than wounds. Lacerations are irregular wounds caused by a blunt impact to soft tissue which lies over hard tissue. Abrasions (grazes) are a superficial wound in which the topmost layers of the skin (the epidermis) are scraped off, often caused by a sliding fall onto a rough surface. Puncture wounds are caused by an object puncturing the skin, such as a nail or needle. Penetration wounds are caused by an object such as a knife entering the body. Gunshot wounds are caused by a bullet or similar projectile driving into or through the body. Since the open wound is a disruption of normal anatomic structure and function,9 it can be classified in many ways. We may call it an acute or chronic wound depending upon its nature or duration or type. By definition, an acute wound is acquired as a result of trauma or an operative procedure and proceeds normally in a timely fashion along the healing pathway with least external manifestations without complications.10 Surgically created wounds include all incisions, excisions, and wounds that are surgically debrided and non-surgical wounds include all skin lesions that have occurred as a result of trauma (e.g. burns, falls) and such acute wounds are usually successfully managed with local wound care. Wounds that fail to heal in the anticipated time frame and often recur are considered chronic wounds. These wounds present major challenges to healthcare professionals and have serious consequences for the patient’s quality of life. These wounds are visible evidence of an underlying condition such as extended pressure on the tissues, poor circulation, or even poor nutrition. Pressure ulcers, venous leg ulcers, and diabetic foot ulcers are examples of chronic wounds. Successful management of chronic wounds demands treatment of the whole body of the person who is suffering with such wounds. It involves meticulous local wound care, an understanding of the need to diagnose the reason for the specific wound and to treat the underlying cause, a working knowledge of modern wound dressings, and correction and management of the patient’s underlying conditions for effective recovery and management. Wound depth is classified by the initial level of tissue destruction evident in the wound: superficial, partial thickness, or full thickness.11 Superficial wounds involve only the epidermis, partial-thickness wounds involve only epidermis and dermis, and full-thickness wounds involve the subcutaneous fat or deeper tissue. Before any medical or paramedical evaluation or intervention is attempted, an open wound is considered as minor if it is superficial and away from natural orifices, if there is only minor bleeding and if it is not caused by a tool or an animal. Any other wound should be considered as severe. For severe open wounds, there is a risk of blood loss which could lead to shock and an increased chance of infection as bacteria may enter a wound from surrounding tissue or air. Owing to the risk of infection, the

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wound should be kept clean, and closed if possible until professional help is available. Closed wounds have fewer categories, but are just as dangerous as open wounds. The types of closed wounds are contusions (more commonly known as bruises), caused by blunt force trauma that damages tissue under the skin; haematoma (also called a blood tumour), caused by damage to a blood vessel that in turn causes blood to collect under the skin; and crushing injuries, caused by a great or extreme amount of force applied over a long period of time. Wounds are also classified as: wounds without tissue loss (e.g. in surgery, cuts, incisions) and wounds with tissue loss, such as burn wounds, wounds caused as a result of trauma, abrasions or as secondary events in chronic ailments, e.g. venous stasis, diabetic ulcers or pressure sores and iatrogenic wounds such as skin graft donor sites and dermabrasions.

9.3

Wounds which require drug delivery

Restoration of tissue continuity after injury is a natural phenomenon. Infection, quality of healing, speed of healing, fluid loss and other complications that enhance the healing time represent a major clinical challenge. Acute wounds are expected to heal within a predictable time frame, although the treatment required to facilitate healing will vary according to the type, site, and depth of a wound. The primary closure of a clean, surgical wound would be expected to require minimal intervention to enable healing to progress naturally and quickly. However, in a more severe traumatic injury such as a burn wound or gunshot wound, the presence of devitalized tissue and contamination with viable (e.g. bacterial) and non-viable foreign material is likely to require surgical debridement and antimicrobial therapy to enable healing to progress through a natural series of processes, including inflammation and granulation, to fi nal reepithelialization and remodelling. In marked contrast, chronic wounds are most frequently caused by endogenous mechanisms associated with a predisposing condition that ultimately compromises the integrity of dermal and epidermal tissue.12 Pathophysiological abnormalities that may predispose to the formation of chronic wounds such as leg ulcers, foot ulcers, and pressure sores include compromised tissue perfusion as a consequence of impaired arterial supply (peripheral vascular disease) or impaired venous drainage (venous hypertension) and metabolic diseases such as diabetes mellitus. Advancing age, obesity, smoking, poor nutrition, and immunosuppression associated with diseases such as AIDS, hepatitis A and B, or cancer, or with drugs (e.g. chemotherapy or radiation therapy) may also exacerbate chronic ulceration. Pressure or decubitus ulcers have a different aetiology from other chronic wounds in that they are caused by sustained

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external skin pressure, most commonly on the buttocks, sacrum, and heels. However, the underlying pathology often contributes to chronicity and, in this situation, pressure sores, like all chronic wound types may sometimes heal slowly and in an unpredictable manner. Chronic wounds involving progressively more tissue loss give rise to the biggest challenge to woundcare product researchers. The second major challenge is the prevention of scarring, keloid formation or contractures and a cosmetically acceptable healing. In these cases, drug delivery dressings prove beneficial for effective and proper wound management.

9.3.1 Wound infections Infection has been defi ned as the deposition and multiplication of organisms in a tissue with an associated host reaction. If the host reaction is small or negligible, then the organism is described as colonizing the wound rather than infecting it. Whether a wound becomes infected or not is determined by the host’s immune competence and the size of the bacterial inoculum. With normal host defences and adequate debridement, a wound may bear a level of 100 000 (105) micro-organisms per gram of tissue and still heal successfully. Beyond this number, a wound may become infected. It is well documented that, if a wound becomes infected, the normal healing is disrupted as the inflammatory phase becomes chronic, disrupting the normal clotting mechanisms and/or promoting disordered leukocyte function. These factors together or independently, prevent the development of new blood vessels and formation of granulation tissue. The production of destructive enzymes and toxins by mixed communities of organisms may also indirectly affect healing. Thus, it is critical to prevent infections which may occur by normal skin wound contaminants. A prolonged inflammatory response results in the release of free radicals and numerous lytic enzymes that could have a detrimental effect on cellular processes involved in wound healing. Proteinases released from a number of bacteria are known to affect growth factors and many other tissue proteins that are necessary for the wound healing process.13,14 The increased production of exudates that often accompanies increased microbial load has been associated with the degradation of growth factors and matrix metalloproteinases (MMPs) which subsequently affect cell proliferation and wound healing.15 Some bacteria are rapidly able to form their own protective microenvironment (biofi lm) following their attachment to a surface and the ability of the host to control these organisms is likely to decrease when this biofi lm community matures. In addition, within a stable, biofilm community, interactions between aerobic and anerobic bacteria would be likely to increase their net pathogenic effect, enhancing their potential to cause infection and delay healing.

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Beta haemolytic streptococci (Streptococcus pyogenes), enterococci (Enterococcus faecalis) and staphylococci (Staphylococcus aureus/MRSA) are the gram positive cocci and Pseudomonas aeruginosa, Gram-negative aerobic rod are the potential wound pathogens. Enterobacter species, Escherichia coli, Klebsiella species and Proteus species are the gramnegative facultative rods and Bacteroides and Clostridium anaerobes are classified as wound pathogens. Yeasts (Candida) and Aspergillus are fungi which are responsible for wound infection.

9.3.2 Acute wounds Acute soft tissue infections Cutaneous abscesses, traumatic wounds, and necrotizing infection are classified as acute soft tissue infections. S. aureus is the single causative bacterium in approximately 25 to 30% of cutaneous abscesses16,17 as shown by microbial investigations, and has been recognized as being the most frequent isolate in superficial infections seen in hospital accidents and emergency departments.18 Contrary to this, studies have revealed the presence of polymicrobial aerobic–anaerobic microflora in approximately 30 to 50% of cutaneous abscesses,19 50% of traumatic injuries of varied aetiology, 20 and 47% of necrotizing soft tissue infections. 21 Necrotizing soft tissue infections occur with different degrees of severity and speed of progression; they involve the skin (e.g. clostridial and non-clostridial anaerobic cellulitis), subcutaneous tissue to the muscle fascia (necrotizing fasciitis), and muscle tissue (streptococcal myositis and clostridial myonecrosis). S. aureus has been described as being the single pathogen in two patients with rapidly progressing necrotizing fasciitis of the lower extremity, 22 and, in a study of necrotizing fasciitis in eight children, 23 the presence was reported of pure S. pyogenes in two patients and a mixed predominance of Peptostreptococcus spp., S. pyogenes, B. fragilis, C. perfringens, E. coli, and Prevotella spp. in the others. Potentiation of infection by microbial synergistic partnerships between aerobes, such as S. aureus and S. pyogenes, and non-sporing anaerobes has been recognized in various types of non-clostridial cellulitis and necrotizing fasciitis. 24 The classification of necrotizing soft tissue infections is complex and based on the assumed causative micro-organism(s), the initial clinical fi ndings, the type and level of tissue involved, the rate of progression, and fi nally the type of therapy required. 25 However, this classification of such infections serves little clinical purpose because the prognosis and treatment are the same and, consequently, differentiation is required only between pure clostridial myonecrosis21 as it involves muscle invasion and is associated with a higher mortality rate and other non-muscle associated soft tissue infections.

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Bite wound infections The reported infection rate for bite wounds in human ranges from 10 to 50% depending on the severity and location of the bite. About 20% of dog bites and 30 to 50% of cat bites become infected.26 In a study reported by Brook, 27 74% of the animal bite wounds infl icted on 39 humans contained, predominantly, a polymicrobial aerobic–anaerobic microflora, comprising S. aureus, Peptostreptococcus spp., and Bacteroides spp. The majority of bite wounds harbour potential pathogens many of which are anaerobes. The common anaerobes in animal bite wounds are Bacteroides, Prevotella, Porphyromonas, and Peptostreptococcus spp. 28 and the less common potential pathogens such as Pasteurella multocida, Capnocytophaga canimorsus, Bartonella henselae, and Eikenella corrodens. 29 Burn wound infections Infection is a major complication in burn wounds, and it is estimated that up to 75% of deaths following burn injury are related to infections. 30 Exposed burnt tissue is susceptible to contamination by micro-organisms from the gastrointestinal and upper respiratory tract; 31 many studies have reported the prevalence of aerobes such as P. aeruginosa, S. aureus, E. coli, Klebsiella spp., Enterococcus spp., and Candida spp. 32 In other studies involving more stringent microbiological techniques, anaerobic bacteria have been shown to represent between 11 and 31% of the total number of microbial isolates from burn wounds. 33 Predominant anaerobic microfloras in burn wound isolates are Peptostreptococcus spp., Bacteroides spp., and Propionibacterium acnes. 34 Mousa 33 also reported the presence of Bacteroides spp. in the wounds of 82% of patients who developed septic shock and concluded that such micro-organisms may play a significant role in burn wound sepsis.

9.3.3 Chronic wounds A chronic wound can be defi ned as a wound in which the normal process of healing has been disrupted at one or more points during the phases of haemostasis, inflammation, proliferation, and remodelling of a wound. Diabetic, decubites and venous ulcers are the most common types of chronic wounds. Diabetic ulcers These are the most common cause of foot and leg amputation. In patients with type I and type II diabetes, the incidence rate of developing foot ulcers is approximately 2% per year. The average cost for 2 years of treatment is $27,987 per patient. 35 The diabetic foot ulcer is mainly neuropathic in

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origin, with secondary pathogenesis being a blunted leukocyte response to bacteria and local ischaemia owing to vascular disease. These wounds usually occur on weight-bearing areas of the foot. Plantar ulcers associated with diabetes mellitus are susceptible to infection due to the high incidence of mixed wound microflora 36 and the inability of the polymorphonuclear neutrophils (PMNs) to deal with invading microorganisms effectively. 37 As in most wound types, S. aureus is a prevalent isolate in diabetic foot ulcers, together with other aerobes including S. epidermidis, Streptococcus spp., P. aeruginosa, Enterococcus spp., and coliform bacteria. 38 With good microbiological techniques, anaerobes have been isolated from up to 95% of diabetic wounds, 39 the predominant isolates being Peptostreptococcus, Bacteroides, and Prevotella spp.40 In view of the polymicrobial nature of diabetic foot ulcers, Karchmer and Gibbons41 suggested that the treatment could be based on a better understanding of the general microbiology of these wounds rather than defi ning the causative microorganism(s). Decubitus (pressure) ulcers Decubitus ulcers develop as a consequence of continued skin pressure over bony prominences; they lead to skin erosion, local tissue ischaemia, and necrosis, and those in the sacral region are particularly susceptible to faecal contamination. The wound tends to occur in patients who are unable to reposition themselves to off-load weight, such as paralyzed, unconscious, or severely debilitated persons. Approximately 25% of decubitus ulcers have underlying osteomyelitis42 and bacteraemia is also common.43 One of the few reported acknowledgements of the role of polymicrobial synergy in chronic wound infection was made by Kingston and Seal,44 who commented that, since the bacteriology of decubitus ulcers is similar to that of some of the acute necrotizing soft tissue infections, the anaerobic and aerobic bacteria involved are likely to contribute to the deterioration of a lesion. The opportunity for microbial synergy in many decubitus ulcers was demonstrated by Brook,45 who reported mixed aerobic and anaerobic microflora in 41% of 58 ulcers in children; S. aureus, Peptostreptococcus spp., Bacteroides spp. (formerly members of the B. fragilis group), and P. aeruginosa were the predominant isolates. Venous ulcers In the venous ulcer, chronic passive venous congestion of the lower extremities results in local hypoxia. One current hypothesis of the pathogenesis of these wounds includes the impediment of oxygen diffusion into the tissue across thick perivascular fibrin cuffs. Another belief is that

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macromolecules leaking into the perivascular tissue trap growth factors needed for the maintenance of skin integrity. Additionally, the flow of large white blood cells slows down owing to venous congestion and occluding capillaries thus becoming activated and fi nally damaging the vascular endothelium leading to ulcer formation. Venous ulcers are the most common form of leg ulcers. Up to 80% of leg ulcers are the result of chronic venous hypertension, most commonly caused by valvular incompetence.46 The microflora of chronic venous leg ulcers is frequently polymicrobial, and anaerobes have been reported to constitute approximately 30% of the total number of isolates in non-infected wounds.47 Although S. aureus is the most prevalent potential pathogen in leg ulcers,48 Bowler and Davies49 reported a significantly greater frequency of anaerobes (particularly Peptostreptococcus spp. and pigmenting and non-pigmenting gram negative bacilli) in clinically infected leg ulcers than in non-infected leg ulcers (49 versus 36% of the total numbers of microbial isolates, respectively). The same investigators also suggested that aerobic–anaerobic synergistic interactions are likely to be more important than specific micro-organisms in the pathogenesis of leg ulcer infection; this mechanism is not widely recognized in the management of surgical 50 and chronic wound infections.

9.4

Delivering drugs to wounds

Once the type of wound is identified and if it is classified as a wound requiring a drug, an appropriate drug that can be effectively or selectively localized on and in the diseased tissue should be the next logical step that requires immediate attention for the recovery of the patient. Delivery of most drugs, whether by oral administration or through injection, follows what is known as fi rst order kinetics. Here, initial high concentrations of the drugs in blood are obtained, followed by an exponential fall in concentrations. This is problematic because therapeutic effectiveness will not ensue once drug concentrations fall below certain levels. Furthermore, some drugs are toxic at high concentrations in blood and it is difficult to achieve a balance between effective levels and toxic levels when the concentration falls off so rapidly. Ideal delivery of drugs should follow zeroorder kinetics, wherein the concentration of drugs in blood would remain constant throughout the delivery period. There are a number of technologies currently available that have been used to provide sustained release, but not necessarily zero-order release, for example, porous polymer microcarriers that contain active pharmaceutical ingredients trapped within interstitial pore channels. The polymers themselves are not reactive, and drug delivery is accomplished utilizing diffusion (Fig. 9.1). This approach allows delivery for extended periods, but there is no evidence that zero-order kinetics is attained. 51,52 In an attempt to approach zero-order

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Advanced textiles for wound care Microparticle containing drug Polymeric matrix

9.1 Schematic diagram showing the diffusion of the drug from a drug loaded micro-particle embedded in a polymeric matrix.

kinetics, extensive work has been carried out in the attachment of biologically active peptides and proteins to poly(lactic acid), poly(lactic co-glycolic acid), and related polyesters. 53 The ideal delivery is particularly important in certain classes of medicines intended, for example, for antibiotic delivery for healing of wounds which include diabetic ulcers, decubitus ulcer, venous static ulcer and other non-healing wounds. Controlled-release systems are most suitable for such wounds. These systems comprise a bioactive agent (a drug) incorporated in a carrier. The main objective of a controlled-release device is to maintain the concentration of the drug within therapeutic limits over the required duration. Compared with conventional drug formulations, such systems typically require smaller and less frequent drug dosage and minimize side effects. Here the release rate is a strong function of the physicochemical properties of the carrier as well as the bioactive agent and may also depend on environmental factors such as pH, ionic strength, temperature, enzymic concentration changes and degree of infection at the site of delivery. The drug release mechanism in some dressings is

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influenced by the inflammatory enzymes or microbial proteases (which are directly proportional to the rate of infection) where the polymer in the drug delivery dressings is degraded by these enzymes thereby releasing the drug from the polymer matrix (Fig. 9.2).

Collagen scaffold containing drug

Macrophage Neutrophil Fibroblast

(a)

MMPs

(b)

(c)

9.2 (a) Infected wound covered with drug-incorporated collagen scaffold; (b) release of MMPs from the inflammatory cells and fibroblast; (c) degradation of scaffold and release of drug to the wound site.

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The design and preparation of pH- and temperature-sensitive drug delivery dressings is another approach in which the dressing has a dual role to play: it must both retain the drug over prolonged periods and then release it relatively rapidly. Here, the drug is incorporated into the copolymer backbone and the solubility of the polymer is altered by temperature, protonation or deprotonation events. In the pH-sensitive linkages, they are designed to undergo hydrolysis under distinct physiological conditions to either directly release the drug, or alter the polymer structure to disrupt or break apart the dressing (see Fig. 9.3). In an ionic binding system, the release of the drug, which is already bound to the polymer backbone by ionic interaction, is regulated by the infected organisms present in the wound. Any alteration in the ionic behaviour of the wound caused by the infected organisms is controlled by the release of the drug from the polymer backbone due to anion–cation interaction (Fig. 9.4). 54 In another method, responsive drug delivery can be achieved by externally triggering the drug administration from a delivery system with magnetic or electronic pulses. An alternative approach involves mixing drugs with an excipient that is slowly dissolved and relying on this

Hydrogel

Change in pH/ ionic strength/ increased temperature

9.3 Schematic diagram showing the drug delivery from an environmentally sensitive hydrogel matrix.

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Succinylated collagen bilayer with drug

O (CH2)4 C O– D+ Ionic binding of drug (D) to succinylated collagen

Wound surface showing moderate infection

Wound surface showing severe infection

9.4 Schematic diagram showing the release profile of an ionically bound drug from the ciprofloxacin-incorporated collagen bilayer dressing based on the rate of wound infection.

prolonged dissolution to deliver effective amount of active ingredients over an extended period. 55

9.5

Types of dressings for drug delivery

There are occasions in surgery that require the use of a temporary cover for raw wounds. These include skin loss secondary to burns, trauma, amputation, chronic ulcers, leprosy and sites of skin transplant. The body needs its own regeneration time, while complications consequent to loss of skin cover wait for no one. The intact skin provides a productive layer over cutaneous nerves and the keratin layer of skin is a very effective antimicrobial barrier. Denuded areas of skin expose the nerves and cause pain and tenderness; they cannot prevent the loss of body heat as normal skin does by controlling vasodilation and sweating formation. Denuded areas continuously lose surface fluid and electrolytes, since the barrier of intact skin and keratin is not present to prevent the same. However, denuded areas are devoid of this protection, thus delaying wound healing by exposing vulnerable areas of subcutaneous tissues to infection. The orderly ingrowth of epithelium over denuded areas needs a layer of cover to act as the scaffold on which to grow and arrange itself but such areas are unable to provide this effectively leading to formation of extensive scars and even keloids. It is for this purpose that denuded areas need a temporary cover (dressing) until such time that the body is able to manufacture its own cover.

