Injectable Fillers: Principles and Practice

Injectable Fillers: Principles and Practice EDITED BY

Derek Jones,

MD

Clinical Associate Professor, Department of Medicine, Division of Dermatology, David Geffen School of Medicine, University of California at Los Angeles

A John Wiley & Sons, Ltd., Publication

Injectable Fillers: Principles and Practice

Companion – CD-ROM This book is accompanied by video of procedures described in the text: • Radiesse and Evolence Breeze for augmentation of the cheeks, oral commissures, lateral brow, nasolabial fold and lips Injector: Jean Carruthers, MD

• Hyaluronic Acid: Juvederm Ultra and Ultra Plus for augmentation of the nasolabial folds, oral commissures, labial mental groove, and lips Injector: Derek Jones, MD

• Sculptra for treatment of facial lipoatrophy (non-HIV) Injector: Derek Jones, MD

• Liquid Injectable Silicone (Silikon-1000) for treatment of HIV-associated facial lipoatrophy Injector: Derek Jones, MD

Total running time: 50 minutes

Injectable Fillers: Principles and Practice EDITED BY

Derek Jones,

MD

Clinical Associate Professor, Department of Medicine, Division of Dermatology, David Geffen School of Medicine, University of California at Los Angeles

A John Wiley & Sons, Ltd., Publication

This edition first published 2010, © 2010 by Blackwell Publishing Ltd Blackwell Publishing was acquired by John Wiley & Sons in February 2007. Blackwell’s publishing program has been merged with Wiley’s global Scientific, Technical and Medical business to form Wiley-Blackwell. Registered office: John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Editorial offices: 9600 Garsington Road, Oxford, OX4 2DQ, UK The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK 111 River Street, Hoboken, NJ 07030-5774, USA For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www. wiley.com/wiley-blackwell The right of the author to be identified as the author of this work has been asserted in accordance with the Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is sold on the understanding that the publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought. The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting a specific method, diagnosis, or treatment by physicians for any particular patient. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. Readers should consult with a specialist where appropriate. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom. Library of Congress Cataloging-in-Publication Data Injectable fillers : principles and practice / [edited by] Derek Jones. p. ; cm. Includes bibliographical references. ISBN 978-1-4051-9289-7 1. Tissue expansion. 2. Fillers (Materials) 3. Surgery, Plastic. 4. Face–Surgery. I. Jones, Derek, 1965[DNLM: 1. Face. 2. Cosmetic Techniques. 3. Dermatologic Agents. 4. Injections. 5. Rejuvenation. WE 705 I505 2010] RD119.5.T57I55 2010 617.9′52–dc22 2009030111 ISBN: 9781405192897 A catalogue record for this book is available from the British Library. Set in 9.5 on 13 pt Meridien by Toppan Best-set Premedia Limited Printed in Singapore 1st impression 2010

Contents Preface, vi Contributors, viii 1 The Cosmetic Patient Consultation, 1 Phil Werschler 2 Guidelines for Local Anesthesia in Use of Injectable Fillers, 8 Mariano Busso 3 Hyaluronic Acids: Basic Science, 19 Nowell Solish and Kenneth Beer 4 Calcium Hydroxylapatite Microspheres in Facial Augmentation, 27 Alastair Carruthers and Jean Carruthers 5 Evolence and Evolence Breeze, 43 Jean Carruthers and Alastair Carruthers 6 Poly-L-Lactic Acid, 54 Rebecca Fitzgerald and Danny Vleggaar 7 Liquid Injectable Silicone, 75 Chad L. Prather 8 Hydrogel Polymers, 91 Naissan O. Wesley 9 Artefill: the First to Last, 103 Adam M. Rotunda and Rhoda S. Narins 10 Complications from Soft-Tissue Augmentation of the Face: A Guide to Understanding, Avoiding, and Managing Periprocedural Issues, 121 Marc D. Glashofer and Joel L. Cohen 11 The Mathematics of Facial Beauty: A Cheek Enhancement Guide for the Aesthetic Injector, 140 Arthur Swift 12 Hyaluronic Acids: Clinical Applications, 158 Derek Jones and Timothy C. Flynn Index, 175 “This book is accompanied by a CD-ROM with videos showing procedures described in the book.”

v

Preface

Since the Food and Drug Administration (FDA) approval of the first injectable hyaluronic acid for correction of facial wrinkles in 2003, there has been an explosion of natural and synthetic fillers in the medical cosmetic market and millions of procedures are now performed annually. At the time of writing, we currently have 14 injectable devices approved by the FDA from which to chose: five collagen products of bovine (Zyplast, Zyderm), porcine (Evolence) or human origin (Cosmoplast, Cosmoderm); six hyaluronic acid products (Restylane/Perlane, Juvéderm Ultra and Ultra Plus, Elevess, Prevelle Silk); calcium hydroxylapatite (Radiesse); and the synthetic poly-L-lactic acid (Sculptra) and the permanent polymethylmethacrylate (Artefill). Liquid injectable silicone (Silikon-1000) is available only off-label as a permanent injectable filler. There is no “one best” filler or “one right way” to achieve a beautiful and natural result. Although the hyaluronic acids dominate the marketplace, all of these fillers have an important and useful role, and are often used to best effect in combination. The goal of this book is to present the basic science, review safety and efficacy data that have led to FDA approval, and outline patient selection, safe, and effective injection techniques, and appropriate indications for each filler. It should be noted that most FDA studies leading to approval have formally studied most fillers only in the nasolabial fold. Other indications that are outlined (such as volumizing the lip and cheek) in this book are considered “off-label” in the USA, meaning that, although it is legal to inject these areas, the FDA has not reviewed safety or efficacy data and granted a formal indication for such use. Lastly, a procedural DVD, running for about 1 hour, is included with this book and demonstrates appropriate injection techniques for most of the fillers discussed. When assessing volume loss in the face, the physician will do best to not concentrate only on one area (such as the nasolabial fold) as a discrete entity, but assess multiple areas of volume loss (lips, cheeks, oral commissures) in relationship to each other and tailor the treatment plan accordingly. A great deal of effort has been put in to teach the reader how to avoid complications and, when they may occasionally

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vii

happen, how to properly identify and treat them. The novice should thoroughly master the anatomy of the skin and subcutaneous tissue of the face, including vascular, muscular, and neural structures, before starting actual injections. In general when injecting, I advocate a very slow, steady, and deliberate injection technique with absolute attention given to the correct plane of injection (intradermal, subcutaneous, epiperiosteal), which is different for each filler and is crucial to achieving a good result. Derek Jones

Contributors

Kenneth Beer MD Director, Kenneth Beer MD PA, Esthetic, Surgical and General Dermatology Voluntary Assistant Professor Department of Dermatology University of Miami West Palm Beach Florida, USA

Mariano Busso MD Private practice in South Florida Voluntary Assistant Clinical Professor at the University of Miami Coral Gables Florida USA

Alastair Carruthers MA, BM, BCH, FRCPC, FRCP (Lon) Clinical Professor Department of Dermatology and Skin Science University of British Columbia Vancouver Canada

Jean Carruthers MD, FRCS (C), FRC(Ophth) Clinical Professor Department of Ophthalmology and Visual Sciences University of British Columbia Vancouver Canada

Joel L. Cohen MD Director, About Skin Dermatology and DermSurgery Associate Clinical Professor University of Colorado Department of Dermatology Englewood Colorado, USA

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Contributors Rebecca Fitzgerald MD Dermatology Private Practice Los Angeles Assistant Clinical Instructor David Geffen School of Medicine University of California Los Angeles USA

Timothy C. Flynn MD Medical Director, Cary Skin Center Cary North Carolina Clinical Professor, Department of Dermatology University of North Carolina Chapel Hill, North Carolina USA

Marc D. Glashofer MD, MS Dermatologic Surgeon Island Dermatology Long Beach New York USA

Derek Jones MD Founder and Director Skin Care and Laser Physicians of Beverly Hills Clinical Associate Professor Dermatology David Geffin School of Medicine University of California Los Angeles USA

Rhoda S. Narins MD Director, Dermatology Surgery and Laser Center Clinical Professor of Dermatology New York University School of Medicine New York USA

Chad L. Prather MD Director, Dermasurgery Center Baton Rouge Louisiana Clinical Assistant Professor Department of Dermatology Louisiana State University New Orleans USA

Adam M. Rotunda MD Assistant Clinical Professor, Division of Dermatology (Medicine) David Geffen School of Medicine University of California Los Angeles USA

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Contributors

Nowell Solish MD, FRCP Assistant Professor, Dermatology University of Toronto Toronto Canada

Arthur Swift MD, Cm, FRCS(C) Director West Mount Institute of Plastic Surgery and Victoria Park Memorial Spa Montreal, Canada Clinical Lecturer, Department of Plastic Surgery, McGill University Montreal Canada

Danny Vleggaar MD Medical Director, Centre Dermato-Cosmetique ‘Roseraie’ Geneva Switzerland

Phil Werschler MD, FAAD, FAACS Assistant Clinical Professor of Medicine/Dermatology University of Washington School of Medicine Seattle USA

Naissan O. Wesley MD Skin Care and Laser Physicians of Beverly Hills Los Angeles, California USA

C H APTER 1

The Cosmetic Patient Consultation Phil Werschler Department of Medicine/Dermatology, University of Washington School of Medicine, Seattle, Washington, USA

As aesthetic, or cosmetic, dermatologists, an integral part of successful practice includes the “cosmetic patient consult” (CPC). Although this term is used liberally, its actual definition remains somewhat nebulous. Certainly, there are portions that are universally agreed upon, such as consent form signing, price quotation, and pre-treatment photographs. However, there are many more less well-defined components to the process that are equally important to both the treating provider and the treated patient for optimal outcome. For the purposes of this introductory chapter, certain assumptions will be made about the CPC process. Chief among these is the accomplished skill set of the treating provider, whether a physician, mid-level provider, registered nurse, or aesthetician/office staff. It is assumed that the CPC will not be performed for the benefit of training the staff in the particular procedure. It is also assumed that the office possesses the requisite resources and capabilities to fully perform and complete the particular procedure being offered. Finally, it is also assumed that the CPC is being conducted in “good faith,” i.e. with full disclosure of the training, experience, and outcomes of the same or similar procedures being fully discussed.

Cosmetic office practice With that as a background, the next step is to determine the cosmetic office practice (COP) level of the dermatology practice. First proposed in the mid-1990s by Craze and Werschler,1 this is a simplified method of determining the relative contribution of resources that a practice devotes to the development of “desire” dermatology. Using a four-point scale, this descriptive methodology is capable of generally categorizing the relative level of sophistication of a dermatology practice toward the delivery of elective cosmetic services. Injectable Fillers: Principles and Practice. Edited by Derek Jones. © 2010 Blackwell Publishing

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Chapter 1

Briefly, the four levels are described as follows: 1. Non-cosmetic, i.e. no particular skills, resources, equipment, marketing, or other efforts made beyond that of the usual general “disease”focused dermatology practice. 2. Some cosmetic, usually represented by a particular focus of expertise of equipment, skills, or other assets that provide elective services. A good example of this would be a center of excellence in lasers within a dermatology practice. 3. Balanced, or blended, practice of disease and desire dermatology: usually represented by a broad range of skills across multiple areas of expertise, all being considered in the “core scope” of dermatology and dermatologic surgery. Many practices in the USA and Canada are considered “balanced.” 4. All cosmetic, or a practice that typically offers only elective services that would be considered cosmetic in nature. These practices may exceed the usual scope of dermatology to reflect the unique skill sets of the providers. Examples of this could include facelift and breast augmentation procedures. Considering that most dermatology offices today operate at the second and third levels of COP (focused or balanced) and those that aspire to these levels all share the same basic challenges, the following discussion targets COP levels 2 and 3.

The three components of CPC The three essential components to a successful CPC consist of the setting, education, and assessment. These three integrated pieces are the proverbial three-legged stool: if any one is missing, the result is an unbalanced and hazardous situation. Of the three, the provider is most crucial in the assessment and, in some cases, assessment cannot be performed without the treating provider. Depending on the personal preferences of the provider, both the setting and education can be either a “hands-on” or “hands-off” affair.

Setting Understanding organizational selling is the first step in achieving a proper “setting” for the CPC process. Although many physicians mistakenly believe that the initial face-to-face contact is the most important step in the process of a successful CPC, it is actually close to the last step of the process. For most cosmetic dermatology practices, there is a preframed geographically determined catchment area. If the practice has been in existence for any significant length of time, there is usually limited general

The Cosmetic Patient Consultation

3

public awareness of the types of procedures and products available. This awareness may be founded on reputation, advertising, marketing efforts, location, etc. Identifying and controlling this “general awareness” is really the first step of the setting for the CPC. Although this chapter is not intended to discuss marketing, advertising, and communication efforts for cosmetic dermatology practices, suffice it to say that this is a commonly overlooked area of practice development. Expert consultation is certainly available for those interested in pursuing further evaluation in this area. What organizational selling means to the cosmetic dermatology practice is the education of all employees on the products, services, and procedures offered by the business. Organizational selling does not mean that every office employee is a salesperson; indeed the actual selling of a product or service needs to be a tightly managed affair. Organizational selling is the systematic, methodical process of educating internally on the resources and capabilities of the entire office. This includes the unique assets of the providers, the equipment, the office setting, design, accreditation, etc. In its truest form, it means that any employee, from the billing clerk to the records clerk to the Mohs’ technician to the medical assistant, is capable of responding to a question, a request, a phone call, or even a third party inquiry about the services offered. This type of education takes dedicated training and frequent communication from the leadership of the office to be relevant and effective. It is essential to the success of the cosmetic dermatology practice. This type of staff training also facilitates the entire process of the setting in that it allows the prospective cosmetic patient to progress seamlessly from being an interested party to an office visitor without receiving any conflicting information. Organizational training also supports collateral information dissemination, such as telephone information scripting, patient handouts, brochures, internet presence, etc. Ideally, the prospect (individuals are not patients until they are actually treated; during the consultative process they are technically a prospect) continues to receive the same, non-conflicting information flow from the first contact with the office (internet, telephone, direct mail, etc.) to their first visit, to the actual consultation, to the day of procedure, and finally to the time of completion of follow-up of any procedure(s) performed. This process should be seamless from the patient’s perspective. Once the patient reaches the office for the scheduled consultation, great care should be taken to ensure that he or she is promptly and politely received. As dermatology differs so greatly from plastic surgery in terms of office patient numbers and flow, it is recommended that consultations not be scheduled during busy clinic hours if performed by the provider.

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Chapter 1

In addition, consideration should be given to alternate times and days of the week, including weekends, for scheduling of the CPC. Further, certain types of procedures or services may be offered in a group setting, such as an evening office information seminar. A good example of this would be new skin care products or services that are generally applicable to larger number of individuals. The actual consultation may be performed by a dedicated patient cosmetic coordinator or by the treating provider, depending on the particular preferences of the office and the nature of the procedure. Certainly, the information needed for a simple botulinum toxin injection requires a more basic level of education than that needed for liposuction. There should be a defined time limit for the consultation; this avoids the potential issue of “not enough time” in the patient’s mind. Commonly, this is 30 minutes and can be varied for different types or combinations of procedures. More than 30 minutes may be excessive, and can actually be counterproductive if the conversation is not kept tightly focused. The actual location of the CPC needs to be carefully evaluated. Although there is no actual correct or incorrect way to locate the consultation, it is generally felt that a separate room is best. This can be the physician’s office, an exam room, or ideally a dedicated space within the office. Sometimes referred to as the “closing” room, a dedicated space provides optimal comfort for both the prospect and the consultant. The dedicated consultation room also has many advantages, including privacy, décor, and ready access to all materials including printed, video, internet, and even photographic. The space is kept free of staff transit during the consultation, and generally there is a different ambiance in the room. Here, patients feel much more comfortable discussing their personal desires and fears, feel more relaxed, and less nervous than in an exam room. The room should be well lit for exam and use of a mirror. Mirrors should include hand-held, magnifying, and full-length varieties. Some offices even use a dressing room-style three-way mirror, especially if body work such as liposuction is discussed. The furnishings should include as a minimum one or two large comfortable chairs and perhaps a small couch. Remember, frequently a cosmetic consult consists of more than just the prospect, and can include spouse/partner, family member(s), or friend. The room may have a completely different interior design and color scheme to the rest of the office, including floor coverings, window treatments, and furnishings. It should be equipped with the necessary hardware and software to access and schedule the patient procedure in private. All necessary collateral materials, including consent forms, lab requisitions, release of information requests, etc., should be readily on hand. The room should be kept spotless at all times and be supplied with fresh bottled water and possibly hot water/coffee for patient convenience.

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The room should be very quiet, even adding extra soundproofing materials if necessary. The necessary diplomas, certificates, awards, etc. should be displayed as a form of external reference for the reassurance of the client. Finally, it is recommended that a clock be prominently displayed in easy view. This helps to establish a timeline for both parties. Consultations can always be extended and/or rescheduled if more time is necessary. With regard to the actual time scheduling of consultations, it is recommended that they not be performed on a “back-to-back” timeline. This is because the consultant should have sufficient time between clients to perform the needed chart documentation, write any personal notes, including a thank-you note to the client, and prepare for the next consultation. Generally, 15 minutes is sufficient for these tasks. Also, this 15minute block in the schedule helps to maintain an on-time performance for late-arriving patients, phone messages, follow-up calls, etc.

Education The ideal CPC is really an exercise in patient education. Generally, in dermatology, the prospective patient will arrive with a narrow set of desires and expectations. They may not know which dermal filler they desire, but they know that they would like bigger lips or higher cheekbones. They usually have some limited education and knowledge from a friend who has had a similar procedure or from a fashion magazine or internet site. Their primary purpose of the consultation is to determine three things: Do you do this procedure (skill)? Do you want to do it to me (appropriate candidate)? How much does it cost? The role of the consultant is to answer these three questions in an expanded format and to include risks, benefits, and alternatives available, whether through this office or another (fillers vs facelift; plastic surgeon vs dermatologist) more appropriate specialty. In addition, the consultant needs to help determine if the patient has the appropriate mental capacity and awareness to give consent and be able to comply with any needed follow-up care or visits. Although the treatment provider will ultimately make this decision, the consultant can play a vital screening role in the process. Once the prospect has been given the basics of education, support materials may be used, such as brochures and consents. These are add-on materials, and should not be used in place of a consultation. Some offices use additional customized materials such as DVDs and photograph albums. Others use reprints of journal articles, website printouts, etc. Regardless of the materials used, all should be documented in the patient chart, and all CPCs should result in a medical chart, even if the prospect has never been and is never treated in the future by the office. This is thorough record keeping, and is an essential part of smart medicolegal practice.

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For some procedures this entire education process is a simple matter. It may be accomplished in a few minutes, documented, and scheduled or performed before the patient leaves the office. For other procedures, it may be just the first step in a lengthy process that may include several pre-treatment visits and sessions to include photography, review of lab work, consultation with referring physicians, and pre-procedure physical examination and even psychological screening questionnaires. With regard to price quotes, there are generally two schools of thought: the first is that every patient is a unique treatment challenge, and prices are individually determined based on these unique attributes. The other is to use a predetermined price list, and if deviations are needed these are explained to the patient individually. Dermatology offices, given the nature of the procedures performed, typically use price lists. Regardless of the approach, the price quote needs to be openly discussed and agreed upon by the patient before performing the procedure. The best method to accomplish this is with the use of consultation sheets. These are two- or three-piece carbon-copy-type forms with a listing of procedures and prices typically hand written on a graphic of the face and/or body. The patient receives a copy of the completed form either at the end of the consultation or in the mail in a day or two after the consult. The other copy is placed in the chart. For price quotes, there is typically a 90-day guarantee that the price will be honored. This allows the prospect to have a reasonable time to consider the options and the procedure before committing. If they have additional questions, they can follow up with a phone call or a second consultation. For the actual cosmetic consultation, office policies very widely with regard to charging: most offices do not charge when the consultation is not performed by the physician. When the physician is using his or her time to do the actual 30-minute consult, it is common to charge a fee. Typically, this ranges from US$100 to $500. This fee is applied to the first procedure. Somewhat different from our plastic surgery colleagues, most cosmetic dermatology procedures are less than $5000, with many in the $1000–2500 range. Therefore, the rationale is that it is difficult to recoup lost revenue with these smaller charges, and the consult fee is one method to minimize these lost fees. The cosmetic coordinator should follow up in 7–10 days (with permission) if the prospect has not scheduled the procedure or contacted the office for additional information. This closure provides for a call to action, and increases the efficiency rate of the cosmetic coordinator. Frequently prospects have a few remaining questions and, if answered to their satisfaction, they will book the procedure. When booking, similar to paying the first night when making a hotel reservation, the usual approach is to pay half of the quoted procedure price to “reserve” the appointment slot; the second half is then usually paid the day of the procedure, before having it done. For cancellation or

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“no-shows,” there should be a very clear and precise written policy that is signed when the appointment is made. Commonly, a 24- to 48-hour cancellation is required to receive a refund. Anything less than 24 hours, unless an emergency, is problematic for the office. Some offices, as a gesture of goodwill, will apply all or a portion of the forfeited deposit to the next appointment if scheduled at the time of cancellation. Good judgment is necessary to manage these last minute no-shows and cancellations. For some minor procedures such as toxins and fillers, where there is a variable in the final price, a deposit of $100 is common to book the appointment. This can be requested by the front office scheduling desk at the time that the appointment is made to facilitate patient convenience.