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Wound dressings can be broadly categorized as natural and synthetic polymeric dressings. The natural polymers collagen, albumin and gelatine, as protein-based polymers, and agarose, alginate, carrageenan, hyaluronic acid, dextran, chitosan and cyclodextrins, as polysaccharides, are both widely used as wound-dressing materials. Both synthetic biodegradable and non-biodegradable polymers have been used successfully in designing wound-dressing materials. Poly(lactic acid), poly(glycolic acid), poly(hydroxybutyrate), poly(ε-caprolactone), poly(β-malic acid), polydioxanes, poly(sebacic acid), poly(adipic acid), poly(terphthalic acid), poly(imino carbonates), polyamino acids, polyphosphates, polyphosphonates, polyphosphazenes, poly(cyanoacrylates), polyurethanes, polyorthoesters, polydihydropyrans and polyacetals are synthetic biodegradable polymers employed currently as wound-dressing materials. Carboxymethylcellulose, cellulose acetate, cellulose acetate propionate, hydroxypropylmethylcellulose, polydimethylsiloxane, colloidal silica, polymethacrylates, poly(methyl methacrylate), poly(hydroxyethyl methacrylate), ethyl vinyl acetate, polyoxamers and polyoxamines are synthetic non-biodegradable polymers used for the same purpose. Cotton and synthetic gauzes are the most commonly used wounddressing materials. 56 They are preferred because of their low cost and high absorptive capacity. However, because of their porous structure they do not have a barrier to bacterial penetration and also, when in a wet condition, they promote migration of bacteria to the wound site. This can be prevented if an antimicrobial compound is present in the gauze. 57 Gauze sticks to a wound surface and disrupts the wound bed when removed; these dressings are used only on minor wounds or as secondary dressings. Another dressing called tulle dressing is a cotton or viscose gauze dressing impregnated with paraffi n with or without antiseptic or antibiotic material. Paraffi n lowers the dressing adherence, but this property is lost if the dressing dries out. The hydrophobic nature of paraffi n prevents absorption of moisture from the wound, and frequent dressing changes are usually needed. Skin sensitization is also common in medicated types. Tulle dressings are mainly indicated for superficial clean wounds, and a secondary dressing is usually needed. Uses of gauze and tulle dressings as drug delivery systems are limited as they hold the drugs only for a limited period. Film dressings are highly comfortable and shower-proof, and their transparent surface facilitates the monitoring of wounds without dressing removal. These vapour-permeable fi lms allow diffusion of gases and water vapour throughout the surface when used on wounds. But these fi lms do not absorb wound exudates and are not preferred for use on heavily exudating wounds as fluid tends to accumulate underneath the fi lm, leading to maceration of the wound and the surrounding skin. Film dressings are suitable for superficial, lightly exudating or epithelializing wounds. These

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dressings vary in size and thickness, and may have an adhesive to hold the dressing on the skin. They conform easily to the patient’s body but do not hold well in high-friction areas, such as the sacrum or buttocks. Also, fi lms are semiocclusive and trap moisture, so they allow autolytic debridement of necrotic wounds and create a moist, healing environment for granulating wounds. They are impermeable to fluids and bacteria, but they are permeable to air and water vapour, control of both is dependent on the moisture and vapour transmission rate of the fi lms and it varies depending on the polymer used in the dressings. Permeability of water and air in these dressings creates a moist wound environment. 58 The shortcoming of fi lm dressings can be overcome by foam dressings. They are lightweight, superabsorbent, and easy to apply; they come as a highly compressed foam pad that wicks away moisture. It is a good choice for patients who have poorly vascularized, heavily draining leg wounds, because it only requires changing once a day. The foam can be attached with tape, gauze, or Ace bandages. In general, it is applied on dry to wet draining wounds as it wicks away the moisture during drainage of the wound. Foam dressings are designed to absorb large amount of exudates, they also maintain a moist wound environment. 59 Hydrogel is another class of fi lm dressings; it consists of polymers with a very high intrinsic water content.60 They conform to wounds with unusual shapes owing to their gel-like nature. In contrast to hydrofibres, hydrogels are used primarily to donate fluid to dry necrotic and sloughing wounds, and their absorbency is limited. They are composed mainly of water in a complex network of fibres that keep the polymer gel intact. Water is released to keep the wound moist. They are used for necrotic or sloughy wound beds to rehydrate and remove dead tissue.61 They are not used for moderate to heavily exudating wounds. There are other dressings called hydrocolloid dressings: they are indicated for minimal to moderately draining wounds. They are lightweight, with adhesive and absorbent characteristics. They can be tailor-made to fit oddly shaped wounds and can be changed depending on the drainage, which may vary from a few days to as long as a week. They are composed of carboxymethylcellulose, gelatin, pectin, elastomers and adhesives that can be formed as a gel.60 Depending on the hydrocolloid dressing chosen, they can be used on wounds with light to heavy exudate, sloughing or granulating wounds and can be made available in many forms such as adhesive or non-adhesive pad, paste, powder. The most common form is self-adhesive pads. Hydrocolloid dressings, owing to their occlusive nature, do not allow water, oxygen, or bacteria into the wound. This may help to facilitate angiogenesis and granulation at the wound site.62 Hydrocolloids also cause the pH of the wound surface to drop and the acidic environment can inhibit

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bacteria growth.63 Hydrocolloids absorb wound exudates and create a warm, moist environment that promotes debridement and healing. Like hydrogels, hydrocolloids helps a clean wound to granulate or epithelialize and encourages autolytic debridement in wounds with necrotic tissue. The occlusive nature of hydrocolloids makes them unsuitable for use if the wound or surrounding skin is infected, but hydrocolloid dressings containing antimicrobial agents may overcome this drawback.64 Hydrofibre dressings are produced from similar materials to hydrocolloids and also form a gel on contact with the wound, but are softer and more fibrous in appearance, with a greater capacity to absorb exudate. Moisture from the gel assists in debridement and facilitates non-traumatic removal. They comprise soft non-woven pads or ribbon dressings made from sodium carboxymethylcellulose fibres. They interact with wound drainage to form a soft gel and they absorb exudate to provide a moist environment in a deep wound that needs packing.65 Alginate dressings are called ‘seaweed’ dressing as it is derived from brown algae. Like polyurethane, it is applied dry so it can wick away moisture, making it another good choice for wet draining wounds. Alginate dressing contains calcium salt of alginic acid, it produces a highly absorbent dressing suitable for heavily exudating wounds. It is capable of absorbing up to 20 times its weight in fluid and possesses haemostatic properties. It is available as flat sheets or as rope, and can be used for packing cavities. Alginates change from a soft fibrous structure to gel when they absorb exudates. This facilitates easy removal of the dressing, thus preventing contamination of the wound and maintaining a moist wound environment. Alginate dressings can be used for both infected and non-infected wounds. On dry wounds or wounds with minimal drainage, these dressings are suitable as they dehydrate the wound and delay the healing process.66 Chitosan dressings are based on the natural biopolymer chitosan, which is derived from chitin, a major component of the outer skeletons of crustaceans. This material is known in the wound management field for its haemostatic properties. Further, it also possesses other biological activities and affects macrophage function to achieve faster wound healing.67 It also has an aptitude to stimulate cell proliferation and histoarchitectural tissue organization.68 The bacteriostatic and fungistatic properties of this dressing are useful for wound management. Both in solution and gel forms, these dressings act as a bacteriostatic, fungistatic and coating agent. Gels and suspensions may act as carriers for the slow release or controlled action of drugs, as an immobilizing medium and as an encapsulation material. Film and membranes are used in dialysis, contact lenses, dressings and the encapsulation of mammallian cells, including cell cultures. Chitosan sponges are used in dressings to stop bleeding of mucous membranes.

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Chitosan in the form of fibres is used as resorbable sutures, non-wovens for dressings, and as drug carriers in the form of hollow fibres. Collagen-based biomaterials are considered to be the most promising substitute for wound healing and skin regeneration. Collagen can be processed into a number of forms such as sheets, tubes, sponges, powders, fleeces, injectable solutions and dispersions, all of which have found use in medical practice.69 Furthermore, attempts have been made to apply these systems in drug delivery in a variety of applications such as ophthalmology, wound and burn dressing, tumour treatment, and tissue engineering. Collagen inserts and shields can be used as a drug-delivery dressing over the corneal surface or to the cornea itself and to deliver the drug intraocularly.70 As a drug delivery dressing, collagen sponges are invaluable in the treatment of severe burns and have found use as a dressing for many other types of wounds, such as pressure sores, donor sites, leg ulcers and decubitus ulcers.71 The major benefits of collagen covers include their ability to easily absorb large quantities of tissue exudate, smooth adherence to the wet wound bed with preservation of this moist microclimate as well as its shielding against mechanical harm and prevention of secondary bacterial infection. Besides these physical effects, collagen promotes cellular mobility and growth and inflammatory cells actively penetrate the porous scaffold.72 This allows a highly vascularized granulation bed to form and encourages the formation of new granulation tissue and epithelium on the wound. Based on the tissue repair and haemostyptic properties of collagen sponges, combinations with antibiotics were developed for local delivery in the treatment and prophylaxis of soft tissue infections. Collagen fi lms have also been used as drug carriers for antibiotics, having application in periodontal regeneration and infected dermal wounds.73 Composite dressings have multiple layers and can be used as primary or secondary dressings. They are appropriate for wounds with minimal to heavy exudates, healthy granulation tissue, necrotic tissue (slough or moist eschar), or a mixture of granulation and necrotic tissue. Composite dressings have two or more layers and each layer has a specific function. Twolayer dressings have a dense upper layer and a spongy lower layer. The outer membrane prevents body fluid loss, controls water evaporation, and protects the wound surface from bacterial invasion, and the inner matrix encourages adherence by tissue growth into the matrix. These dressings may be considered to constitute an ideal structure that promotes wound healing. These dressings have excellent oxygen permeability, control the water vapour transmission rate, and promote water uptake capability.74 The spongy layer will usually be an antibiotic-impregnated polymer. Applications of both the collagen and chitosan bilayer dressings either alone or in combination with other polymers have been widely reported.75,76

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Three-layer dressings consisting of chitosan, synthetic polymer, and a gauze layer have been developed. The second layer functions to transport exudates, protect the wound, and prevent the outer gauze layer from adhering to the wound. It is the second line of defence against bacteria that may try to invade after the chitosan layer breaks down. This polymer film layer, having the consistency of cellophane degrades and becomes part of the healed skin. The outermost layer, made of cotton or cotton–viscose, absorbs exudates and must be changed periodically. Because the wound is well protected underneath, removing the gauze layer does not hurt as much as removing traditional adhesive bandages. In some cases, a three-layer dressing consists of, fi rst, a semi-adherent or non-adherent layer that touches the wound and protects the wound from adhering to other material. This layer allows the dressing to be removed without disturbing new tissue growth and exudates pass through it into the next layer, which is absorptive. If a topical agent is applied to the wound, such as an antibiotic ointment, this inner layer will not stick to the topical product. The second layer is absorptive and wicks drainage and debris away from the wound’s surface to prevent skin maceration and bacterial growth and maintain a moist healing environment. This absorptive layer is made of material other than an alginate, foam, hydrocolloid, or hydrogel. Besides protecting the intact skin from excessive moisture, the absorptive layer helps liquify eschar and necrotic debris, facilitating autolytic debridement. A bacterial barrier forms the third or outer layer that may have an adhesive border. This layer allows moisture vapour to pass from the wound to the air and keeps bacteria and particles out of the wound. It also helps maintain a moist healing environment. Unlike gauze, the bacterial barrier layer prevents moisture leakage to the outside of the dressing (strike-through), meaning that the dressing can be changed less frequently.

9.6

Applications of drug delivery dressings

9.6.1 Infection control Minor wounds usually are not serious, but even cuts and scrapes require care. A serious and infected wound requires infection control and attention. Goals of management of wounds are to avoid infection, minimize discomfort, facilitate healing and minimize scar formation. The use of topical antibiotics and antiseptics is a key approach for reducing the microbial load in wounds. There are several commercially available topical formulations (powders/creams) that release antimicrobial agents into the wound bed. Commonly used antibiotics include bacitracin, mupirocin and neosporin. However, owing to the increasing incidence of

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bacterial resistance, antibiotics are being used less frequently and antiseptic agents such as slow-release iodine and silver ions have the advantage of rarely inducing any bacterial resistance. The combination of wound dressing with direct antibiotic release at the wound site provides obvious advantages over traditional wound dressings in preventing bacterial infection, especially in high-risk patients. The role of drug delivery dressing on an infected wound is to control the bacterial proliferation, absorb wound exudates and protect the wound from secondary bacterial contamination, thereby enhancing the healing process. A number of sophisticated dressings (dry and moist dressings) with antimicrobial properties have been introduced in the market for treating infected wounds.77 Some occlusive dressings, such as hydrogels and hydrocolloids, have bacterial and viral barrier properties. These dressings can be used to prevent contamination of the wound and reduce the spread of pathogens and cross-infection. Hydrogels allow them to be utilized to deliver topical wound medications like metronidazole and silver sulfadiazine by diffusion mechanism. The release of medications can be controlled by the degree of cross linkage in the gel. Both temperature- and pH-sensitive gels have been the subject of investigation with the objective of developing new products. The biological properties of chitosan including bacteriostatic and fungistatic properties are particularly useful for the treatment of infected wounds. These properties have been exploited in various forms: in gels and suspensions, Chitosan acts as an immobilising medium and an encapsulation material for slow release or controlled action of drugs; and as sponges and hollow fibres, it acts as a drug-carrier dressing.78 Collagen sponges impregnated with gentamicin and amikacin have been used for many years in human soft tissue and orthopaedic surgery.79

9.6.2 Healing improvement Although the main emphasis in the making of drug delivery dressings is on the prevention and control of infection, certain non-healing ulcers require additional care. Use of growth factors for the treatment of nonhealing human wounds holds great therapeutic potential. Cytokines and growth factors, the major regulators, which are produced by various cell types and are recruited to or present at the wound site, are responsible for the successful repair of the injured tissues.80–83 Release of some substances from the dressings stimulates the cells to release cytokines, which enhance wound healing. For example, the release of acemannan from hydrogels has the ability to stimulate macrophages to release fibrogenic and angiogenic cytokines (Interleukin-1 and TNF-α) which results in a positive effect on wound healing.

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Various topical systems for delivery of cytokines and growth factors to the injured tissues have been examined. These include covering the wound with a gel, cream or ointment containing a cytokine or a growth factor,84 spraying the growth factor over the wounded site, 85 application of the cytokine–soaked gauze86 to the wound, pre-incubation of the skin graft with a cytokine before grafting, 87 and use of a genetically engineered biological bandage containing the culture of the cells producing growth hormone.88 Topical delivery of cytokines such as recombinant human granulocyte–macrophage colony stimulating factor (rhGM-CSF) and recombinant human granulocyte colony stimulating factor (rhG-CSF) by using collagen and polyurethane dressings may serve as effective tools for wound healing.89 Growth factors have also been incorporated into poly(lactic-co-glycolic acid) scaffolds successfully, leading to the formation of more viable tissue structures.90,91 Recombinant human-platelet derived growth factor-bb (rhPDGF-BB, Becaplermin) is the first approved growth factor available for clinical use. In clinical trials, it has been shown to increase the incidence of complete wound closure and decrease the time to achieve complete wound healing. Collagen matrix with bovine transforming growth factor-β2 can be used as a potential dressing on closure of venous stasis ulcers. Controlled release of biologically active fibroblast growth factor (FGF-2) molecules from chitosan hydrogels caused induction of angiogenesis and collateral circulation occurred in healing-impaired diabetic patients. Some hydrocolloids have been shown to bridge the interactive and bioactive classifications by exhibiting fibrinolytic, chemotactic and angiogenic effects.92

9.6.3 Controlling transport of biological fluid Wound exudates can pose problems in the treatment and care of a wound site and need to be handled. In the treatment of many wounds, it is beneficial to keep the wound moist while removing excess exudate. This provides an optimum wound healing environment, reduces pain, and helps autolytic debridement and re-epithelialization. Excess fluid, however, can lead to problems such as maceration (skin breakdown) and microbial infection at the wound site. For this reason, many wound dressings are sometimes designed to have an absorbent pad with high moisture vapour transmission rates, i.e. the excess fluid is allowed to transmit or evaporate through the wound dressing during application on the wound. Drug delivery dressings have been developed that contain a reservoir of a suitable medicament. The reservoir is directly placed in contact with the skin and the medicament is allowed or assisted to permeate the skin. Unfortunately, the amount of the drug contained within the dressing is

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limited for a particular size of the dressing and these dressings do not have a capability to be recharged from a remote reservoir. Many of these dressings are not suitable for application over open wounds. For example, many transdermal drug delivery devices rely on the barrier provided by the dermis to regulate the rate of delivery of the drug. Hydrocolloids and hydrofibres form a gel on contact with the wound and thus have a greater capacity to absorb exudates. Moisture from the gel assists in debridement and facilitates non-traumatic removal. This also enhances autolytic debridement of necrotic and sloughing tissues and promotes the formation of granulation tissue. Hydrogels are used primarily to donate fluid to dry necrotic and sloughing wounds, and their absorbency is limited. For burn dressings, it is a most important to control evaporative water loss in addition to the drug delivery. Therefore, materials impregnated with antimicrobial agent are required and wound-dressing materials developed in recent years meet these requirements.93,94

9.6.4 Haemostatic properties There exists a need for a wound dressing that can safely and effectively deliver a number of drugs to targeted tissue at a controlled rate, along with haemostatic function. A good example is oxidized cellulose dressing, which, owing to its biodegradable, bactericidal, and haemostatic properties, has been used as a topical haemostatic wound dressing in a variety of surgical procedures, which includes neurosurgery, abdominal surgery, cardiovascular surgery, thoracic surgery, head and neck surgery, pelvic surgery, and skin and subcutaneous tissue procedures. Collagen, in forms such as powder, fibres or sponge, also has haemostatic properties when used as a wound dressing. Collagen in the form of fine fibres demonstrates an unexpected and entirely unique self-adhesive property when wet with blood or fluids in live warm-blooded animals: it adheres to severed tissues and requires no suturing. Similarly, chitosan dressing having chitosan fibre with microporous polysaccharide microspheres containing a therapeutic agent provides both the functions of drug delivery and haemostatic property when applied on a wound. Gelatine sponge is another absorbent, haemostatic material used in surgical procedures characterized by venous or oozing bleeding. The sponge adheres to the bleeding site and absorbs approximately 45 times its own weight in fluids. Owing to the uniform porosity of the gelatine sponge, blood platelets are caught within its pores, activating a coagulation cascade. Soluble fibrinogen transforms into a net of insoluble fibrin, which stops the bleeding.

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9.7

Future trends

9.7.1

Tissue engineering

Scaffolds (a term used for the latest innovations in wound-management and drug delivery dressings) are the central components of many tissue engineering strategies because they provide an architectural context in which extracellular matrix, cell and growth factor interactions combine to generate regenerative niches. Although three-dimensional porous structures have been recognized as the most appropriate design to sustain cell adhesion and proliferation, several specific applications in tissue engineering may take advantage of other design formats or a combination of different material designs. In fact, as the demand for new and more sophisticated scaffolds develops, materials are being designed that have a more active role in guiding tissue development. Instead of merely holding the cells in place, these matrices are designed to accomplish other functions through the combination of different format features and materials. A good example of this is the use of drug delivery devices that can act simultaneously as scaffolds for cell growth. Drug delivery creates an appropriate chemical environment via soluble factors directly to cells. Controlled drug delivery and its applications for tissue engineering to support and stimulate tissue growth have attracted much attention over the last decade. Controlled release devices open the possibility of combining drugs and growth factors within scaffolds to promote tissue development and formation.95–99 In other approaches, microspheres or nanospheres with encapsulated cells, growth factors or other therapeutic agents in a polymeric matrix can enhance the ability of drug delivery dressings to resemble natural human tissues and therefore perform a better functioning in vivo condition.

9.7.2 Stem cell research Stem cells have the potential to reconstitute dermal, vascular and other elements required for optimum wound healing. Through tissue engineering and drug delivery, one may recapitulate developmental cues in a manner which is more physiologically relevant than the simple addition of growth factors to two-dimensional cultures. By combining microspheres containing different drugs with unique release profi les, one can start to emulate the environment seen during development; this has profound implications for stem cell research. Thus, one may be able to gain greater control and insight into the capacity of stem cells and achieve the replacement and repair of complex tissues.

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9.7.3 Micro and nanotechnology in drug delivery dressings The use of microspheres for sustained release in the drug delivery system has been of increasing interest. There are potential advantages for controlled release and absorbability. One of the most common methods in which growth factors have been incorporated into polymers is through the formation of microspheres.100–102 Microspheres that release growth factors have been used as scaffolds, providing another means to generate tissueengineered structures with the necessary chemical environment to foster repair.103 Sustained release of bFGF from the gelatine microsphere incorporated in the bilayer dressing (inner gelatine sponge and outer polyurethane membrane) has shown improved healing on a York pig model.104 Cefazolin incorporated poly(lactide-co-glycolide) (PLAGA) nanofibres as antibiotic delivery system has shown potential healing in the treatment of wounds. 2

9.7.4 Gene delivery Gene delivery is a versatile approach, capable of targeting any cellular process through localized expression of tissue inductive factors. Introduction of the gene rather than a product such as a growth factor is thought to be cheaper and more efficient for treating non-healing wounds. Polymeric scaffolds, either natural, synthetic, or a combination of the two, and capable of controlled DNA delivery, can provide a fundamental tool for directing progenitor cell function; this has applications in the engineering of numerous types of tissue. Scaffolds are designed either to release the viral and non-viral vector into the local tissue environment or to maintain the vector at the polymer surface, which is regulated by the effective affinity of the vector for the polymer. For example, DNA delivery by using a chitosan scaffold has been evaluated as wound-dressing materials105 and the in vivo delivery of a plasmid DNA encoding a platelet-derived growth factor gene using a polymer matrix, poly(lactide-co-glycolide), enhanced matrix deposition and blood vessel formation in the developing tissue.106,107 Efficiency of hydrogel formed by PEG–PLGA–PEG was evaluated as nonviral delivery of pDNA for gene therapy in a skin wound model in CD-1 mice, which has shown promising wound healing.108

9.7.5 Environment-sensitive drug delivery dressings Some of the scaffolds under evaluation respond to several physiological stimuli such as pH, ionic strength, temperature or enzymic concentration changes and infection. Several studies have aimed to construct novel

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triggered drug delivery systems that release antimicrobials at specific locations at required times. These new systems are usually triggered by certain endogenous host infection responses such as inflammationrelated enzymes, thrombin activity or microbial proteases. For example, S. aureus infection increases the local concentration of thrombin. A PVA– peptide–gentamicin conjugate was developed and investigated where the release of gentamicin depends on local thrombin concentration.109 In the same manner, ciprofloxacin-conjugated polymers, synthesized from 1,6hexane diisocyanate (HDI) and polycaprolactone diol (PCL), release ciprofloxacin when the polymer degrades by the inflammatory cell-derived enzyme cholesterol esterase.110 Thermosensitive micelles or thermoresponsive hydrogels are selfregulating carriers because the release can be induced by small temperature differences in the human body.111–112 Another way of achieving self-regulating drug delivery involves the application of hydrogels, which are swelling-controlled polymers that allow the release of incorporated drugs only at a certain pH.113 Responsive drug delivery can be achieved by externally triggering the drug administration from a delivery system with magnetic or electronic pulses.114 In a succinylated collagen bilayer system (outer membrane and inner sponge) with Ciprofloxacin, collagen behaves as an anion after swelling and Ciprofloxacin forms cations in the swelled network of sponge when applied on the wound. Owing to ionic binding, the drug diffuses slowly and its release rate is controlled. If wound exudates are greater, more drugs will be released to the wound site, which facilitates controlled delivery of the drug. When poly(vinyl-1-pyrrolidone) (PVP) is used along with the drug in the bilayer system, the drug is released as cations from the PVP and is then ionically bound to the succinylated collagen matrix under wet conditions. This further regulates the release of the drug. Infected wounds are polar in nature and therefore the release of the drug from the sponge is regulated by the ionic nature of the succinylated dressing. Once the dressing becomes wet, the role of PVP is negligible and the drug is released by overcoming the ionic binding between the drug and the sponge.115

9.8

Conclusions

The design and development of drug delivery dressings involve various scientific approaches. Drug delivery dressings require the drug delivery molecule to be designed to give it a enhanced chemical stability and pharmacokinetic properties. Thus, the drug can be tailored to give the required properties, in terms of its absorption, distribution, metabolism, excretion and transfer across biological barriers, to better target the site of action. Similarly, an understanding of the process by which the drugs pass through

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the membranes, then choose their best route of administration followed by transportation to the target tissue, is essential for reliable drug delivery. Using various delivery devices the drug reaches the site of action and stays there to repair and heal the wound. While drug delivery dressings have their role in wound management, good nutrition is necessary for wound healing. During the healing process, the body needs an increased amount of calories, proteins, vitamin A and C and, sometimes, some minerals to promote wound healing and prevent infection and complications. If the patient has diabetes, it is necessary to monitor his blood sugar levels at regular intervals to ensure wound healing and control infection. Patients are advised that, if their appetite remains poor and the wound is not healing well and/or they are losing weight, they should make an appointment to see a doctor. Wound healing needs an integrated approach and regular monitoring. Though drug delivery dressings may play a major role in the wound-healing process, other factors mentioned here are equally important and add to the successful management of a wound.