Assessment For the actual procedure on any specific patient, it is clearly the responsibility of the treating provider to determine to the appropriateness of the patient and the requested procedure. This may consist of the actual physical evaluation, a mental status evaluation, comorbidities and overall health status, and any other complicating factors. Remembering the acronym “ICG/RBE” for informed consent given and risks and benefits explained for the particular patient is an excellent way to approach the assessment. Some patients are clearly not good candidates for their desired procedures. Although this alone is not cause to withhold or deny cosmetic treatment, it should always be explored with the patient. Some, by virtue of age, health, medication, risk tolerance, timeline, or budget, may actually be better candidates for a suboptimal treatment than one would expect. The facelift patient who requests non-surgical facial tightening may be doing so because of a variety of valid reasons. However, if they discuss the procedure as a shortcut or budget version of what they really desire, or because their spouse or significant other wants them to have it done, it may be a better option to decline treatment. There is an old adage in cosmetic work that “you don’t regret the patients you turn down, you regret the ones you should have turned down.” From personal experience I find this to be true. As the experience level of the cosmetic dermatology office develops, it will become easier and easier to create a smooth and seamless experience for the prospect who becomes a client who then becomes a patient, and when satisfied with their experience, becomes an advocate for your practice. When careful, purposeful, and consistent staff education and training are combined with a dedicated approach to patient education, it is a natural result for the cosmetic portion of a dermatology practice to flourish.

References 1. Werschler WP, Craze MG. Cosmetic Office Practice – A Novel Perspective. Progressive Clinical Insights January/February 1998;6(1):24–5.

C H AP TER 2

Guidelines for Local Anesthesia in Use of Injectable Fillers Mariano Busso Private practice, South Florida

Anticipation of – and treatment for – pain remains an important consideration for physicians preparing to administer injectable dermal fillers. Historically, anesthesia protocols constituted the “pre-treatment” part of the injecting regimen. Recently, some physicians have started to combine anesthesia, such as lidocaine, with the injectable dermal filler itself. The combined solution of dermal filler and anesthesia is administered together. Both of these categories – mixing and pre-treating – are discussed in this chapter.

Option I: Mixing anesthetic with dermal filler immediately before administration In the relatively short period of the arrival of dermal fillers for aesthetic applications, the conventional anesthetic protocol has been pre-treatment of the area with anesthetic agents. However, some of the dermal fillers lend themselves nicely to a different anesthetic approach, namely mixing the anesthetic with the dermal filler itself, just before treatment. This mixing approach with calcium hydroxylapatite (CaHA – Radiesse) first appeared in the literature in late 2007.1 Anecdotal reports suggest both rapid and widespread adoption by physicians (personal communication, Brian Pilcher, Vice President of Medical Affairs, BioForm Medical, 2009). The mixing itself is fairly straightforward. It requires the injectable dermal filler in one syringe and the lidocaine – or lidocaine plus epinephrine – in another. In the case of Radiesse, the 1.3 mL syringe is connected to a 3.0 mL syringe of anesthetic, using a Rapid Fill LuerLok-to-Luer-Lok adapter (Baxa, Englewood, CO). The dermal filler is introduced into the syringe containing the anesthetic first; then the newly combined Radiesse and lidocaine is pushed back and forth from syringe to syringe (Figure 2.1). Approximately 10 passes are sufficient for homogeneous distribution of Radiesse and anesthetic.2 Injectable Fillers: Principles and Practice. Edited by Derek Jones. © 2010 Blackwell Publishing

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Figure 2.1 Radiesse (1.3 mL) combined with lidocaine (0.1 mL), immediately before

injection.

An article published in 2008 explored in detail possible changes to the calcium hydroxylapatite that might arise when the compound was mixed with lidocaine.2 In setting up the study, researchers examined several lidocaine concentrations to determine the dynamic viscosity, extrusion force, and needle jamming rate of the mixture compared with the commercially available Radiesse. Researchers found that the pH of the Radiesse–lidocaine admixture remains closely equivalent to the pH of the Radiesse alone. The viscosity of the blend is lower than the viscosity of the Radiesse by itself, as is the extrusion force. In addition, the “spreadability” of the dermal filler is improved, making it more malleable after its injection into soft tissue. Nevertheless, the mixing does not appear to compromise the inherent physical properties of the dermal filler. Interestingly enough, the use of this admixture first arose in the context of treatment options for the aging hand. Treatment of the hand had heretofore been considerably constrained by the pain induced by injection of any dermal filler in that area. An alternate approach was conceptualized. Rather than administer anesthetic to the hand, a bolus of the dermal filler plus lidocaine mixture was instead injected directly under the skin. The mixture was then spread throughout the hand using firm massage. The immediate result of this approach – mixing anesthetic with CaHA – was a treatment that is easier to massage and disseminate, less painful to the

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patient than conventional hand injection, and characterized by less swelling and bruising, with minimal post-treatment downtime. Benefits for physicians who choose to mix this dermal filler with lidocaine may include reduction of “confounding edema” that arises from pretreatment infiltration of the lidocaine alone, less need for nerve blocks, and shortened treatment times. The authors opine that mixing the dermal filler with lidocaine “allow larger volumes to be injected in one treatment session, such as those necessary for full facial recontouring.”2 Note Injection of the dermal filler Radiesse mixed with lidocaine received approval by the Food and Drug Administration in the second half of 2009. Although this mixing approach would appear to be applicable to other dermal fillers in addition to calcium hydroxylapatite, some caution is warranted until more information appears in the clinical literature.

Option II: Pre-treatment with anesthetic agents Unless the physician is using the mixed combination of anesthetic and injectable dermal filler, the use of local anesthesia is ordinarily advised. Pre-treatment anesthetic agents include nerve blocks, tissue infiltration, topical anesthetic, and skin cooling. Nerve blocks provide total anesthesia to the area being treated, by anesthetizing the main trunk of a nerve. In tissue infiltration, anesthesia is injected just below the skin in the surrounding area that is to be treated with dermal filler.

Topical anesthetics EMLA Cream, one of the first and most studied topical creams, is a eutectic mixture of local anesthetics, a prilocaine 2.5% and lidocaine 2.5% cream. Onset of action is within 1 hour and duration 1–2 hours after removal of the cream.3 LMX-4 (previously called ELA-Max) is a liposomal delivery system that allows a 4% lidocaine preparation to be rapidly absorbed by the skin. The rapid absorption also results in a rapid dissipation of the drug, with diminishing anesthesia approximately 40–60 min after application.4 Synera (formerly S-Caine Patch) consists of tetracaine and lidocaine mixed 7%:7% in a self-contained patch. The product is designed to look like a child’s bandage and is recommended for children aged 3 years and older. Synera contains a heating element that, when activated, enhances absorption, allowing for rapid anesthesia and some degree of vasodilation.

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Side effects of topicals warrant discussion. EMLA, in particular, is associated with angioedema, contact dermatitis, burning, stinging, and even methemoglobinemia. Although rare, methemoglobinemia is more likely in preterm infants. It is contraindicated in children less than 1 month of age.3 All of these topical agents likely require some time before numbing is complete. In addition, lidocaine tips (“Caine tips”) and mucosal swabs are helpful for numbing the mouth.

Physical aids Physical aids include vibrating, icing, and cooling (Zimmer Chiller). The use of vibration for analgesic purposes is based on the gate control theory. Vibration information is received by vibration receptors (pacinian corpuscles and Meissner’s corpuscles) and is conducted by Aβ nerve fibers which stimulate inhibitory interneurons in the spinal cord. These neurons reduce the amount of pain signal transmitted from thinly myelinated Aδ-fibres and fine unmyelinated C-fibers across the midline of the spinal cord and from there to the brain. Vibrations, icing, and chilling provide a temporary anesthetic condition so that the pain of injection is somewhat mitigated.

Environmental aids Finally, environmental aspects can be modulated so that anxieties of the patient are lessened. These include soothing music and talking softly (“talkesthesia”) with the patient throughout the injection period.

Tips for reducing discomfort Pain is always a consideration by providers and patients alike. These tips can help reduce discomfort of anesthesia as well as injection of dermal filler: • Introduce the needle as slowly as possible • Inject as slowly as possible • Use the thinnest needle gauge possible • Inject through areas that are already numb • Use longer needles if possible, to reduce the likelihood of needle pricks • Warm up anesthetics and injectable fillers to body temperature • Buffer xylocaine, if possible.

General comments about use of local anesthesia using lidocaine solutions Generally speaking, use of 1% or 2% solutions is preferred, due to safety of the decreased milligram per milliliter concentration. Epinephrine may be added to help reduce tissue swelling and bruising. However, side effects of

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its administration include tachycardia and increased anxiety. Before the addition of epinephrine, the physician should determine whether the patient has a known sensitivity to it. In addition, the weight of the patient is a consideration in use of epinephrine. Maximum lidocaine dosing without epinephrine should not exceed 3.5 mg/lb of body weight. Maximum lidocaine dosing with epinephrine should not exceed 2.0 mg/lb of body weight. Use of 1.0 mg/lb reduces the likelihood of untoward lesser adverse events.

Treatment supplies for dermal filler injections The following list of supplies may be helpful for physicians as they develop their protocols for pretreatment anesthesia and dermal injection: • 27G 1¼-inch and ½-inch needles • Nerve block medication – lidocaine 1–2% • Localized infiltration medication – lidocaine 1–2% with 1:100 000 epinephrine • 3 mL syringes and needles for numbing • 30G 1-inch or 27G 1¼- or ½-inch needles for numbing • Crushed ice or gel cool packs • Non-latex gloves • Mirror • 3 × 3 gauze pads • Sharps container • Camera for before and after photos • Signed consent form • White eyeliner pencil for marking • Alcohol pads for cleansing area • Arnica gel or other topical ointment for massaging area (optional).

Distribution of sensory nerves in the mid- and lower face Sensation for the middle and lower thirds of the face is provided by the two branches of the trigeminal nerve (cranial nerve V – Figure 2.2). The infraorbital nerve (V2) exits the infraorbital foramen. It supplies sensations to the middle third of the face, i.e. infraorbital area, nasolabial folds (NLFs), and cutaneous lip. The mental nerve (V3) exits the mental foramen. It supplies sensation to the lower third of the face, i.e. the lower lip, the medial/lateral chin, and parts of the jawline.

An infraorbital block From the author’s clinical perspective, a true infraorbital nerve block is required only when treating the lips. Nevertheless, some physicians

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Figure 2.2 Distribution of sensory nerves in the mid- and lower face.

maintain that an infraorbital nerve block is ordinarily required for midface augmentation, unless the anesthetic is being added to the dermal filler itself (see “Mixing anesthetic with dermal filler immediately before administration” above). The anatomy of the infraorbital nerve is easily located. It exits the foramen along a line between the patient’s pupil and canine tooth, bifurcating almost completely medially, then again down toward the ala, with a third large branch descending almost directly beneath the foramen to just above the oral commissure (Figure 2.3). A 30G, 1¼-inch needle is typically used. Injection is into the buccal mucosal groove, in line with the base of the ala, aiming diagonally up toward the pupil. Aspiration should be deployed to avoid injection of anesthetic intravascularly. With the needle inserted from ½ inch to ¾ inch and with the bevel facing down toward the bone, one microdrop should be injected, followed by a pause, and then additional microdrop injections for a total of 0.5–0.75 mL of lidocaine solution. The area should be massaged before repeating the procedure on the contralateral side. Care must be taken with large volumes of injected lidocaine; they may distort tissues and mask the area to be augmented.

A “mini-block” for treatment of NLF When treating NLF, a total infraorbital block is usually not required. Instead, a “mini-block” can provide enough anesthesia to the area of injection (Figure 2.4). This mini-block limits the length of time that the patient’s

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Figure 2.3 Anesthetic injection route and pathways of the infraorbital nerve.

Figure 2.4 Anesthetic injection routes for “mini-block.”

face will be numbed. This procedure will infiltrate branches of the infraorbital nerve but it is not a true infraorbital block. For the mini-block, either a 27 or 30G 1¼-inch needle is acceptable. Injection of anesthetic may be transcutaneous or through the mucosa. If injecting through the

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mucosa, injection of local anesthetic (0.25 or 0.3 mL) should be above each canine and the second bicuspid of the buccal mucosal groove. The needle should be inserted slightly lateral to the canine (third tooth from midline), with the tip of the needle directed toward the ala. Insertion of the needle should only be approximately 2–3 mm above the canine. No further insertion is recommended. The syringe should be aspirated, so that intravascular anesthetic is avoided. One microdrop can be injected, followed by a momentary stop, and then advancement of needle another millimeter or so, continuing to inject microdrops. The key to painless injection is to inject very slowly. Pain upon injection of local anesthesia is associated with distension of tissues from too-rapid injection.

A mental nerve block A mental nerve block is ordinarily required for lower-third face augmentation, unless the anesthetic is being added to the dermal filler. The mental nerve can be visualized by pulling the lower lip away from the gum (Figure 2.5). The same length and gauges mentioned earlier may be used. Injection is a two-phase process: first, the needle is inserted into the buccal mucosal groove, aiming toward the “papillary” line. One microdrop should be injected, followed by a pause, then a resumption of microdrop injection

Figure 2.5 Anesthetic injection routes and pathways of the mental nerve.

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of 0.5–0.75 mL of anesthetic. When the lateral microdrop injections have been completed, the needle is backed toward the insertion point, and reoriented halfway between the previous injection area and the chin midline, i.e., moving vertically toward the midjowl sulcus. Another 0.25 mL anesthetic can be injected in this area. The injected region should be massaged, and the procedure repeated before dermal filler injections on the contralateral side.

Local tissue infiltration Some of the areas injected in facial contouring applications are not served by either the infraorbital or the mental nerves (Figure 2.6). These areas include the lateral brow, malar and submalar regions, the nasal dorsum, inferior NLF, corners of the mouth, marionette lines, the prejowl and mandibular lines, and areas of scar tissue. Injection is performed in the subdermal layer of the skin to provide anesthesia to the immediate areas of injection. Tissue infiltration is used to provide anesthesia to areas not supplied by infraorbital or mental nerves. Tissue infiltration may also be a substitute for blocks and used to numb any area where filler is to be placed, incorporating blanching properties of epinephrine in the area of potential filler injection. However, the infiltration may also distort the tissue.

Figure 2.6 Areas not served by infraorbital and/or mental nerves may require tissue infiltration.

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Injection of small volumes is preferable, to minimize distortion of the augmentation area. A lidocaine solution containing epinephrine can significantly reduce ecchymoses, edema, and erythema due to the accompanying vasoconstriction. The recommended ratio of lidocaine to epinephrine is 1% : 2% lidocaine, with 1:100 000 epinephrine. Although diluting the epinephrine even further can reduce the risk of these adverse events, patients who are sensitive to epinephrine should still be counseled about potential tachycardia and generalized anxiety. For malar, submalar, prejowl sulcus, inferior mandible, and midface infiltration, a 30G, 1¼-inch needle should be used. For marionette lines, oral commissures, nasal dorsum, and lateral brow, a ½-inch, 27G needle is appropriate. Before injection of anesthetic, areas should be cleaned with alcohol. Ice before anesthetic injection helps minimize bruising potential. Post anesthetic injection, the area should be massaged lightly to help disperse the solution into the tissue.

Conclusion Physicians have a choice of mixing their dermal filler with anesthetic or, if they choose, administering conventional pre-treatment anesthetic agents and then administering injectable dermal filler. Those topical agents can be supplemented with physical and environmental aids to reduce discomfort. The option of combining the dermal filler to be injected with the anesthetic of choice provides physicians the benefit of faster treatment times without sacrificing outcomes. Moreover, patients who feel less pain tend to be more satisfied patients, who in turn tell their friends. The result for the physician is a larger and more satisfied patient base. The result for the patient is higher satisfaction. Both results are equally desirable.

Acknowledgments Some of this material originally appeared in a publication produced by BioForm Medical, Inc. (ML00299-00). The author appreciates the cooperation of BioForm Medical, Inc. in the use of the illustrations in this chapter and the editorial assistance of David J. Howell, PhD, RRT (San Francisco, CA).

References 1. Busso M, Applebaum D. Hand augmentation with Radiesse® (calcium hydroxylapatite). J Dermatol Ther 2007;20:315–17.

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2. Busso M, Voigts R. An investigation of changes in physical properties of injectable calcium hydroxylapatite in a carrier gel when mixed with lidocaine and with lidocaine/epinephrine. Dermatol Surg 2008;34:S16–24. 3. Lacy CF, Armstrong LL, Goldman MP, Lance LL, eds. Drug Information Handbook, 9th edn. Hudson, Ohio: Lexi-Comp Inc., 2001. 4. Britt R. Using EMLA cream before venipuncture. Nursing 2005;35(1):17.

C H APTER 3

Hyaluronic Acids: Basic Science Nowell Solish Dermatologic Surgery University of Toronto, Toronto Canada

Kenneth Beer Esthetic, Surgical and General Dermatology and Department of Dermatology, University of Miami, Florida, USA

Differences in hyaluronic acid fillers have profound consequences for their interactions when injected into the skin and subcutaneous tissues. The literature about fillers is replete with anecdotal evidence and opinions about which hyaluron is better or worse, more or less inclined to bruise, softer, harder, or more durable. The science behind these various claims is not only fascinating but also helpful in understanding the strengths and weaknesses of the various products. This, in turn, may help clinicians select products to achieve optimal patient outcomes. In order to understand the differences between the hyaluronic acid fillers (also known as hyalurons, HAs), it is useful to understand their similarities. All HA molecules are naturally occurring linear polysaccharides which are uniquely conserved throughout species. These polymeric chains are identical in all species. There is no antigenic specificity for species or tissue, and therefore a low potential for allergic reactions, so different sources of HA will produce identically structured polymers. The only difference is that bacterially derived HA chains tend to be shorter than those that are derived from animals. Hyalurons are found in the extracellular matrix of connective tissue, synovial fluid, and other tissues including the ground substance of the dermis, fascia, extracellular matrix of the eye, hyaline cartilage, synovial joint fluid, and many other support structures in the body.1 Structurally, these molecules are polyanionic disaccharide units of glucuronic acid and N-acetylglucosamine2,3 (Figure 3.1). The disaccharide monomer has a molecular weight of approximately 400 Da.2 Monomers

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Figure 3.1 Hyaluronic acid monomeric unit.

are connected by alternating β1–3 and β1–4 bonds.2 When connected these repeating disaccharide units form long linear chains. This is referred to as a polymer. These, in turn, may be crosslinked to form very large macromolecules. When exposed to aqueous solutions, hydrogen bonding between adjacent carboxyl and N-acetyl groups occurs. Hydrogen bonding results in a clear viscous gel which is not only stiff but also retains water. Hyaluronic acid molecules are very hygroscopic and 1 g HA can bind up to 6 L of water.1

Hyaluronic acids as dermal fillers HAs have a very short half-life when injected into human tissues. The half-life in humans is at most only a few days. After injection, naturally occurring hyaluronidase will digest non-crosslinked HAs, resulting in water and carbon dioxide. In order to stabilize these molecules and make them persist, it is necessary to crosslink the chains. There are various methods to crosslink these chains and various degrees of crosslinkage that occur. The method and degree of crosslinking have a significant impact on the physical characteristics of the molecules. The raw HA used by various companies to produce their soft tissue augmentation products is frequently obtained from similar sources. Supplied as a raw powder, this material forms a viscous liquid when exposed to water. However, in order to create a gel that is able to persist once injected, the raw material gel must be modified. It is the method of modification that imparts the various attributes to the different gels and it is essential to understand these differences in order

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to understand what is or is not different between various commercial preparations.

Crosslinking Crosslinking is a must for stabilization of the HA for cosmetic injection. Most companies obtain their HAs from similar sources, usually supplied as a powder of raw HAs. Being hygroscopic they form a viscous structure when exposed to water. This gel starts to resemble the products injected into patients for soft-tissue augmentation as well as for intraarticular injections for arthritis. However, it is still unstable and must be crosslinked to provide stability or it will quickly degrade once injected into a person. To link the HA chains and prevent them from being digested, at the present time, there are three different crosslinkers approved by the Food and Drug Administration (FDA). Restylane, Perlane, and the Juvéderm line use BDDE (1,4-butanediol diglycidyl ether) as the crosslinking agent. Prevelle Silk uses DVS (divinyl sulfone) and Elevess uses BCDI (biscarbodiimide).1,2,4 Each of these chemical agents will provide stability to the HA chains and has its own advantages. However, once these products have done their job, it is essential that they be removed from the finished product, mostly by extensive washing steps built into the manufacturing process. Each of these agents is toxic to tissue in any meaningful concentrations, and their final concentrations are limited to trace amounts by the FDA. The residual concentration of crosslinking molecules is a potential hazard for the safety of the final product and is one factor considered by the FDA and physicians injecting these products. For practical purposes, the amount of crosslinking molecule in many of the HA fillers is virtually non-detectable. As each of the molecules has its own proprietary crosslinking mechanism and each has a different degree of crosslinking, it is important to have some benchmarks against which to measure. Typically, the amount of crosslinking is reported as a percentage or degree. This compares the ratio of disaccharides with crosslinkers present in the formulation. One consequence of increased crosslinking is to increase the viscosity as well as the longevity of the HAs (all other factors remaining equal.2,5,6 This implies that increased crosslinking is optimal for injectable HA products. However, crosslinking the molecules beyond a certain point might make the product less biocompatible and result in a foreign body reaction. However, none of the currently FDA-approved products has passed this point of extensive crosslinking.

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Concentration One of the most important determinants of the degree of correction obtained is the amount of HA concentration, but this is not a straightforward measurement. The concentration of HA (mg/mL) includes both crosslinked HA and free (non-crosslinked) HA. Non-crosslinked HA is added to the various fillers as a lubricant and it helps to make the products flow. However, the non-crosslinked products add nothing to the final correction and a new term, ‘effective HA concentration’ (effective HA (EFA) = total HA – non-crosslinked HA) is a better measure of the HA that will contribute to tissue correction. The concentration of HA has not only important implications for longterm correction but also material bearing on initial reactions once injected. Their hygroscopic nature means that the more concentrated products will tend to imbibe more water and, thus, have more tissue swelling after injection. After a steady-state equilibrium has been reached with the surrounding tissue, more concentrated products will maintain more swelling and have more fullness in the area injected.