9.9

References

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29. fleischer g r (1999), ‘The management of bite wounds’, N Engl J Med, 340, 138–140. 30. revathi g, puri j and jain b k (1998), ‘Bacteriology of burns’, Burns, 24, 347–349. 31. vindenes h and bjerknes r (1995), ‘Microbial colonisation of large wounds’, Burns, 21, 575–579. 32. bariar l m, vasenwala s m, malik a, ansari g h and chowdhury t e (1997), ‘A clinicopathological study of infections in burn patients and importance of biopsy’, J Indian Med Soc, 95, 573–575. 33. mousa h a (1997), ‘Aerobic, anaerobic and fungal burn wound infections’, J Hosp Infect, 37, 317–323. 34. brook i and randolph j g (1981), ‘Aerobic and anaerobic bacterial flora of burns in children’, J Trauma, 21, 313–318. 35. ramsey s d, newton k, blough d, mcculloch d k, sandhu n, reiber g e and wagner e h (1999), ‘Incidence, outcomes, and cost of foot ulcers in patients with diabetes’, Diabetes Care, 22, 382–387. 36. diamantopoulos e j, haritos d, yfandi g, grigoriadou m, margariti g, paniara o and raptis s a (1998), ‘Management and outcome of severe diabetic foot infections’, Exp Clin Endocrinol Diabetes, 106, 346–352. 37. armstrong d g, liswood p j and todd w f (1995), ‘Prevalence of mixed infections in the diabetic pedal wound. A retrospective review of 112 infections’, J Am Podiatr Med Assoc, 85, 533–537. 38. pathare n a, bal a, talvalkar g v and antani d u (1998), ‘Diabetic foot infections: a study of micro-organisms associated with the different Wagner grades’, Indian J Pathol Microbiol, 41, 437–441. 39. gerding d n (1995), ‘Foot infections in diabetic patients: the role of anaerobes’, Clin Infect Dis, 20, S283–S288. 40. johnson s, lebahn f, peterson l r and gerding d n (1995), ‘Use of an anaerobic collection and transport swab device to recover anaerobic bacteria from infected foot ulcers in diabetics’, Clin Infect Dis, 20, S289–S290. 41. karchmer a w and gibbons g w (1994), ‘Foot infections in diabetics: evaluation and management’, Curr Clin Top Infect Dis, 14, 1–22. 42. brown d l and smith d j (1999), ‘Bacterial colonisation/infection and the surgical management of pressure ulcers’, Ostomy Wound Manag, 45, 119S–120S. 43. lance george w (1989), ‘Other infections of skin, soft tissue, and muscle, in Finegold S M, and Lance George W, Anaerobic infections in humans, Academic Press, Inc., San Diego, Calif, 1491–1492. 44. kingston d and seal d v (1990), ‘Current hypotheses on synergistic microbial gangrene’, Br J Surg, 77, 260–264. 45. brook i (1991), ‘Microbiological studies of decubitus ulcers in children’, J Pediatr Surg, 26, 207–209. 46. valencia i c, falabella a, kirsner r s, eaglstein w h (2001), ‘Chronic venous insufficiency and venous leg ulceration’, J Am Acad Dermatol, 44, 401–421. 47. hansson c, hoborn j, moller a and swanbeck g (1995), ‘The microbial flora in venous leg ulcers without clinical signs of infection’, Acta Dermatol Venereol (Stockh), 75, 24–30. 48. brook i and frazier e h (1990), ‘Aerobic and anaerobic bacteriology of wounds and cutaneous abscesses’, Arch Surg, 125, 1445–1451.

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49. bowler p g and davies b j (1999), ‘The microbiology of infected and noninfected leg ulcers’, Int J Dermatol, 38, 101–106. 50. rotstein o d, pruett t l and simmons r l (1985), ‘Mechanisms of microbial synergy in polymicrobial surgical infections’, Rev Infect Dis, 7, 151–170. 51. deluca p, kanke m, sato t and schroeder h (1989), ‘Porous microspheres for drug delivery and methods for making same’, US Patent No. 4,818,542. 52. jankower l and shipley w (1989), ‘Controlled release formulation employing resilient microbeads’, US Patent No. 4,873,091. 53. wise d, fellman t, danderson j and wentworth r (1979), ‘Lactide/glycolide polymers used as surgical suture material, raw material for osteosynthesis and in sustained release forms of drugs’, in Gregoriadis G, Drug carriers in biology and medicine, London, UK, Academic Press, 237. 54. sripriya r, senthil kumar m, rafi uddin ahmed md and sehgal p k (2007), ‘Collagen bilayer dressing with ciprofloxacin, an effective system for infected wound healing’, J Biomater Sci Polym Ed, 18, 335–351. 55. odagiri m (1994), ‘Drug delivery system using keratin hydrolyzate as carrier’, Japanese Patent Number JP6293631. 56. ponder r b and krasner d (1993), ‘Gauzes and related dressings’, Ostomy Wound Manag, 39, 48. 57. angelique m r and rodeheaver g t (2001), ‘Effectiveness of a new antimicrobial gauze dressing as a bacteria barrier’ (pamphlet). Kendall, Wound care research and development, Mansfield, MA. 58. hien n t, prawer s e and katz h i (1988), ‘Facilitated wound healing using transparent fi lm dressing following Mohs micrographic surgery’, Arch dermatol, 124 (6), 903–906 (Source: Scopus database). 59. palamand s, brenden r a and reed a m (1991), ‘Intelligent wound dressings and their physical characteristics’, Wounds, 3, 149. 60. merkle leiby d and lott g (1997), ‘Topical wound product ingredient guide’, Ostomy Wound Manag, 7, 42. 61. flanagan m (1995), ‘The efficacy of hydrogel in the treatment of wounds with non-viable tissue’, J Wound Care, 6, 264–267. 62. turner t d (1997), ‘Interactive dressings used in the management of human soft tissue injuries and their potential in veterinary practice’, Vet Dermatol, 8, 235–232. 63. feldman d l, rogers ann and karpinski h s (1991), ‘A prospective trial comparing Biomembrane, Duoderm and Xerofoam for skin grant donor sites’, Surg Gynec Obstet, 173, 1–5. 64. toshihiko s, rie y, masahide t, naoto y, eiju u and yoshimitsu k (2000), ‘Development of new hydrocolloid-type wound dressing containing silver sulfadiazine. Multi-centre’s clinical reports’, Jpn Pharmacol Ther, 28, 621–633. 65. vloemans a f m p, soesman a m, kreis r w and middelkoop e (2001), ‘A newly developed hydrofiber dressing in the treatment of partial-thickness burns’, Burns, 27, 167–73. 66. tonnesen h h and karlsen j (2002), ‘Alginate in drug delivery systems. Drug Dev Ind Pharm, 28, 621–630. 67. balassa l l and prudden j f (1984), ‘Applications of chitin and chitosan in wound healing acceleration, in John P. Zikakis, Chitin, chitosan and related enzymes, Academic Press, San Diego, 296–305.

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68. muzzarelli r a a (1989), ‘Amphoteric derivatives of chitosan and their biological significance’, in Chitin and chitosan, Elsevier Applied Science, London, 87–99. 69. chvapil m, kronentahl r l, van winkle w jr (1973), ‘Medical and surgical applications of collagen’, in Hall D A, Jackson D S, International Review of Connective Tissue Research, Academic Press, New York, 1–61. 70. poland d e and kaufman h e (1988), ‘Clinical uses of collagen shields’, J Cataract Refr Surg, 14, 489–491. 71. gorham s d (1991), ‘Collagen’, in Byrom D, Biomaterials, Stockton Press, New York, 55–122. 72. doillon c j, whyne c f, brandwein s and silver f h (1986), ‘Collagen-based wound dressings: control of pore structure and morphology’, J Biomed Mater Res, 20, 1219–1228. 73. panduranga rao k (1995), ‘Recent developments of collagen-based materials for medical applications and drug delivery systems’, J Biomater Sci Polym Ed, 7, 623–645. 74. fwu-long m i, yu-bey w u, shin-shing s, jen-yu s, yaw-bin h, yi-hung t and jong-yun h a o (2002), ‘Control of wound infections using a bilayer chitosan wound dressing with sustainable antibiotic delivery’, J Biomed Mater Res, 59, 438–449. 75. ma l, gao c y, mao z w, zhou j, shen j c, hu x q and hang c m (2003), ‘Collagen/chitosan porous scaffolds with improved biostability for skin tissue engineering’, Biomaterials, 24, 4833. 76. shi y, ma l, zhou j, mao z and gao c (2005), ‘Collagen/chitosan–silicone membrane bilayer scaffold as a dermal equivalent’, Polym Adv Technol, 16, 789–794. 77. bates-jensen bm (2001), ‘Management of exudates and infection’, in Sussman C, Bates-Jensen BM, Wound care: a collaborative practice manual for physical therapists and nurses, Aspen Publishers, Inc., Gaithersburg, MD, 216–234. 78. niekraszewicz a (2005), ‘Chitosan Medical Dressings’, Fibres Text East Eur, 13, 16–18. 79. stemberger h, grimm f, bader h d, rahn and ascherl r (1997), ‘Local treatment of bone and soft tissue infections with the collagen gentamicin sponge’, Eur J Surg, 578, 17–26. 80. bennett n t and schultz g s (1993), ‘Growth factors and wound healing: Part II. Role in normal and chronic wound healing’, Am J Surg, 166, 74–81. 81. ono i, gunji h, zhang j z, maruyama k and kaneko f (1995), ‘A study of cytokines in burn blister fluid related to wound healing’, Burns, 21, 352–355. 82. martin p (1997), ‘Wound healing – aiming for perfect skin regeneration’, Science, 276, 75–81. 83. slavin j (1996), ‘The role of cytokines in wound healing’, J Pathol, 178, 5–10. 84. brown g l, curtsinge l j, brightwell j r, ackerman d m, tobin g r, polk h c, george-nascimento c, vanezuela p and scholtz g s (1989), ‘Enhancement of wound healing by topical treatment with epidermal growth factor’, New Engl J Med, 321, 76–79.

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85. wang h j, wan h l, yang t s, wang d s, chen t m and chang d m (1996), ‘Acceleration of skin healing by growth factors’, Burns, 22, 10–14. 86. hui e p, yeo w and wickham n w r (1995), ‘Rapid healing of a indolent leg ulcer with topical rhGM-CSF’, Aust New Zealand J Med, 26, 420–421. 87. pojda z and struzyna j (1994), ‘Treatment of non-healing ulcers with rhGMCSF and skin grafts’, Lancet, 343, 1100. 88. andreatta-van leynen s, smith d j, bulgrin j p, schafer i a and eckert r l (1993), ‘Delivery of growth factor to wound using a genetically engineered biological bandage’, J Biomed Mat Res, 27, 1201–1208. 89. grzybowski j, oldak e, antos-bielska m, janiak m k and pojda z (1999), ‘New cytokine dressings. I. Kinetics of the in vitro rhG-CSF, rhGM-CSF, and rhEGF release from the dressings’, Int J Pharm, 184, 173–178. 90. murphy w l, peters m c, kohn d h and mooney d j (2000), ‘Sustained release of vascular endothelial growth factor from mineralized poly (lactide-co-glycolide) scaffolds for tissue engineering’, Biomaterials, 21, 2521–2527. 91. richardson t p, peters m c, ennett a b and mooney d j (2001), ‘Polymeric system for dual growth factor delivery’, Nature Biotechnol, 19, 1029–1034. 92. turner t d (1997), ‘Interactive dressings used in the management of human soft tissue injuries and their potential in veterinary practice’, Vet Dermatol, 8, 235–232. 93. vogt p m, hauser j, rossbach o, et al. (2001), ‘Polyvinyl pyrrolidone-iodine liposome hydrogel improves epithelialization by combining moisture and antisepsis. A new concept in wound therapy’, Wound Repair Regen, 9, 116–122. 94. masters k s, leibovich s j, belem p, et al. (2002), ‘Effects of nitric oxide releasing poly(vinyl alcohol) hydrogel dressings on dermal wound healing in diabetic mice’, Wound Repair Regen, 10, 286–294. 95. langer r (1998), ‘Drug delivery and targeting’, Nature, 392S, 5–10. 96. babensee j e, mcintire l v and mikos a g (2000), ‘Growth factor delivery for tissue engineering’, Pharm Res, 17, 497–504. 97. benoit j p, faisant n, venier-julienne m c and menei p (2000), ‘Development of microspheres for neurological disorders: from basics to clinical applications’, J Controlled Release, 65, 285–296. 98. whitaker m j, quirk r a, howdle s m and shakesheff k m (2001), ‘Growth factor release from tissue engineering scaffolds’, J Pharm Pharmacol, 53, 1427–1437. 99. saltzman w m, olbricht w l (2002), ‘Building drug delivery into tissue engineering’, Nat Rev Drug Discov, 1, 177–186. 100. nam y s and park t g (1999), ‘Protein loaded biodegradable microspheres based on PLGA–protein bioconjugates’, J Microencapsulation, 16, 625–637. 101. benoit j p, faisant n, venier-julienne m c and menei p (2000), ‘Development of microspheres for neurological disorders: from basics to clinical applications’, J Control Release, 65, 285–296. 102. fu k, harrell r, zinski k, um c, jaklenec a, frazier j, lotan n, burke p, klibanov a m and langer r (2003), ‘A potential approach for decreasing the burst effect of protein from PLGA microspheres’, J Pharm Sci, 92, 1582–1591.

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103. mahoney m j and saltzman w m (2001), ‘Transplantation of brain cells assembled around a programmable synthetic microenvironment’, Nature Biotechnol, 19, 934–939. 104. sha huang, yan jin, tianzheng deng and hong wu (2006), ‘Wound dressings containing bFGF-impregnated microspheres: Preparation, characterization, in vitro and in vivo studies’, J Appl Polym Sci, 100, 4772–4781. 105. felt o, buri p and gurny r (1998), ‘Chitosan: A unique polysaccharide for drug delivery’, Drug Dev Ind Pharm, 24, 979–993. 106. shea l d, smiley e, bonadio j and mooney d j (1999), ‘DNA delivery from polymer matrices for tissue engineering’, Nature Biotechnol, 17, 551–554. 107. murphy w l and mooney d j (1999), ‘Controlled delivery of inductive proteins, plasmid DNA and cells from tissue engineering matrices’, J Periodontal Res, 34, 413–419. 108. li z, ning w, wang j, choi a, lee p y, tyagi p and huang l (2003), ‘Controlled gene delivery system based on thermosensitive biodegradable hydrogel’, Pharm Res, 20, 884–888. 109. tanihara m, suzuki y, nishimura y, suzuki k and kakimaru y (1998), ‘Thrombin-sensitive peptide linkers for biological signal-responsive drug release systems’, Peptides (New York), 19, 421–425. 110. woo g l y, mittelman m w and santerre j p (2000), ‘Synthesis and characterization of a novel biodegradable antimicrobial polymer’, Biomaterials, 21, 1235–1246. 111. kim i, jeong y, cho c and kim s (2000), ‘Thermo-responsive self-assembled polymeric micelles for drug delivery in vitro’, Int J Pharm, 205, 165–172. 112. bae y h, okano t and kim s w (1991), ‘On-off thermocontrol of solute transport. II Solute release from thermosensitive hydrogels’, Pharm Res, 8, 624–628. 113. peppas n a (1991), ‘Physiologically responsive hydrogels’, J Bioact Compat Polym, 6, 241–246. 114. kost j and langer r (1991), ‘Responsive drug delivery systems’, Adv Drug Deliver Rev, 6, 19–50. 115. sripriya r, senthil kumar m and sehgal p k (2004), ‘Improved collagen bilayer dressing for the controlled release of drug’, J Biomed Mater Res Part B: Appl Biomater, 70B, 389–396.

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10 The use of ‘smart’ textiles for wound care J. F. K E N N E DY and K. BU N KO, Advanced Science and Technology Institute, UK

Abstract: Some recently developed ‘intelligent’ or advanced dressings, are reviewed and their mechanisms are detailed. Applications including the use of sensors, temperature control and non-contact dressings are described. The potential of such smart textiles in the treatment of particular wounds is explored. Key words: wound care, smart textiles, wound dressings, sensors.

10.1

Introduction

A ‘smart’ textile may be defi ned generally as a material designed to sense and react to differing stimuli or environmental conditions. The ‘intelligent’ textile industry is expanding very quickly and developing wearable composite materials for use in fields such as sport, defence, the military, aerospace or medicine. Garments equipped with electronic units, detector devices for ailments or various sensors designed to monitor changes in body temperature and moisture are becoming increasingly real, and not just the stock-in-trade of science fiction fi lms. Smart textiles are being broadly developed in the field of sports, e.g. outdoor garments with smart membranes to allow moisture to penetrate only in one direction, to keep the wearer warm and protect against the wind. Moreover, this development of ‘smart’ textiles is facilitating advances in the area of medical textiles. The system of wearable pads designed to monitor the vital signs of mother and foetus during pregnancy is one of many ‘smart’ material approaches in the health field. In addition, special attention is being paid to the application of smart textiles in medical devices for the care of wounds. These innovative dressings have perhaps not yet been as fully investigated and developed as ‘smart’ garments, but this approach in medicine shows defi nite promise for improving and accelerating the healing process. 254

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10.2 Basic principles and types of smart textiles The term ‘smart textiles’ is used to describe materials that are advanced in their structure, composition and ‘behaviour’ in special conditions. Their ‘intelligence’ is classified into three subgroups:1–3 •

Passive smart textiles, which are sensors and can only sense the environment; • Active smart textiles, which can sense stimuli from the environment and also react to them; simultaneously with the sensor function, they also play an actuator role; • Very smart textiles, which are able to adapt their behaviour to the circumstances.

To achieve an ideal wound care product, which may be classified as ‘smart’, it is necessary to refi ne plain dressings. A deep understanding of the processes that occur on the injured surface (e.g. inflammation, secretion of the exudate or epidermal regeneration) is fundamental when initiating trials to design intelligent textiles for wound care.4–6 It is very important for the healing process to provide a moist environment for wounds (a moist wound free from infection is an environment rich in white blood cells, enzymes, cytokines and growth factors beneficial to wound healing), while still enabling adequate gaseous exchange. Therefore, the occlusive and adherent properties of covering dressings must be preserved. On the other hand, dressings should also be easily removable, without causing additional post-wound trauma, and they should support epithelialisation – the process of new epidermal cells moving across the wound surface and settling on it, which in turn causes wound closure and therefore healing. Epithelialisation occurs more effectively in moist environments. It is also very important to use the sort of dressing which will support healing but reduce scar size, e.g. pressure garments.7,8 Moreover, as a cover, the dressing should protect the wounded area from secondary contamination. It will ideally also provide the antiseptic and healing agents and accelerate the regeneration process. Hence, today, textiles with controlled drug-delivery systems are one of the most investigated categories of dressings. Finally, dressings should absorb excess wound exudate so as to provide relatively stable conditions for healing.4–6 In the light of these challenges, scientists are working to design innovative dressings which will fulfi l all these functions and provide the correct responses to particular wound conditions. These dressings, described as ‘intelligent’ or ‘smart’, will be able to react in different ways in various wound environments. The aim of this chapter is to gather information on the most sophisticated wound care textiles, which accelerate and

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improve healing processes, and therefore provide more comfortable conditions for patients.