Gel hardness Gel hardness is affected primarily by the degree of crosslinking between the chains and the total HA concentration. More heavily crosslinked products tend to be stiffer than less crosslinked products.2,5,6 Gel hardness is measured as different values of G′, the elastic modulus. Every other parameter being equal, gels with low G′ will have less crosslinking and be less stiff than those with higher G′. Products with higher G′ will be stiffer, harder to displace.2,5,6 Again every other parameter being equal, the higher the G′ the more difficult it will be to push the product through a needle. Measuring G′ is typically done by putting a gel between two metal plates. The amount of resistance encountered by the top plate as it slides over the gel correlates with the G′ for that gel (Figure 3.2). Besides HA

Plate 1 HA Plate 2

Fixed

Figure 3.2 Gel Harness is measured by placing the gel between two plates. The bottom plate is fixed and the top plate is moved horizontally. The force required to move the top plate relative to the lower plate results in the G′ (Elastic modulus).

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concentration, other factors will also effect the G′ and these can include the amount of free HA present in a gel and the molecular weight of the raw material used in the formulation, e.g. the more free HA present, the more lubricant the gel and the easier the product will flow.

Particle size HA gels are usually produced in large blocks of material (Figure 3.3). Once the gel blocks are manufactured they have to be reduced in size in order to pass through a syringe and needle. The gel blocks may be reduced by methods that behave as screens, as is done with NASHA particles. These NASHA particles (Restylane and Perlane) are produced so that the final particles are of a similar size with standardized shapes. Particulate gel particles have some interesting physical features. Some will conform and bend when pushed through a needle, and others will become sheared if pushed through a small orifice with sufficient force. One hypothesis holds that the larger particles found in Restylane, and especially in Perlane, have a surface to volume ratio that is resistant to

Figure 3.3 NAHSA™ molecule prior to shearing.

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enzymatic breakdown by hyaluronidase. This implies that larger particles will have longer tissue residence and that they will maintain more of a correction for increased amounts of time. However, contradicting this assertion is the fact that both Restylane and Perlane (which have very different particle sizes) have the same duration of correction in the nasolabial crease. This is believed to be due to the porous nature of the particles which negates the surface area affects. A second way of changing the size of the gel-blocked produced is referred to as homogenization. This method is used for the Juvéderm family of products.2 Homogenization results in particles that are less consistent in their size. The variation in particle size is partially responsible for the lower G′ of the products. This lower G′ has positive effects on the flow characteristics, not only as it passes through the needle orifice but also as it dissects the dermal plane once injected. The increased homogenization products have more consistent injection properties, resulting in better injection characteristics. It should be noted that easier injections may also be obtained by adding free HA but the latter will not result in any meaningful correction or duration. In addition to the method of particle production and free HA, another variable that affects the extrusion force is the viscosity (η′) of the gel particle.2,5,6 A gel that has a higher degree of crosslinking will have a higher viscosity and therefore a higher extrusion force. Higher extrusion force products are more difficult to inject and require more force to get them into the dermal planes. One other variable that affects the physical characteristics of the gel is the cohesivity of the product. This is the parameter that is related to the product’s ability to retain its shape on injection. When a dermal filler is implanted into the skin, the natural elasticity or tension of the skin will tend to deform and flatten out the implant, reducing the initial desired correction. In principle, the “lifting” capabilities of a dermal filler (opposing its deformation) primarily rely in two material properties, namely the elastic (also known as storage) modulus G′ and the cohesivity of the fluid. Of these two parameters G′ can be measured using a standard test protocol on a rheometer.2,5,6 Cohesivity, on the other hand, can be measured with the use of a parallel plate rheometer, by lowering the upper plate at a constant speed against a known mass of the filler, while measuring the normal force opposing its deformation. A higher value of the normal force represents a higher resistance to deformation and a higher cohesivity of the product. Nowadays, some dermal filler products in the market rely on high values of G′ to provide the lift necessary to achieve optimal correction. However, these products require the incorporation of higher amounts of non-crosslinked HA in order to aid the extrusion of the gel through a

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thin needle; as a counteraction the addition of non-crosslinked HA (acting as a lubricant) will result in decreased cohesivity of the product. Thus, it can be inferred that the presence of the non-crosslinked HA surrounding the gel particles will lubricate and therefore facilitate the motion of the gel particles within the material, whereas products with less free HA (i.e. the Juvéderm line of dermal fillers) the gel particles tend to be held together, being harder to deform or pull the material apart (therefore retaining its form or shape under stress), resulting in higher cohesivity. An example of when lifting characteristics are paramount is injections into the cheek and zygomatic arches. These are at the level of the periosteum and their goal is to lift the midface upward and outward. Thus, gels that have better lifting characteristics are better suited for this area and indication than those that are smoother.

Conclusion The plethora of HA gel products that are presently approved or under consideration for approval come with a plethora of product claims: some claim to be smooth, others claim to be the longest lived and still others purport to be ideal at lifting the face. To decipher these claims and understand how to select the correct product for a given indication in a particular individual, it behooves the physician to understand the physical chemical properties that are responsible for the various clinical features observed. The concentration of HA, degree of crosslinking, cohesivity, G′, and particle size all interact to create the unique properties of a particular product. Each of these factors may be determined and compared with those of other products being considered. Once they are understood, one should have a better appreciation of how to use the various HA products to obtain optimal patient outcomes.

References 1. Monheit GD, Coleman KM. Hyaluronic acid fillers. Dermatol Ther 2006;19:141–50. 2. Tezel A, Fredrickson GH. The science of hyaluronic acid dermal fillers. J Cosmet Laser Ther 2008;10(1):35–42. 3. Price RD, Berry MG, Navsaria HA. Hyaluronic acid: the scientific and clinical evidence. J Plast Reconstr Aesthet Surg 2007;60:1110–19. 4. Monheit GD, Prather CL. Juvéderm: a hyaluronic acid dermal filler. J Drugs Dermatol 2007;6:1091–5.

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5. Falcone SJ, Berg RA. Crosslinked hyaluronic acid dermal fillers: a comparison of rheological properties. J Biomed Mater Res A 2008;87:264–71. 6. Collins MN, Birkinshaw C. Physical properties of crosslinked hyaluronic acid hydrogels. J Mater Sci Mater Med 2008;19:3335–43

C H APTER 4

Calcium Hydroxylapatite Microspheres in Facial Augmentation Alastair Carruthers Department of Dermatology and Skin Science, University of British Columbia, Vancouver, Canada

Jean Carruthers Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, Canada

Over the last decade, the popularity of non-invasive procedures in facial rejuvenation – compared with surgical intervention – has risen dramatically. In particular, the number of soft-tissue fillers available has grown exponentially and includes collagen, cross-linked hyaluronic acid (HA), poly-L-lactic acid, and polymethylmethacrylate beads, among others. Calcium hydroxylapatite (CaHA) microspheres (Radiesse; Bioform Medical, Inc., San Mateo, CA) is the latest of these augmenting agents designed to combat the signs of volume loss in the face. Approved in 2006 by the Food and Drug Administration (FDA) for the correction of moderate-to-severe facial folds and wrinkles (nasolabial folds), and for the correction of signs of lipoatrophy associated with human immunodeficiency virus (HIV), CaHA is considered an effective, long-lasting, biocompatible, easy-to-use filling agent with a favorable safety profile and a high level of patient satisfaction.

Properties and mechanism of action An injectable implant, Radiesse is composed of uniform, smooth, synthetic CaHA microspheres (25-45 μm) suspended in an aqueous carboxymethylcellulose gel carrier. CaHA comes in pre-filled 1.5-mL (initial treatment) and 0.3-mL (touch-up applications) syringes for ease of use, is delivered via a fine-gauge needle (usually 27G), and provides immediate correction for facial folds and depressions. After implantation, the carrier gel is gradually absorbed; the remaining synthetic implant acts as a scaffold for new tissue formation, inducing local histiocytic and fibroblastic response and Injectable Fillers: Principles and Practice. Edited by Derek Jones. © 2010 Blackwell Publishing

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(a)

(b)

Figure 4.1 Photomicrograph of beads after implantation showing collagen formation.

stimulating the production of collagen around the CaHA microspheres (Figure 4.1).1 The particles are fixed in place as fibroblasts grow, discouraging migration.2 Over time, the synthetic microspheres, which are identical in composition to the mineral content of human bone and teeth,3 are broken down into calcium and phosphate ions and are excreted.4,5 Injectable CaHA has been shown to be nontoxic, nonirritating, and nonantigentic.6 No calcification or ossification has been observed, and skin testing is not required before treatment.4

Pivotal trials Two pivotal trials led to the FDA approval of CaHA for the treatment of nasolabial folds and HIV-associated lipoatrophy in 2006. In a multicenter, randomized, bilateral, evaluator-blinded trial, Smith and colleagues compared the efficacy and safety of CaHA microspheres versus collagen in 117 patients with moderate-to-severe nasolabial folds.7 Individuals received injections of CaHA on one side of the face, and human collagen (Cosmoplast; Allergan Inc., Irvine, CA) on the other, with up to two touch-ups. At 6 months, evaluators rated nasolabial folds treated with CaHA more improved in 79% of those treated, compared with only 5% in those who received collagen (p < 0.0001), with significantly less volume and fewer injections required. Adverse event (AE) rates and duration were similar for both groups, although the incidence of bruising and edema was slightly higher with CaHA than with collagen. A second, pivotal, open-label, 18-month trial of CaHA in 100 individuals with HIV-associated lipoatrophy demonstrated high levels of efficacy and safety over 18 months.8 All assessable patients were rated as improved or better at all time points through 12 months, as measured by the Global Aesthetic Improvement Scale (GAIS), and 91% were improved or better

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at 18 months. Moreover, patient satisfaction remained high: at 12 months, 100% considered treatment beneficial. Skin-thickness measurements at 12 months remained statistically better than those at baseline, and AEs (ecchymosis, edema, erythema, pain, and pruritis) were mild and generally short in duration.

Clinical experience The use of CaHA has been well documented for the treatment of nasolabial folds3,7,9–13 and HIV-associated lipoatrophy,3,14–17 and has had FDA clearance for the treatment of oral–maxillofacial defects, vocal fold insufficiency, and radiographic tissue marking in the USA for over 20 years.4 In addition, practitioners use CaHA off-label for a variety of aesthetic applications, including nasal contouring, cheek augmentation, and the correction of marionette lines and depressed scars.2,3,8,9,16,18,19 Published reports consistently show a high level of patient and injector satisfaction, with minimal side effects and long-lasting results.

Efficacy In a study of 609 patients who received CaHA in the nasolabial folds, marionette lines, oral commissure, cheeks, chin, lips, and radial lip lines, Jansen and Graivier conducted follow-up patient satisfaction surveys (via self-evaluation of preoperative photographs) at 6 months (155 individuals), and again between 12 and 24 months (112 individuals).11 At 12 months, 89% of those involved stated that they would receive the treatment again. Likewise, Roy and colleagues evaluated 82 individuals injected with CaHA for facial rejuvenation (most commonly in the meilolabial folds); both individuals and physicians reported satisfaction with the look and feel of the implants at 3 and 6 months.20 A multicenter, blinded, randomized trial compared CaHA with two HA derivatives in terms of patient satisfaction (surveys), efficacy (GAIS), and duration of correction in 205 individuals who received treatment in the nasolabial folds.21 Individuals received touch-ups at 4 months and were followed for an additional 12 months after the second injection. More individuals who received CaHA were “satisfied” or “extremely satisfied” than those who received either HA product, and CaHA showed a higher level of efficacy in the treatment of nasolabial folds at 8 months, as measured by the GAIS. Sadick and colleagues investigated the efficacy of CaHA in the nasolabial folds and other areas of the face 6 months after treatment and found that 90% of 41 individuals reported very good or excellent results.13 Average physician ratings of the look and feel of the implant were 4.5 and 4.9, respectively, on a scale of 1 to 5 (1 = unsatisfactory; 5 = excellent).

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(a)

(b)

(c)

(d)

Figure 4.2 Representative photographs of PSR-stained histologic specimens. (a) 4

weeks; (b) 16 weeks; (c) 32 weeks; (d) 78 weeks. Original magnification: a,b, ×40; c,d, ×60.

A 12-month, open-label, prospective trial investigated the efficacy of CaHA in 30 individuals with HIV-associated lipoatrophy;17 29 men and 1 woman received up to two injections given 30 days apart, with assessment 3, 6, and 12 months after the last treatment session. Touch-ups were offered at 6 and 12 months. Efficacy was measured by changes from baseline on the GAIS and in cheek thickness at follow-up. In addition, patients completed satisfaction surveys at every visit. All patients were rated as improved or better on the GAIS at all time points; there were no ratings of no improvement or worse. Likewise, changes from baseline in cheek thickness were statistically significant at all follow-up assessments. At 3, 6, and

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12 months, 100% of patients reported treatment satisfaction at all visits on all measures.

Duration Clinical experience suggests that injectable CaHA provides correction for an average duration of 12 months in the face,4,5,16,22 though some reports suggest a longer duration of 12–18 months2,10,11 (Figure 4.2). In 1000 individuals treated for a variety of facial augmentation procedures (primarily nasolabial folds, marionette lines, prejowl depressions, acne scars, malar eminence enhancement, and generalized soft-tissue defects) over a period of 52 months, Tzikas found that patients experienced at least 80% persistence at 1-year follow-up without retreatment, and the majority returned for follow-up injections between 12 and 18 months.5

Safety of CaHA in facial augmentation CaHA is generally well tolerated. To date, there have been no reports of antibody formation or hypersensitivity. Transient erythema, edema, ecchymosis, pain on injection, and pruritis are the most frequently reported AEs,23 and reports indicate that most side effects are mild, minimal, and transient in nature.5,7,8,10,13,17 Sadick and colleagues investigated the safety of CaHA in 113 patients treated primarily in the nasolabial folds, among other sites;13 75 and 38 patients had single or multiple injection sessions, respectively, with volumes of 1.0–2.0 mL per session, and were followed for 6–12 months after the last treatment. Injections were well tolerated in all patients. There were no allergic reactions, and mild erythema and minimal edema lasting from a few hours to a few days were the most common side effects. Seven patients reported minor, transient AEs (ecchymosis, inflammation, and edema, and two cases of submucosal nodules of the lip that were treated successfully with triamcinolone injections). Tzikas injected 1000 patients with CaHA for a variety of facial aesthetic applications (primarily nasolabial folds and marionette lines) over 52 months.5 Injections were mostly well tolerated. Erythema and ecchymosis were the most commonly reported side effects but were mild and transient, typically resolving within 2 weeks. The incidence of nodules in patients treated for lip augmentation was 5.9%.

Nodules Marmur and colleagues examined punch biopsy samples from human volunteers at 1 and 6 months after injection of CaHA into the dermis

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and found no evidence of granuloma formation, migration, or other foreign-body reactions.1 However, nodules and foreign-body reaction to CaHA in the lips are the most commonly reported complications,3,5,11,13,19,24 including one case of nodule formation from a distant injection site,25 with a 5–8% rate of nodule formation reported in the literature.2 Nodules require treatment with either intralesional steroids or incision and drainage.3,19 Some practitioners believe that lack of experience and poor injection technique may affect the incidence of nodule formation. Jansen and Graivier found nodules in 12.4% of patients treated for lip augmentation and in 3.7% of those treated for radial lip lines.11 However, the incidence decreased to 8.8% by using a smaller injection volume and more conservative threading technique. A 47-month study investigated the safety profile of CaHA for the treatment of nasolabial folds and other areas of the face in 113 patients.13 Two of 14 individuals (15%) who received CaHA in the lips experienced nongranulomatous submucosal nodules; the authors postulate that the higher rate of nodule formation was due to small sample size. In 349 lip augmentation procedures performed over 52 months, Tzikas found an overall incidence of nodule formation of 5.9%, but the incidence declined to less than 2% for the last 100 lips treated.5 The formation of nodules outside of the lips was rare (0.002%) and resulted from an injection technique that was too superficial. However, some practitioners, the author included, prefer to avoid CaHA for lip augmentation.

Radiographic properties Radiopaque in nature, CaHA particles are clearly visible on computed tomography (CT) scans and may be visible in standard radiography. However, there is no indication that CaHA potentially masks abnormal tissues or may be interpreted as tumors on CT scans.26 The authors and colleagues investigated whether the implant presented any confounding radiographic properties that could cause problems in the interpretation of radiographs or CT scans; 58 patients with facial lipoatrophy or pronounced nasolabial folds who had been treated with CaHA underwent radiographic and CT imaging studies over an extended time period (up to 427 days after injection) and with varying amounts of CaHA (from 1.3 mL to 34.1 mL in total). Although CaHA appeared inconsistently on the radiographs (Figure 4.3), the implant was easily visualized on CT scans in almost all patients, with no obscuration of underlying structures and no evidence of migration (Figure 4.4). With proper patient history, the material is therefore easily seen soon after injection and does not compromise the assessment of adjacent structures.

Calcium Hydroxylapatite Microspheres in Facial Augmentation

(a)

33

(b)

Figure 4.3 (a) Radiograph after injection of Radiesse showing no radiopacity resulting from the Radiesse.

(a)

(b)

Figure 4.4 CT Scan of an individual before (a) and 2 weeks after (b) injection of Radiesse into the nasolabial fold. The opacity can be seen in the underlying tissue.

Considerations for facial augmentation with CaHA As with any augmentation procedure, proper patient education and communication are critical in ensuring optimal satisfaction and understanding of the associated risks and benefits. A pre-injection discussion should include a review of past medical history and current prescription or nonprescription medications, counseling about pain or other common side

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effects that may occur with treatment, as well as expected short-term and long-term outcomes. CaHA is contraindicated in individuals with a history of anaphylaxis or the presence of multiple severe allergies and should not be used in those with known hypersensitivity to any of the product components.23 Likewise, treatment should be deferred in any person with active skin inflammation or infection in or near the treatment areas. CaHA has been reported to activate herpes zoster;27 patients with a history of herpesvirus infection may wish to receive prophylactic antiviral therapy.28 The safety of CaHA has not been studied in pregnancy or lactation, or in individuals under the age of 18 years.

Pain management As a result of the size of the needle used (in most cases, 27G), injections of CaHA can be painful and may even deter patients from repeating the procedure. Pain can be alleviated by ice, nerve-block anesthesia, topical anesthesia, or infiltration of small amounts of local anesthetic into the treatment area4,29 and will depend on physician and patient preference, as well as site of implantation. For the treatment of HIVassociated lipoatrophy, for example, infraorbital blocks are sometimes used to provide anesthesia extending from the lower lids down through the cheeks to the upper lip.4 In the authors’ experience, however, a combination of topical anesthesia and local infiltration (as described below) provides adequate relief. Regardless of the method used, the treatment area should be marked on the skin before any anesthetic application.4 In addition to using a topical anesthetic 30 min before injection (see Injection techniques below), the author always adds approximately 0.15 mL of 2% lidocaine with 1:100 000 epinephrine, drawn up in a 1-mL Luer-Lok syringe and connected to the CaHA syringe with a Braun fluiddispensing connector (FDC 1000; Braun Medical Inc., Melsungen, Germany). The filler is passed into the lidocaine solution and back into the CaHA syringe about 10 times minimum. The addition of lidocaine to CaHA does not appear to alter the physical properties of the filling agent, although 10 mixing passes are recommended to ensure optimal homogeneity.30 The diluted material is then divided equally between the two syringes.

Injection techniques A 27G, ½- or 1¼ -inch needle is recommended due to the product’s relative viscosity.4,23 Needle jams are more likely to occur with needles smaller than 27G.23 The author uses a wide-bore, 1-inch, 28G needle or, on occasion, a 1½-inch, 25G needle. Before treatment, the injection site is marked with a soft white pencil, and pretreatment photographs are taken. The author pre-

Calcium Hydroxylapatite Microspheres in Facial Augmentation

35

pares the skin with an antiseptic solution, then applies a topical anesthetic (Betacaine; 15% lidocaine, 5% prilocaine in an occlusive base) left on for approximately 30 min. After the skin has been wiped clean, the patient is positioned appropriately so that the volume defects can be seen – usually an upright position with head supported. The skin is tensed, and the needle is gently inserted through the skin bevel down at an approximate 30° angle to the skin,23 with the needle tip positioned at the appropriate depth. Injection techniques and volumes vary according to the size and location of the fold or volume deficit. CaHA can be injected at the subdermal plane, just in the subcutaneous space but superior to the periosteum, or on the periosteum itself.4 It is always the authors’ practice to inject CaHA deeply, either close to the bone or deep in the subcutaneous tissues. An attempt to inject too superficially is likely to produce short- or long-term lumpiness, and deep injections can reduce the incidence of prolonged swelling, particularly in the cheek or midface area. Placement close to the bone usually requires a bolus injection, with massage of the treated area to ensure proper distribution. Depending on the location, CaHA may be injected in a retrograde fashion, using a linear threading, cross-hatching, or fanning technique to deposit transversing threads of material in multiple layers as needed.4,5 In general, it is best to avoid numerous percutaneous punctures or too much motion at the tip of the needle, as both will increase the incidence of bruising. CaHA provides a 1 : 1 correction, with less volume required than collagen or HA filling agents,7,21 particularly when layered with other products,31 and no need for overcorrection.5 Massage is often used after injection to evenly distribute the filler material. In some instances, additional follow-up treatments may be necessary, depending on the size of the defect and the needs of the patient, and some injectors prefer to use smaller amounts in a scheduled sequence of treatment sessions.

Midface injections Signs of aging can be most apparent in the midface, where volume loss initiates the descent of malar fat pads, in turn leading to drooping and increasing prominence of folds and depressions in the lower face (Figure 4.5). Malar and submalar augmentation with a volumizing filler such as CaHA produces a healthier, rounded appearance of youth, and can affect the face as a whole (Figure 4.6); for that reason, cheek augmentation should always be performed first when treating multiple sites on the face in one session.16 Injections are placed in crisscrossing linear threads, with cross-hatching and layering as the needle is withdrawn for structural support (Figure 4.7), and should be avoided above the orbital rim or into the tear troughs.4 Deep (subcutaneous to pre-periosteal) placement of injections can lower the risk of prolonged swelling that can occur

36

(a)

Chapter 4

(b)

Figure 4.5 Woman with marionette lines before (a) and after (b) Radiesse treatment. The replacement of volume in the entire area is apparent in these photographs.

(a) (d)

(b) (e)

(c)

(f)

Figure 4.6 (a–c) Woman with volume loss in the cheeks from the front before (a),

from the side before (b,c); (d–f) similar images of the same patient 2 weeks after volume replacement to the cheeks.

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37

Figure 4.7 Diagram showing the fanning technique for enhancement of the malar/zygomatic area.

in the midface. Extension of the correction laterally and slightly inferiorly along the zygoma may provide better support for crow’s feet and can enhance the overall appearance of the face.16 Some practitioners use the intraoral–supraperiosteal injection approach, which may lessen the need for additional filler in the nasolabial fold and marionette lines, and reduce the incidence of short-term side effects, such as bruising and swelling.4 HIV-associated facial lipoatrophy primarily affects the temporal, infraorbital, submalar, and malar regions, as well as the nasolabial folds (Figure 4.8). Although injections are usually placed deeply in the submalar area using a fanning technique, with additional threads layered into a deeper plane, some practitioners find that extending the filling agent to the malar eminence and periorbital region may result in a more complete correction.4

Lower face As faces lose volume from the malar and medial cheek pads, nasolabial folds begin to deepen. CaHA is particularly beneficial for the treatment of nasolabial folds (Figure 4.9). Deep dermal injections fill the creases, while deeper injections in the subdermal plane using a linear threading and fanning technique can add structural support.4 Using a V formation or injecting the material in a triangular shape, cross-hatching with transversely oriented threads, adds greater support and can lead to a more pleasing aesthetic result.4

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(a)

(b)

Figure 4.8 HIV-positive individual with grade 1–2 facial lipoatrophy before (a) and after (b) correction with 2.6 mL of Radiesse per side.

(a)

(b)

Figure 4.9 Correction of volume loss of the cheeks and nasolabial folds with

Radiesse.

Superficial lines in the oral commissure are best treated with an HA derivative or collagen, although deeper lines can be filled with CaHA. However, this area is more at risk of palpability or nodule formation. Adequate correction involves volume to fill the lines and folds and lift the corners of the mouth. Injections are placed in the deep dermis inferior to the corner of the mouth, extending into the marionette lines, with threads of small amounts (around 0.05 mL) deposited in a fanning and crisscrossing pattern. Marionette lines are difficult to eradicate completely and may need adjunctive therapy with additional fillers (Figure 4.10). To fill, conservative amounts of CaHA are injected subdermally, with HA layered superficially. Some practitioners prefer to schedule multiple sessions using very small amounts of material at each session.4

Calcium Hydroxylapatite Microspheres in Facial Augmentation

(a)

39

(b)

Figure 4.10 Marionette lines before and after correction with Radiesse and a

hyaluronic acid.

(a)

(b)

Figure 4.11 Enhancement of the jawline with Radiesse.

Treatment of marionette lines and the oral commissure should include additional augmentation of the prejowl and perimental area. In the prejowl sulcus, CaHA is deposited in the subdermal plane, taking care to recreate the inferior border of the mandible rather than focusing on simple volume replacement in the body of the mandible (Figure 4.11). For the best results along the chin and jaw, the filler should be injected in increments, followed by gentle massage to help the material blend with the chin and jaw contours.4 An atrophic jawline can be treated with injections placed along the periosteum of the inferior mandible. The marionette and jawline, where the facial artery is superficial, are particularly susceptible to bruising. There are two ways to avoid bruising in this area: inject the chin from the midline or anteriorly (as described above), or insert the material via intraoral–supraperiosteal bolus placement of CaHA (through the oral mucosa). There are definite risks associated with injecting through the oral cavity, with a significant increase in the likelihood of infection. The authors recommend using a prophylactic dose of oral antibiotic 30 min before injecting (1000 mg Keflex or 500 mg Biaxin for individuals who are allergic to penicillin), as well as the use of an antiseptic mouthwash before the

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procedure. The needle can then be inserted through the sulcus and positioned accurately, and the risk of bruising and swelling is dramatically reduced. As there is no percutaneous puncture, the short-term side effects are generally much reduced.

Post-treatment procedures Post-procedure photographs accurately document response to treatment and may be taken immediately after injection and at any follow-up visits. Edema and ecchymosis can be alleviated by gentle compression with an ice-pack for several hours after treatment.5 Advising patients to remain upright for a period of time after treatment and sleeping with their heads elevated may also aid in relieving swelling.4 Patients should avoid excessive sun or heat exposure for approximately 24 hours, or until transient redness or swelling has subsided.21 Follow-up appointments can be scheduled beginning at 2 weeks to assess improvement and address any adverse events. Depending on age, skin elasticity, and depth of deficit, CaHA usually lasts for 10–12 months, and most patients return between 12 and 18 months for follow-up treatment.5

Conclusion CaHA is a durable and versatile injectable filler that has received high marks from practitioners for its durability, versatility, and safety. Approved by the FDA for facial augmentation in 2006, CaHA provides immediate correction of wrinkles and folds, and is particularly useful for filling lines and depressions and replacing volume lost through illness or the aging process. CaHA augmentation lasts for up to a year (or more), and is remarkably popular among patients and physicians alike. With volume enhancement an integral component of any cosmetic practice, the use of CaHA is only likely to increase.

References 1. Marmur ES, Phelps R, Goldberg DJ. Clinical, histologic, and electron microscopic findings after injection of a calcium hdroxylapatite filler. J Cosmet Laser Ther 2004;6:223–6. 2. Goldberg DJ. Calcium Hydroxylapatite. Fillers in cosmetic dermatology. Abingdon: Informa UK Ltd, 2006. 3. Tzikas TL. Evaluation of Radiance FN soft tissue filler for facial soft tissue augmentation. Arch Facial Plast Surg 2004;6:234–9. 4. Graivier MH, Bass LS, Busso M, Jasin ME, Narins RS, Tzikas TL. Calcium hydroxylapatite (Radiesse) for correction of the mid- and lower face: consensus recommendations. Plast Reconstr Surg 2007;120(6 suppl):55S–66S.

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5. Tzikas TL. A 52-month summary of results using calcium hydroxylapatite for facial soft tissue augmentation. Dermatol Surg 2008;34(suppl 1):S9–15. 6. Hubbard W. BioForm Implants: Biocompatibility. Franksville, WI: BioForm, Inc., 2003. 7. Smith S, Busso M, McClaren M, Bass LS. A randomized, bilateral, prospective comparison of calcium hydroxylapatite microspheres versus human-based collagen for the correction of nasolabial folds. Dermatol Surg 2007;33(suppl 2):S112–21. 8. Silvers SL, Eviatar JA, Echavez MI, Pappas AL. Prospective, open-label, 18-month trial of calcium hydroxylapatite (Radiesse) for facial soft-tissue augmentation in patients with human immunodeficiency virus-associated lipoatrophy: one-year durability. Plast Reconstr Surg 2006;118(3 suppl):34S–45S. 9. Cuevas S, Rivas MP, Amini S, Weiss E. Radiesse for aesthetic soft tissue augmentation. Am J Cosmet Surg 2006;23:190–6. 10. Jacovella PF, Peiretti CB, Cunille D, Salzamendi M, Schechtel SA. Long-lasting results with hydroxylapatite (Radiesse) facial filler. Plast Reconstr Surg 2006;118 (3 suppl):15S–21S. 11. Jansen DA, Graivier MH. Evaluation of a calcium hydroxylapatite-based implant (Radiesse) for facial soft tissue augmentation. Plast Reconstr Surg 2006;118 (suppl):22S–30S. 12. Alam M, Yoo SS. Technique for calcium hydroxylapatite injection for correction of nasolabial fold depressions. J Am Acad Dermatol 2007;56:285–9. 13. Sadick NS, Katz BE, Roy D. A multicenter, 47-month study of safety and efficacy of calcium hydroxylapatite for soft tissue augmentation of nasolabial folds and other areas of the face. Dermatol Surg 2007;33(suppl 2):S122–6. 14. Comite SL, Liu JF, Balasubramanian S, Christian MA. Treatment of HIV-associated facial lipoatrophy with Radiance FN (Radiesse). Dermatol Online J 2004;10:2. 15. Roth JS. Restorative approaches for HIV-associated lipoatrophy. PRS Notebook 2005;10:24–8. 16. Busso M, Karlsberg PL. Cheek augmentation and rejuvenation using injectable calcium hydroxylapatite (Radiesse). Cosmet Dermatol 2006;19:583–8. 17. Carruthers A, Carruthers J. Evaluation of injectable calcium hydroxylapatite for the treatment of facial lipoatrophy associated with human immunodeficiency virus. Dermatol Surg 2008;34:1486–99. 18. Flaharty P. Radiance. Facial Plast Surg 2004;20:165–9. 19. Sklar JA, White SM. Radiance FN: A new soft tissue filler. Dermatol Surg 2004; 30:764–8. 20. Roy D, Sadick N, Mangat D. Clinical trial of a novel filler material for soft-tissue augmentation of the face containing synthetic calcium hydroxylapatite microspheres. Dermatol Surg 2006;32:1134–9. 21. Moers-Carpi M, Vogt S, Santos BM, Planas J, Vallve SR, Howell DJ. A multicenter, randomized trial comparing calcium hydroxylapatite to two hyaluronic acids for treatment of nasolabial folds. Dermatol Surg 2007;33(suppl 2):S144–51. 22. Felderman LI. Radiesse for facial rejuvenation. Cosmetic Dermatol 2005;18:823–6. 23. BioForm Medical, Inc. Radiesse® Injectable Implant: Instructions for use. Franksville, WI: BioForm Medical, Inc., 2008. 24. Sankar V, McGuff HS. Foreign body reaction to calcium hydroxylapatite after lip augmentation. J Am Dent Assoc 2007;138:1093–6. 25. Beer KR. Radiesse nodule of the lips from a distant injection site: report of a case and consideration of etiology and management. J Drugs Dermatol 2007;6:846–7. 26. Carruthers A, Liebeskind M, Carruthers J, Forster BB. Radiographic and computed tomographic studies of calcium hydroxylapatite for treatment of HIV-associated facial lipoatrophy and correction of nasolabial folds. Dermatol Surg 2008;34(suppl 1):S78–84.

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27. Sires B, Laukaitis S, Whitehouse P. Radiesse-induced herpes zoster. Ophthal Plast Reconstr Surg 2008;24:218–19. 28. Jones JK. Patient safety considerations regarding dermal filler injections. Plast Surg Nursing 2006;26:156–63. 29. Comite S, Greene A, Cieszynski SA, Zaroovabeli P, Marks K. Minimizing discomfort during the injection of Radiesse with the use of either local anesthetic or ice. Dermatol Online J 2007;13:5. 30. Busso M, Voigts R. An investigation of changes in physical properties of injectable calcium hydroxylapatite in a carrier gel when mixed with lidocaine and with lidocaine/epinephrine. Dermatol Surg 2008;34(suppl 1):S16–23. 31. Godin MS, Majmundar MV, Chrzanowski DS, Dodson KM. Use of Radiesse in combination with Restylane for facial augmentation. Arch Facial Plast Surg 2006;8:92–7.

C H APTER 5

Evolence and Evolence Breeze Jean Carruthers Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, Canada

Alastair Carruthers Department of Dermatology and Skin Science, University of British Columbia, Vancouver, Canada

Injectable bovine collagen (Zyderm; Collagen Corporation, Santa Barbara, CA) was the first soft-tissue augmenting agent approved by the Food and Drug Administration (FDA) for use in humans in 1981.1 Dermal correction with bovine collagen implants is generally of short duration and requires frequent touch-ups after 3–4 months. In addition, hypersensitivity reactions are common, and skin testing is necessary before treatment.2 Human bioengineered collagen (CosmoDerm and CosmoPlast; Inamed Aesthetics, Santa Barbara, CA), the second-generation injectable collagen, was developed to give the same fine texture and quality of injectable product with a great advantage: its human origin meant that skin testing was no longer required. However, bioengineered collagen, similar to its animal-based counterpart, typically lasts for only 3 months before dissipating.3 Evolence and Evolence Breeze (ColBar Life Science Ltd, Herzeliya, Israel) are newly approved, third-generation collagen fillers with enormous potential in the field of facial rejuvenation. Specifically designed with a reduced risk of antigenicity and an increased durability of up to 12 months, this thirdgeneration collagen has a real value in our armamentarium of dermal fillers, delivering good correction with immediate results and minimal down time.

History of injectable collagen implants The first indication that collagen – the most abundant protein in the body – could play an important role in a variety of applications came when Gross and Kirk formed a rigid gel by heating collagen extracted from fresh calf skin in 1958.4 In the late 1960s, investigators purified collagen, identified subtypes in mammals, and discovered that the immunogenicity of the material could be reduced by removing the nonhelical amino acid Injectable Fillers: Principles and Practice. Edited by Derek Jones. © 2010 Blackwell Publishing

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carboxy-terminal telopeptides.5,6 In 1977, Knapp and colleagues demonstrated the first successful dermal implants in rats using human, rabbit, and rat collagen,7 and the first injections of human and bovine collagen were performed shortly thereafter in 28 patients for the correction of acne scars, subcutaneous atrophy, and wrinkling.8 Results demonstrated a 50– 85% correction sustained over 3–18 months. Stegman and Tromovitch assessed bovine collagen for the correction of depressed scars (mainly acne) and found a 50–80% improvement after three to five treatments.9 By 1981, when the US Food and Drug Administration (FDA) approved bovine collagen (Zyderm I) for general use in the nasolabial fold, 728 physician investigators had treated 5109 patients with a high level of safety and efficacy.10 The FDA subsequently approved two other injectable formulations, Zyderm II and Zyplast, in 1983 and 1985, respectively. The initial collagen fillers are xenografts, in that they are derived from a different animal species (bovine), and do meet many of the criteria of the ideal soft-tissue filling agent: ambulatory, reproducible, minimally invasive with few side effects or little down time, and predictable efficacy. Human-derived collagen (CosmoDerm I, CosmoDerm II, and CosmoPlast) was developed to reduce the skin-test requirement or risk of antigenicity, and was approved by the FDA in 2003.11 Vertebrate collagen has a natural triple helical structure. If the three collagen chains are not crosslinked, the injected material will be rapidly removed from the body and the clinical aesthetic effect will be lost. The crosslinking agent in the first two generations of injectable collagen was glutaraldehyde, an electron microscopy fixative. Thus very small amounts of crosslinking were possible and the clinical effect, while excellent, waned unacceptably quickly. Bovine and human collagens typically dissipate after 3 or 4 months.2,3

Evolence/Evolence Breeze Evolence – developed in Haifa, Israel, by ColBar Corporation, now a division of Johnson and Johnson – uses only type I collagen harvested from the porcine Achilles tendon. Type I collagen forms the largest and strongest of fibers, and has been used for heart valve replacements, corneal shields, wound dressings, and surgical meshes for tissue repair.12 Evolence is prepared via a process that includes enzymatic digestion to carefully remove the N-terminus, the locus of major antigenicity between collagens of differing vertebrate origin: pepsin separates the monomeric collagen fibers from the immunogenic telopeptides, which are thus removed to eliminate the risk of xenogenic allergy. The fibers are then polymerized as reconstituted polymeric collagen and crosslinked with a naturally occur-

Evolence and Evolence Breeze

45

Figure 5.1 Glymatrix technology. Pepsin separates collagen fibers from the immunogenic telopeptides ; fibers are polymerized as reconstituted collagen and crosslinked with D-ribose.

1800 EVOLENCE EVOLENCE Breeze Zyplast

Viscosity (pas)

1500 1200 900 600 300 0 0.0

1.0

2.0

3.0 4.0 Shear Rate (rad/s)

5.0

6.0

7.0

Figure 5.2 Viscosity of Evolence, Evolence Breeze and Zyplast is similar when

injected through the appropriate needles.

ring sugar metabolite, D-ribose, via Glymatrix technology to slow the rate of absorption in vivo (Figure 5.1).13 The Glymatrix process of crosslinking is unique to fillers and, as organic sugar produces no toxicity, larger amounts can be used, unlike glutaraldehyde, 1,4-butanediol diglycidyl ether (BDDE), or other cross-linking agents that may be potentially toxic and are used sparingly according to FDA safety parameters. The Glymatrix technology creates a longer-lasting, more robust product, which can provide correction for up to 1 year. Despite this strength, the viscosity of Evolence, Evolence Breeze, and Zyplast is extremely similar when extruded through the appropriate needles (Figure 5.2).

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Duration and clinical efficacy A preclinical trial of Evolence-30 versus bovine collagen (Zyplast) in the nasolabial folds of 12 patients revealed similar efficacy in the first few months, but ultimately a longer-lasting correction; in an average followup of 18 months, Evolence-30 was superior in 9 of 11 patients treated (p = 0.022).14 In a double-blind, randomized, multicenter, within-individual bilateral facial comparison, Narins and colleagues investigated the efficacy, safety, and longevity of Evolence versus hyaluronic acid (HA; Restylane) in 149 patients.15 Individuals were selected with moderate-todeep nasolabial folds on the modified Fitzpatrick wrinkle scale (a score of 2 or more), and up to two injections were used to correct both folds: one with Evolence, the other with Restylane. Patients were followed for 6 months initially, and then for a year for efficacy and safety.13 Skin tests and sequential antibody levels were performed and followed throughout the study. The results from immunoglobulin titers and skin tests indicated no potential for allergic reactions. Data from the initial 6 months of the study indicated no meaningful difference between the Evolence- or Restylane-treated nasolabial folds at any point. Patient evaluation also indicated a 90% improvement over baseline at 6 months on both sides. Out of the 148 individuals followed for 6 months, 145 were followed for efficacy and safety for an additional 6 months, a total of 12 months.13 Filler persistence or a wrinkle severity score of 1 over baseline was maintained at 12 months in 75% of the individuals.

Safety Evolence has been used successfully in Europe for over 5 years as a facial wrinkle and groove filler, with few reported side effects or complications.11 Preclinical studies of Evolence show no evidence of cytotoxicity, delayed dermal contact sensitization, intracutaneous reactivity, systemic toxicity, mutagenicity, or genotoxicity.13,16 A biopsy study in an animal model confirms the good tissue integration and host response with demonstrable evidence of fibroblastic activity and neocollagenesis.17 Intradermal skin testing before the use of Evolence appears unnecessary; multiple studies have found no histopathological signs or clinical symptoms of hypersensitivity.12–15 Shoshani and colleagues investigated the incidence of hypersensitivity of Evolence in a group of 530 patients who received intradermal injections of 0.1 mL Evolence in the left forearm, and a second injection in the right after 2 weeks.12 Clinical assessments and serum anticollagen antibody tests in 519 patients detected no significant erythematous reactions or changes in porcine type I collagen antibodies at any time. Moreover, Evolence is nonhydrophilic and hemostatic, minimizing the incidence of swelling, bruising, and bleeding.14

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Complications As with all fillers, minor adverse events (AEs) associated with Evolence and Evolence Breeze include pain on injection, erythema, edema, ecchymosis, and urticaria.18,19 When injecting Evolence or Evolence Breeze, knowledge of anatomy is crucial; embolism, ulceration, and necrosis can occur with injection in an artery. In addition, Evolence should not be injected into the glabellar region, following restrictions in that area for use of other crosslinked collagen fillers. Clinical experience to date has demonstrated a high level of safety and only minor side effects. A small pilot study using a preparation containing a lower concentration of crosslinked porcine collagen (Evolence-30) in 12 patients revealed no serious side effects.14 A pivotal trial of Evolence and HA (Restylane) in 149 patients with moderate-to-deep nasolabial folds showed similar safety profiles for both products, with no significant AEs (indeed, induration, swelling, bruising, and pain were higher in patients treated with HA).15 A long-term assessment of the same patients (n = 145) noted only mild skin reactions in three individuals (mild erythema in two, and mild nodule formation in one) at 9 and 12 months after injection; no side effects were considered serious or severe, and there were no reports of delayed granuloma or infection.13 Evolence should not be injected into the lips or infraorbital region due to the high incidence of nodule formation. Braun and Braun report on 16 of 20 women injected with Evolence for lip augmentation who experienced multiple lip nodules, many of which required treatment; some nodules were visible in six patients 1 year after injection.20 However, Evolence Breeze can be used in the lips, particularly together with botulinum toxin type A (BTX-A); Landau found only transient lumpiness which disappeared spontaneously by week 4 in 15 women.21 In addition, a recent study by De Boulle and colleagues report a very low incidence of nodules or bumps after the injection of Evolence Breeze in 57 individuals for lip border and volume enhancement.22

Clinical use of Evolence/Evolence Breeze Opaque gels comprising collagen at a concentration of 35 mg/mL are supplied in 0.5- and 1-mL prefilled syringes that can be stored at room temperature; Evolence and Evolence Breeze are third-generation, purified porcine collagens crosslinked with D-ribose and suspended in phosphatebuffered physiological saline. The production processes are slightly different for Evolence and Evolence Breeze, with modified shearing, filtration, and homogenization practices. The modifications to the production line results in a product (Evolence Breeze) that it is softer, lighter, and less

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Figure 5.3 Evolence treatment areas.

(a)

(b)

Figure 5.4 Nasolabial folds and perioral region (a) before and (b) after treatment with Evolence and Evolence Breeze.

viscous, with collagen fibers of shorter lengths, allowing the product to flow through a smaller lumen needle (30G) in a more finely textured consistency.21 Evolence was approved by the FDA in 2008 for the correction of moderate-to-deep facial wrinkles and folds (Figure 5.3), and has been available in Canada, western and eastern Europe, Israel, South Korea, and Russia since 2004. Evolence is used to treat a variety of pronounced rhytids, often in combination with other procedures, such as BTX-A (Figure 5.4), and is ideal for three-dimensional volumizing in the cheeks, malar area, chin, nasolabial folds, and temples (Figure 5.5). Evolence is not indicated for the lips or periorbital regions.

Evolence and Evolence Breeze

(a)

49

(b)

Figure 5.5 Cheek volume (a) before and (b) after augmentation with Evolence.

Figure 5.6 Evolence Breeze treatment

areas.