10.3 Characteristics of smart textiles 10.3.1 Sensors in smart textiles Living in the 21st century, we cannot imagine the world without electronic devices, computers and incredibly fast intercommunication. It follows that even wearable textiles might be controlled and manipulated by biosensors, and that all the components of their interactive electromechanical systems (such as sensors, actuators and power sources) can be incorporated or woven directly into garments (sensing and actuating micro-fibers) or printed/applied onto fabrics (flexible electronics).9 This means that science is heading towards the development of ‘intelligent’ communication between human beings and their inanimate creations. Electro-active fabrics and wearable biomonitoring devices are now being actively developed.10 Since electro-sensor-monitored garments are being extensively investigated, it seems probable that such electronic devices will soon be applicable as an element of wound dressings, tracking the changes in particular wounds, such as post-operative wounds which defi nitely need continual monitoring, and also providing cover-protection. Nowadays, dressings may contain different types of sensors, e.g. macromolecules such as environment-responsive polymers (ERP).10 These chemical sensors respond to the wound environment with a change of colour, release of fragrance, and swelling/de-swelling. On the other hand, the actuating mechanism for their action may be caused by different factors, e.g. changes in wound temperature, high secretion of exudate or pH changes in the local environment. How are sensors arranged in dressings? Because different types of sensors monitor the wound environment, their location in the structure of the dressing depends on the particular situation. The structure of the dressing itself may allow the arrangement of the sensor within it. This occurs, for instance, in newly developed technology designed to diagnose infection in the wound using a silicon-based biosensor. This dressing detects lipid A, a component of the bacterial endotoxin lipopolysaccharide. Traditional detection of bacteria in the wound has been carried out using technology that involved several stages. Checking the presence of gram negative bacteria in the injured site involved making a smear slide of the wound sample, then performing staining, decolorisation, and fi nally

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examining the slide under a microscope. Using cutting-edge technology based on luminescence principles, it is possible to detect Gram-negative bacteria in situ, applying appropriate sensors within the dressing. This invention, developed by Miller, Fauchet and their colleagues from the Department of Chemistry, Rochester University (NY, USA),11 uses a porous silicon wafer on which millions of tiny holes are etched. This porous structure allows contact of the target molecules with a large surface area. In addition, this structure comprises nanocrystals, which are photoluminescent in the visible range of the spectrum at room temperature. Moreover, for improved use of the luminescence method, it is possible to apply a proper bandwidth of light. The sensor material, therefore, is placed between further layers of porous silicon that only allow the escape of light for selected wavelengths. These devices are only a few micrometres thick and are known as porous silicon microcavity resonators.12 How does it work? In the detection process for lipid A, specific binding occurs between the organic receptor molecule and the diphosphoryl lipid A in the water, via the precisely shaped molecular cavity. This organic molecular receptor, known as ter-tryptophan ter-cyclopentane (TWTCP), is blocked by added amine. This prevents all the TWTCP binding sites from binding to the silicon substrate. Finally, when the binding of lipid A with TWTCP takes place, causing a change in the refractive index of the silicon, an 8-nm red shift occurs in the wavelength of its photoluminescence peak. Unfortunately, this is not visible to the naked eye and an expensive machine reader must be used.11 However, when the process of reading the peak has been improved and simplified, this potential for easier and quicker detection of wound infection and the presence of hazardous bacteria will certainly be realised.

10.3.2 Temperature-controlled textiles Keeping wounds covered provides insulation from further injuries and helps to maintain normal body temperature. It has long been known that temperature may have a beneficial influence on wound healing. All cellular functions, especially enzymic and biochemical reactions, are optimised at normal body temperature (normothermia), defi ned approximately as 37 °C.10,12,13–15 This is a very important point in the design of ‘smart’ textiles. But, on the other hand, body temperature may also be a factor that stimulates the ‘behaviour’ of the dressing and influences wound healing. The latest investigations in the field of ‘smart’ wound dressings that are managed by temperature have revealed two directions:

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• Textiles which change their properties (e.g. forming a gel) in response to different skin temperature; • Dressings that may be heated by specific devices and thereby promote wound healing.

10.3.3 Temperature-sensitive dressings The ‘intelligence’ of hydrogels has long been recognised. These smart polymers absorb high amounts of water and have a soft consistency that renders them similar to natural tissue. Moreover, the hydrogel may take up water from the surroundings under special, strictly defi ned conditions, e.g. the correct temperature. This means that this same polymer may exhibit hydrophobic or hydrophilic behaviour, according to the environment. When coating an area, or when embedded into membranes, hydrogels may therefore control the wettability of the surface. This feature has been exploited in the design of ‘smart’ dressings that combine hydrogel with textile. How does it work? Hydrogels have been used in new cutting-edge textiles that protect the wound and support its healing. Being ‘smart’ chemical sensors, they respond to the wound environment in a special, predicted way. Poly(N-isopropylacrylamide) is a well-known thermosensitive polymer, which has both isopropyl (hydrophobic) and amide (hydrophilic) groups (Fig. 10.1).10,12,16 This polymer is able to assimilate water under strictly defined conditions. Its lower critical solution temperature is set at 32–33 °C, and below this point it absorbs water and extends its chain conformation. On the other hand, when immersed in aqueous solution above 32 °C, polyN-isopropylacrylamide is extensively dehydrated and compact. This thermoresponsive nature of poly-N-isopropylacrylamide microgel polymer has, therefore, found an application in wound dressing.17,18 It may swell

H3C

H2 C

H2 C CH2

CH

CO HN

CO

CO HN

HN

CH H3C

CH2

CH

CH CH3

H3C

CH3

n

H3C

CH3

10.1 The chemical structure of poly(N-isopropylacrylamide) microgel.

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and shrink according to the temperature of the aqueous solution (in this case the exudate). Below the lower critical solution temperature of polyN-isopropylacrylamide, the swelling of the poly-N-isopropylacrylamide microgel beads will decrease the adhesive property of the polymer, resulting in lower peel strength and fi nally in easier and more comfortable removal of the dressing from the wound. The studies have shown that polyN-isopropylacrylamide microgel beads may be embedded into fi lms, membranes or non-woven fabrics made from various materials (e.g. chitosan, polystyrene or polypropylene).10,19 The membranes have nanoporous structures and are very often transparent.

10.3.4 Applications A recently designed and studied dressing, which is sensitive to skin temperature, shows great and remarkable possibilities for the application of the poly-N-isopropylacrylamide polymer. It is a tri-layer membrane, which partially resembles artificial skin and may be applied to extensive burn injuries (Fig. 10.2).19 The fi rst layer is a three-dimensional tri-copolymeric sponge composed of gelatin, hyaluronan and chondroitin-6-sulphate. It has 70% porosity with a 20–100 μm range pore size. This layer fulfi ls the function of the extra-cellular matrix of the skin for cell retention. It is therefore a dermis-analogous layer, which stimulates capillary penetration, promotes dermal fibroblast migration and induces the secretion of an extra-cellular matrix. After migration of the dermal fibroblasts, which recognise the host dermis structure on the wound site, the biodegradable tri-copolymer matrix is gradually degraded by endogenous enzymes. The middle layer is composed of poly-N-isopropylacrylamide (PNIPAAm) and is called the auto-stripped layer. As explained earlier, poly-Nisopropylacrylamide is a polymer which exhibits hydrophilic properties below lower critical solution temperature (33 °C), and a hydrophobic nature above this temperature.

Non-woven polypropylene material PNIPAAm hydrogel

Tri-copolymer sponge

10.2 Structure of the dressing with arranged poly(N-isopropylacrylamide) (PNIPAAm) microgel.

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The third, external layer is a non-woven fabric made of polypropylene. Its function is to protect the wound from infection and facilitate exudate drainage. The most important property of this dressing is that the polyN-isopropylacrylamide keeps the three layers together if the wound temperature is maintained in the inflammation state (above 37 °C). But when the healing process is advanced, new skin is being formed and the temperature decreases to normal skin level (31 °C), then the two exterior layers of dressing can be peeled off from the tri-copolymer layer. Wound dressings designed in this way can be used as biodegradable scaffolds for the induction of a ‘neodermis’ synthesis. ‘Neodermis’ is rebuilt new skin which covers the wounded areas. This dressing has huge potential application in large-surface burns, where skin grafts are required.19

10.3.5 Non-contact normothermic wound therapy (NNWT) It is obvious that open wounds endanger the organism as a result of the changing local environment in the body. Uncovered wounds are prone to internal contamination and are also being cooled, which is not beneficial to the healing process. Therefore, plain dressings such as bandages provide basic care of the injured surface, although they sometimes cause additional trauma when being applied or removed. It is very important, therefore, that the normothermic environment (at normal body temperature of about 37 °C) provides optimal conditions for enzymic and other biochemical reactions, and improves local circulation and tissue oxygen tension. Moreover, correct body temperature increases the availability of immune cells, e.g. macrophages, which may destroy and digest pathogens.13 Warming the wound, therefore, may stimulate the healing process by increasing blood flow to the tissues, maintaining an optimal oxygen level and supporting the immune system.14,15,20 In the development of sophisticated dressings, designers have invented new dressings in the form of small wearable apparatus. The product called Warm Up ® Active Wound Therapy (Augustine Medical, Inc., Eden Prairie, MN) is one example of a dressing-device that supports heat input into the wound. This method of healing uses a non-contact radiant-heat bandage to treat chronic venous ulcers or acute injuries, when conventional treatment has failed. How does it work? Warm Up ® Active Wound Therapy is a non-contact thermal dressing, which consists of a bandage, two plastic fi lms, a heating element, a control unit and a power supply (Fig. 10.3).

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B

261

C

38 °C

A1 A2

A3

A4

10.3 Diagram of a non-contact normothermic wound dressing. A: dressing with the heating element in the pocket (A1 foam ring pad, A2 pad window with two layers of the plastic films, which form a pocket for the heating element, A3 heating element, A4 fragment of bandage that surrounds the dressing pad); B: control unit that sets the temperature in the heating element; C: power supply, which is also a charger for the batteries located in the control unit.

The bandage surrounds two layers of plastic fi lm supported by and attached to an open-cell pad. The pad adheres to the skin surrounding the wound. The open window in the bandage is a two-layered pocket where the heating element is situated. The window is located straight over the wound and enables direct monitoring of the wound when the heating element is removed. The thin, flat, resistant heating element, which is reusable, fits into the pocket of the bandage and is linked to the control unit by a cable (Fig. 10.4). It is important that the heating element does not come into contact with the patient, but is held above the wound by the bandage and separated by one or more insulating layers. The temperature at the heating element is automatically maintained by the control unit at 38 °C. The power supply is a wall outlet pack that reduces the voltage to a safe level and recharges the batteries, which are located in the control unit. The treatment profi le There are different ways of using Warm Up ® Active Wound Therapy. According to one method, 21 this treatment was applied four times a day over a two-week period. The heating element was activated for one hour, followed by a period of one hour of non-heating. This regime was repeated four times a day. At the end of the last daily session, the radiant heat bandage was removed, the wounds were dressed with collagen–alginate

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4 6

1

3

5

10.4 Diagram of the dressing section of Warm Up ® Active Wound Therapy. 1: wound, 2: foam ring pad, which supports two plastic transparent films, 3: two layers of plastic films with a space between them, 4: heating element, 5: bandage around the pad, 6: connection to the heating control unit.

dressing and wrapped in an elastic compression bandage that was left in place overnight. Results The method of use of Warm Up ® Active Wound Therapy described above is one of several proposed. Generally, clinical treatment indicated that heating wounds defi nitely accelerated healing. The following results are significant: • The use of local heat delivered by the non-contact normothermic wound therapy was shown to increase subcutaneous oxygen tension by 50% above the baseline measures in normal volunteers.15 • Healing with non-contact normothermic wound therapy is faster than the use of standard dressings and no adverse effects occur.15 • From the beginning to the end of the study, pain decreased in 92% of cases, while in the control group given standard treatment, the decrease was only in 27%, and the wound size decreased in 45% (for non-healing venous stasis ulcers). 20 These results confi rm the beneficial influence of non-contact normothermic wound therapy on the healing process.

10.4 Textiles in control of exudate from wounds It is very well known, and accepted by clinicians for more than 40 years, that a moist wound environment is beneficial during the healing process. 21 Therefore, many modern textiles used in dressings are designed to provide moist and warm conditions for wounds. Body injuries are caused as a result of different stimuli, accidents or diseases (e.g. burns, acute wounds, post-operative wounds and ulcers). Some results suggests that

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the secreting fluid from wounds may have a beneficial effect on healing, but, on the other hand, it may also inhibit this process. Studies have demonstrated that exudate from chronic wounds, e.g. ulcers, in fact causes deterioration of healing, whereas fluid secreting from acute wounds may support the recovery of healthy skin. 21,22 For this reason, it is common practice to manage the wound exudate and utilise its beneficial effects for the healing process. 23

10.4.1 Why does exudate play such an important role during the healing process? Within the injured area of the body, various inflammatory reactions occur and fluid derived from serum passes through the vessel walls into the wound bed in the process called extravasation. Finally, the exudate emerges at the wound surface and, according to the local environment, may contain micro-organisms or tissue debris.24 However, the wound exudate is derived from body serum and is therefore rich in components such as glucose, lactic acid, inorganic salts, proteolytic enzymes, growth factors, immune cells (e.g. macrophages and lymphocytes), plasma proteins, albumin, globulin, and fibrinogen. Some of these play remarkably significant roles in the healing process. For example, macrophages play an immune-defence role releasing growth factors and proinflammatory cytokines. In addition, some components are a source of energy (glucose) while inorganic salts create typical pH values and cause the exudates to play the role of buffer solution. 22 Moreover, the fluid coming from the body through the wounded areas may be utilised as a medium for drugs that accelerate healing or for (other) antibacterial agents, which have bactericidal properties. When drugs have previously been administered into the digestion and circulation systems, they may subsequently appear in the exudate from the wound area. 25 Thus it can be seen that the exudate is a heterogeneous liquid with dissolved contents, which undeniably has an influence on the healing process. Dressing selection should, therefore, be related to the type and size of wound, and – most importantly – it should be chosen according to the volume, viscosity and nature of the exudate.

10.4.2 Selecting a dressing After entering the wound area, the exudate may demonstrate either a beneficial or a noxious tendency in the healing process. Depending on the wound type, the exudate may appear as a clear, straw-coloured, thin fluid, which is very similar to serum and common in acute wounds. 22 The seropurulent type of exudate, which has a characteristic yellow,

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cream–coffee colour and creamy-thick consistency, indicates that infection is under way, as occurs in infected blisters. In chronic wounds on the other hand, the colour and consistency of the exudate may vary. In addition, an unpleasant odour from chronic wound exudate and excessive drainage on clothing or bedding are common causes of patients’ discomfort and distress. 26 The features of the wound exudate also change over time after injury. Therefore, it is very important to select the dressing which is appropriate for current wound conditions. Ideally, the wound-care product would respond in a specific ‘smart’ way to the various fluid environments, but, currently available dressings react in a predictable way to the defi ned circumstances and features of the exudate. Various mechanisms exist for handling the dressing of fluid: gelling, absorption, retention and moisture vapour transmission. Some of these mechanisms sometimes occur simultaneously in one product.22 But all of these actions of dressing are clear objectives in the design of smart textiles, in order to manage the exudate and, as a result, provide the optimal environment for the quickest wound healing. 27 Today, it is still necessary for us to assess which dressing will support the healing of a particular type of wound. We have to choose with care the product that can manage appropriately the predicted amount and type of exudate. Absorbent textiles that form a gel with the exudate A wide range of dressings is available that uses gel formation as a response to interaction with the exudate. When incorporated in the dressing, the gel is the part of the system which not only protects the wound, but also accelerates the healing. The absorption and gelling functions of the dressing are very often combined and supplemented within one product. The gels applied in wound dressings might be set in sheets, pads or saturated gauzes. The most commonly used are alginates (and their combinations with other contents, e.g. with gelatine), poly(N-isopropylacrylamide) gels or hydrocolloid dressings. Hydrogels applied in wound dressings are well known for their hydroaffi nity properties. One very important feature of particular hydrogels is the amount of aqueous solution that they are able to donate or absorb. However, when excess exudate must be removed, a moist environment at the wound surface is still desirable. 28 A further property that promotes the beneficial use of hydrogels in dressings is the fact that gel contact with the exudate causes easier dressing removal, without additional pain and trauma for the patient.17 Other gelling dressings in use are hydrofibres, which are soft, non-woven pads, useful for wounds with a heavy level of wound drainage, and for deep wounds. It is also important that hydrogels stay fi rmly in contact with the wound for a long period without removal, resulting in the reduction of scar formation. 21,29

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Fluid-retention dressings Another type of gelling dressing absorbs the exudate and causes retention of fluid. The gel which is then formed can be directly removed from contact with the wound. However, this does not necessarily sustain the moist environment. One example of this kind of product is Hydrofiber®, made from sodium carboxymethylcellulose fibres. These are soft non-woven pads, which are useful for a heavy level of wound drainage, and for wounds that are deep and need packing. 30 Hydrofiber® may be used in dressings with a combination of other layers, e.g. with a polyurethane foam/fi lm layer (in the product VersivaTM). Foams and absorbent pad dressings This type of dressing is appropriate for the fi rst stage of healing when drainage from the wound is greatest because a large amount of exudate can be absorbed. The advantage is that foams can be applied in a variety of sizes, shapes and thicknesses and are gentle on the skin. While foam pads have good adhesive properties, some of them stick too fi rmly to the wound or surrounding skin area, causing additional trauma upon removal. To prevent this, soft foam pads with an incorporated silicone layer have been designed.4 This allows for repositioning or gentle removing of the dressing. A model of moisture vapour transmission in wound dressings Moisture vapour transmission through the dressing is a very important process. Depending on the dressing’s water absorption capacity, it determines the fluid balance at the wound site. 31,32 The rate of moisture vapour transmission is a feature of all dressings which absorb and remove liquids. One type of dressing that absorbs particularly large amounts of liquid is hydrocolloid dressing, which usually has two layers. The fi rst, which comes into contact with the wound site, is a hydrocolloid membrane with a large potential for swelling when taking up water. This layer is covered by another one, made of a polymeric material (e.g. polyurethane). Hydrocolloid dressings maintain a moist environment for healing, but also allow the liquid to permeate outside the dressing and facilitate autolytic debridement of the non-viable tissue. 33

10.5 Examples of ‘smart’ textiles for wound care 10.5.1 Hydrogel dressings Some of the gel-containing dressings on the market are: Tegagel (from 3M Health Care), Curasol Hydrogel Saturated Dressing (from Healthpoint), DuoDerm Hydroactive Wound Gel (from Convatec), and Carrasyn

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Hydrogel Wound Dressing (Carrington Laboratories). One of the examples of wound dressings that has gel formed in situ is based on oxidised alginate, gelatine and borax. 34 Each of these components has a specific function in the dressing. The gelatine has a haemostatic effect, while the alginate is well known for promoting wound healing and is supported by the antiseptic quality of borax. The combination of these functions makes the dressings very effective for moist wound healing. The alginate is oxidised, rapidly cross-links the gelatine and in the presence of borax gives in situ formation of hydrogel. It does not wrinkle or flute in the wound bed and moreover is non-toxic and biodegradable. It protects the wound bed from the accumulation of excess exudate because it has a capacity of fluid uptake that is 90% of its weight. It takes up the exudate, but still maintains the moist environment to facilitate and stimulate epithelial cell migration during the healing process. 34

10.5.2 Fluid-retention dressings Dressings that are well known for fluid retention very often contain hydrofibres. Examples are Aquacel® Hydrofiber® Wound Dressing and Versiva Composite Adhesive Exudate Management Dressing (both from ConvaTec). 35 Versiva, for example, contains three components: a top polyurethane foam/fi lm layer, an absorptive non-woven fibrous blend layer (with Hydrofiber®), and a thin perforated adhesive layer. All the components play specific roles in the dressing. The thin perforated adhesive layer has direct contact with the wound and accelerates exudate absorption. The non-woven fibrous-blend layer absorbs and retains the exudate by performing as a cohesive gel. The third layer, the outer-side polyurethane foam/ fi lm, protects the wound from contamination and manages the moisture vapour transmission of the exudate. This dressing is recommended for use in different types of ulcers (on legs, diabetic, pressure), and for surgical wounds, second-degree burns and traumatic wounds.

10.5.3 Foam dressings Some of the best known foam-dressing products are: Lyofoam (from ConvaTec), Polymem Non-Adhesive Dressings (from Ferris) and Allevyn Adhesive Dressings (from Smith and Nephew).

10.5.4 Silicone-foam pads Some brand-name dressings which contain soft silicone are: Tendra Mepitel (a silicone mesh contact layer), Tendra Mepilex Lite and Tendra Mepilex Border (all from Molnlycke Health Care).

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10.5.5 Hydrocolloid dressings Some examples of hydrocolloid dressings available on the market are: Tegasorb (from 3M Health Care), Comfeel Ulcer Care Dressing (from Coloplast) and DuoDerm CGF Control Gel Formula Dressing (from ConvaTec).

10.6 Response of dressings to bacteria Wound infections caused by pathogens have always been a major problem that has slowed the healing process. Although the practice of dressing wounds dates from the start of civilisation, utilising dressings for infection control is relatively new. Dressings exist today that have specific properties to inhibit infection in the wound site. There are different ways of achieving this. Sometimes the dressing applied may release drugs or other chemical compounds, which have bactericidal properties and kill the pathogen. 36,37 In other cases, the dressings catch the whole bacteria population and close them within their own structure. 38 All these treatments exploit advanced and ‘smart’ methods of accelerating wound healing, because while removing bacteria, they reduce the state of inflammation.

10.6.1 Dressings that remove bacteria from the wound site In the early 1990s, it was shown that bacteria may be removed from the wound site within the moisture-retentive hydrocolloid. 38,39 Later, investigations demonstrated that alginate-fibre dressings, which form a gel, may also partially immobilise bacteria in the fibrous matrix and, thus, effectively remove them from the wound site. 39,40 Further investigations revealed other dressings that remove bacteria from the infected site with greater efficacy than alginate. 39,41,42

10.6.2 Application of textiles for removal of bacteria Wound dressings based on carboxymethylated spun cellulose, e.g. CMCH (carboxymethyl cellulose ), absorb the exudate and form a cohesive gel. Along with the exudate, whole populations of bacteria occupying the wound space are entrapped within the gel structure. In contact with the exudate, the CMCH dressing forms a coherent, continuous gel. The fibres of the dressing, therefore, become fully hydrated, swell and are indistinguishable from each other. The fluid is rapidly absorbed and the bacteria from the wound space are enclosed inside the gel. Most importantly, the great majority of the bacteria is taken into the cohesive gel structure and none are present on the non-hydrated

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fibres surrounding the gelled area. These investigations have all been confi rmed using a scanning electron microscope (SEM). 38 This application has, therefore, the potential to inhibit wound infection without the release of drugs.

10.7 Future trends The wound dressing textile industry has a very fast rate of development. Smart devices or sensors, which may be incorporated into dressings, play a special role and are currently being investigated with particular urgency. In the past, people mostly considered the protective function of dressings, but today, they are loaded with drugs, different sensors and devices. On the basis of the achievements of current techniques and science, we can imagine that in the future, structures and applications of wound-care products will become more and more sophisticated, and patients’ recovery to health will be faster, painless and continually monitored.