Evolence Breeze has not been approved by the FDA but is available in Canada and Europe for the treatment of fine-to-moderate wrinkles and folds (Figure 5.6). The lower viscosity of Evolence Breeze makes it ideal for use in the lips (Figure 5.7), superficial lines and scars, and in infraorbital hollows, and it is indicated as a low-volume, intradermal injection for deep, resting, glabellar folds in tandem with BTX-A treatment of the dynamic component of the glabellar frown (Figure 5.8). Evolence and Evolence Breeze are contraindicated in patients with known hypersensitivity reactions to any collagen product, a history of anaphylactic reactions or serious reactions, bleeding disorders, or compromised immune function (e.g. collagen vascular disease).18,19 Neither formulation should be injected into blood vessels, as collagen can initiate

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(a)

(b)

Figure 5.7 The lips (a) before and (b) after augmentation with Evolence Breeze.

(a)

(b)

Figure 5.8 Evolence Breeze is indicated as a low-volume, intradermal injection for deep, resting, glabellar folds in tandem with botulinum type A (BTX-A) treatment. (a) Before and (b) after combination therapy.

platelet aggregation and cause vascular occlusion and localized infarction or embolism. Overfilling intradermal bovine collagen injections in the glabella has been associated with dermal necrosis.18,19 Evolence should not be injected in the infraorbital hollows or the lips due to long-lasting lumps (see “Complications”), although the lower viscosity Evolence Breeze can be useful in those areas.

Injection techniques Evolence contains no lidocaine. For pain relief, we apply topical 15% lidocaine and 5% prilocaine in a petroleum jelly base to a clean face free of make-up for 10–15 min before injection. If required, we use regional and nerve blocks (4% articaine with 1 : 200 000 epinephrine). In most cases, however, we simply add lidocaine (10–20% by volume with 1:100 000 epinephrine) to the Evolence or Evolence Breeze using a sterile

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disposable female-to-female double Luer-Lok. Ten passes of the material back and forth will ensure adequate mixing of the product with the local anesthetic. Slow antegrade injection of the mixed product will reduce any discomfort to easily manageable levels. In our experience, most patients prefer the combination of lidocaine plus Evolence/Evolence Breeze for pain control over the blocks that we used to use when injecting the lips. In accordance with the gate control theory of pain,23 we also use a massager on the chin (the HT-1220 Acuvibe) during injection to minimize pain. As both Evolence and Evolence Breeze differ from their bovine collagen predecessors, the technique of injection is therefore different. Evolence is injected into the deep tissues using the supplied 1-mL syringe with a 27G needle or the Excel needle (27G inside bore, 28G outside bore). The less viscous Evolence Breeze is injected through a 30G needle more superficially. It can be injected into the mid-dermis for lines or into scars to elevate them. The recommended treatment protocol for Evolence is a deep injection using an antero- or retro-grade tunneling technique. We use a linear threading technique with a slow, steady injection and no overcorrection. The slow, continuous flow of the product – which requires less pressure on the plunger than is necessary with HA injections – will produce an even distribution of implant through the area to be corrected. We can use this technique with Evolence Breeze in the lips and infraorbital hollows, but we may also use a very superficial, multiple-stab technique for superficial lines and scars. After and during injection, the implant should be massaged to ensure even correction with no papules or nodules. Lumps should be massaged flat immediately. It is important to note that immediate massage is required to remodel and sculpt the injected area; the product sets quickly but does not move from the injected area, unlike HA. Indeed, the biggest novice mistake is not to massage completely as soon as the nodule or lump is noted. Nodules persisting after 24 hours can be treated with saline injection to break up the collagen fibers, or conservative use of diluted triamcinolone acetamide (2.5% in saline).

Conclusion Evolence and Evolence Breeze are newly approved, third-generation collagen fillers that provide immediate results, which last for up to 12 months and require no skin testing. Evolence is used for the correction of moderate-to-deep nasolabial wrinkles and folds, contour deficiencies, and soft-tissue defects, and has been available in Canada, Europe, Israel, South Korea, and Russia since 2004. Evolence Breeze is also approved by Health

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Canada for the correction of fine-to-moderate wrinkles and folds. Although other filling agents had begun to replace the first two generations of collagen as ideal volumizers, the advent of the more viscous Evolence and Evolence Breeze – longer-lasting collagens delivering good correction, immediate results, and few side effects – has challenged that replacement. Johnson and Johnson in early November 2009 informed its’ customers that it would no longer be distributing Evolence in the US, citing apparent market forces. At the time this book goes to press the product is not available. However, there is always a possibility that he product will be available in the future through a new distributor.

References 1. Sclafani AP, Romo T III. Collagen, human collagen, and fat: The search for a threedimensional soft tissue filler. Facial Plast Surg 2001;17:79–85. 2. Murray CA, Zloty D, Warshawski L. The evolution of soft-tissue fillers in clinical practice. Dermatol Clin 2005;23:343–63. 3. Baumann L. CosmoDerm/CosmoPlast (human bioengineered collagen) for the aging face. Facial Plast Surg 2004;20:125–8. 4. Gross J, Kirk D. The heat precipitation of collagen from neutral salt solutions: Some rate-regulating factors. J Biol Chem 1958;233:355–60. 5. McPherson JM, Ledger PW, Sawamura S, et al. The preparation and physiochemical characterization of an injectable form of reconstituted, glutaraldehyde cross-linked, bovine corium collagen. J Biomed Meter Res 1986;20:79–92. 6. Dzubow LM, Goldman G. Introduction to soft-tissue augmentation: A historical perspective. In: Klein AW (ed.), Tissue Augmentation in Clinical Practice: Procedures and techniques. New York: Marcel Dekker, 1998;1–7. 7. Knapp TR, Luck E, Daniels JR. Behavior of a solubilized collagen as a bioimplant. J Surg Res 1977;23:96–105. 8. Knapp TR, Kaplan EN, Daniels JR. Injectable collagen for soft tissue augmentation. Plast Reconstr Surg 1977;60:398–405. 9. Stegman SJ, Tromovitch TA. Implantation of collagen for depressed scars. J Dermatol Surg Oncol 1980;6:450–3. 10. Watson W, Ray RL, Klein AW, Stegman S. Collagen: A clinical overview. Cutis 1983;31:543–6. 11. Matarasso SL, Sadick NS. Soft tissue augmentation. In: Bolognia J, Jorizzo JL, Rapini RV, Horn T (eds), Dermatology. London: Mosby, Harcourt Health Sciences, 2003: 2439–49. 12. Shoshani D, Markovitz E, Cohen Y, et al. A skin test hypersensitivity study of a cross-linked porcine collagen implant for aesthetic surgery. Dermatol Surg 2007; 33:S152–8. 13. Narins RS, Brandt FS, Lorenc P, et al. Twelve-month persistency of a novel Ribosecross-linked collagen dermal filler. Dermatol Surg 2008;34:S31–9. 14. Monstrey SJ, Pitrau S, Hamdi M, et al. A two stage phase I trial of Evolence collagen for soft tissue contour correction. Plast Reconstr Surg 2007;120:303–11.

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15. Narins RS, Brandt FS, Lorenc ZP, et al. A randomized, multicenter study of the safety and efficacy of Dermicol-P35 and non-animal-stabilized hyaluronic acid gel for the correction of nasolabial folds. Dermatol Surg 2007;33(suppl 2):S213–21. 16. Nir E, Azachi M, Shoshani D, Goldlust A. Long-term in vivo evaluation of the safety and efficacy of a new procine collagen dermal filler cross-linked with ribose. Poster presented at the American Academy of Dermatology 66th Annual Meeting, San Antonio, TX, February, 2008. 17. Pitrau S, Noff M, Blok L, et al. Long term efficacy of a novel ribose-cross-linked collagen dermal filler: a histologic and histomorphometric study in an animal model. Dermatol Surg 2007;53:1–10. 18. ColBar Life Science Ltd. Evolence Instructions for Use. Herzeliya, Israel: ColBar Life Science, 2007. 19. ColBar Life Science Ltd. Evolence Breeze Instructions for Use. Herzeliya, Israel: ColBar Life Science, 2007. 20. Braun M, Braun S. Nodule formation following lip augmentation using porcine collagen-derived filler. J Drugs Dermatol 2008;7:579–81. 21. Landau M. Lip augmentation and rejuvenation using a novel, porcine collagenderived filler. J Drugs Dermatol 2008;7:236–40. 22. De Boulle K, Swingberghe S, Engman M, et al. Lip augmentation and contour correction with a ribose cross-linked collagen dermal filler. J Drugs Dermatol 2009;8 (3 suppl):1–8. 23. Melzack R, Wall PD. Pain mechanisms: A new theory. Science 1965;150:171–9.

C H AP TER 6

Poly-L-Lactic Acid Rebecca Fitzgerald Dermatology Private Practice and David Geffen School of Medicine, University of California, Los Angeles, USA

Danny Vleggaar Centre Dermato-Cosmetique ‘Roseraie’, Geneva, Switzerland

Introduction The purpose of this chapter is to discuss current techniques used with polyL-lactic acid (PLLA) to effectively and safely address changes observed in the aging face. Two simple, yet critically important points should be observed in order to use this product to its best advantage. First, this unique agent is not a filler, but a stimulator of the host’s own collagen which then acts to volumize tissues in a gradual, progressive manner. This mechanism of action has important clinical implications in the manner in which it is used. Biostimulatory agents work through employment of the host response and their biocompatibility is contingent on the ability of the material to perform with an appropriate host response in a specific application.1 As experience has been gained with this product over the last decade, and our techniques adjusted accordingly, we have found it to be a very safe and versatile agent that can be used in a manner that is both predictable and reproducible. Currently recommended preparation and placement techniques will be addressed in detail. The second point is to recognize that changes in different tissue layers of the face within a single individual occur interdependently, as an interlocking three-dimensional puzzle. Therefore, where to place the product to optimize results is enhanced by looking at the face as a whole, rather than focusing on the nasolabial folds or marionette lines, for example, as isolated entities. Seemingly small changes in shape, topography, proportions, balance, and symmetry can have a large impact on the face. This is a large part of the learning curve with this product and for this reason much of this chapter is devoted to analyzing and mapping the face.

Injectable Fillers: Principles and Practice. Edited by Derek Jones. © 2010 Blackwell Publishing

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History Poly-L-lactic acid (PLLA) was first synthesized in the 1950’s and has a long history of safe use in medical applications including suture material, plates, screws, fracture fixation devices and drug delivery systems (figure 6.1). Studies carried out almost a decade ago to evaluate the use of PLLA in the treatment of facial lipoatrophy associated with the human immunodeficiency virus (HIV) showed it to be a safe and effective product capable of replacing significant amounts of volume. Initial reports of a relatively high number of palpable, nonvisible subcutaneous papules in these HIV patients, as well as subsequent isolated case reports of granulomas in the cosmetic population, resulted in early skepticism among physicians.2–4 It should be noted that the early HIV studies were carried out with 3–4 cc dilutions, little or no hydration time, and superficial (as well as large bolus) injections of product in multiple treatment sessions spaced only 2 weeks apart.2 Dramatic decreases in the number of PLLA device related adverse events with adjustments in technique have been documented in the literature over the last decade with safety and efficacy now well established.3 Additionally, granulomatous reactions are now widely recognized to occur with all commercially available filler products. Fortunately this is a rare (and usually self resolving) complication with all agents, as their seemingly unpredictable appearance is still poorly understood.4

Figure 6.1 Historical timeline.

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The currently commercially available formulation of injectable PLLA (Sculptra and Sculptra Aesthetic, Sanofi-Aventis Bridgewater, New Jersey) received Federal Food and Drug Administration (FDA) approval in the United States (US) for the restoration and/or correction of the signs of facial fat loss in patients with HIV associated facial lipoatrophy in 2004. Approval for aesthetic use was gained in 2009, based on the results of a randomized, evaluator-blinded, parallel-group, multicenter study of 233 immunocompetent patients designed at the time of HIV approval using a 5cc dilution, a 2 hour hydration time, and a deep dermal grid pattern injection technique to place product in the nasolabial fold in multiple treatment sessions placed 3 weeks apart. Collagen was used as the comparator in order to adhere to a precedent already familiar to the FDA (from previous filler studies). Although refinements in methodology continue to evolve and it is currently commonplace to use an 8–9 cc dilution, >24 hour hydration time, and subdermal placement, the current aesthetic label reflects this early study design. Particularly useful information from this study is it’s documentation of effects lasting 25 months (the cut off time in the study) with high patient satisfaction (80% at 25 months).5

Mechanism of action of PLLA PLLA is a synthetic polymer of l-lactic acid linked by ester bonds. Polyesters such as PLLA are both biocompatible and biodegradable and are desirable biomaterials because of lack of toxicity in the human host (they degrade to lactic acid which is then metabolized via the citrate cycle).6 The currently commercially available injectable PLLA product (Sculptra, Sculptra Aesthetic, Sanofi-Aventis Bridgewater, New Jersey) is composed of nonpyrogenic mannitol (to enhance lyophilization), sodium carboxymethylcellulose (an emulsifier) and PLLA microparticles. It is supplied as a lyophilized powder in a sterile glass vial which must then be reconstituted with H2O prior to use. A particle size of 40–63 μm in diameter ensures that they are large enough to avoid phagocytosis by dermal macrophages (heterogeneity in size as well as phagocytosis of smaller particles could lead to a more intense inflammatory response) or passage through capillary walls (which could lead to vascular compromise), but small enough to be easily injected by needles as fine as 26G.6 The mechanism of action of injectable PLLA is thought to involve the initiation of a desired subclinical inflammatory tissue response to the polylactides leading to encapsulation of the microparticles and subsequent

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fibroplasia. Over time, the product degrades, the inflammatory response wanes, and the ensuing collagen deposition increases providing a gradual and progressive increase in tissue volume.6 The inflammatory response against an implanted polymeric biomaterial is determined by many factors – some having largely to do with the host, such as the implantation site and the concentration of material; some having largely to do with the implant, such as the physical (shape, size, surface area) and chemical (pH, charge, hydrophilic vs. hydrophobic) properties of the biomaterial.7 As this holds true for both the initial and degraded forms of the product, predictable degradation kinetics is an important factor in ensuring a predictable host response.7 A word about biocompatibility is warranted here, as an understanding of this concept is key to successful use of this product. Although the initial concept of biocompatibility was simply inertness, biomaterials are now used in clinical medicine to purposely harness a desired host response for a specific purpose. Simply put, the effect of a biomaterial on the host is to stimulate an inflammatory/immune response and the response of the host on the biomaterial is to attempt to eliminate or encapsulate the foreign material.7 This is taken into account by the widely accepted “William’s definition” of biocompatibility as the ability of a material to perform with an appropriate host response in a specific application.1 It is critical to note that the mechanism of action of PLLA links biocompatibility of the product to the manner in which it is used i.e., how, where, and how much of the product is used may greatly influence the type and intensity of the host response. Again, a subclinical inflammatory response followed by encapsulation and fibroplasia is the desired end-point for application of this agent as a soft-tissue augmentation device. Understanding the role of the degradation kinetics of the PLLA polymer in it’s ultimate biocompatibility may help explain the importance of avoiding overcorrection in achieving this desired endpoint. PLLA primarily degrades through hydrolysis of ester bonds (although enzymatic metabolism may play a very minor role). The polymer is a very hydrophobic molecule and this hydrolysis is noted to occur in stages. The first and longest stage is hydration of the polymer. The time required is proportional to the molecular weight of the polymerPLLA is a high molecular weight polymer taking months to hydrate.8,9 The final and shortest stage is dissolution into degradation fragmentslargely monomers, dimers, and oligomers of lactic acid. At this final stage the product becomes progressively more hydrophilic and the rate of chain scission, and therefore production of degradation fragments, accelerates.8–11 Phagocytosis of small degradation particles by macrophages and foreign body giant cells then occurs as an expected ‘next step’ in the host response to the biomaterial. This ‘intracellular’ phase of degradation in

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vivo correlates with an observed change in the type and/or intensity of a preexisting inflammatory response which seems to correlate with the concentration of material present.12 While small volumes of material do not reach toxic concentrations in the host, high initial concentrations or rapid sustained release of degradation products may do so. Large volumes of material, both initially, and at this late phase of degradation may lead to an undesired amount of inflammation resulting in an inappropriate host response for the specific application for which it was intended.12 This physiologic response to overcorrection was observed in early orthopedic applications where implants with considerable size were used. Newer processing methods as well as copolymers have addressed these concerns.13 These factors may all play a role in why overcorrection should be avoided with PLLA in the application of soft tissue augmentation. It is interesting to speculate that overcorrection could conceivably cause an adverse event for the life of the product (up to 2 years), perhaps accounting for occasional reports of adverse reactions 12–18 months after treatment. On a positive note, this would also imply that the occurrence of these reactions – both early and late – are preventable by adhering to the currently recommended guidelines for use (designed to avoid overcorrection).

Product preparation and injection technique: optimizing outcomes The manner in which a biostimulatory agent is used determines it’s biocompatibility in a specific application. Experience has taught us that “too much, too soon” with collagen stimulators may lead to overcorrection, where an overabundance of stimulating microparticles may lead to an undesired host reaction in the specific application of these devices in tissue augmentation. It is for this reason that it is recommended that patients are brought to a gradual progressive correction with multiple treatment sessions with these agents. Important technical considerations of which the practitioner should be aware all relate to avoiding overcorrection and include the following.

Product reconstitution Sculptra is composed of PLLA microparticles, nonpyrogenic mannitol, and sodium carboxymethylcellulose, and is supplied as a lyophilized powder. The product insert recommends that Sculptra be reconstituted with 3–5 mL of sterile water for injection and then left to hydrate >2 h

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to disperse the particles. The vial can then be shaken to suspend the microparticles. Lidocaine may be added to the suspension immediately before injection. Much literature now strongly supports a final dilution of at least 5 mL left to hydrate overnight.2–4,6,10 Adequate hydration time avoids the risk of injecting dry microclumps of material which may then hydrate in vivo. Experience over the last several years has shown us that a dilution of 8–9ml provides more product while still maintaining the ability to stimulate a clinically relevant response.

Product amount The amount of product used at any single treatment session should be determined solely and completely by the amount of surface area to be treated at that session using approximately 0.2–0.3 mL/cm. The final volumetric correction is addressed by the number of treatment sessions. The novice injector should be aware that it is initially difficult to resist the temptation to treat to full correction at any one session (although this may be possible with patients needing minimal treatment.) The endpoint is ‘blanketing’ the surface area to be treated at that session. The appropriate volume of product to be used at each session is therefore easily predetermined, i.e. a large atrophic cheek in a male HIV-positive lipoatrophy patient measuring 6 × 8 cm could require as much as an entire vial of product, whereas a 2 × 2 cm cheek hollow in a typical 50-year-old woman may require only 2–4 mL.11

Product placement This can be done with a 1-mL or 3-mL syringe and a 25G (long or short) or 26G (short) needle. Depth of placement varies with location. The product is placed in the subcutaneous layer in the cheeks, preauricular area, nasolabial folds, and lower face using the crosshatch or fanning technique. Superficial placement should be avoided.3,4,6 • Slow injections in a crosshatch pattern facilitate careful control of injection amounts when becoming familiar with the product. • Fanning has the advantage of fewer needle sticks, but the novice injector should be vigilant to avoid multiple deposits at the apex of the fan. • It may be placed as depot injections supraperiosteally along the zygoma, maxilla, canine fossa/pyriform aperture, and mandible. • Be aware that deep subcutaneous or supraperiosteal treatments in the area of the canine fossa/pyriform aperture with bulking agents has led to ischemia and necrosis.14 It is unclear whether this vascular

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compromise is the result of occlusion of a vessel or vascular compression from adjacent swelling. The low viscosity of this product eliminates the risk of compression in this area; however, a reflux maneuver should be done routinely to avoid intravascular injection of product. • Temple injections are placed deeply, under the temporalis fascia. Manufacturer’s instructions are to place 0.05-mL depots in the temple; however, it is common practice among experienced users to place a 0.3–0.6 mL depot in this area, followed by firm pressure and massage to distribute the product ev en l y . If the product has been placed in the correct plane, there should be virtually no resistance to the spread of the product. Again, a routine reflux maneuver before injection of product will eradicate any risk of inadvertent intravascular injection. • Bear in mind that this product is mixed in water, making for a very low viscosity solution when compared with a hyaluronic acid gel. The novice injector must be vigilant to ration the product carefully to avoid inadvertent overcorrection.

Product placement precaution Positional stability of a biostimulatory implant is critical to its safe use. Avoid placement in or through areas of dynamic muscle movement. Frequent reports of ‘lip lumps’ led to recommendations against the use of all collagen-stimulating devices, including polymethylmethacrylate (PMMA), PLLA, and calcium hydroxylapatite, in this area. It is assumed that the perioral muscle movement in this area leads to a clumping of particles, which in turn leads to localized overcorrection and lumps. Injections in the modiolus or depressor anguli oris muscle may behave in a similar fashion. In addition, periorbital supraperiosteal injections approached through the orbicularis oculi muscle have resulted in papules shown to be clumps of product embedded in muscle on histopathology.15 It may be that the path of the needle leaves a tract through which more deeply placed material may be extruded during muscular contraction resulting in clumping in the muscle.

Treat, wait, assess • Remember that this product is not a filler, but a stimulator of the host’s collagen. • Allow time for that response to develop before retreatment. • Wait a minimum of 4 weeks between treatments. • Be aware that, although the majority of the response will be clinically apparent approximately 4 weeks after treatment, it may continue to improve for some time. If there is any question in your mind about the need for an additional treatment, don’t do it. This is especially important

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in young patients who need very little volume. An additional treatment in this case may result in an overvolumized face.

Aftercare Massage after every two to three injections and again at the end of the treatment. Have the patient massage over the next few days using the “rule of 5s” (5 min/5 times daily/5 days). This massage may increase circulation during the initial inflammatory response and has been shown to reduce the incidence of papules.2–4,6,10

Predicting and planning outcomes/Patient selection and preparation Predicting outcomes We have observed what seems to be a common perception that very volume depleted patients are the “optimal candidates” for PLLA treatments. PLLA can certainly be used in these patients with pleasing results, but it will likely require a sizable investment of product, time, and money. Very volume-depleted patients are in fact difficult patients to “fill” regardless of product choice. Keep in mind that with any product, revolumizing is more expensive than recontouring and reshaping. Be aware that this is patient selection at play here, not product choice. In a younger or fuller face, a very pleasing, cost-effective, and durable result can be achieved with a very conservative amount of product. Successfully predicting outcomes for patients depends on many factors; however, a few generalizations can be made: • Very volume depleted faces (usually secondary to HIV lipoatrophy or endurance exercise) often require a lot of product and a lot of treatment sessions to fill, and it is often difficult to sustain the fill without relatively frequent (<1 year) touchups.16 Figure 6.2 shows an extremely lipoatrophic face. The loss of underlying volume is most extreme in the

Figure 6.2 A 48-year-old HIV-positive man: three vials/treatment, three treatments

(nine vials in total).

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Figure 6.3 A 42 year old: two vials/treatment, three treatments (six vials in total).

temples, the mid and lower cheek, and the preauricular area. Loss of fat in the midface leaves the face with a muscular prominence in the same location as a “marionette” fold. This prominence is likely in the same location that it has usually occupied – it is just made visible by the loss of tissue both above and below it. This is improved therefore not by filling the fold, but by replacing the missing volume superior and inferior to the prominence. Note also that the volume loss in this face, combined with solar elastosis, has resulted in an outer skin envelope slightly too large for its now “smaller” face, and in this case has led to skin redundancy along the mandible and under the chin. This redundancy improves after volume replacement in the preauricular area, mid and lateral cheek. • Severely lipoatrophic patients such as seen in Figure 6.2, offer a “road map” of how to effectively treat younger faces, or even plumper faces, with similar, but less obvious, changes. All of the faces pictured in figures 6.3–6.6, show volume loss and deflation in the temples, mid and lower cheek, and preauricular area similar to that seen in Figure 6.2. It is just less obvious in these faces because it is not as extreme and is in fact, even obscured, by the folds that it has created. Note, however, that in all cases replacement of volume done in a fashion similar to that used in the patient in Figure 6.2 resulted in an improvement. This improvement is seen even in areas not directly treated including an in increase in brow elevation (from temporal injections), a decrease in infraorbital shadowing (from refilling the mid cheek) as well as a lifting of redundant skin along the mandible. (from refilling the mid and lateral cheek, as well as the preauricular area). Also, note that the more volume the patient had to start with, the less product was required to achieve the same result. The very volume depleted patient in Figure 6.2 required 9 vials, the patients in their 40’s in Figure 6.3 and 6.4 required 5–6 vials each, while the younger face in Figure 6.5 and the plumper face in Figure 6.6 required only 2 vials each.

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Figure 6.4 A 48 year old: two vials/ treatment × 2, one vial/treatment × 1 (five vials

in total).

Figure 6.5 A 32 year old: one vial/treatment, two treatments (two vials in total)

baseline, 1 month after last treatment and 6 months after last treatment.

• As one would predict, older faces with poor skin quality, fat loss, and a lack of craniofacial support need a large amount of product and several treatments to obtain a satisfactory result (Figure 6.7). Some patients prefer this choice over a surgical procedure regardless of the investment in time and money, although the combination of surgery and volume replacement would be the most ideal in this sort of patient. Take the time to sort this out together before treating a patient who may otherwise become frustrated.

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Figure 6.6 A 46 year old: one vial/treatment, two treatments (two vials in total).

Figure 6.7 A 57 year old: two vials/treatment, four treatments (eight vials in total).

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• Before and after photographs of the subtle and natural results attainable are useful in discussing the product with new patients. They should be aware that the ultimate treatment plan and result are contingent on the quality and volume of tissue with which they start. Patient satisfaction is generally very high when the patient understands the process. Word of mouth from satisfied patients has been a powerful ally in our practices and accounts for the vast majority of our patients.

Patient selection Patient education is important as with any procedure. The durability of this product underscores this need. Obtain a true informed consent. As with all procedures, there is no guarantee of a specific or perfect result. • As with any procedure the patient must demonstrate sufficient “psychosocial maturity” to weather any potential complications. • Anxious or demanding patients are poor candidates. • Manage expectations. Be sure that the patient’s goals are realistic and attainable. PLLA offers a natural and durable, but not an immediate, result. It is not an “event” filler and may not be the best choice for someone with an upcoming wedding or reunion. • A careful and thorough medical history should be taken before treatment. Granuloma formation has been described in isolated case reports in patients with autoimmune diseases (especially collagen vascular disease), and in those with poor dental hygiene and dental caries.17,18 • Although there are no established absolute contraindications, caution is advised in treating a patient who has received a permanent filler (silicone, polymethylmethacrylate, polyalkylmide gel, acrylic hydrogel particles (hydroxy-ethylmethacrylate and ethyl methacrylate)) because confusion would ensue about the source of a complication should this occur. • As with all filler procedures, the patient should expect some swelling and bruising. Bruising is exacerbated if the patient is on anticoagulants. • Avoid any elective procedure in pregnant or nursing women.

Patient preparation • Photographs document baseline and allow patients to follow their progress. • Place the patient in an upright position to take into account the effect of gravity on facial contours before marking for injection. • The facial skin should be cleaned with a bacteriostatic wash and sterile water followed by alcohol (cases of Mycobacterium chelonei infection with injectable procedures have been traced to tap water).19 • A topical anesthetic is optional. Ice is helpful.

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Understanding the aging face and the effects of volume loss It is now widely recognized by the medical community that volume changes in the skin and soft tissue, as well as in their underlying skeletal support, contribute greatly to the changes observed in facial aging. Although gravity was once thought to be the main culprit in this process, we are now realizing that it is simply our vulnerability to gravity that changes as our tissues “deflate” with age. In addition, although the sequence of changes observed as we age is somewhat predictable, the pace of these changes is unique to each individual. As no two faces age identically, there is no one algorithm of what every face needs. Most of us lose a little volume in all structures of the face; others clearly lose more in one structure than the other. These structural changes then lead to changes in the morphology of the face in terms of both the three-dimensional contours that dictate how we reflect or shadow light, and in the shape, balance, and proportions of our face. One way that this information can be used in order to evaluate the face is to look at the integrity of all the structural tissues individually – skin, fat, muscle, and bone – and then evaluate the subsequent morphology in this context. Train your eye to look at the face as an interlocking threedimensional puzzle, rather than focusing on lines and folds.

Skin Both intrinsic and extrinsic aging in the skin impact its ability to adjust well to underlying volume loss. Voorhees recently presented research20,21 showing that as the extracellular collagen matrix is progressively fragmented with time and extrinsic insults, the fibroblasts produce less collagen and more collagenase, leading to a deleterious self-perpetuating cycle. This landmark research reveals that the deteriorating extracellular collagen matrix both contributes to and fuels loss of skin integrity. The collagen stimulation reported with hyaluronic acid fillers by Wang et al.22 was thought to work through mechanical stretch of the fibroblast. An improvement in the texture and tone of the skin is a common finding after PLLA treatments. It is interesting to speculate that since collagen stimulation may produce both direct (through fibroplasia) and indirect (through increased extracellular matrix and stretch effect) stimulation of fibroblasts, that repeat treatments with these agents could both replace significant amounts of collagen and slow it’s loss.

Fat The youthful face has an ample amount of volume evenly distributed, which displays a smooth transition from one area to another and

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Figure 6.8 A youthful face represents a point in time when a particular set of skeletal proportions are ideal for their soft-tissue envelope. (Reproduced from Stuzin J. Restoring facial shape in face lifting. Plast Reconstr Surg 2007;119:362–76 with permission.)

confers a well-rounded three-dimensional topography delineated by a series of arcs and convexities. As we age, these smooth transitions give way to sharper delineations where different areas seem to become their own isolated entities (Figure 6.8). Rohrich and Pessa23 recently demonstrated that subcutaneous fat is partitioned into discrete compartments and that these compartments each age independently of each other. In addition, the loss or gain of volume in one compartment may have a great influence on surrounding areas.24 Figure 6.9 demonstrates how treatment of fat loss in the temple and preauricular area serves to “lift” redundant skin along the jawline. Figure 6.10 demonstrates how refilling the deep medical cheek fat pad serves to indirectly efface the lid–cheek junction and nasolabial fold. Pessa25 recently noted that creases and folds occur at a transition point between two areas of varying thickness of subcutaneous fat as seen in the lid–cheek junction, and the nasolabial, labiomental, preauricular, and submental creases.

Muscle LeLouarn et al.26 used MRI (magnetic resonance imaging) to show that the facial mimetic muscles in youth have a curvilinear contour, and thus present an anterior surface convexity, due to the presence of underlying

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Figure 6.9 Treatment in the area of the temporal and preauricular fat pads: lift sagging skin in a 60 year old – two vials/treatment, two treatments. Final photograph taken 8 months after treatment (Photo courtesy of Rhonda Baldone.)

deep fat pads. The authors speculate that this fat may redistribute over lifetime of repeated animations. This may have practical clinical significance, informing the depth of placement of fillers and the areas of concomittant use of toxins.

Bone Shaw et al.27 utilizing computed tomography (CT) in 60 patients from 3 age ranges, concluded that the bony elements of the face change dramatically with age. This remodeling leaves less underlying surface support (the “table”) for the outer soft-tissue envelope (the “tablecloth”), causing it to fold or sag. There is some evidence that this bony platform changes most between young and mid-adulthood which may be reflected in softtissue changes (as fat shifts over the changing underlying support).28 This may be one of the reasons why we have observed that supraperiosteal injections seem to have additional value in the younger patient population. In Figure 6.11 supraperiosteal injections in the temple and along the supraorbital rim elevate the brow. Treatment around the pyriform

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Figure 6.10 A 58 year old: two vials/treatment, three treatments (six vials in total).

Botulinum toxin type A was used in the mentalis and bilateral depressor anguli oris muscles at the start of treatment. The last photograph was taken >4 months after the final treatment. Treatment in the deep medial cheek fat pad indirectly effaces the lid cheek junction and the nasolabial fold.

Figure 6.11 A 38 year old: two vials/treatment, two treatments (four vials in total).

Last photograph taken 6 months after final treatment. The patient received no other treatment. Note brow elevation and changing position (increased curl) of upper lip with supraperiosteal treatment above the supraorbital rim and along the medial maxilla.

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Figure 6.12 A 30 year old: two vials/treatment, two treatments (four vials in total).

The patient received no other treatment. Note the brow elevation and change in the perioral area with supraperiosteal injections along the supraorbital rim, zygoma, maxilla, and mandible.

aperture in the canine fossa, and in Ristow’s space (a distinct region for augmentation of the midface lying directly above the central maxilla24) increase the anterior projection of the cheek which then “smoothes out” the skin in the infraorbital area. Interestingly, these injections also seem to “push” the soft tissue forward resulting in increased eversion of the lips. Finally, Figure 6.12 shows a young patient with good skin texture and ample soft tissue, but lacking adequate craniofacial support for the overlying soft-tissue envelope. Note the change in shape and proportions of the face with supraperiosteal treatments. A closer look highlights the subtle, but significant changes achieved in the perioral area with supraperiosteal treatments along the maxilla and mandible. Note the increased upper lip eversion obtained without direct treatment of the lip, and the change in position of the base of the nose.

Facial analysis and mapping A youthful face represents a point in time when a particular set of skeletal proportions is ideal for their soft-tissue envelope.29 We grow into this from infancy and then lose it with age.30 As mentioned previously, although the sequence of changes as we age is somewhat predictable, the pace is not. In addition, the changes in each structural layer of the face do not occur independently, but interdependently, as an interlocking three-

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dimensional puzzle. Subsequently, there is no one algorithm to address facial aging. Facial analysis is a process of observation and palpation/ provocation that allows us to determine the nature and extent of the structural tissue changes aging the face in front of us at that particular point in time, and to then plan a treatment accordingly. It is not a “recipe,” it is a “read.” What you choose to address depends on the extent of the changes noted in each layer and the parity of these changes between layers, i.e. if there is a great deal of disparity, try to blend them all back to a more similar place (i.e. we have likely all experienced at some point the undesirability of putting a pair of young lips on an old face). If there is just a little change in all layers, almost any interventional approach will work. If there is a lot of loss of integrity in multiple layers, then multiple interventions may be needed to obtain optimal results. PLLA is a versatile agent to use to address these changes because it can be used to strengthen the dermis, or to mimic volume elsewhere with “space-occupying” collagen: i.e. it mimics fat if placed in fat, or bone if placed supraperiosteally – allowing the practitioner to tailor the treatment according to the specific aging changes manifested in that individual face.31 Deep supraperiosteal injections are done wherever possible, and subcutaneous injections are carried out where there is no underlying skeletal support as outlined above in the section on technique.

Complications Overall, PLLA injections are associated with low complication rates. As with all injectable procedures, short-term complications such as bruising and edema may occur, but are self-limiting. Careful scrutiny of the available literature reveals the vast majority of complications to be secondary to technical errors in product preparation or placement.4,6,32 Granulomatous reactions, sometimes occurring months to years after administration, have been reported with all currently available commercial devices, including collagen, hyaluronic acid, PLLA, silicone, calcium hydroxyl apatite, polymethylmethacrylate, hydroxyethylmethacrylate, and polyacrylamide gel;32 in fact, this list seems to grow with every newly introduced product. True inflammatory granulomas are rare and unpredictable, and the events leading to their appearance are not yet clearly understood. Fortunately, the rate of clinically detectable granuloma formation is very low (reported to vary between 0.01 and 0.1%) and most resolve with or without treatment.32

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Summary PLLA is a versatile agent that may be used to effectively address facial aging. Its relatively unique mechanism of action allows the product to be used to provide gradual, natural and subtle results. It is now widely recognized by the medical community that volume changes in the skin and soft tissue, as well as in their underlying skeletal support, greatly contribute to the changes observed in the aging face. This appreciation, accompanied by an ever-evolving understanding of the facial aging process (including the relatively early occurrence of changes in the craniofacial platform), focus the use of injectable PLLA basically on two levels (which are most often done in concert with each other): softtissue injections to provide volume, as well as strengthening and support to these tissues, and supraperiosteal placement to address facial contours and ratios.31 Its safety, efficacy, and durability have been consistently demonstrated.2,3,4,6,31,32 Optimizing outcomes, and minimizing adverse events, with this product are not difficult, but do require awareness of and attention to its specific and evolved injection methodology, and are enhanced by a careful facial analysis before treatment. Performed correctly, PLLA injections are associated with low complication rates and high patient satisfaction.

References 1. Williams D. On the mechanisms of biocompatibility. Biomaterials 2008;29: 2941–53. 2. Butterwick K, Lowe NJ. Injectable poly-l-lactic for cosmetic enhancement: Learning from the European experience. J Amer Acad Derm 2009;61(2);281–93. 3. Burgess CM, Lowe NJ. NewFill® for skin augmentation: a new filler or failure? Dermatol Surg 2006;32:1530–32. 4. Lowe NJ. Dispelling the myth: appropriate use of poly-l-lactic acid and clinical considerations. J Eur Acad Dermatol Venereol 2006;20(suppl 1):2–6. 5. Dermik Laboratories. Sculptra Aesthetic Product Information. Bridgewater, NJ: Dermik Laboratories, 2009. 6. Vleggaar D. Facial volumetric correction with injectable poly-l-lactic acid. Dermatol Surg 2005;31 (2):1511–17. 7. Ratner B, Bryant S. Biomaterials: Where we have been and where we are going. Annu Rev Biomed Eng 2004;6:41–75. 8. Gunatillake PA, Adhikari R. Biodegradable synthetic polymers for tissue engineering. Eur Cells Materials 2003; 5:1–16. 9. Mainil-Varlet P. Rahn B, Gogolewski S. Long-term in vivo degradation and bone reaction to various polyactides One-year results. Biomaterials 1997;18:257–66. 10. Tokiwa Y, Calabia BP. Biodegradability and biodegradation of poly(lactide). Appl Microbio Biotechnol 2006;72:244–51.

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11. Ishii D, Ying TH, Mahara A et al. (2009). In vivo tissue response and degradation behavior of PLLA and stereocomplexed PLA nanofibers. Biomacromolecules. http://pubs.acs.org. Downloaded February 7, 2009. 12. Lam KH, Schakenraad JM, Esselbrugge H, Feijen J, Nieuwenhuis P. The effect of phagocytosis of poly (L-lactic acid) fragments on cellular morphology and viability. J Biomed Mat Res 1993;27:1569–77. 13. Ashammakhi N, Serio W. Reflections on complications to Bioabsorbable osteofixation devices J Cranio Surg 2007;18(5):1242–43. 14. Kinoue K, Sato D, Matsumoto K et al. Arterial embolization and skin necrosis of the nasal ala following injection of dermal fillers. Plast Reconstr Surg 2008; 121:127e–28e. 15. Stewart DB, Morganroth GS, Mooney MA et al. Management of visible granulomas following periorbital injection of poly-l-lactic acid. Ophthomal Plast Reconstr Surg 2007;23:298–301. 16. Mest DR, Humble GM. Retreatment with injectable poly-L-lactic acid for HIVassociated facial lipoatrophy 24-month extension of the Blue Pacific Study. Dermatol Surg 2009;35:350–59. 17. Reszko AE, Sadick NE, Magro CM, Farber J. Late-onset subcutaneous nodules after poly-L-lactic acid injection. Dermatol Surg 2009;35(Suppl 1):380–84. 18. Lemperle G, Rullan PP, Gauthier-Hazan N. Avoiding and treating dermal filler complications. Plast and Reconst Surg 2006;118(suppl 3):92S–107S. 19. Narins RS, Jewell M, Rubin M et al. Clinical conference: Management of rare events following dermal fillers-focal necrosis and angry red bumps. Dermatol Surg 2006;32(3):426–34. 20. Fisher GJ, Quan T, Purohit T, et al. Collagen fragmentation promotes oxidative stress and elevates matrix metalloproteinase-1 in fibroblasts in aged human skin. Am J Pathol. 2009;174(1);101–14. 21. Fisher GJ, Varani J, Voorhees JJ. Looking older: Fibroblast collapse and therapeutic implications. Arch Dermatol. 2008;144(5):666–72. 22. Wang F, Garza LA, Kang S, et al. In vivo stimulation of de novo collagen production caused by cross-linked hyaluronic acid dermal filler injections in photodamaged human skin. Arch Dermatol. 2007;143(2):155–63. 23. Rohrich RJ, Pessa JE. The fat compartments of the face: Anatomyand clinical implications fro consmetic surgery. Plast Reconstr Surg. 2007;119:2219–27. 24. Rohrich RJ, Pessa JE, Ristow B. The youthful cheek and the deep medial fat compartment. Plast Reconstr Surg. 2008;121(6):2107–12. 25. Pessa J. Discussion: The tear trough and lid/cheek junction: anatomy and implications for surgical correction. Plast Reconstr Surg 2009;123:1341–42. 26. Le Louarn CL, Buthiau D, Buis J. Structural aging: The facial recurve concept. Aesthetic Plast Surg. 2007;31:213–18. 27. Shaw RB Jr, Kahn DM. Aging of the midface bony elements: A three-dimensional computed tomographic study. Plast Reconstr Surg. 2007;119:675–81. 28. Pecora NG, McNamara JA. The aging craniofacial complex: A longitudinal cephalometric study from late adolescence to late adulthood. Am J Orthod Dentofacial Orthop. 2008;134(4):496–505. 29. Stuzin JM. Restoring facial shape in face lifting: The role of skeletal support in facial analysis and midface soft-tissue repositioning. Plast Reconstr Surg. 2007; 119(1):362–76. 30. Pessa JE, Zadoo VP, Yuan C, et al. Concertina effect and facialaging: nonlinear aspects of youthfulness and skeletal remodeling, and why, perhaps, infants have jowls. Plast Reconstr Surg. 1999;103(2):635–44.

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31. Fitzgerald R, Vleggaar D. Using Poly-l-lactic acid to mimic volume in multiple tissue layers. J Drugs Derm. 2009;8(s10):s5–14. 32. Lemperle G, Gauthier-Hazan N, Wolters M. Foreign Body Granulomas after all injectable dermal fillers: Part I. Possible causes. Plast Reconstr Surg 2009; 123(6):1842–63.

C H APTER 7

Liquid Injectable Silicone Chad L. Prather Department of Dermatology, Louisiana State University, New Orleans and Dermasurgery Center, Baton Rouge, Louisiana, USA

In the age of minimally invasive aesthetic improvement, practitioners and patients continue to strive for the “ideal filler.” The theoretical ideal filler would be versatile and biocompatible, achieve consistent results, have a natural feel in vivo, remain safe, and be affordable. Furthermore, it would be easy to inject, have minimal side effects, and not require allergy testing. The ideal filler would also achieve some degree of longevity and, arguably, permanence. In the modern era, one existing augmenting agent retains many attributes of the ideal filler: liquid injectable silicone (LIS). LIS is the original, permanent, synthetic, soft-tissue-augmenting agent that may correct a variety of cutaneous and subcutaneous atrophies. It uniquely meets most the ideal filler criteria, including versatility, reliability of results, a natural feel, and an excellent cost–benefit ratio. Although its use has historically met with some controversy, when LIS is appropriately administered with the microdroplet serial puncture technique, patients may obtain enduring correction of scars, rhytids, and depressions, as well as lasting augmentation of lips and other facial contour atrophies and deformities. Yet the permanent nature of LIS in vivo is ambiguous. Although it is an attribute when the filler is placed correctly, it may also be a liability when the product is placed incorrectly, results in undesired augmentation, or serves as a nidus for inflammation and infection. For this reason, silicone and other permanent fillers are much less forgiving than temporary fillers: overcorrection or undesired augmentation will also persist. Hence, experience and precise technique are prerequisites to favorable patient outcomes. Physicians should use LIS only after extensive training in the proper technique, and in the appropriate patient. Candidates for treatment should have clear treatment objectives and sufficient insight into the goal of gradual augmentation over multiple treatment sessions. Patients who desire immediate correction or are uncertain of treatment aims are better treated with shorter-duration, temporary fillers rather than LIS.