10.7.1 Dressings and pathogens Dressings currently being investigated for detection of noxious bacteria in wound sites include, for example, dressings with a silicone-based biosensor that binds lipid A, which may be detected using the photoluminescence method.11 However, there is the potential development of new dressings, which can not only recognise the presence of microbiological organisms, but also distinguish between particular species and strains. However, detection methods will need to be simplified and avoid becoming too expensive. There is also the potential to develop new dressings containing antibacterial agents, which will only be active in the presence of the pathogen. Dressings already exist today which are loaded with drugs and antibiotics.43 Products containing silver as a bactericidal agent are especially popular, e.g. the nanocrystalline silver dressing ActicoatTM or SilvaSorb. Acticoat is a smart dressing which aims to accelerate the healing of burns. This product not only prevents wound adhesion, but is also an antibacterial agent. The Acticoat dressing contains a rayon/polyester nonwoven core, laminated between layers of silver-coated high-density polyethylene mesh. This dressing is effective against many bacterial strains, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci. 37, 44–46 SilvaSorb is a synthetic, polyacrylate hydrophilic matrix which contains dispersed or suspended microscopic silvercontaining particles. In contact with the moist exudate, the silver is released into the wound. 3 These dressings are already smart because, apart from their protective function, they are also a source of antibacterial agents. The challenge for

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future investigations is to design a dressing capable of releasing the antimicrobial agents in a controlled way, e.g. so that the amount of antimicrobial agent released to the wound site is just sufficient for the amount of pathogen, thereby preventing the adverse effects of any excess.

10.7.2 pH-sensitive textiles The pH value of the exudate is very important and significantly influences patients’ health. A huge challenge remains for scientists to learn how the pH level may be used to accelerate the healing process, and how to monitor dangerous changes in the wound environment. As described above, wound liquids are particular mixtures of dissolved biological micro- and macromolecules. Some of them may be noxious and some may promote the healing process. Sometimes they have a negative or positive charge, which significantly influences the pH of the exudate. There is, therefore, the possibility of designing dressings which can detect pH changes, or even react to them. Studies are currently under way to investigate how pH-sensitive chemical compounds may be applied in textiles and how they react in different conditions. Some colorimetric pH sensors react very rapidly and allow detection of changes with the naked eye, which makes them particularly attractive. On the other hand, fluorescent sensors are even more sensitive than colorimetric ones.47 Fabrics which are chromic or chameleon materials, and can change their colour in different conditions (e.g. light, heat, electricity, pressure, liquid, electron beam), are representative of ‘intelligent’ textiles.48 How do colorimetric pH chemosensors work? It is well known that fluorescent or colorimetric agents are good pH sensors.49 These compounds are highly sensitive to environmental changes, and when they possess high fluorescence intensity with thermal and photostable properties, they may be used to dye natural or synthetic textile fibres50 or as dyes for the structural coloration of polymer materials. 51 One of the compounds investigated, which may be embedded on to a fabric matrix, is 1-[(7-oxo-7-benzo[de]anthracen-3-ylcarbamoyl)-methyl]-pyridinium chloride dye (BD).47,49 This novel water-soluble organic compound retains colorimetric pH-sensor properties even when it is immobilised on viscose textile. When BD is placed in acidic solution, it occurs in protonated form and produces a bright-yellow colour. At pH >10.4, deprotonation of BD occurs and the colour becomes reddish orange. Figure 10.5 shows two forms of electron movement as a result of deprotonation or protonation. BD may therefore occur in two canonical forms, as shown in Fig. 10.5. The absorption spectra of the dye are strongly dependent on the pH of the solution. It shows that the absorption maximum

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OH–

pH 3.3–7.3 H N ..

N

O

O

O

O

H+

OH–

H+

OH–

H3O+ .. N

H3O+ .. N

pH 10.4–12.6

N

N ..O– ..

O

..O– ..

N

O

10.5 Mechanism of protonation and deprotonation of BD dye. In acidic solution, the dye is bright yellow and in alkaline solution, a reddish orange.

occurs at two different wavelengths for the two ranges of pH. At pH 3.3– 7.3, the absorption maximum occurs at λ = 413 nm, whereas at pH 10.4– 12.6 the absorption maximum is at λ = 457 nm. Reaction is very fast and reversible.47 The example outlined above shows a dyed fabric which also plays a pH-sensor role. It would be a great challenge to investigate the textile matrix further, as an application for pH-sensitive dressings. Fabric dyeing with colorimetric agents gives a large sensory area, which might be convenient in the case of wound dressings, allowing the monitoring of the whole wounded surface. Furthermore, an immediate answer indicated by a colour change would give a warning in case of any dangerous pH variations. Although the ‘smart textile’ industry is expanding greatly, ‘smart dressings’ are still a relatively new branch. Therefore, some products already under development might not be included here because they have not yet been reported in the public domain. However, this chapter provides a

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review of some ‘intelligent’ or advanced dressings, which have been invented and developed over the last few years. This detailed presentation of their mechanisms should encourage further investigation since it shows the potential of dressings in the treatment of particular wounds.

10.8 Sources of further information and advice Those interested in ‘smart’ wound dressings may fi nd other sources of further information, but the following reference list gives the most accessible and fundamental resources. Smart textiles for medicine and healthcare, edited by L. Van Langenhove, is a significant source of information not only for the wound care products area, but also for different smart textiles, such as intelligent garments for pre-hospital emergency care, smart textiles in rehabilitation or in pregnancy monitoring. The following volumes are also recommended: Medical textiles and biomaterials for healthcare, edited by S. C. Anand, J. F. Kennedy, M. Miraftab and S. Rajendran (Woodhead Publishing Limited, Cambridge, UK, 2006), which discusses issues relating to wound-care materials and intelligent textiles for medical applications. The previous editions of this book series are Medical textiles (2000) and Medical textiles 96 (1997), both edited by S. C. Anand. Conferences including discussion of topics relating to smart fabrics, textiles or dressings are an alternative source of information. During such events, changes are proposed in the functionality of textiles by applying new technologies and creating sensitive, interactive and intelligent materials. The most recent conferences and events are: •

• • • • •

MEDTEX 07, Fourth International Conference and Exhibition on Healthcare and Medical Textiles, the latest conference of a series of MEDTEX conferences, The Holiday Inn Bolton Centre, Bolton, UK (16–18 July 2007), www.bolton.ac.uk/uni/research/medtex07 Nanocomposites 2007 in Brussels, The Crown Plaza Europa in Brussels, Belgium (14–16 March 2007) The Middle East’s fi rst symposium and exhibition, dedicated to nonwovens, Dubai, United Arab Emirates, (20, 21 February 2007) 3rd International Congress on Innovations in Textiles and Fabrics, Berlin, Germany, (14, 15 February 2007) Smart Textiles Europe, Paramount Carlton, Edinburgh, UK (13, 14 December 2006), www.paramount-carlton.co.uk European Conference on Textiles and the Skin, Apolda, Germany, (11–13 April 2002), http://www.derma.uni-jena.de/04tagung/2002ects. pdf.

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More information about conferences held over the last few years on textiles, fabrics and new trends in medical applications can be found on the website http://www.technical-textiles.net.

10.9 References 1. x zhang, x tao, ‘Smart textiles: passive smart’, June 2001, pp. 45–49; ‘Smart textiles: Active smart’, July 2001, pp 49–52; ‘Smart textiles: Very smart’, August 2001, pp. 35–37, Textile Asia. 2. l v langenhove, r puers and d matthys, ‘Intelligent textiles for medical applications: An overview’ In: S C Anand, J F Kennedy, M Miraftab & S Rajendran (eds.), Medical textiles and biomaterials for healthcare, Woodhead Publishing, Cambridge, 2006, 451–472. 3. l v langenhove, ‘Smart textiles for medicine and health care. Materials, systems and applications’, Woodhead Publishing, Cambridge, 2007. 4. t s stashak, e farstvedt and a othic, ‘Update on wound dressings: indications and best use’ Clinical Techniques in Equine Practice, 2004 3 149–163. 5. g m menaker, ‘Wound dressings in the new millennium’, Seminars in Cutaneous Medicine and Surgery, 2002 21(2) 171–175. 6. s-y lin, k-s chen and l run-chu, ‘Design and evaluation of drug-loaded wound dressing having thermoresponsive, adhesive, absorptive and easy peeling properties’, Biomaterials 2001 22 2999–3004. 7. n yýldýz, ‘A novel technique to determine pressure in pressure garments for hypertrophic burn scars and comfort properties’, Burns, 2007 33 59–64. 8. l macintyre, m baird, ‘Pressure garments for use in treatment of hypertrophic scars – a review of the problems associated with their use’, Burns, 2006 33 10–15. 9. m engin, a demirel, e z engin and m fedakar, ‘Recent developments and trends in biomedical sensors’, Measurement, 2005 37 173–188. 10. b liu, j hu, ‘The application of temperature–sensitive hydrogels to textiles: a review of Chinese and Japanese investigations’, Fibers and Textiles in Eastern Europe, 2005 13(6) 54. 11. j whelan, ‘Smart bandages diagnose wound infection’, Drug Discovery Today, 2002 7(1) 9–10. 12. m-y zhou, l–y chu, w–m chen and x–j ju, ‘Flow aggregation characteristic of thermo-responsive poly(N-isopropylacrylamide) spheres during the phase transition’, Chemical Engineering Science, 2006 61 6337–6347. 13. j d whitney and m m wickline, ‘Treating chronic and acute wounds with warming: review of the science and practice implications’, J WOCN, 2003 30(4) 199–209. 14. j d whitney, g salvadalena, l higa and m mich, ‘Treatment of pressure ulcers with noncontact normothermic wound therapy: Healing and warming effects’, J WOCN, 2001 28(5) 244–252. 15. t ikeda, f tayefeh, d i sessler, a kurz, o plattner and b petschnigg, ‘Local radiant heating increases subcutaneous oxygen tension’, Am J Surg, 1998 175 33–37. 16. l m geever, d m devine, m j d nugent, j e kennedy, j g lyons, a hanley and c l higginbotham, ‘Lower critical solution temperature control and swelling

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17.

18.

19.

20.

21.

22. 23. 24. 25.

26. 27. 28. 29. 30.

31.

32. 33.

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behaviour of physically crosslinked thermosensitive copolymers based on N-isopropylacrylamide’, European Polymer Journal, 2006 42 2540–2548. l-s wang, p-y chow, t-t phan, i j lim and y-y yang, ‘Fabrication and characterisation of nanostructured and thermosensitive polymer membranes for wound healing and cell grafting’, Advanced Functional Materials, 2006 16 1171–1178. m r guilherme, g m campese, e radovanovic, a f rubira, e b tambourgi and e c muniz, ‘Thermo-responsive sandwiched-like membranes of IPNpoly-N-isopropylacrylamide/PAAm hydrogels’, Journal of Membrane Science, 2006 275 187–194. f-h lin, j-c tsai, t-m chen, k-s, j-m chen yang, p-l kang and t-h wu, ‘Fabrication and evaluation of auto-stripped tri-layer wound dressing for extensive burn injury’, Materials Chemistry and Physics, 2007 102 152–158. c robinson and s m santilli, ‘Warm-Up Active Wound Therapy: A novel approach to the management of chronic venous stasis ulcers’, Journal of Vascular Nursing, 1998 2 38–42. a jones and d vaughan, ‘Hydrogel dressings in the management of a variety of wound types: A review’, Journal of Orthopaedic Nursing, 2005 9 51–511. r white and k f cutting ‘Modern exudate management: a review of wound treatments’, World Wide Wound (Revision 1.0) 2006. k lay-flurrie, ‘The properties of hydrogel dressings and their impact on wound healing’, Prof Nurse, 2004 19 269–73. k f cutting, ‘Exudate: composition and functions’, in White RJ (editor): Trends in wound care Volume III. London: Quay Books, 2004. t yotsuyanagi, s urushidate, k yokoi, y sawada, m suno and t ohkubo ‘A study of the concentration of orally administered sparfloxacin found in exudates from suture wounds beneath occlusive dressings’, Burns 1998 24 751–753. s seaman, ‘Management of fungating wounds in advanced cancer’, Seminars in Oncology Nursing, 2006 22(3) 185–193. t j coats, c edwards, r newton and e staun, ‘The effect of gel burns dressings on skin temperature’, Emerg Med J, 2002 19 224–225. s thomas and p hay, ‘Fluid handling properties of hydrogel dressings’, Ostomy Wound Manage, 1995 41 54–56, 58–59. d eisenbud, h hunter, l kessier and k zulkowski, ‘Hydrogel wound dressings: where do we stand in 2003?’, Ostomy Wound Manage, 2003 49 52–7. g r newman, m walker, j a hobot and p g bowler, ‘Visualisation of bacterial sequestration and bacterial activity within hydrating Hydrofiber® wound dressing’, Biomaterials, 2006 27 1129–1139. c m mouës, g j c m van den bemd, f heule and s e r hovius, ‘Comparing conventional gauze therapy to vacuum assisted closure wound therapy: A prospective randomized trial’, Journal of Plastic, Reconstructive and Aesthetic Surgery, 2007 60 672–681. p wu and j d s gaylor, ‘A model of water vapour transmission in hydrocolloid wound dressing’, Journal of Membrane Science, 1994 97 27–36. m límová and j troyer-caudle, ‘Controlled, randomised clinical trail of 2 hydrocolloid dressings in the management of venous insufficiency ulcers’, Journal of Vascular Nursing, 2002 1 22–33.

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34. b balakrishnan, m mohanty, p r umashankar and a jayakrishnan, ‘Evaluation of an in situ forming hydrogel wound dressing based on oxidized alginate and gelatin’, Biomaterials, 2005 26 6335–6342. 35. y qin, ‘Superabsorbent cellulosic fibres for wound management’, Textiles, 2005 1 12–14. 36. k moore, a thomas and k g harding, ‘Iodine released from the wound dressing modulates the secretion of cytokines by human macrophages responding to bacterial lipopolysaccharide’, International Journal of Biochemistry Cell Biology 1997 29 163–171. 37. f-l mi, y-b wu, s-s shyu, a-c chao, j-y lai and c-c su, ‘Asymmetric chitosan membranes prepared by dry/wet phase separation: a new type of wound dressing for controlled antibacterial release’, Journal of Membrane Science, 2003 212 237–254. 38. m walker, ja hobot, g r newman and p g bowler, ‘Scanning electron microscopic examination of bacterial immobilisation in carboxymethyl cellulose (AQUACEL®) and alginate dressings’, Biomaterials, 2003 24 883–890. 39. j lawrence, ‘Dressings and wound infection’, American Journal of Surgery, 1994 167 21S–4S. 40. f dehaut and m maingault, ‘Kinetic binding of bacteria on two types of dressing: algosteril (calcium alginate) and gauze’, Poster presentation, First European Workshop Surgery-Engineering: Synergy in Biomaterial Applications. Montpelier, France, 1994. 41. p g bowler, s a jones, b j davies and e coyle, ‘Infection control properties of some wound dressings’, Journal of Wound Care, 1999 8 499–502. 42. m j waring and d parsons, ‘Physico-chemical characterisation of carboxymethylated spun cellulose fibers’, Biomaterials, 2001 22 903–12. 43. l martineau and p n shek, ‘Evaluation of bi-layer wound dressing for burn care. II In vitro and in vivo bactericidal properties’, Burns, 2006 32 172–179. 44. h n paddock, r fabia, s giles, j hayes, w lowell, d adams and g e besner, ‘A silver-impregnated antimicrobial dressing reduces hospital costs for pediatric burn patients’, Journal of Pediatric Surgery, 2007 42 211–213. 45. k kok, g a georgeu and w y wilson, ‘The acticoat glove – an effective dressing for the completely burnt hand. How we do it’, Burns, 2006 32 487–489. 46. r rustogi, j mill, j f fraser and r m kimble, ‘The use of ActicoatTM in neonatal burns’, Burns, 2005 31 878–882. 47. d staneva and r betcheva, ‘Synthesis and functional properties of new optical pH sensor based on benzo[de]anthracen-7-one immobilized on the viscose’, Dyes and Pigments, 2006 74 148–153. 48. c a norstebo, ‘Intelligent textiles, soft products’, Journal of Future Materials 2003 1–14. 49. d staneva, r betcheva and j-m chovelon, ‘Fluorescent benzo[de]anthracen7-one pH-sensor in aqueous solution and immobilized on viscose fabrics’, Journal of Photochemistry and Photobiology A: Chemistry, 2006 183 159–164. 50. n ayangar, r lahoti and r wagle, Indian Journal of Chemistry 1973 16B 106–108. 51. t konstantinova, p meallier, h konstantinov and d staneva, Polym. Degrad. Stab., 1995 48 161–166.

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11 Composite dressings for wound care M. JO SH I and R. P U RWA R, Indian Institute of Technology Delhi, India

Abstract: The structure of composite dressings is described as a combination of different textile structures such as woven, non-woven, knitted, net fi lm and spacer fabrics. They are multi-layered, each layer having its distinct property to enhance the wound-healing process. Research and development in composite dressings is mainly focused on enhancing the functionality of these different layers so as to promote rapid wound healing and a reduction in the pain associated with wound treatment, and all this at a reduced cost. Recent developments towards improvements in non-adherent, absorbent and bacterial barrier layers are described that can reduce the frequent changes of the dressing and, thus, improve wound healing. Key words: composite dressings, wound care, wound healing, multilayer dressings, wound dressing.

11.1

Introduction

Wound management has recently become more complex because of new insights into wound healing and the increasing need to manage complex wounds outside the hospital. Modern wound dressings are designed to facilitate the function of wound healing rather than to just cover it. Healing of wounds is a biological cellular process linked to the process of repair. The physiological process of wound healing is a dynamic process and follows a complex pattern of four continuous phases, namely haemostasis, inflammation, proliferation and maturation or remodeling.1 The best dressing is the patient’s own skin, which is permeable to vapor and protects the deeper layer tissue against mechanical injuries and infection. The disadvantage of such dressings is their antigen properties, which limits the span of the application. A wound dressing creates a suitable microclimate for rapid and effective healing.2 A good wound dressing prevents dehydration and scab formation, is permeable to oxygen, is sterilizable, absorbs blood and exudates, protects against secondary infections, supplies mechanical protection to the wound, is non-adherent, non-toxic, non-allergic and non-sensitizing. A dressing should also be tear- and soil-resistant, stable over the range of 275

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temperatures and humidity encountered during use, have a long shelf-life and be economical. 3 Wounds require several kinds of dressing, depending on the type and dimension of the wound, its positioning on the body and, in particular, on the effusion intensity, the depth of tissue damage and the stage of healing. Appropriately used dressings may prevent complications such as infection, tissue maceration, excessive effusion, swelling, pain and smell. The dressing supports the body’s own cleaning mechanism and provides clean conditions in the wound.4 A traditional wound dressing comprises an absorbent pad of a fibrous material with gauze, which is in immediate contact with the wound. The diffusing wound fluid will thus extend into the interstices and around the fibre of the dressing so that the dressing is eventually adhesively and mechanically anchored into the wound surface and produces a protective covering to the wound. Commonly used wound dressings comprise cotton gauze, foams, sponges, cotton wads or other fibrous materials. Gauze and other fibrous materials absorb fluid by capillary action with the disadvantage that when new tissue is formed as a part of healing process, it engulfs the fibre and tears when the material is removed causing wound injury and disturbing new tissue growth. Consequently, removal or changing of dressings can cause disruptions of the healing process, delaying the healing process as well as being a painful procedure for the patient. 5 Moreover, cotton gauze is generally used because of its good absorption properties and soft handle. However, a disadvantage of cotton gauze is that it allows moisture to evaporate from the wound which means that cotton gauze dressings do not maintain the moist environment that is said to facilitate faster wound healing. These dressings also need frequent changing. Thus, there is a need for a dressing which is non-adherent while being absorbent. The expectation from an ideal wound dressing at times may be very demanding and can not be fulfi lled by only one layer of material. A multilayered composite dressing provides the ultimate wound protection, layer by layer. Such modern dressings have more than one layer of material that can be universally used as an initial form of treatment of the wound. They can be applied over a wound in one simple and efficient step and prevent adherence of the dressing to the wound as well as help maintain a proper moisture level at the wound and prevent disturbance of wound caused by dressing changes.

11.2

Definition of composite dressings

Composite dressings are the products obtained by combining physically distinct components in to a single dressing that provides multiple functions. These functions must include (a) bacterial barrier (b) absorption (c) either

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Table 11.1 Commercially available composite dressings Serial number

Commercial name

Manufacturing company

Features

1 2

StratasorbTM 3M Tegaderm

Medline 3M

3

Alldress

4 5 6

COVADERM PLUS CD-1000 adult Versiva ®

Molnlycke Health Care DeRoyal SDA Product Inc. ConvaTech

Island Sterile, thin film transparent Multi-layer

7

Coversite plus

8 9

Invacare Sterile TELFA VENTEX MPM Viasorb

10 11 12

Silon Dual-Dress 04P® Silon Dual-Dress 20F®

Smith & Nephew Inc. Aracent Healthcare Kendall MPM Sherwood-Davis & Geck Bio Med Sciences

Adhesive barrier Waterproof Adhesive dressing with Hydrofiber® Waterproof Polyurethane foam Island Multi-layer boderless Multi-layer Multi-function

semi-adherence or non-adherence over the wound site and (d) an adhesive border. Composite dressings are extremely easy to use with a ‘band-aid’ type application. A composite dressing is defi ned as a multi-layer product with an adhesive border which comprises: 6 (a) a physical (not chemical) bacterial barrier that is present over the entire dressing pad and extends out into the adhesive border; (b) an absorptive layer other than an alginate or other fiber-gelling dressing, foam, hydrocolloid or hydrogel; (c) a semi-adherent or non-adherent layer over the wound site. Table 11.1 summarizes the commercially available composite dressings in the market. The shape and size of the composite dressing depend on the wound size and its place.