Injectable Fillers: Principles and Practice. Edited by Derek Jones. © 2010 Blackwell Publishing

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Figure 7.1 Chemical structure of polydimethylsiloxane with repeating trimethylsiloxane units.

Basic science Silicon (Si) is second only to oxygen as the most abundant element of the earth’s crust.1 It is a relatively inert element that is essential to humans in small amounts. “Silicone” (SI) describes the group of synthetic polymers containing elemental silicon. Polymers in the silicone family may exist in solid (elastomer), liquid, and gel states, with various chemical, physical, mechanical, and thermal properties. Synthetic polymers also vary with regard to purity, sterility, and biocompatibility.2,3 Although various silicone polymers are employed for medical use, polydimethylsiloxane is the liquid injectable silicone used for soft-tissue augmentation. The molecular structure of this colorless, odorless, nonvolatile oil consists of repeating dimethylsiloxane units with terminal trimethylsiloxane ends (Figure 7.1). The viscosity of a given LIS product is dependent on the mean chain length of the dimethylsiloxane molecular units of which it is composed. Longer-chain molecules have a higher viscosity, and individual polymers are formulated to a set viscosity dependent on mean chain length. Silicone viscosity is measured in centistokes (cs), where 1 cs equals the viscosity of water. Practically, those LIS products employed for injection into the human body have a viscosity of 350 cs (similar to mineral oil), 1000 cs (similar to honey), or 5000 cs.3 LIS has not been found to be carcinogenic, and has demonstrated “an enviable record of safety” according to a 1998 National Science Panel investigating its use.4 Importantly, viscosity remains stable after tissue implantation. Pure LIS is not altered in vivo, although small amounts may be phagocytosed and enter the reticuloendothelial system.5,6

Mechanism of action LIS is the original fibroplastic filler, and its mechanism of augmentation is twofold: it causes both the gross displacement of dermal and subcutaneous tissue and the deposition of new collagen via fibroplasia. After a localized inflammatory reaction consisting of neutrophil migration and some degree of macrophage phagocytic activity, fibroblasts deposit a thin-walled

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collagen capsule around the silicone microdroplet.7 This capsule effectively anchors the microdroplet in place and prevents migration. Although the process of fibroplasia is classically conceptualized in wound healing, several filler products, both temporary and permanent, are now known to induce collagen fibroplasia as their mechanism of action for aesthetic improvement.8 Fibroplasia accounts for significant tissue augmentation over time, and the practitioner’s approach to volume enhancement differs when using products such as LIS that work by this mechanism. Rather than attempting to reach the final treatment endpoint in a single session, as is often done with fillers that work mostly by tissue displacement, fibroplastic fillers require smaller amounts of product broken up into several sessions adequately spaced over time. Appropriate spacing of treatment sessions 1–2 months apart allows the fibroplastic process adequate time to occur before subsequent treatment sessions and avoids overcorrection and undesired augmentation.

History Dow Corning (DC) introduced the first commercially available silicone for industrial use during World War II. Soon after, however, reports of its use for soft-tissue augmentation began to surface in Japan, Germany, and Switzerland. The US medical experience with silicone began in the 1950s, when physicians and nonphysicians alike began injecting silicone oil into the human body for soft-tissue augmentation.9 Large boluses of silicone were found to result in migration of the product along tissue planes to distant body sites, which led some injectors to add known tissue irritants, such as vegetable fatty acids, to the silicone products in the hope of producing implant-site fibrous reactions to limit product migration. However, granulomatous reactions at implantation sites of the adulterated products frequently occurred. Over the subsequent decades, the widespread use of various silicone oils for augmentation continued, unfortunately without common standards with regard to sterility, purity, injection protocol, injection site, or injection volume. The silicones intended for industrial and medical device use were later joined by products that were to be investigated for soft-tissue augmentation, yet no controlled product source existed. In 1965, DC gained US Food and Drug Administration (FDA) approval for investigation of a sterilized, highly purified silicone oil specifically intended for soft-tissue augmentation. Over 1300 patients were treated, with only 1 report of a severe complication in a patient treated with a large volume of silicone in a single injection. However, study protocol was not rigorously

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controlled with respect to patient eligibility, injection technique, or treatment volume and interval, and DC stopped investigation due to poor study control and inability to prevent product misuse. Before the introduction of bovine collagen in the early 1980s, liquid silicone was indeed the most popular injectable filler due to its natural texture and long-lasting results. But continued reports of complications, such as granuloma formation and migration, brought mounting negative publicity and the passage of a 1975 Nevada law criminalizing the use of injectable silicone in that state. Nationwide, its use declined as collagen quickly became the filler of choice. Although the FDA banned the use of LIS for cosmetic implantation in the early 1990s, its legal use as a filler was restored in 1997 with the passage of the US Modernization Act, which reaffirmed the physician’s right to employ approved medical devices in an off-label manner.10 That same year, Silikon-1000 (Alcon, Fort Worth, TX), a 1000 cs, highly purified silicone, was approved for intraocular retinal detachment. Thus, with an approved product on the US market, LIS could be legally used off-label for soft-tissue augmentation. The FDA has since affirmed that off-label injection of approved products is legal as long as it is based on the unique needs of the patient and is not advertised or marketed for that purpose.3,5 In 2001 and 2003, the FDA also agreed to allow limited clinical studies investigating the use of approved LIS for the cosmetic improvement of nasolabial folds, labiomental folds, mid-malar depressions, and HIVassociated facial lipoatrophy. These studies are currently ongoing.11

Controversy Although the efficacy of LIS is seldom challenged, the past few decades have seen debate about its safety, with both critics and advocates basing their positions largely on anecdotal data rather than rigorously controlled trials.12 Well-controlled, long-term studies of LIS for soft-tissue augmentation have, until recently, been lacking, and the number of patients who have historically experienced treatment success versus the number who have experienced significant complications is simply unknown. A further difficulty in historically analyzing the safety of “silicone” as an augmenting agent is that, outside of the modern, FDA-approved products available since 1997, an unknown number of products claiming to be silicone have likely been adulterated, impure, or other substances altogether. Although highly purified, 350 cs and 1000 cs products intended for injection into the human body were not introduced until the late 1960s and 1990s respectively, various substances masquerading as “silicone” have been injected for the past 60 years, at times with significant

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complications.13–16 Even products labeled as “medical-grade” silicone have not historically been regulated or authenticated. A 1989 analysis of six “medical-grade” silicone oils commonly used for injection revealed six different products of variable viscosity, each with significant amounts of elemental impurities and low-molecular-weight adulterants.17 Critics argue that LIS in an inherently unpredictable implant, fraught with potential complications. Several anecdotal reports and series of complications such as cellulitis, nodules, granulomatous reactions, and migration have been described,13–15 although variables such as product purity, volume, and injection technique could not be established with certainty. Furthermore, complications have been reported to occur as long as 36 years after treatment.16 Migration of product to other areas of the body may occur when large boluses of LIS are injected, but this has never been reported when using the microdroplet serial puncture technique.18,19 Advocates, on the other hand, maintain that the product is extremely safe and beneficial when three tenets of treatment are strictly adhered to: (1) only FDA-approved products intended for injection into the human body should be used; (2) the microdroplet serial puncture technique must be exclusively employed; and (3) a protocol must be followed involving limited per-session injection volumes, spaced over multiple injection sessions, with adequate intersession spacing. Several authors have published excellent safety records after prolonged LIS use. Balkin reported long-term follow-up over 41 years using LIS as a soft-tissue substitute for plantar fat loss in over 1500 patients, with 25 000 recorded silicone injections. He found that the host response to injections consisted of a “banal and stable fibrous tissue formation”.7,20 Advocates such as Orentreich, Carruthers, and Jones have also published multiple reports of their extensive and successful experience with LIS, and reiterate that the three principles of product purity, appropriate technique, and proper protocol are imperative for success.11,21–23 Duffy, who has written extensively on the subject, gathers that LIS has been used for softtissue augmentation worldwide for at least 40 years, and in at least 200 000 patients in the USA.24,25 He pragmatically cautions that, although pure LIS may be a superior filler for the permanent correction of certain defects, physicians who use it must realize that its misuse, or the use of other materials masquerading as LIS, have created “a pervasive climate of distrust and a veritable minefield of extraordinarily unpleasant medicolegal possibilities.” Such perceptions reiterate the importance of ongoing trials as they replace anecdotal reports with rigorously controlled data. Despite 60 years of use, only within the past 8 years have well-controlled trials, with the newer generation of standardized, highly purified products injected according to strict protocol, begun. These studies have so far demonstrated an excellent profile of safety and efficacy. The ongoing

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collection of objective data and longer-term follow-up are necessary to provide clarity into the true risks and benefits of soft-tissue augmentation with the modern silicones.

Indications and patient selection Although there are currently no FDA-approved cosmetic indications for LIS, it has been effectively employed off-label for the augmentation nasolabial folds (Figure 7.2), labiomental folds, mid-malar depressions, lip atrophy26 (Figures 7.3 and 7.4), hemifacial atrophy, acne and other atrophic scarring27 (Figure 7.5), age-related atrophy of the hands, corns and calluses of the feet, and healed diabetic neuropathic foot ulcers.20 It is most practical for the correction of HIV facial lipoatrophy and some acne scarring (Figures 7.6 and 7.7). Many of the above atrophies are also well served by modern, temporary fillers, but, with HIV lipoatrophy,

(a)

(b)

Figure 7.2 (a) Pre- and (b) post-treatment of marionette lines and nasolabial folds.

(Courtesy of Doris Hexsel.)

(a)

(b)

Figure 7.3 (a) Pre- and (b) post-treatment of lip and vertical lip rhytids. (Courtesy of

Doris Hexsel.)

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(b)

Figure 7.4 (a) Pre- and (b) post-treatment of atrophic lip scarring.(Courtesy of Doris

Hexsel.)

(a)

(b)

Figure 7.5 Long-term correction of facial acne scarring with LIS. (a) Pre-treatment and (b) 30-year follow-up. (Courtesy of Jay G. Barnett and Channing R. Barnett.)

(a)

(b)

Figure 7.6 (a) Pre- and (b) post-treatment of HIV-associated facial lipoatrophy: 22 mL

of LIS were injected over 12 monthly sessions. (Courtesy of Derek Jones.)

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(b)

Figure 7.7 (a) Pre- and (b) post-treatment of HIV-associated facial lipoatrophy:

12.5 mL of LIS were injected over 8 monthly treatments (photograph b was taken 6 months after the last silicone injection). (Courtesy of Derek Jones.)

LIS retains several advantages over other fillers for patients requiring a significant degree of durable correction. In HIV-related facial lipoatrophy, LIS presents a highly cost-effective, durable, natural feeling, efficacious treatment option that results in sustained improvement to help combat the social and professional stigmas routinely experienced with this condition. For these reasons, LIS remains an incredibly useful filler in the experienced injector’s armamentarium. In contrast, LIS is specifically contraindicated for injection into the breasts, eyelids, bound-down scars, or an actively inflamed site, and its safety has not been studied in pregnant women. Nor should it be injected into patients with dental carries, chronic bacterial sinusitis, or other active bacterial infection, or in those who may predisposed to facial trauma through contact sports due to an increased risk for chronic infection associated with an implant in such patients. In addition, LIS is not a substitute for surgical re-draping, chemical or mechanical resurfacing, or improvement of dynamic rhytids with botulinum toxin. Rather, the ideal patient is one with appropriate insight into the permanent and off-label nature of LIS, a realistic attitude regarding achievable results, in good physical health, and compliant with recommendations. Those who seek immediate correction or temporary augmentation are best served by temporary fillers. Serious consideration by both the physician and the patient must be given to the longevity of results obtained with LIS. Although permanent fillers such as LIS might reflexively seem preferred to temporary fillers due to their longevity, one must contemplate the possibility that both societal and personal aesthetic goals may change over time. Furthermore, an undesirable outcome will be unlikely to diminish with time and may be difficult to correct.

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Figure 7.8 Silikon-1000. (Courtesy of

Derek Jones.)

Figure 7.9 Instrumentation. (Courtesy of Derek Jones.)

Instrumentation Although 350 cs LIS is approved in Europe, in the USA the most appropriate LIS for off-label soft-tissue augmentation is Silikon-1000 (Alcon, Fort Worth, TX) (Figure 7.8). Adatosil 5000 cs (Bausch & Lomb, Rochester, NY) may also be used off-label, but proves to be rather viscous as a softtissue filler; 0.5 mL LIS is drawn through a 16G Nokor needle into a 1-mL Becton Dickinson (BD) Luer-Lok syringe using sterile technique (Figure 7.9). As molecules from the rubber stopper of the syringe could theoretically contaminate the LIS after a long exposure period, LIS should be drawn into the injecting syringe immediately before treatment, and should never be stored in the syringe. LIS is most easily injected through a 27G, ½-inch Kendall Monoject aluminum-hubbed needle. Plastichubbed needles tend to pop off with the higher injection pressures needed for injection through smaller gauge needles. To increase injector comfort, ½-inch inner diameter rubber electrical bushings purchased from a hardware store may be autoclaved and placed over the barrel of the syringe to cushion the physician’s second and third finger during

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Figure 7.10 Assembled

instrumentation. (Courtesy of Derek Jones.)

Figure 7.11 Patient marking: the

patient should be marked in both the smiling and the resting positions. (Courtesy of Derek Jones.)

injection (Figure 7.10). A BD 3/10 mL insulin syringe, similar to that often used for botulinum toxin, may also be used for injection of LIS, but these syringes must be backloaded.28

Patient preparation As with all fillers, patients should avoid aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), and anticoagulants for 7–10 days before injection. Perhaps more than with any other minimally invasive procedure, a thorough discussion about the risks, benefits, and alternative treatments to LIS should occur and be documented before injecting LIS. Patients must understand that LIS is a permanent filler and that it is being used off-label. Written informed consent must be obtained. Furthermore, high-quality pre-treatment photographs should be taken. Make-up is removed, and the skin is washed with an antibacterial cleanser and prepped with a povidone–iodine antiseptic or other surgical preparatory solution. Areas to be injected are outlined under good lighting with the patient in a sitting position, using a fine-tip marking pen (Figure 7.11). Target areas for volume restoration should be marked in both the smiling and the resting position, as these often change remarkably with facial activity. When treating HIV facial lipoatrophy, mid-malar depressions

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often become slightly elevated on smiling, and overcorrection of this area may result in a “chipmunk” appearance when the patient smiles. A topical anesthetic such as lidocaine or other topical amide mixture is then placed on the treatment area and wiped off after 30 min with clean gauze.

Injection technique Although temporary fillers may be injected by varied techniques, LIS should be injected only by the microdroplet serial puncture technique originally described by Orentreich.5 Other injection techniques risk undesirable consequences, including pooling or beading of silicone macrodroplets in the injection tract and possible migration via escape from the anchoring fibroplastic capsules. A microdroplet is defined as 0.005–0.01 mL of product, an amount that possesses a very large surface area compared with volume. A larger surface area:volume ratio effectively allows the microdroplet to be anchored into place by the ensuing fibroplasia that occurs around it. With larger macrodroplets, defined as >0.01 mL, encapsulation may not be sufficient to prevent product migration. A larger surface area:volume ratio also allows for a greater amount of fibroplasia – and thus augmentation – per unit volume, since a given volume of LIS dispersed into many microdroplets provides a greater total surface area than would be provided by fewer, larger droplets. Maximizing the total surface area of injected product effectively maximizes the degree of augmentation. Injections are made into the immediate subdermal plane or deeper. Often, as the needle enters the subdermal plane, there is a slight give in the tissue resistance to the needle. Intradermal injection should be diligently avoided, because it may result in dermal erythema and ridging (Figure 7.12). Care should be taken to make sure that the needle is in the subdermal plane before depressing the plunger. Furthermore, the injector’s thumb should be removed from the plunger before removing the needle. Injections should be placed at 2- to 5-mm intervals along the skin

Figure 7.12 Dermal erythema and

ridging secondary to intradermal injection. (Courtesy of Derek Jones.)

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surface at the optimal angle for penetration and deposition into the subdermal plane. The optimal angle varies with the intended depth of LIS placement. For areas where deeper placement is desired, a more oblique (approaching perpendicular to the skin surface) angle of insertion is best, whereas a more acute (approaching parallel to the skin surface) angle of insertion works best for more superficial deposition. As a rule, multiple passes over the same treatment area in a single session should be avoided, although experienced injectors may sometimes make a second pass at a different subcutaneous level. Importantly, greater correction should be accomplished over a longer period of time rather than with a larger per-session volume. Per session treatment volumes should be limited to 0.5 mL for smaller surface areas such as the nasolabial fold, and no more than 2.0 mL for larger surface areas such as facial lipoatrophy. Such per-session volumes allow around 100–200 individual injections with microdroplet deposition at 2- to 5-mm intervals, allowing a large treatment area to be covered in a single session if necessary. Moreover, injection sessions should be spaced at least 1 month apart, or longer, to allow for a limited fibrous tissue reaction to occur around each silicone microdroplet. As with all fillers working mainly by fibroplasia, intentional overcorrection immediately after injection should be avoided. As optimal correction approaches, treatment intervals should be extended to allow complete deposition of fibrous tissue before the next injection. Intervals on the order of every 2–6 months are appropriate in the late treatment period in order to allow for delayed fibroplasia, during which continued treatment could result in overcorrection.

Side and effects and managing complications The immediate injection-related side effects commonly seen with all fillers occur with LIS as well. The mild pain of needle insertion is usually well controlled with pretreatment topical lidocaine anesthetics. Occasionally, pre-treatment with oral analgesics (i.e. 0.5 mg alprazolam and two tablets of acetaminophen/hydrocodone 5/500 mg) 1 hour before treatment may be necessary in the pain-intolerant patient. Post-injection edema and erythema are common, usually mild, and resolve within a few days. The transient edema may even be representative of what optimal correction may look like after several treatments. Ecchymosis, when it occurs, also usually resolves within a few days. When injected with the appropriate technique, LIS is remarkably similar in texture and sensation to natural soft tissue. However, when larger cumulative volumes are employed, such as in HIV facial lipoatrophy, the treated area may occasionally feel slightly rubbery and firmer than natural

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soft tissue. Migration of LIS is an often-mentioned and undesired side effect of LIS. Using small volumes over multiple treatment sessions with the microdroplet technique avoids this problem, because microdroplets of silicone are anchored to the surrounding soft tissue by fibroplasia. However, LIS may track along tissue planes in the path of least resistance when injected in large boluses all at once. Skin dyschromia is a rare side effect of LIS, occurring most often when LIS is inadvertently injected into the dermis. When the inflammatory response to LIS extends into the dermis, postinflammatory erythema, postinflammatory hyperpigmentation, and telangiectasias may occur. Often, dermal ridging occurs in conjunction with the dyschromia. Erythema and telangiectasia may be treated with a pulsed dye laser or intense pulsed light device. Hyperpigmentation may be treated with hydroquinone and sun protection. And dermal ridging may improve with intralesional steroid injection, but the response is often incomplete and the problem persistent. A more concerning potential adverse event to LIS is granuloma formation, presenting as edematous, inflamed, indurated nodules or plaques in the subcutis or dermis. Such reactions have been described with LIS as well as a variety of other permanent or longer-lasting fillers such as polymethylmethacrylate and polylactic acid.21 These reactions are thought to be immune mediated, yet the basis of the immune mechanism remains unclear. It has been postulated that granulomatous reactions may be a result of infection at a distant site, as granulomatous reactions to LIS have been noted with acute bacterial dental abscesses or sinusitis to resolve upon treatment of the infection. Another leading, and perhaps complementary, theory is that bacterial biofilm formation around the LIS microdroplet may serve as a nidus for a chronic infection and resultant inflammatory host response.29 Biofilms may occur if bacterial organisms are introduced upon filler injection or seed the filler later during bacteremic episodes, and once present may remain dormant for months or years on foreign body surfaces such as implanted LIS. Biofilms may serve as a target of a delayed immune response by the patient when organisms convert back to a planktonic state, explaining the potential for granuloma formation years after LIS injection. In theory, immune restoration in HIV might also then predispose the patient to granuloma formation years later,25 but this has not been frequently observed by experienced injectors.21,27 It is estimated that some fraction of 1% of patients correctly treated with injectable grade LIS may eventually develop such granulomatous reactions.5 Should granulomatous reactions develop, they may be treated with high concentrations of intralesional triamcinolone (20– 40 mg/mL) at 2- to 4-week intervals. However, based on the biofilm hypothesis, institution of a full-dose, broad-spectrum antibiotic such as

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minocycline once or twice daily should also occur. Isotretinoin, etanercept, and topical imiquimod have also been used successfully to treat LIS granulomas.30–33 Ultimately, however, granulomas that fail to resolve may require surgical removal.

Summary In an era of expanding soft-tissue augmenting agents, liquid injectable silicone remains a unique and effective filler when appropriately employed by experienced injectors using the microdroplet serial puncture technique. Although LIS is effective for the correction of a variety of facial atrophies and deformities, currently its greatest application is for the permanent correction of HIV-associated facial lipoatrophy. Although LIS has generated controversy in the past, the modern, highly purified silicone oils studied in controlled clinical settings have so far proven to be extremely safe agents that warrant distinction from their predecessors. Yet, as with any procedure, complications may still occur, and may be more difficult to treat due to the permanent nature of the product. For this reason, LIS should be considered only in appropriate patients who have had full disclosure as to the off-label nature of its use and adequate informed consent. When all criteria are met, LIS may be one of the most cost-effective and natural fillers available, and continued studies are ongoing to further examine both long-term safety and efficacy.