11.3

Structure of composite dressings

Composite dressings have multiple layers and can be used as primary or secondary dressings. Most composite dressings have three layers, namely a semi-adherent or non-adherent layer, an absorptive layer and a bacterial barrier layer as shown in Fig. 11.1. A semi-adherent or non-adherent layer

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Bacterial barrier layer

Adsorptive layer Exudates Moisture

Non-adherent or semiadherent layer

Wound

11.1 Layered structure of a composite dressing.

touches the wound and protects the wound from adhering to other material. This layer allows the dressing to be removed without disturbing new tissue growth. Since exudates pass through it into the next layer, it has to be permeable to fluids. An absorptive layer wicks the drainage and debris away from the surface of the wound and this prevent skin maceration and bacterial growth and maintains a moist healing environment. In addition to protecting the intact skin from excessive moisture, the absorptive layer helps liquify eschar and necrotic debris, facilitating autolytic debridement. A bacterial barrier layer may have an adhesive border. This outer layer allows moisture vapor to pass from the wound to the air and keeps bacteria

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and particles out of the wound. It prevents moisture leakage to the outside of the dressing (strike-through), meaning that the dressing can be changed less frequently.7

11.4

Materials and textile structures used in composite dressings

11.4.1 Non-adherent or semi-adherent layer In the composite dressing, the fi rst layer needs to be a fi ne mesh ‘nonadherent’ type material. ‘Non-adherent’ is actually a misnomer since the purpose of this layer is to allow the substances that come out of the wound to go through this layer and then be removed with the dressing change. The major function of the non-adherent layer is that it reduces shearing of the epithelium, permits passage of blood and fluids, does not trap heat or moisture, is non-absorbent and non-adhesive. This layer does not promote or speed up the healing process. Instead, it just allows for simple dressing changes to occur without disturbing the healing process. The non-adherent material is generally only one layer thick.8 Various textile materials such as nylon, cotton, polyester, polypropylene, rayon, silk, and cellulose derivatives in the form of woven, non-woven, net, and perforated fi lm structure can be used as a non-adherent layer as shown in Fig. 11.2. Initially, paraffi n gauze was used as non-adherent material for dressings. Jelonet, Paranet, Paratulle and Unitulle are some of the commercial non-adherent dressings based on paraffi n gauze; these consist of a cotton or rayon cloth impregnated with white or yellow soft paraffin. The soft paraffi n in the dressing reduces adherence to the wound bed, if applied in sufficient layers. However, these dressings require frequent changing in order to prevent drying out and incorporation into the granulation tissue in the wound.9 The main drawback of the natural polymer-based textile structure is that although they are non-adherent relative to the absorbent layer, they are not completely non-adherent. Woven or net structures have interstices in which the exudates can dry. Moreover, in certain situations such as pressure dressing or a packing dressing, the dressing is pressed on to the treatment area causing nonadherent material to be pressed into the wound so that granulation tissue and epithelial cells are forced into the interstices of the non-adherent material. The non-adherent layer of composite dressing can be prepared by changing the texture of the surface. The US patent 3 006 33810 discloses the preparation of a non-adherent surface of the dressing, wherein the non-woven fabric gets impregnated with minute particles or globules of

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Non-woven

Perforated film

Woven net

Woven (gauze)

11.2 Basic textile structures for non-adherent layer of composite dressing.

polythene and then passes through a hot calendar to provide a smooth surface covered with fi lm-like patches of polythene and free of projecting fibres. In general, a non-adherent layer comprises a highly porous, selfsustaining, discontinuous fi lm of fused and coalesced non-woven inert thermoplastic synthetic polypropylene.11 N-TERFACE (high-density polyethylene sheeting) by Winfield laboratory is an example for non-adherent layer composite dressing.12 More recently, a polyamide fabric partially embedded into the biosynthetic silicon fi lms has been used. Collagen is incorporated in silicon and polyamide components. Mepitel® is a non-adherent silicon dressing made of a medical-grade silicon gel, bound to a soft and pliable polyamide net. Another example is a fi ne polyamide net, containing pores of 50 μm in diameter, under the trade name of Tegapore. These pores are big enough to permit the free passage of exudates into the secondary absorbent layer but are too small to allow the ingress of granulation tissue. The perforated net prevents the dressing from adhering to the surface of the wound while the holes allow the passage of exudates to the absorbent layer. The net dressings themselves do not absorb any body fluids. A non-adherent dressing layer is also produced by coating them with a thin layer of aluminum by vacuum deposition. Such dressings are commercially available under

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Spun bonded

Needle punch

Air laid

Wet laid

281

Woven fabric

Spun lace

11.3 Various textile structures used for absorptive layer in composite dressing.

the trade name Metallene®.13 In general, the non-adherent layer comprises a porous polyethylene fi lm having a thickness of about 3.5–5.0 mil.

11.4.2 Absorbent layer As the name suggests, the second layer comprises an absorbent material for absorbing exudates, blood, moisture, and other fluid materials from the inner layer and also maintain the wound moist environment. The absorbent layer may contain one or more layers of absorbent material in an adequate quantity. Many non-toxic conventionally known absorbent materials are readily available. The most commonly used absorbent materials are gauze, non-woven sheet materials such as needle-punched non-woven rayon, cellulosic pulp, synthetic pulp, cotton rayon, creped cellulose wadding, an airfelt or airlaid pulp fibers and absorbent sponges, some of which are shown in Fig. 11.3. The absorptive layer needs to be flexible, soft and approximately 0.1–0.5 cm thick. The absorptive layer size and shape will vary with the size and shape of the wound. It should be large enough to cover the wound and capable of absorbing at least 2 to 20 cm3 g−1 of exudate.12 Superabsorbents are water-insoluble materials, capable of absorbing and retaining large amounts of water or aqueous fluid in comparison to their

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own weight. A cellulose matrix containing a superabsorbent, e.g. carboxymethylcellulose, sodium polyacrylate in powder form is generally used for the absorbent layer in composite dressings. Other absorbents used are composed of alginic acid, dextran, carboxymethyldextran, starch, modified starch, hydroxyethyl starch, hydrolyzed polyacrylonitrile, polyacrylamide, carboxymethylcellulose and their derivatives in the form of powder or granules. The most preferred superabsorbent material is a crosslinked dextran derivative which absorbs 2 to 10 g g−1 of liquid. These are commercially available under the trade names Sephadex® (from Sigma Chemical Co. St. Louis, MO), Debrisan® (from Pharmacia of Sweden) and Separan®, AP30 (from Dow Chemical Co.). It is preferable that the absorbent is uniformly laid so as to wick the blood and body fluids away from the wound surface and prevent the pooling of fluids next to the wound to prevent maceration of the wound. The absorbent should breathe and not trap excessive heat. The absorbent can be designed to dispense microencapsulated medication or traditional medication to the wound. The absorbent can be moistened with various medications or solutions before application or can be impregnated with a desired medicament. Examples of medicaments that may be absorbed into the absorbent are antimicrobial drugs, analgesics, metal oxides and enzymes. The absorbent should readily wick away any fluids before they dry, thereby helping to prevent any bonding or adherence of the contact component to the wound surface. Commercially available absorbent textiles such as Sunbeam Process absorbent materials (Gelman Technology), the Composite Air Laid Superabsorbent Pad (Dry Forming Processes) and Polyester Superabsorbent Fiber Flock SAFF (Hanfspinnerei Steen & Co.) are the preferred materials for making composite dressings.12 US patents 516761314 and 546573515 disclose the combination of highdensity and low-density absorbent pad structures to absorb the exudates. Such structures consist of two separate but contiguous elements, namely a lower high-density woven or non-woven fabric having optimum spreading or wicking characteristics and upper low density fabric having optimum absorption capacity. The high-density fabric will have a density of the order of 0.1 to 0.2 g cm−3 while the low-density fabric will have a density 0.05 g cm−3. The high-density and low-density fabric can be prepared by using rayon, rayon/polyester blend, polyester/cotton blend or cellulosic material. US patent 607752616 discloses the gradient density needle-punch felt of polyester and viscose fiber, which absorbs a large quantity of exudate. Material with varying density across its depth is achieved by varying the degree of needle penetration and thus fibre entanglement across the material depth. Thus, a graded density felt may have a relatively loose voluminous central region and more dense surface layers. The increased density

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of the surface layer is achieved by more entanglement, with the result that there is less spacing at its surface. This construction of graded density felt, acts as a regulator or gate. Another US patent17 claims a composite wound dressing having an outer layer having controlled permeability and an absorptive layer which is highly blood and exudate absorbent. It comprises a PTFE fibril matrix having hydrophilic absorptive particles enmeshed in a matrix and optionally a partially occlusive fi lm coated on one surface of the matrix.

11.4.3 Bacterial barrier layer The third or outer layer comprises a bacteria-impermeable and airpermeable cover sheet. The cover sheet also consists of a layer of pressuresensitive adhesive in its peripheral as shown in Fig. 11.4. The adhesive layer may be of the order of 1 mil thick. This layer helps to seal the cover sheet in a liquid and bacteria tight relationship around their common periphery so that exudate cannot escape through the edges of the dressing nor can any external contaminants, including bacteria, enter into the dressing and then pass through the slits to the underlying wound. The bacterial barrier layer comprises a flexible, waterproof and breathable material which protects the injury from exposure to contaminants from the outer atmosphere, while preventing leakage of any moisture from the injury. In general, this layer comprises a waterproof, breathable polyurethane fi lm of an approximately 0.5–1.5 mil thickness. Low density, opaque polyethylene or polypropylene fi lm, or waterproof and breathable fi lms are other suitable materials for the bacterial barrier layer. The bacterial

Bacteria impermeable, waterproof

Bacterial barrier layer

Adhesive layer Air permeable

11.4 Function of bacterial barrier layer along with adhesive layer.

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barrier layer may be of the order of 1.0–3.0 mil thick.18 A bacterial barrier air fi lter that can also be used as an outer layer is commercially available as Nucleopore®, Millipore® or Gellman®.

11.5

Types of composite dressings

Various types of composite dressings of differing absorbances for wound exudates have been patented and are commercially available. The major classification includes (a) island composite dressings (b) multi-layer and functional composite dressings.

11.5.1 Island composite dressings Island dressings consists of an absorbent layer sandwiched between semipermeable backing sheets as shown in Fig. 11.5. The absorbent pad is substantially centrally disposed on an adhesive layer of greater dimension so that the free adhesive surface surrounds the periphery of the absorbent pad for securing the dressing to the skin. The backing sheet thus extends outwardly from the edges of the absorbent layer for the attachment of the dressing over a wound by adhesion to the skin surrounding the wound. US patent 656657719 discloses a low-adherence island dressing for a bleeding or weakly exuding wound. The wound dressing consists of an absorbent layer cover with a thermoplastic fi lm. The fi lm has a textured perforated surface on the front and a smooth perforated surface on the back. The back is covered with a semi-permeable backing sheet. This sheet is extended to the sides as an adhesive material. US patent 6168800 20 discloses the antimicrobial multilayer island dressing which includes an inner absorbent assembly having a fi rst layer comprising of a wound contacting non-absorbent, non-adhering porous polymeric fi lm, which is impregnated with an antimicrobial agent, a second layer comprising a semi-permeable continuous polymeric fi lm joined to

Semi-permeable backing sheet Sandwiched absorbent material

Absorbent layer Adhesive layer Bacterial barrier layer Non-adherent layer

Island dressing

Island composite dressing

11.5 Schematic representation of island dressing and island composite dressing.

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the fi rst layer to form a sealed interior reservoir compartment, an absorbent material positioned within the interior reservoir compartment to collect discharged exudate from a wound, and an outer layer extending beyond the peripheral edges of the inner absorbent assembly, the outer layer having at least a portion coated with an adhesive material for adhering the island dressing to the wound area. US patent 560738821 discloses a liquid and pathogen impermeable island wound dressing that can be adhesively bonded to the skin surrounding a wound and is provided with a liquid and gas permeable exudateabsorbing pad, and a plurality of sequentially removable liquid and micro-organism impermeable, but gas and moisture vapor permeable cover sheets disposed adjacent to and covering the pad.

11.5.2 Multi-layer and functional composite dressing US patent 634842322 discloses a multi-layer wound dressing which includes a fibrous absorbent layer for absorbing wound exudate, an odor layer for absorbing odor and a barrier layer interposed between the fibrous absorbent and barrier layers. Preferably, the barrier layer is vacuum perforated and the fibrous absorbent layer is of highly absorbent fibers capable of absorbing 25 g g−1 of exudate. US patent 487547323 discloses a multi-layer wound dressing that facilitates wound healing by creating hypoxia followed, after 3 to 72 h, by an aerobic environment. The dressing is made of (a) an outer layer of low oxygen permeability; (b) an oxygen-permeable inner layer, affi xed on one side to the outer layer; and (c) an adhesive applied to the other side of the inner layer. The adhesive may be applied in a continuous or discontinuous manner, and may be applied only around the perimeter of the dressing, leaving an adhesive-free window. The entire dressing is applied to the wound and creates a hypoxic environment until the outer layer of low oxygen permeability is removed after 3 to 72 h. The oxygen-permeable layer is left on to provide protection during a subsequent aerobic healing phase. An absorbent dressing containing a slow-release agent comprises a wound-contacting layer covered with tapered apertures. The bottom surface of the said tapered aperture contacts a wound area to discharge exudate from the wound area and transmit exudate via a guiding layer to an absorbent layer. The absorbent layer formed of high-molecular polymeric fibers is mixed with a certain concentration of water-soluble agents, such as antiseptic agents, enzymes and growth factor agents, in a suitable proportion. After the exudate passes into the absorbent layer, the polymeric fibers expand becoming gel-like and forming into a shape that prevents exudates flowing backward to the wound area. Also, a

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translucent evaporating layer having numerous micro-pores for air venting is above the absorbent layer and the peripheral edges are joined together in the form of a sealed structure by heat-sealing to stop side escape of exudate, which is more effective in preventing secondary infection in the wound area. 23 CarboFlexTM is a non-adhesive multi-layer dressing. The fi rst layer is an absorbent wound contact layer consisting of fibers of AquacelTM and KaltostatTM. This layer absorbs and retains exudate, so the problem of maceration and excoriation is reduced as the retention of exudate controls the lateral wicking. As this layer forms a soft gel, a moist environment is maintained and so should allow pain-free removal of the dressing. The second layer is an ethylene methyl acrylate (EMA) fi lm that contains one-way water-resistant micro-valves, which delay strike-through to the charcoal layer. This mechanism prolongs the action of the odor-absorptive properties of the dressing. The third layer is a black activated charcoal cloth for the absorption of odor. The fourth layer consists of a soft nonwoven absorbent pad that will absorb any excess exudate, thus delaying the strike-through and providing extra softness to the dressing for patient comfort. It is also thought that patients may dislike the appearance of a black dressing, so this layer makes it esthetically pleasing to patients. The fi nal fi fth layer is another layer of ethylene methyl acrylate (EMA) fi lm, which again delays strike-through of exudate and makes the dressing soft, smooth and water resistant.9 CarbonetTM is another multi-layered, low-adherent, absorbent deodorizing dressing. The fi rst layer is a TricotexTM wound contact layer that protects any granulation tissue in the wound bed and allows pain-free removal of the dressing. The middle layer is an absorbent layer of MelolinTM fleece, that absorbs exudate, and the top layer is made of activated charcoal cloth.9 The Triosyn T40 TM Antimicrobial Wound Dressing is a sterile, primary wound dressing. It is a multi-layer composite dressing consisting of an absorbent polyester non-woven pad, a permeable adhesive, a single layer of Triosyn iodinated resin beads, and a non-adherent high-density polyethylene (HDPE) mesh.

11.6

Trends in composite dressings: embroidery technology

Embroidery technology is being widely used for medical textiles and tissue engineering. Non-healing wounds require intensive wound care for a very long time. In textile-based implant materials, tissue formation and vascularization depend on the size and distribution of pores and fibers.

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11.6 Embroidery technology for wound dressing. 23

An arrangement of pores of different orders of magnitude will favor tissue growth and the formation of new blood vessel and capillaries. St. Gallen, Switzerland have developed a wound dressing TISSUPOR® as shown in Fig. 11.6 based on embroidery for treatment of chronically non-healing wounds. Embroidery technology allows a 3-dimensionally structured textile architecture to be achieved that combines pores for directed angiogenesis and elements for local mechanical stimulation of wound ground. In TISSUPOR pad, the layers of dense fabric and spacer fabric are made of polyester and the superabsorbing material used is polyacrylate. 24 Wound dressings based on using woven fabric have the disadvantage that it has a hard surface, which adapts poorly to the wound. For this reason many wound dressings are made up of knitted structures which are soft because of the movements of the threads within the interfacing. However, the disadvantage is that they harden because of exudates emerging from the wound and thus lose their flexibility. Mono-fi laments, multi-fi laments or mixtures of these can be used in the embroidery process. The advantage of embroidery over knit structure is that the thread cannot move in the interfacings. The mechanical properties of the embroidery are defi ned by the arrangements of the interfacings and hardly affected by the incorporation of exudates or extracellular matrix into the thread, which leads to interfacings sticking together. In knitted structures, the mechanical properties are mainly defi ned by the moveability of the thread in the open interfacing. Thus, adhesive exudate leads to an increase in the rigidness of the textile in some circumstances far more than an order of size. Stiffness can cause local loading conditions, which can lead to local tissue necrosis. 25

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11.7

Conclusions

A composite dressing is a multilayered product, which is a combination of different textile structures such as woven, non-woven, knitted, net fi lm and spacer fabric. Each layer has its distinct property to enhance the wound healing process. Research and new developments in composite dressings are mainly focused in enhancing the functionality of its different layers so as to promote rapid wound healing, reduction in pain associated with wound treatment and all this at a reduced cost. The improvements in nonadherent, absorbent and bacterial barrier layers can thus reduce the frequent changes of the dressing, which helps improve wound healing.

11.8

References

1. w paul and c p sharma, Trends in Biomaterials and Artifi cial Organs, 18(1) (2004) 18. 2. r f diegelmann and m c evans, Bioscience, 9 (2004) 283. 3. v jones, j e grey and k g harding, British Medical Journal, 332 (2006) 777. 4. n f s waston and w hodgkin, Surgery, 23(2) (2005) 52. 5. b griffi ths, e jacques and s bishop, US Patent No. 6458460 (2002). 6. tri-centurian, Region A/B DME PSC Bulletin September 2006, www. tricenturian.com. 7. c thomas, Nursing 2000, 30(5) (2000) 26. 8. s thomas (1990) Primary wound contact material, In Wound Management and Dressing, London. The Pharmaceutical Press. 9. d morgan (2000), Formulary of Wound Management Products 8th Ed. Haslemere Euromed Communication Ltd. 10. p thomas davies, US Patent 3006388 (1961). 11. c l eldredge and k j petters, US Patent 3285245 (1966). 12. g w cummings and r cummings, U S Patent 5910125 (1999). 13. r punder, JCN online 15(8) (2001). 14. h karami and r f vitaris, US Patent 5167613 (1992) 15. h a patel, US Patent 5465735 (1994). 16. d c scully and c mccabe, US Patent 6077526 (2000). 17. l a errede, j d stoesz and g d winter, US Patent 4373519 (1981). 18. w andrews, l hammett and c robert, US Patent 5437621 (1993). 19. d addison, j s mellor, m w stow and m c biott, US Patent 6566577 (2003). 20. j a dobos and r d mabry, US Patent 6168800 (1998). 21. r ewall, US Patent 5607388 (1994). 22. b griffi ths, e jacques and s bishop, US Patent 6348423 (1999). 23. o m alvarez, US Patent 4875473 (1986). 24. e karamuk, m billia, b bischoff, r ferrario, b wagner, r mose, m wanner and j mayer, European Cells and Materials, 1 (2001) 3. 25. tissupore ag, US Patent 6737149 (2004).

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12 Textile-based scaffolds for tissue engineering M. K U N, C. C H A N and S. R A M A K R I SH NA, National University of Singapore, Singapore

Abstract: The principles of tissue engineering are described and the properties required for fibrous scaffolds are discussed. A review is presented of the various types of textile structure and common fabrication technologies, with a wide range of examples of tissueengineered scaffolds for repair or replacement of various organs or tissues. Key words: tissue engineering, textile scaffolds, nanofibers, stem cells.

12.1

Introduction: principles of tissue engineering

Tissue engineering is the application of engineering and life sciences principles in the development of biological substitutes for restoration, maintenance, or improvement of tissue function or a whole organ (Lanza et al. 2000). There are three essential components as shown in Fig. 12.1. Firstly, a porous matrix or scaffold, preferably biocompatible, i.e. absorbable, is required to serve as an extracellular matrix (ECM) support structure for self-organization of cells. Secondly, various cell types including autologous, allogeneic, xenogeneic cells or cell lines can be cultured on scaffolds for proliferation, differentiation or other biomedical purposes. Lastly, key biomolecules such as growth factors, differentiation factors or other cytokines can also be incorporated into the scaffolds for the desired molecular cues or cellular signals imparted to the seeded cells. Besides the above-mentioned triad, various tissue engineering parameters, such as two-dimensional (2D) cell expansion, three-dimensional (3D) tissue formation, in vitro cell culture conditions, e.g. static, stirred or dynamic flow conditions with or without bioreactors, can be manipulated to enhance the performance of the biological functions of the engineered tissue in an artificial matrix. This chapter is divided into six sections. The fi rst section provides a brief overview of principles of tissue engineering. The second section is concerned with the major functions, specific requirements and current materials used for fibrous scaffolds as well as the relationship between 289

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Cells

A scaffold Regulators: growth factors, cytokines, etc.

Cell–matrix interaction: attachment, migration, proliferation, differentiation

A triad

12.1 Elements of tissue engineering (a triad): cells, a scaffold/matrix and regulators.

textile architecture and cell behaviors. The third section presents various types of textiles classified by fabrication methods and intended applications. The fourth section covers an ever-expanding range of applications of tissue engineering for replacement and repair of various organs or tissues. This section also introduces several novel smart scaffold devices. The fi fth section offers insight into new trends and future directions for tissue engineering developments. The last section is a survey of some important sources of information and references.

12.2 Properties required for fibrous scaffolds Of the three key components in tissue engineering, scaffolds is the one that can be manipulated to the greatest extent. A 3D scaffold similar to natural ECM topography is considered to be a critical component for a successful tissue engineering strategy. The desirable scaffold is a regeneration substrate with special properties such as: • architectures and functions that are similar to natural ECM; • a pore size within a critically defi ned range; and • a degradation rate that matches the rate of tissue regeneration at the host bed.

12.2.1 Functions of fibrous scaffolds Living cells in tissue engineering are generally seeded into an artificial architecture capable of retaining cells and guiding their growth and tissue

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regeneration in three dimensions. This artificial ECM plays an important role in mimicking the in vivo milieu to allow cells to interact in their own micro-environments. The fibrous scaffolds fabricated may have a branched configuration extending outwardly from a central stem (Vancanti et al. 1998), and serves at least one of the several purposes. Firstly, fibrous scaffolds with hierarchical structures can provide a superior surface area for cell attachment, migration, proliferation and differentiation. Secondly, they can also serve as a carrier for biochemical factors to deliver the biochemical factors to the target organs for therapeutic purposes. In addition, these highly porous fibrous scaffolds allow free entrance of vital cell nutrients such as oxygen and cell growth factors, and allow easy diffusion of secreted biomolecules during cell growth. Recently, scaffolds fabricated from nanofibers (NF), referred to here as fibers with diameters below 1000 nm, are gaining increasing attention. It is being recognized that nanofibers when used as scaffold materials in tissue engineering exhibit superior functions when compared with macrofibers. Some of the attributed advantages are as follows (Li et al. 2002, Li et al. 2007): 1.

2.

3. 4.

5.

The high surface area-to-volume ratio of nanofibrous scaffolds has enhanced absorption of adhesion molecules such as vitronectin and fibronectin which are important for cell adhesion to the scaffold. Nanofibers being smaller by two-orders than a cell create a 3D environment that resembles extracellular matrix (ECM) favorable for cell interaction. Nanofibrous scaffolds provide a favorable environment for proliferation and maintenance of certain cell phenotypes. Stem cells maintained in nanofibrous scaffolds can be induced to differentiate into different cell lines, thus offering the possibility of engineering complex tissue consisting of different cell lines starting from a single stem cell line. It appears that nanofibrous scaffolds can provide physical as well as spatial cues that are essential to mimic natural tissue growth.

12.2.2 Specific requirements for fibrous scaffolds To achieve successful tissue restoration and organ functions, a fibrous scaffold must meet certain fundamental criteria. First, the pore size must be adequate and the porosity sufficiently high to facilitate cell seeding and allow for an efficient exchange of cell nutrient and metabolic waste between the adherent cells and the host bed. Cells residing in a fibrous scaffold are capable of amoeboid movement pushing the surrounding fibers aside and thus expanding pores within the scaffold. In this way, fibrous scaffold offers

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cells the opportunity to optimally adjust the pore diameter and migrate into areas where some of the initial pores are relatively small (Li et al. 2002). The relationship between pore diameter and tissue in-growth will be discussed in the section 12.4. In addition, mechanical properties of a fibrous scaffold is another contributor to its success in tissue engineering because a scaffold not only provides a substrate for cell residence but also assists to maintain the mechanical stability at the defect site of the host (Li et al. 2002). An effective tissue-engineered scaffold has to meet at least two mechanical requirements. First, it must be sufficiently stable for a physician to handle and implant the scaffold into the target site of the host. Second, after transplantation the architectures of the scaffold in the process of biodegradation need to provide sufficient biomechanical supports during tissue regeneration (Li et al. 2002). The mechanical properties of an engineered scaffold are determined not only by intrinsic factors like chemical compositions of the material, but also by extrinsic factors, such as construction geometry or architectural arrangement of the building blocks (Li et al. 2002). For certain applications such as vascular grafts involving pulsatile stress, there will be special requirements in terms of compliance and elasticity of the materials (Wang et al. 2005). If the graft’s compliance and distensibility are not met, blood flow disturbance would occur and endothelial injuries would be caused by the increase in mechanical stress near the anastomotic sites (Doi et al. 1997). However, incorporation of elastic fibers or polymers in scaffolds for vascular grafts will enhance the compliance of the scaffolds to hemodynamic pressure (Wang et al. 2005). Last but not least, biodegradability is an important consideration for selecting a scaffold material. Ideally, a biodegradable scaffold is absorbed by the surrounding tissues and metabolized in the body after fulfi lling its intended purposes. For example, poly-(dl-lactide-co-glycolide) (PLGA) is a widely used biomaterial that can hydrolyze into monomers of lactide and glycolide, which subsequently break down into water and carbon dioxide through the Krebs cycle (Bazile et al. 1992). The degradation rate should match the rate of tissue formation. This means the residing cells should proliferate, differentiate and build up ECM sufficient for tissue reconstruction while the scaffold materials gradually degrade over time. An ideal skin substitute is expected to have certain characteristics: 1. 2. 3.

Easy to manipulate for transplantation and readily adherent to wound sites. Impervious to bacteria, but porous for nutrients and oxygen diffusion. Sterile, non-toxic and non-antigenic.

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Have physical and mechanical properties appropriate to wound coverage. Have a controlled degradation rate. Ability to regain lost skin functions, including sensitivity, elasticity, normal physiological function and pigmentation. Assimilated into the host with minimal scarring and pain. Readily vascularized.

The ultimate goal of the skin tissue engineering is to satisfy most if not all of the criteria, and meeting these criteria can be better achieved with novel, smart skin substitutes (Metcalfe et al. 2007).

12.3 Materials used for scaffolds Currently, there are a variety of biomaterials suitable for the fabrication of scaffolds. Biomaterials can be defi ned as any biocompatible substances other than those used for food or drugs (Peppas et al. 2007). Owing to their functional properties and design flexibility, polymers are the primary class of materials for fabrication of scaffolds (Murugan et al. 2006). The polymers used in scaffold fabrication can be classified into two groups: naturally derived polymers and synthetic polymers. The naturally derived polymers are biodegradable, such as collagen, dextran, elastin, fibrin, hyaluronic acid, fibronectin, polypeptides, hydroxyapatites, chitosan, and glycosaminoglycans (GAGs) (Metcalfe et al. 2007, Pellegrini et al. 1999, Ronfard et al. 2000, Feng et al. 2006). Such materials have the advantage that they facilitate biological recognition and provide a better environment for tissue regeneration. However, rapid absorption and weak mechanical strength often compromise efficient applications of natural biomaterials. They may also elicit inflammatory and allergic responses. Amongst the naturally derived polymers, collagen elicits the least immunological response. Synthetic polymers can be classified further as either biodegradable or non-biodegradable. Biodegradable polymers are of great interest in the development of tissue engineering. Synthetic polymers such as polyl-lactide (PLA), polyglycolide (PGA), polycaprolactone (PCL) and polyglactin are biodegradable. The degradation rate of these synthetic polymers varies greatly, with PGA degrading in weeks whereas PCL may take up to several years. As the seeded cells begin to break down the scaffold, the surface of the polymer is continuously replaced by ECM secreted by the cells. This is a dynamic process of cell–substrate interactions (Lanza et al. 2000). Recently, copolymers such as PLGA and poly-(l-lactic acid-co-ε-caprolactone) (PLLA-CL) are increasingly used for fabricating tissue-engineered scaffolds or as implants because the

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degradation rates can be readily controlled by adjusting the ratio of their components. Another advantage of synthetic polymers lies in their potential to be produced in large quantities with controlled properties in terms of strength, degradation rate, and microstructure. However, compared with natural polymers, synthetic polymers lack biological recognition signals for cellular interaction. Current strategies to address this problem include immobilization of naturally derived polymers on the surface of synthetic polymer matrix or simply physically blending a natural polymer with a synthetic polymer before fabrication. This is to improve biocompatibility of the hybrid scaffold while preserving their mechanical strength (Feng et al. 2006, He et al. 2005).

12.4 Relationship between textile architecture and cell behavior Cellular responses to fibrous scaffolds as discussed previously are influenced by various characteristics of the scaffold including surface chemistry and texture. The following properties are of particular importance:

12.4.1 Scaffold topography Micro-architecture of a porous scaffold is known to affect cell behaviors. For example, from 5–500 nm to 7–10 μm, topographic alterations on 2D substratum can result in different cell responses (Curtis et al. 2007, Massia et al. 1991, Sun et al. 2006). In addition, it is well documented that cell responses to 2D and 3D environment are quite different. Compared with 2D substrates, cells loaded within a 3D matrix display enhanced biological activities and a lower requirement of integrin usage for cell adhesion (Cukierman et al. 2001). Other reports also observed that epithelial cells and fibroblasts are more likely to proliferate in 3D than 2D culture conditions (Sanders et al. 2003b, Sanders et al. 2000). This is attributed to the 3D environment being similar to natural ECM in terms of structural dimension. Fiber orientation within a fibrous scaffold is also found to affect cellular behavior. In our studies, smooth muscle cells (SMCs) tended to orientate and elongate themselves along the alignment of the fibers and to express a spindle-like contractile phenotype, as shown in Fig. 12.2 (Xu et al. 2004a).

12.4.2 Fiber diameter Cells are able to organize around the fibers with diameters smaller than themselves (Pham et al. 2006). Sanders and co-workers showed that, for

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200.00 μm

12.2 Laser scanning confocal microscopy image of immunostained α-actin filaments in SMCs after one day of culture on aligned PLLA-CL nanofibrous scaffold (Xu et al. 2004a).

five weeks after polypropylene fibers were implanted in the subcutaneous tissue in the dorsum of rats, small fibers with diameters less than 6.0 μm had significantly less macrophage density than those fibers between 6.0 and 27.0 μm in diameter, which had substantial fibrous encapsulation, a sign of a foreign-body reaction (Sanders et al. 2000). This may be because of the reduced cell–material contact surface area or due to a curvature threshold effect that triggers certain cell signaling (Sanders et al. 2000). Induction of a fibrous layer between a scaffold implant and host soft tissue can create unstable mechanical coupling at the material–tissue interface. This can trigger local stress responses and fibrous capsule formation. It has been shown that the threshold value of microfibers to form fibrous capsules is 5.9 μm in diameter (Sanders et al. 2003a). One explanation why fibers with diameters above this threshold value can elicit capsule formation is that the larger fibers may separate from collagen fibers in ECM, thus creating dead space regions adjacent to themselves, and recruit inflammatory cells to stimulate fibrous capsule formation (Sanders et al. 2003b).

12.4.3 Scaffold porosity Porosity is a measure of void spaces in a material. The volume of void spaces and the distribution of pore size are two important parameters that characterize the scaffold porosity. Of particular importance in tissue engineering is the inter-connectivity of the pores. Most studies have focused on the effect of the pore size.

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A scaffold with a high porosity tends to have a large surface area for cellular attachment and formation of multiple focal adhesion points on the interconnected fibers (Pham et al. 2006). The relationship between pore diameter and tissue ingrowth has been extensively investigated. For percutaneous implants, it was reported that epithelial migration was significantly improved when pore size is 0.025–3 μm (Squier et al. 1981). For corneal implants, stratification was more often observed for materials with a pore size of 0.1–0.8 μm than for 0.8–3.0 μm (Dalton et al. 1999, Evans et al. 1999, Fitton et al. 1998). In addition, a pore size of 40–50 μm was shown to facilitate migration of endothelial cells cultured on vascular grafts (Hermens et al. 1995, Takahisa et al. 1996). Another study indicated that the optimal pore dimensions for encouraging neovascularization is 0.8–8.0 μm (Brauker et al. 1995), whereas for effective osteoblast ingrowth for bone graft, the optimal pore diameter is 75–150 μm (Desai, 2000). The porosity of fibrous scaffolds can also affect the degradation rates. Highly porous fibers degrade more slowly because acidic by-products secreted by cells would be removed from the implanted sites at a faster rate (Wang et al. 2005). Porosity, fiber diameter and mechanical strength are inter-related parameters for nanofibrous scaffolds. It has been shown that a decrease in the porosity of a nanofibrous scaffold is associated with a decrease in fiber diameter and an increase in mechanical strength and density (Wang et al. 2005).

12.4.4 Surface property Surface properties of a fibrous scaffold, such as surface hydrophobicity, charge, and roughness, are largely dominated by free functional groups of the materials used in fabricating the scaffolds. Chemical composition and biological functions of these materials play an important role in determining cell–scaffold interactions. Hydrophobic surfaces are usually considered initiators of the foreignbody reaction and reduced biocompatibility (Sanders et al. 2003a). Therefore, a preferred current approach for scaffolds that are constructed from hydrophobic synthetic materials is to either incorporate hydrophilic natural materials or to modify the surface of the material to make it less hydrophobic. For instance, it was reported that grafting concentrated hydrochloric acid on a PGA fibrous scaffold enhanced the surface hydrophilicity of the scaffold, indicated by increased attachment and proliferation rates of rat cardiac fibroblasts cultured on it (Boland et al. 2004). Similarly, incorporation of chitosan in fibrous scaffolds was used in skin

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tissue engineering because chitosan can improve the biocompatibility of the scaffold and have wound-healing effects and anti-microbial properties as well (Wang et al. 2005). Some in vitro studies have shown the effects of surface charge of scaffolds on cell adhesion and expansion. The proliferation rate of fibroblasts is greater on positively charged copolymers such as hydroxyethyl methacrylate and amine-containing N,N-dimethylaminoethyl methacrylate hydrochloride; hydroxyethyl methacrylate and trimethylaminoethyl methacrylate chloride than on negatively charged copolymers (such as methacrylic acid and hydroxyethyl methacrylate) or on a neutral homopolymer such as hydroxyethyl methacrylate (Hattori et al. 1985). Another group demonstrated that the preferred scaffold surface charge for endothelial cells is in the following order: a positively charged hydroxyethyl methacrylate copolymer (with trimethylaminoethyl methacrylate HCl) > tissue culture polystyrene (TCP) (slightly negative charge) > a negatively charged hydroxyethylmethacrylate copolymer (with methacrylic acid) (Vanwachem et al. 1987). However, this is not always the case. The interaction between seeded cells and a scaffold surface can vary with different surface materials. For example, the proliferation rate of endothelial cells on either negatively charged or positively charged methylmethacrylate copolymers (with methacrylic acid and trimethylaminoethyl methacrylate HCl salt, respectively) was observed to be higher than that on the TCP surface. In contrast, positively charged hydroxyethyl methacrylate copolymer (with trimethylaminoethyl methacrylate HCl) was found to support attachment of endothelial cells, while the same copolymer, when being negatively charged (with methacrylic acid), would not facilitate endothelial cell adherence (Vanwachem et al. 1987). Subtle differences in the surface roughness of fibrous scaffolds can affect cellular responses. It has been observed by seeding human coronary artery endothelial cells (HCAECs) on a smooth solvent-cast film and on an electrospun PLA nanofiber mesh that there is an inverse relationship between surface roughness of substrates and adhesion and proliferation rates of HCAECs. Cells on the smooth fi lm exhibited round morphology and can organize into capillary-like microtubes, which is the expected functional phenotype. In contrast, cells on the nanofiber mesh have an undesired spread-out morphology (Wang et al. 2005). However, different cell types have different preferences for surface roughness. Another group reported that the attachment and expansion of human umbilical vein endothelial cells were significantly enhanced when the surface roughness was increased. This roughness was created by grafting polyethylene glycol (PEG, mol. wt. 2000) and a cell surface peptide (GRGD) onto the polyurethan (PU) surface (Chung et al. 2003). Similarly, vascular smooth

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muscle cells have lower cell adhesion and proliferation on the smooth PLA surfaces (Xu et al. 2004b). However, each of the above-mentioned properties is only a component factor rather than an exclusive determinant for directing cell–matrix interactions. It should also be kept in mind that the overall effects of fibrous scaffolds on behaviors of their resident cells can be tailored by adjusting these component factors.

12.5 Textiles used for tissue scaffolds and scaffold fabrication A multitude of research work on various types of optimum scaffolds for tissue engineering has been carried out in the last decade. According to processing methods, these scaffolds can be broadly categorized into three groups: (1) foams/sponges, (2) 3D printed substrates/templates, (3) textile structures (Ramakrishna 2001). Textile structures form an important class of porous scaffold in tissue engineering.

12.5.1 Textile structures for medical application Textile structures including non-woven, weave, braid and knit have been applied in the medical field for many years, from the initial uses, in sutures, wound gauze, plasters, vessel prosthesis and hernia nets, etc., to current applications, in vascular implants, artificial liver, tendons, skin and other vital organs or tissues. Table 12.1 shows a wide range of applications of textile structures in tissue-engineered scaffolds. Microstructural aspects of textile structures Textile structures can be customized to give the required porosity in terms of size, amount, and distribution pattern. Table 12.2 lists the microstructural aspects of different textiles and their wide uses in healthcarerelated fields. The porosity of scaffolds is governed by the construction of textile fabrics. A typical textile scaffold shows three levels of porosity that can be selectively controlled. The fi rst level is the inter-fiber gap that can be controlled by changing the number of fibers in the yarn and the yarnpacking density. The gap between yarns forms the second level of porosity. For knitted scaffolds, variations in stitch density and stitch pattern can affect this level of porosity, whereas in the case of woven scaffolds, the porosity can be changed by controlling the inter-yarn gaps through a beating action. The third level of porosity is created by subjecting the textile structures to secondary operations including crimping, folding, rolling and stacking.

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Table 12.1 Various scaffolds used in tissue engineering (Tao, 2001) Examples of scaffold materials*

Scaffold structures: yarn (y), weave (w), braid (b), knit (k), non-woven (n)

Bladder Blood vessel

PGA Polyester(Dacron); PETE; polyurethane; PGA; PTFE; PLA; PLGA (Vicryl), PLLA-CL PGA; PLLA; PLGA + hydroxyapatite; polyethylene PGA; PLLA; PLGA Collagen, fibrin, polyester, copolymer of PDMS and PNIPAAM PLA; PLGA (Vicryl) PGA Collagen; PETE; polyethylene; PGA; PLGA; PGA; PLA; PLGA; polyorthoesters; Polyanhydride; PLGA; viscose rayon Collagen-glycosaminoglycan; PGA PGA, PLGA, nylon, collagen-glycosaminoglycan; chitin/ chitosan, alginates PGA; PETE; silk

Textile (n) Textile (n, w, b, k)

Bone Cartilage Cornea Dental Heart valve Ligament Liver Nerve Skin Tendon

Textile Textile Foam Textile Textile Textile Textile

(n), foam (n) (n), foam (porous membrane) (n, w) (y, b, n, k), foam (n), Foam, 3D printed

Textile (n), foam Textile (n, w, k), foam Textile (n, y)

* PLGA: poly(dl-lactide-co-glycolide), PGA: poly(glycolide), PLA: poly(l-lactide), PLLA-CL: poly(l-lactic acid-co-ε-caprolactone), PETE: polyethylene terephthalate, PTFE: polytetrafluoroethylene, PDMS: poly(dimethyl siloxane), PNIPAAM: Poly(N-isopropylacrylamide)

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Pore size (μm) Porosity (%) Pore distribution Reproducibility of porosity Pore connectivity Processability Medical applications

Others

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Non-woven

Woven

Braided

Knitted

10–1000 40–95 Random Poor

0.5–1000 30–90 Uniform Excellent

0.5–1000 30–90 Uniform Excellent

50–1000 40–95 Uniform Good to excellent

Good Good Surgical gowns, incontinence pads, nappies, sanitary wear, artifical ligment, tissue engineering scaffold

Excellent Excellent Surgical gowns, vascular implants, dressing, plasters, tissue engineering scaffolds, hospital bedding and uniforms Limited shape

Excellent Excellent Artifical ligaments, sutures, vascular implants

Excellent Good Vascular implants, artifical tendons and ligaments, stents, compression bandages

Only tubular or uniform crosssectional shapes

Limitations of low bending properties of current biodegradable fibers

High equipment cost, questionable control over porosity

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Table 12.2 Microstructural aspects and medical applications of textile scaffolds (Tao, 2001)

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Table 12.3 Mechanical properties of textile scaffolds (Tao, 2001) Non-woven

Woven

Braided

Knitted

Strength Stiffness

Low Low

High High

High High

Low Medium

Structural stability

Poor to good

Excellent

Excellent

Poor to good

Others

Isotropic behavior

Anisotropic behavior

Anisotropic, with good properties in axial direction and poor properties in transverse direction

The behavior can be tailored from anisotropic to isotropic

Mechanical properties of textile structures For certain applications, the scaffold is more than a simple vehicle for cell delivery. It must maintain its structural integrity and a certain amount of load-carrying capacity for the desired amount of time, for example in bone, cartilage and ligament reconstructure (Yang et al. 2001). Table 12.3 compares the mechanical properties of various textile structures. In general, non-woven fabrics are webs of non-aligned fi laments allowing for the largest variation in pore characteristics, while woven fabrics possess a dimensionally stable structure, characterized by pores of regular size and shape. Warp-knitted fabrics, in which threads are laid along the direction of fabric production, have been proven to be suitable for the demand of high elastic deformation, for example, in vascular grafts applications, the grafts are required to resist continuous dynamic stress. Braided fabrics are formed by interlacing three or more threads, so that threads cross one another in a diagonal formation. They can be made either flat or tubular to meet for different purposes (Mather, 2006, Wollina et al. 2003). Compared with woven or knitted fabrics, the braided textile composites can better resist twisting, shearing and impact. However, they show their poor stability under an axial compression (Wollina et al. 2003, Tan et al. 1997).

12.5.2 Technologies for fabrication of textile scaffolds Embroidery technology Recently, embroidery technology in which thread direction can be arranged at almost any angle, has elicited great interests in the design and fabrication

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of tissue-engineered scaffolds. The process involves a needlework pattern of sewing reinforcing fibers onto a ground material. The arrangement of these reinforcing fibers is computer controlled and, thus, almost any desired textile forms can be produced. Various materials including woven and nonwoven fabrics or foils mentioned above can be used as the ground material. By stacking the embroidery, a multi-layered construct can be built to form 3D textile scaffolds (Ramakrishna et al. 2001). Custom-made embroidery technology has been widely employed to design and construct tissue-engineered scaffolds. For example, Ellis and co-workers have successfully developed hernia patches, stents for the repair of abdominal aortic aneurysms and implants for intervertebral disc (Ramakrishna et al. 2001). Another group has developed a 3D embroidered substrate for the improved regeneration of skin tissue in chronic wounds. Besides, Mai et al. (2006) observed that osteoblast-seeded poly3-hydroxybutyrate (PHB) embroidery can successfully induce ectopic bone formation. Embroidery technology is particularly attractive for making tissue-engineered scaffolds. The degree of construction of the embroidery can be controlled and, therefore, a broad spectrum of scaffolds with a wide range of properties is possible. Technologies for fabrication of textile nanofibers The processing of fibers with diameters less than 1000 nm plays an increasingly important role in the construction of tissue-engineered scaffolds. Several fabrication techniques such as electrospinning, phase separation, melt-blown, template synthesis and self-assembly have been used to produce suitable polymer nanofibers for various purposes (Zhang et al. 2005). Among the techniques mentioned above, electrospinning is the most commonly used method to fabricate nanofibers because it is relatively easy to set up in the laboratory and the resultant scaffolds have a large surface area-to-volume ratio and interconnected pores. Synthetic and natural polymers, as well as ceramics have been electrospun into nanofibers. The fabrication process involves an electrostatic field of the order of 5–30 kV between a collector and the spinneret (usually in the form of a needle). The polymer melt or solution is pumped out of the spinneret at a controlled rate. When the sufficiently high electric field overcomes the polymer solution surface tension, a thin jet of liquid fl ies towards the collector plate. The thin jet of liquid solidifies owing to evaporation of the solvent or cooling of the molten polymer and nanofibers are collected on the collector. The fiber morphology is controlled by adjusting the electrospinning conditions, such as applied voltage, feed rate, types of collector, diameters of needle (spinneret) and distance between the needle tip and the collector. It is observed that the shorter the distance between needle tip and

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collector, the more beads are formed along the fibers. It has been reported that increased voltage correlates with increased beads density and at an even higher voltage, the beads will join to form a thicker diameter fiber (Demir et al. 2002, Zong et al. 2002, Megelski et al. 2002). For a given voltage and a given needle–collector distance, reducing the internal diameter of the needle orifice or reducing the feed rate often leads to a decrease in the fiber diameter or size of beads. In addition, the type of collectors will influence the morphology of the collected nanofibers. For instance, collectors made from conductive materials such as aluminum foil are observed to have a higher fiber-packing density than non-conductive ones. Thus, nanofibers collected on a non-conductive plate are more likely to form a 3D structure, such as honeycomb architecture, owing to the repulsive forces of the accumulated charges on the non-conductive collector (Deitzel et al. 2001). Additionally, experiments on collectors with smooth surfaces such as metal foils showed a high fiber-packing density compared with collectors with porous surfaces such as metal mesh. Moreover, the texture of the fibers formed can also be varied by using a patterned collector like a braided Teflon sheet, on which the yield fibers take a topography that follows the surface pattern of the Teflon sheet (Ramakrishna et al. 2005). Additionally, whether or not the collector is static or moving may have an effect on the morphology of fibers. A rotating cylinder collector can be used to obtain unidirectional nanofibers with alignment along the rotating direction. Other ambient parameters that would influence the evaporation rate of the solvent, including concentration of the polymer solution, temperature and humidity, also influence fiber morphology. By varying those parameters synergistically, several special morphologies can be achieved, for instance, porous nanofibers (Bognitzki et al. 2001), flattened (Koski et al. 2004), ribbon-like fibers (Huang et al. 2000), helical fibers (Kessick et al. 2004) and hollow fibers (Kessick et al. 2004, Hou et al. 2002). Nanofibers have an extensive application in tissue engineering.

12.6 Applications of textile scaffolds in tissue engineering The range of tissue engineering applications has expanded in recent years. Some typical examples, with special emphasis on the use of textile scaffolds, are described here.

12.6.1 Skin grafts Skin grafts are perhaps the most successful tissue-engineered constructs and several have been approved by the US Food and Drug Administration

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(FDA) and commercially manufactured. For example, in 1998, Advanced Tissue Science, Inc. introduced Dermagraft®, a cryopreserved dermal substitute, in which human fibroblast cells derived from newborn foreskin tissue were seeded on a biodegradable polyglactin mesh scaffold. The fibroblasts were found to proliferate and fill interstices of the scaffold and secrete dermal collagen, matrix proteins, growth factors and cytokines suitable as dermal substitute. Some commercialized skin graft substitutes employ natural ECM molecules in their fibrous scaffolds, such as collagen (BiobraneTM, IntegraTM, AllodermTM), fibrin (BioseedTM), hyaluronic acid (LaserskinTM), fibronectin (TransCyteTM), and glycosaminoglycans (GAGs) (TransCyteTM). Although there have been considerable improvements in tissueengineered skin grafts, none of them could reproduce the normal architecture of natural skin, including hair follicles, Langerhans cells, sebaceous glands, and sweat glands. Therefore, intensive research is still ongoing in order to improve existing skin graft substitutes to regenerate the important properties of natural skin.

12.6.2 Vascular grafts An important requirement for tissue-engineered vascular grafts is that the tubular conduits are made of materials capable of incorporating into host tissues with a functioning self-renewing endothelial layer. Scaffold materials can be either synthetic or natural polymers. Synthetic materials for fabricating vascular grafts include biodegradable polymers such as PGA, PLA, PLGA, or non-biodegradable polymers such as polyurethanes (Kim et al. 1998, Tiwari et al. 2002, Niklason et al. 2001) and polyethylene terephthalate (DacronTM). Biological materials that have been used in vascular grafts can be generally classified into three groups: acellular xenogeneic grafts (Clarke et al. 2001, Lantz et al. 1992, Huynh et al. 1999), acellular allogeneic grafts (Conklin et al. 2002, Schaner et al. 2004, Teebken et al. 2000, Kaushal et al. 2001, Yow et al. 2006) and prefabricated grafts made with natural polymers (Yow et al. 2006, Weinberg et al. 1986). Major disadvantages of natural material-based scaffolds are their rapid absorption rate and poor mechanical strength. To improve both biocompatibility and mechanical strength, many novel grafts use a combination of synthetic and biological materials. For example, a collagen-coated PLLACL (70 : 30) nanofiber vascular conduit is shown in Fig. 12.3. It demonstrated in such a construct that there are enhanced attachment, proliferation and viability of human coronary artery endothelial cells (HCAECs) and, more importantly, the cellular phenotype is preserved (He et al. 2005). Traditional problems associated with vascular grafts, including clotting and scar tissue formation, is still a problem for current vascular grafts and

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12.3 Electrospun PLLA-CL nanofibrous vascular conduit (length 3.8 cm, diameter 3 mm) (He et al. 2005).

this has prevented new grafts from entering clinical trials (Sanders et al. 2000). Recently the US FDA has approved a vascular graft (Gore Propaten), made of expanded polytetrafluoroethylene (ePTFE)-heparin for treatment of peripheral artery disease. The addition of heparin to the luminal surface of the graft via proprietary end-point covalent bonding was intended to reduce the occurrence of thrombosis in clinical performance between synthetic and vein grafts. Other strategies such as embedding antibiotics and antithrombotic agents in the graft materials have also been attempted in order to improve the performance of vascular substitutes (Blanchemain et al. 2005, Guimond et al. 2006, Peeters et al. 2006).

12.6.3 Tissue-engineered liver Several extracorporeal bioartificial liver (BAL) systems have been developed to support essential hepatic functions. In a typical BAL device, patient’s plasma or blood is circulated through a bioreactor with immobilized primary hepatocytes or hepatoma cell lines between artificial plates or capillaries (Strain et al. 2002, Cao et al. 1998). From 1990, nine BAL systems have been tested clinically and most of them performed well in preclinical tests (Park et al. 2005). The BAL devices may be based on hollow fiber technologies such as ELAD (Sussman et al. 1994 and 1993, Ellis et al. 1996), HepatAssist (Demetriou et al. 1995), LSS (Gerlach 1996, Sauer et al. 2001), and BLSS (Mazariegos et al. 2001); porous matrix systems such as RFB-BAL (Morsiani et al. 2001), AMC-BAL (Flendrig et al. 1998, Sosef et al. 2003, Van De Kerkhove et al. 2002), encapsulation systems such as UCLA, (Strain et al. 2002), and AHS-BAL (Lee et al. 2004); or flat membrane systems such as FMB-BAL (De Bartolo et al.

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2000). For instance, the HepatAssist liver device, developed by Demetriou and co-workers (1995), consists of a microcarrier for attachment of primary porcine hepatocytes, two charcoal fi lters, a membrane oxygenator, and a pump. The hollow fiber open membrane has a pore size of 0.2 μm, small enough to prevent the passage of hepatocytes, but large enough to allow an exchange of proteins and protein-bound toxins between plasma and hepatocytes. The hepatocytes are housed in the extracapillary space (Demetriou et al. 1995). As liver is a vital and complex organ, investigation into a BAL with the broader essential functions of liver is ongoing.

12.6.4 Nerve grafts Neural tissue engineering involves the use of biomaterials as scaffolds with tissue-specific architecture and a controlled pore structure that facilitates growth and organization of resident cells for nerve repair (Liu et al. 1997). Nerve guidance conduits to bridge the gap between the nerve stumps and to direct nerve regeneration have been developed recently (Widmer et al. 1998, Seckel 1990, Giardino et al. 1995, Foidart et al. 1997). For example, Bini et al. (2004) fabricated a peripheral nerve conduit made of microbraided PLGA biodegradable polymer fibers. Fibrin matrix cable formation was observed one week after implantation into the right sciatic nerve of the rat and nerve generation was seen in nine out of ten rats tested three weeks later. Many biodegradable and non-biodegradable materials have been investigated to construct nerve conduits such as collagen (Archibald et al. 1991, Chamberlain et al. 1998, Yoshii et al. 2001, Yoshii et al. 2001), polyethylene (Seckel et al. 1995, Hekimian et al. 1995, Stevenson et al. 1994), PLGA (Hadlock et al. 1998, Hadlock et al. 2000), polyphosphoester (Wang et al. 2001, Wan et al. 2001), silicone (Valentini et al. 1989, Lundborg et al. 1997), PTFE (Valentini et al. 1989). Electrospun biodegradable PLA nanofibers have been used to fabricate a nerve conduit. Neural stem cells (NSC) seeded on these conduits were observed to attach and interact favorably with the aligned nanofiber ECM (Yang et al. 2004). For future research, the challenge is to develop more efficient nerve conduits so that nerve generation can occur across extended gaps.

12.6.5 Bone grafts Tissue engineering in bone has also undergone major advances in recent years. Natural materials such as collagen (Komaki et al. 2006, von Arx et al. 2006, Tal et al. 2005), fibrin (Ito et al. 2003, Ito et al. 2006, Huh et al. 2006), chitosan (Kong et al. 2005, Rhee et al. 2005), hyaluronic acid (HA) (Aslan et al. 2006) and the synthetic polymers such as PCL

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(La et al. 2005, Rhee et al. 2004), poly(propylene fumarates) (Shung et al. 2002, Behravesh et al. 1999), poly(phosphazenes) (Laurencin et al. 1993, Ibim et al. 1997, Laurencin et al. 1996), and PLGA (OsteofoamTM) (Holy et al. 2000) have been applied to establish 3D bone scaffolds. Cell sources include osteoblasts (Heath 2000, Platt 1996), adult stem cells from bone marrow (Aslan H et al. 2006, Dong et al. 2002, Mendes et al. 2002, Dong et al. 2001) or periosteum (Perka et al. 2000). Meanwhile, a plethora of growth factors including bone morphogenetic proteins (BMPs), transforming growth factor beta (TGF β), fibroblast growth factors (FGFs), insulin growth factor I and II (IGF I/II), platelet derived growth factor (PDGF), and chrysalin have been incorporated into scaffolds for ingrowth and differentiation of osteoblasts and bone tissue formation (Jadlowiec et al. 2003, Boden 1999, Lind et al. 2001, Yoon et al. 2002, Malafaya et al. 2002).

12.6.6 Other organs Besides the applications mentioned above, rapid developments in tissue engineering have extended its scope to encompass many other important human organs, such as cartilage, (Hoben et al. 2006, Kafienah et al. 2006, Moroni et al. 2006, Shangkai et al. 2006), ligament (Freeman et al. 2006, Heckmann et al. 2006, Doroski et al. 2007), heart (Wu et al. 2006, Batten et al. 2006, Mendelson et al. 2006), pancreas (Cui et al. 2001, Iwata et al. 2004, Papas et al. 1999), larynx (Blaimauer et al. 2006, Kingham et al. 2006, Ringel et al. 2006), and cornea (Lai et al. 2006, Alaminos et al. 2006, Zorlutuna et al. 2006). However, further research and development are still required before ‘off-the-shelf’ products are available.

12.6.7 Examples of smart textile scaffolds The convergence of information technologies and advances in textile materials has created smart textile fabrics. Smart textiles are intelligent textile structures or fabrics that can sense and react to environmental stimuli, which may be mechanical, thermal, chemical, biological, and magnetic amongst others (Tao 2001). The initial application was in military and defense systems and it is currently being introduced in biomedicine and tissue engineering; two examples are described here. The incorporation of miniature electronic devices into textiles promises to have a tremendous impact on tissue engineering and medical textiles. Calvert and his team created an electronic sensor-studded textile using ink-jet printers (Sawhney et al. 2006). In the process, ‘wires’ made of the conducting polymer, poly(3,4-ethylenedioxythiophene)–poly(4-styrene sulfonate) (PEDOT-PSS) were printed between the silver lines on the

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fabric. This intelligent textile device has been used to sense body motions like twisting of a wrist and bending of a knee using its piezoresistive properties (Bethany et al. 2005). Another example is smart textile scaffolds made of shape memory materials. These shape memory scaffolds can be transferred into memorized, permanent shapes from their original temporary configuration upon an external stimulus, e.g. an increase in temperature. Therefore, such a smart textile scaffold made of biodegradable materials such as PCL and copolyesters of diglycolide and dilactides may be introduced into the human body through a small incision and the implanted device then returns to its original shape to fulfi l the desired functions. Such a device would degrade after successfully completing the desired function (Tao 2001).

12.7 Future trends The burgeoning research in tissue engineering has impacted significantly on how tissue replacement and restoration will be done in the future. Further developments in material sciences, molecular biology, and scaffold fabrication technologies, as well as further understanding of stem cells and controlled manipulation of cell differentiation, will further broaden and enhance successful applications of tissue engineering. Advances in intelligent materials will give textile scaffolds greater functions, and allow novel materials to be fabricated. For example, electroactive polymers and elastomers could be used in artificial muscles (Tao 2001). Auxetic fibers made from polymers like PTFE, polypropylene and nylon can be constructed into knitted and woven textiles that are particularly suitable for skin grafts as these scaffolds will expand in response to wound swelling (Alderson 2002). Growth factors, drugs or monitoring devices may also be incorporated into textile scaffolds and implanted in the human body to perform certain functions that are not possible today. For example, a novel temperaturesensitive and biodegradable glycidyl methacrylated dextran (Dex-GMA)/ gelatin scaffold containing micro-spheres loaded with BMP has been developed. The phase transition temperature of the resulting scaffold could be tailored for controlled release with a half-life ranging from 18 days to more than 28 days by changing the ratio of Dex-GMA to gelatine. Such smart hybrid scaffolds have both self-regulated drug delivery and tissue scaffold functions (Chen et al. 2006). The electrospinning technique is versatile and relatively cost-effective and therefore is likely to continue to be used in the future for fabrication of nanofibers. Applications of nanofibers in the biomedical and biotechnological fields are increasingly important as these applications exploit

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some of the unique properties attributable to the nanoscale effects. It is envisaged that more natural polymers will be incorporated into nanofibrous scaffold designs in order to improve biological compatibility and enhance functional performance. The challenge of scaling up and making better quality fibers is being met with the introduction of novel and improved electrospinning techniques. Progenitor or stem cells with high capabilities of self-renewal and multilineage differentiation have a remarkable potential to develop into many different cell types in various tissues. For instance, embryonic stem cells could give rise to almost all cells deriving from three germ lines (Salgado et al. 2004). Adult stem cells, residing in the fully differentiated or adult tissues, e.g. bone marrow, periosteum, muscle, fat, brain, and skin, can differentiate into a specific cell lineage from which they derive (Salgado et al. 2004). Moreover, recent studies found higher plasticity of adult stem cells than what was previously expected. For example, it was indicated that adult stem cells derived from the dermis could differentiate into muscle, brain and fat cells (Toma et al. 2001), and another group found that adult stem cells isolated from bone marrow would differentiate into keratinocytes in vivo (Borue et al. 2004). Mesenchymal stem cells have been used for regeneration and repair of tendon, (Chong et al. 2007), bone (Rust et al. 2006) and heart (Zhou et al. 2006). Loading these multipotent cells onto textile scaffolds and directing them to differentiate into desired lineages broadens the potential applications of textile scaffolds. Gene modulation will make possible the seeding of recombinant proteins or genetically modified cells on textile fabrics for specific therapeutic applications. For example, one recent group loaded the Bcl-2 transduced human umbilical vein endothelial cells (HUVECs) on a skin substitute. Enhanced vascularization and engraftment were observed after transplanting to immunodeficient (C.B-17SCID/Bg) mice. The improved angiogenesis was attributed to Bcl-2 resulting in secretion of an antiapoptotic protein which increases the capacity of HUVEC to form mature vessels. (Enis et al. 2005). Therefore, it is hoped that, by loading genetically modified cells on textile scaffolds as skin graft substitutes, improved functions, including those provided by hair follicles, sebaceous glands, sweat glands and dendritic cells, will be achieved in the near future (Hermens et al. 1995). In addition, the transgenic approach may be employed to produce biomaterials with unique characteristics for fabricating fibrous textile scaffolds. For example, in 1999, Nexia Biotechnologies Inc. succeeded in extracting a recombinant spider silk proteins (BioSteel®) from the milk of transgenic goats. Although the strength of BioSteel® is far from satisfactory, its ductility is unique as it can undergo a high degree of elongation

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before it breaks. Following this, a research group has successfully coelectrospun this spider silk protein with carbon nanotubes. Such a combination enabled tailoring nanofibers with mechanical properties superior to that of natural spider silk. The feasibility of using such ‘super silk’ as tissue engineering scaffolds has been explored (Ko et al. 2004). However, there are a number of potential risks that are not fully addressed at this time including the toxic effects of textiles with nanoscale texture and the unknown risks of nanopolymer materials on human health. Other issues of contention are the ethics of using stem cells and genetically modified cells. As there is no single ideal scaffold for all tissue types, rapid advances in fibrous textile scaffold research will allow more flexibility in tailoring scaffolds for different requirements. The unique properties attributable to nanoscale effects are just beginning to be exploited in textile scaffold. We expect further developments will progress along this line.

12.8 Sources of further information and advice 12.8.1 Books Cohn D., Reis R. L. (2002), Polymer based systems on tissue engineering, replacement and regeneration, The Netherlands, Kluwer Academic Publishers. Ikada Y. (2006), Tissue engineering: fundamentals and applications, UK, Elsevier Ltd. Lewandrowski K. U. (2002), Tissue engineering and biodegradable equivalents: scientific and clinical applications, New York, Marcel Dekker, Inc. Ma P. X., Elisseeff J. H. (2005), Scaffolding in tissue engineering, Boca Raton, FL, US, CRC Press. Peppas N. A., Hilt J. Z., Thomas J. B. (2007), Nanotechnology in therapeutics: current technology and applications, UK, Horizon Bioscience. Ramakrishna S. (2005), An introduction to electrospinning and nanofi bers, Singapore, World Scientific Publishing Co. Pte. Ltd. Reis R. L., Román J. S. (2005), Biodegradable systems in tissue engineering and regenerative medicine, USA, CRC Press. Saltzman W. M. (2004), Tissue engineering: engineering principles for the design of replacement organs and tissues, New York, Oxford University Press, Inc. Selcuk I. Güceri, Vladimir. Kuznetsov (2004), Nanoengineered nanofibrous materials, Netherlands, Kluwer Academic Publishers. Yannas, I. V. (2001), Tissue and Organ Regeneration in Adults, New York, Springer.

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12.8.2 Trade and professional bodies CellTran Limited, UK, http://www.celltran.co.uk/index.php. Degradable Solutions AG, http://www.degradable.ch/. Exploit Technologies Private Limited, Singapore, http://www.exploit-tech. com/Home.aspx/. Japan Tissue Engineering Co., Ltd., http://www.jpte.co.jp/english/index. html. Nanomatrix, http://www.nanomatrix.biz/. The Japanese Society for Tissue Engineering, http://www.jste.net/english. htm. Tissue Engineering Inc. (TEI), www.tissueengineering.com. Tissue Engineering International and Regenerative Medicine Society, http://www.termis.org/. Tissue Engineering Sciences (TES), www.tissueeng.com. Transtissue technologies, www.transtissue.com.

12.8.3 Research groups Centre for Biomaterials and Tissue Engineering, University of Sheffield, UK, http://www.cbte.group.shef.ac.uk/. Center for Biomedical Engineering, Massachusetts Institute of Technology, USA, http://web.mit.edu/afs/athena.mit.edu/org/c/cbe/www/. Charité Tissue Engineering Laboratory, Germany, http://ctel.tissueengineering.net/index.php?seite=Startseite. Healthcare and Energy Materials Laboratories, http://www.bioeng.nus. edu.sg/seeram_ramakrishna/ Polymeric Biomaterials and Tissue Engineering Laboratory, University of Michigan, USA, http://www.dent.umich.edu/depts/bms/personnel/ faculty.php?uname=mapx. Tissue Engineering and Organ Fabrication Laboratory, Boston, USA, http://www.mgh.harvard.edu/tissue/. Tissue Engineering Laboratory, National University of Singapore, http:// www.bioeng.nus.edu.sg/research/tissueengineering/.

12.8.4 Websites http://www.ameriburn.org. http://www.collagenesis.com/documents/products.htm. http://www.collagenmatrix.com/. http://www.lifecell.com. http://www.netdoctor.co.uk/diseases/facts/footandlegulcers.htm. http://www.organogenesis.com.

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http://www.ortecinternational.com. http://www.synthecon.com/products/bioscaffold.htm. http://www.tissue-engineering.net/. http://www.worldwidewounds.com.

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