References 1. Turekian KK, Wedepohl KH. (Distribution of the elements in some major units of the earth’s crust. Bull Geol Soc Am 1961;72:175–92. 2. Spanoudis S, Koski G. Sci.polymers. Available at www.plasnet.com.au/ index.php?option=com_content&view=article&id=89:polymer-faq&catid=118: FAQ&Itemid=258 (accessed January 31, 2009). 3. Orentreich DS, Jones DH. Liquid injectable silicone. In: Carruthers J, Carruthers A (eds), Soft Tissue Augmentation, 1st edn. New York: Elsevier, 2005: 77–91. 4. Diamond B, Hulka B, Kerkvliet N, Tugwell P. Summary of report of national science panel: silicone breast implants in relation to connective tissue diseases and immunologic dysfunction, 1998. Available at: www.fjc.gov/BREIMLIT/SCIENCE/ summary.htm (accessed January 31, 2009). 5. Orentreich DS. Liquid injectable silicone: techniques for soft tissue augmentation. Clinics Plast Surg 2000;27:595–612. 6. Selmanowitz VJ, Orentreich N. Medical grade fluid silicone: a monographic review. J Dermatol Surg Oncol 1977;3:597–611. 7. Wallace WD, Balkin SW, Kaplan L, Nelson SD. The histological host response of liquid silicone injections for prevention of pressure-related ulcers of the foot: a 38year study. J Am Pod Med Assocn 2004;94, 550-557.

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8. Carruthers J, Carruthers A, Mandy SH, Lowe NJ, Prather CL, Jones DH. Fillers working by fibroplasia. In: Carruthers J, Carruthers A (eds), Soft Tissue Augmentation, 2nd edn. New York: Elsevier, 2008: 90–100. 9. Klein AW. Skin filling: collagen and other injectables of the skin. Dermatol Clinics 2001;19:491–508. 10. Food and Drug Administration. Physicians to stop injecting silicone for cosmetic treatment of wrinkles, Press Release P92-5, 1992. Available at: www.fda.gov/bbs/ topics/NEWS/NEW00267.html (accessed January 31, 2009). 11. Jones DH, Carruthers A, Orentreich D, et al. Highly purified 1000-cSt silicone oil for treatment of human immunodeficiency virus-associated facial lipoatrophy: an open pilot trial. Dermatol Surg 2004;30:1279–86. 12. Duffy DM. (2002) The silicone conundrum: a battle of anecdotes. Dermatologic Surgery 28, 590. 13. Delage C, Shane JJ, Johnson FB. Mammary silicone granuloma: Migration of silicone fluid to abdominal wall and inguinal region. Arch Dermatol 1973;108(1): 105–7. 14. Baselga E, Pujol R. Indurated plaques and persistent ulcers in an HIV-1 seropositive man. Arch Dermatol 1994;130:785–9. 15. Rapaport MJ, Vinnik C, Zarem H. Injectable silicone: cause of facial nodules, cellulitis, ulceration, and migration. Aesthet Plast Surg 1996;20:267–76. 16. Rapaport MR. Silicone injections revisited. Dermatol Surg 2002;28:594–5. 17. Parel JM. Silicone oils: physiochemical properties. In: Glaser BM, Michels RG (eds), Retina, Vol 3. St Louis, MI: Mosby, 1989: 261–77. 18. Duffy DM. Liquid silicone for soft tissue augmentation. Dermatol Surg 2005;31(11 Pt 2):1530–51. 19. Price EA, Schueler H, Perper JA. Massive systemic silicone embolism: a case report and review of literature. Am J Forensic Med Pathol 2006;27(2):97–102. 20. Balkin SW. Injectable silicone and the foot: a 41-year clinical and histologic history. Dermatol Surg 2005;31(11 Pt 2):1555–9. 21. Jones D. HIV facial lipoatrophy: causes and treatment options. Dermatol Surg 2005;31(11 Pt 2):1519–29. 22. Jones DH. Injectable silicone for facial lipoatrophy. Cosmet Dermatol 2002; 15:13–15. 23. Orentreich D, Leone AS. A case of HIV-associated facial lipoatrophy treated with 1000-cs liquid injectable silicone. Dermatol Surg 2004;30:548–51. 24. Duffy DM. Tissue injectable liquid silicone: new perspectives. In: Klein AW (ed.), Augmentation in Clinical Practice: Procedures and techniques. New York: Marcel Dekker, 1998: 237–63. 25. Duffy DM. Liquid silicone for soft tissue augmentation: histological, clinical, and molecular perspectives. In: Klein A (ed.), Tissue Augmentation in Clinical Practice, 2nd edn. New York: Taylor & Francis, 2006: 141–237. 26. Fulton JE Jr, Porumb S, Caruso JC, Shitabata PK. Lip augmentation with liquid silicone. Dermatol Surg 2005;31(11 Pt 2):1577–86. 27. Barnett JG, Barnett CR. Treatment of acne scars with liquid silicone injections: 30-year perspective. Dermatol Surg 2005;31(11 Pt 2):1542–9. 28. Benedetto AV, Lewis AT. Injecting 1000 centistoke liquid silicone with ease and precision. Dermatol Surg 2003;29:211–14. 29. Christensen L. Normal and pathologic tissue reactions to soft tissue gel fillers. Dermatol Surg 2007;33:S168–75. 30. Desai AM, Browning J, Rosen T. Etanercept therapy for silicone granuloma. J Drugs Dermatol 2006;5:894–6.

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31. Baumann LS, Halem ML. Lip silicone granulomatous foreign body reaction treated with aldara (imiquimod 5%). Dermatol Surg 2003;29:429–32. 32. Lloret P, Espana A, Leache A, et al. Successful treatment of granulomatous reactions secondary to injection of esthetic implants. Dermatol Surg 2005;31:486–90. 33. Pasternack FR, Fox LP, Engler DE. Silicone granulomas treated with etanercept. Arch Dermatol 2005;141:13–15.

C H APTER 8

Hydrogel Polymers Naissan O. Wesley Skin Care and Laser Physicians of Beverly Hills, Los Angeles, USA

History and science Hydrogel polymers are hydrophilic substances that are made up of polyacrylamide subunits.1 Acrylamide is a highly water-soluble vinyl monomer formed from the hydration of acrylonitrile. As a monomer, acrylamide has been shown to be neurotoxic and teratogenic.2,3 However, when the monomers are crosslinked to the polymer form, the potential neurotoxicity and teratogenicity effects cease.3 Most commercial uses of acrylamide are available in the form of polymers. Polyacrylamide can hold between 300 and 400 times its weight in water and has been used for many years in medical applications, drug delivery, intraocular lenses and soft contact lenses, water purification, paper processing, mining and mineral processing, food packaging, and agriculture.3,4 Their use for aesthetic procedures was first reported in 2001. Soft-tissue hydrogel polymer fillers are gels that are permanent, nonbiodegradable, and hydrophilic.1 They have a high degree of elasticity. With regard to Bio-Alcamid, its oxidizability is <1, its spontaneous pH is 6.9 and there is no monomer (PPM 0).5 When used as soft-tissue fillers, hydrogel polymers are classified as class IIB medical devices (Box 8.1). Hydrogel polymers used for soft-tissue augmentation include Aquamid (Contura International A/S, Soborg, Denmark), Bio-Alcamid (Polymekon, Milan, Italy), Argiform (Bioform, Moscow, Russia), and Interfall (Interfall Co. Ltd, Ukraine). Former hydrogel fillers Bioformacryl, Formacryl, Royamid, Amazing-gel, Evolution, and Outline were available in Europe, Russia, and China but are no longer on the market.6 Aquamid is a 5% polyacrylamide polymer with 97.5% water.7 BioAlcamid is composed of a backbone of 2.5–5% crosslinked polyalkylimide and 95–97.5% water. It does not contain free acrylamide monomers.8

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Box 8.1 Properties of hydrogel polymer fillers Permanent Nonbiodegradable Radiolucent gel Hydrophilic High degree of elasticity Class IIB medical device

Polyalkylimide is a subtype of polyacrylamide. In the past, the manufacturer’s website has referred to the product’s composition as polyacrylamide. Recently, the information on the website has changed to state that the gel is composed of polyalkylimide (see www.ascentemedical. com/content/view/27/206 and www.purmedical.com/bioAlcamid.htm). Argiform is a second-generation polyacrylamide gel made up to 95% polyacrylamide, with 0.03% residual unpolymerized acrylamide monomer and 5% water. It is identical in composition to its predecessor Formacryl, except that a silver ion has been added to the manufacturing process to help repel bacteria (see www.bioform.ru). Interfall is 3.5–6% crosslinked polyacrylamide with water; it also contains crosslinking agents, such as methylene-bisacrylamide, and a mixture of ammonium persulfate and tetramethylethylenediamine as the initiator of polymerization (see www. bpg.bg/interfall/index.htm). After injection in to tissue, the polymer becomes an “endoprosthesis” due to fibroblast activity around the substance, which forms a thin approximately 0.2-mm fibrous capsule.5,9–12 After approximately 2 months, the fibroblast activity within and around the capsule ceases and the capsule remains 0.2 mm thick without further thickening or sclerosis.13 The thin capsule contrasts with thicker capsules found surrounding silicone, which is a hydrophobic permanent filler.8,12

Indications Bio-Alcamid received the CE (Conformitié Européene) certificate in October 2001, and has been used in Europe as a permanent filler substance for age-related volume loss and for HIV- and highly active antiretroviral therapy (HAART)-associated lipodystrophy9 (Figure 8.1). In Canada, BioAlcamid is approved only for the treatment of HIV- and HAART-associated facial lipoatrophy (see www.purmedical.com/bioAlcamid.htm). Aquamid has been used outside the USA since 1993, but was first reported to be used for cosmetic procedures in Europe in 2001.14 Since 2001, approximately 150 000 patients have received more than 250 000 injections with

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Figure 8.1 (a) Patient with HIV-associated lipoatrophy pre-Bio-Alcamid injection. (b)

Two months post Bio-Alcamid injection. (Photograph courtesy of Derek Jones.)

Aquamid for aesthetic purposes and for HIV-associated lipoatrophy.15 A US-based double-masked, randomized, multi-center study of 315 subjects comparing Aquamid versus Restylane found that Aquamid was as effective as Restylane in the aesthetic enhancement of nasolabial folds, and that the effectiveness of Aquamid was maintained at 12 months.16 Argiform is available in Russia and is marketed and used for lip enhancement. Interfall is a volume filler manufactured in the Ukraine. None of these products currently have approval by the US Food and Drug Administration (FDA) for use in the USA. Although not approved in every country, these hydrogel polymers are used worldwide for aesthetic purposes. In addition to facial volume correction, both Bio-Alcamid and Aquamid have also been used for breast, calf, and buttock augmentation, often combined with liposculpture.5

Technique Bio-Alcamid Bio-Alcamid is available in 1-mL, 3-mL and 5-mL Luer-Lok syringes. Injections are made with an 18G 1.5-inch needle or 2–3 mm diameter

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cannula. Smaller 21–23G needles may be used to fill facial rhytids. BioAlcamid 1–3 mL of is typically injected into each nasolabial fold, cheek, chin, or jawline for aesthetic purposes. For HIV-associated lipoatrophy, a total of 10–30 mL is typically injected, depending on degree of volume loss.1 For breast augmentation or pectus excavatum 40–120 mL may be injected into the breasts or chest. For buttock augmentation, 100–500 mL may be injected.5 Sterile preparation is recommended before injection. Local anesthesia is typically obtained with lidocaine with epinephrine either by nerve block or directly infiltrated into the treatment area. A skin incision is made with a sharp scalpel blade. Then the 18G needle or 2- to 3-mm cannula is introduced into the incised skin and Bio-Alcamid is injected retrograde with one single lodging. Most authors recommend placing a new parallel lodging with a separate puncture point in the event of irregularities or insufficiency.5

Aquamid Aquamid is available in Europe in pre-filled 1-mL syringes and is injected as a clear gel with a 27G needle (see www.aquamid.info/ifs.htm). The product may be stored at room temperature. Similar to Bio-Alcamid, Aquamid should be injected under sterile conditions, under local anesthesia, and in a retrograde manner. Approximately 1–4 mL are typically injected into the nasolabial folds, 1–4 mL into the lips, and 1 mL into the glabella.15

Argiform Argiform is used for lip enhancement. The gel is injected with a 25G 5/8-inch (0.50 × 16 mm) needle into the vermillion border and lip body in a retrograde manner. Similar to Bio-Alcamid and Aquamid, Argiform is laid down in a parallel array. The manufacturer reports that the gel does not extrude via puncture sites after injection; however, they do recommend light pressure at puncture sites to prevent extrusion from occurring. The amount of gel injected depends on the amount of volume desired to achieve a fuller lip, but typically does not exceed 0.5 mL into each lip (1.0 mL total). If more than 1 mL is injected, there is a higher risk of nodule formation during lip movement. Immediately after injection, the gel is molded into place by grasping the lip between the thumb and index fingers and smoothing out any irregularities. Over the next 2–4 weeks after injection, some reduction in tissue volume may be expected. Thus, patients should be informed about the possibility of additional future injection(s) (see www.bioform.ru).

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Interfall Interfall is available in the Ukraine and was called Amazing-gel when produced by a Chinese manufacturer (Fuhua Co., China) until it was banned in China in April, 2006 (see www.physorg.com/news68374349. html). According to the manufacturer’s website, Interfall is available in sterile vials of 20 mL, 50 mL, and 250 mL volume for use in the face, body, breasts, genitals, vocal folds, and scars.12 It should be stored at room temperature and has a shelf-life of 2 years. Further information about Interfall is not available at the time of writing.

Potential adverse reactions Although the permanent nature of the hydrogel fillers is often considered an advantage, there are numerous reports of adverse events. Common reactions seen immediately after injection include erythema, edema, and bruising that may last up to 1 week, as with any soft-tissue filler. However, adverse reactions unique to hydrogel polymers also occur. Complications related to hydrogel filler therapy can be early and late occurring and include infection, nodule formation, product migration, and sterile inflammatory abscesses.1,6,7,14,17–20 Capsular contraction may also occur, changing the shape of the endoprosthesis, and causing the depot to feel unnaturally hard to touch. Although complications do not occur in every case of hydrogel polymer injection, an analysis of 2000 cases of Bio-Alcamid treatments for a variety of aesthetic purposes over 3 years revealed that 12 of 2000 implants were infected with Staphylococcus aureus, requiring incision and drainage of the implant and antibiotic therapy in all 12 cases.21 Late-occurring reactions can occur months to years after injection and can be recurrent (Figure 8.2). In one report of 25 patients with late-occurring adverse effects due to polyalkylimide fillers, the mean latency between injection and symptoms was 13.4 months.8 Late-occurring complications can be spontaneous. However, many are often preceded by disruption of the fibrocellular layer surrounding the product after invasive procedures such as injection of additional filler material, blepharoplasty, and dental work. The most common presentation is that of an inflammatory abscess where patients present with pain and edema at or near the site of prior filler placement1,6,7,14,17–20 (Figure 8.3). Serologies most commonly reveal elevated acute phase reactants, but increased angiotensin-converting enzyme or ACE (with normal calcium levels), lactate dehydrogenase (LDH), positive ANAs (anti-neutrophil antibodies), and abnormal electrophoresis abnormalities may be found.8,9

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Figure 8.2 (a) Presentation of acute inflammatory reaction 3 years after Bio-Alcamid injection. Cultures of the exudates grew α-hemolytic streptococci of the viridians group. (b) Ten days after incision and drainage, intravenous vancomycin and subsequent oral clindamycin were given. (c) Nine months later, presentation of recurrent, chronic inflammatory reaction of 5 months’ duration. (d) Appearance 1 week after incision and drainage and cephalexin 500 mg orally four times a day for 7 days. (Reprinted with permission from Jones DH, Carruthers A, Fitzgerald R, Sarantopoulos GP, Binder S. Late-appearing abscesses after injections of nonabsorbable hydrogel polymer for HIV-associated facial lipoatrophy. Dermatol Surg 2007;33(suppl 2):S193–8.)

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Figure 8.3 (a,b) Acute inflammatory reaction with nondrainable rock hard nodules in the glabella and nasolabial fold after a dental visit, 2 years after Bio-Alcamid injection. (c,d) Resolution of the nodules 1 month after 1.0 mL intralesional triamcinolone 40 mg/mL to the subcutis of the glabella and 1.0 mL intralesional triamcinolone 20 mg/mL into the nasolabial fold, and 6 weeks of oral minocycline 135 mg daily (Solodyn, Medicis, Scottsdale, AZ). (Photograph courtesy of Derek Jones)

Negative cultures of aspirated material from inflammatory reactions are the norm, but Gram stains of the exudates have shown Gram-positive cocci in singlets, doublets, and chains.19 In the rare instance that positive cultures are obtained, Streptococcus viridians has been the most common organism identified.18–20 Several cases of cultures growing Propionibacterium acnes, coagulase-negative staphylococci, meticillin-resistant Staphylococcus

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aureus, group G streptococci, and Candida species have also been reported.19 Nonspecific foreign body granulomas are seen on histopathological examination.7,19 The filler can also be visualized on T2-weighted magnetic resonance imaging (MRI) with fat-suppressing spectro-presaturation inversion recovery (SPIR).1 In most cases, patients are given antibiotics while cultures are pending. Patients with an inflammatory response to hydrogel polymers usually improve with a combination of antibiotics, drainage, and steroid injections, but improvement is usually not achieved with antibiotics alone. One hypothesis for the cause of inflammation is that puncture of the capsule by a needle from dental work or injection of a secondary filler may introduce bacteria that are not detectable in culture, but may stimulate chronic inflammation.6 Therefore, the implant of temporary or permanent fillers may serve as a growth medium for biofilm formation. It has recently been shown that Staph. aureus forms a bacterial biofilm on hydrophilic substances, whereas Escherichia coli prefers hydrophobic substances.22 The introduction of a staphylococcal, streptococcal, or other bacterial species through skin and implant puncture could explain biofilm formation. Once a bacterial biofilm is established, elimination of the bacteria stimulating the inflammation is extremely difficult. Removal of all of the filler material plus long-term broadspectrum antibiotics that are able to penetrate the implant capsule is advocated. Distinguishing inflammation due to a bacterial biofilm from a low-grade sensitivity reaction is difficult. Most filler substances have been reported to have immunogenicity, including hyaluronic acid (HA). A study of delayed immune-mediated effects from HA and HA combined with polymethylmethacrylate included 25 cases of patients with symptoms starting 1–60 months after injection. The adverse effects were inflammatory nodules, cutaneous leukocytoclastic vasculitis, sarcoid-like reaction, and labial granulomas, and serum abnormalities were present in all of those tested.23 Although rare, hypersensitivity should always be considered in the differential diagnosis of a patient presenting with an inflammatory reaction after receiving an injection of a filler. Intradermal skin testing with a filler substance before treatment may be helpful in susceptible individuals.24 Migration of hydrogel fillers has also been reported.6,14 It has been speculated that the thin capsule formed around these hydrogel polymers may be flaccid in subcutaneous and mammary tissue, which could result in capsular rupture with force, muscle activity, or vigorous massage, especially in patients with a thin subcutaneous layer.25 An incomplete or absence of capsule in or near muscle has also been reported.6 The pumping

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action of the muscles may therefore result in gel migration, especially years after injection. Although complications with hydrogel fillers can be severe and difficult to manage, their use can still significantly impact quality of life. In a prospective study of 17 patients in the Netherlands with significant HIVassociated lipoatrophy, 4 of 17 patients suffered complications including infection requiring drainage, gel migration, and hardened capsule formation after one session of polyalkylimide injection. In this study all patients demonstrated decreased subjective severity of lipoatrophy and improved quality of life, even in the four patients who had complications.25 In addition, larger amounts of Bio-Alcamid and Aquamid can be injected in one session compared with other long-lasting soft-tissue fillers such as silicone and polylactic acid (Sculptra, Newfill), making it more desirable for some patients with severe lipoatrophy who desire a single-stage procedure.13,24

Management of adverse reactions Complications have been managed with antibiotics, incision and drainage, oral or intralesional steroids, nonsteroidal antiinflammatory drugs (NSAIDs), hydroxychloroquine, and removal of the product, with varying results.1,6,7,17–20 Despite resolution with these methods, patients may have recurrent symptoms. Removal of the product has been performed via incision with a large-gauge needle and squeezing the gel out. However, the filler substance may not be easily removed with puncturing and squeezing; thus, surgery with complete excision may be required to remove all of the injected material. Gel that has migrated in the breasts or calves must usually be managed by surgical excision. For small, inflamed nodules, intralesional corticosteroids should be attempted first. When intralesional corticosteroids have failed or for larger abscesses, an attempt at incision and drainage with culture and pathology of the expressed material is recommended. Although cultures are often negative, starting broad-spectrum antibiotics in addition to incision and drainage may still be useful for their antiinflammatory properties. Amoxicillin/clavulanate potassium (Augmentin), clarithromycin, clindamycin, and minocycline, among others, have been tried with some success.19,24 A novel approach using an irrigation system to remove the hydrogel polymer has recently been published.18 Under sterile conditions and ultrasound guidance, a 14–16G intravenous cannula is inserted into the site of filler placement. The cannula is secured in place with a suture. Frequent

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irrigation, up to eight times a day, is performed by injecting and aspirating solutions such as Hartmann’s, saline, or 10% povidone–iodine solution. Irrigation has been reported to be slightly painful in some patients. Complete implant removal can be achieved; however, in cases where removal was not complete, the amount of filler was reduced considerably and symptoms were alleviated. In this report, this approach was performed in patients who were concerned about having larger scars as a result of incision and drainage or excision. However, patients were hospitalized for several days for this procedure, which may not always be feasible in most US healthcare settings. If hydrogel fillers are to be utilized, strict antiseptic precautions should be taken to ensure that they are injected in a sterile fashion. Once injected, caution must also be taken when additional fillers are injected at a later date so as not to puncture the endoprosthesis for risk of inflammatory reaction or biofilm formation. Prophylactic antibiotics may be warranted before initial injection and before repeat soft-tissue filler injections, surgery in the affected area, or dental procedures. One study recommends that patients should be instructed not to touch the injected sites for 4 hours after the procedure and to avoid high pressure at the site for 3 weeks.25

Conclusion Hydrogel polymers are permanent volume fillers available outside the United States. They are useful for patients with severe volume loss or lipoatrophy as large amounts of product may be injected in one session. Although infrequent, difficult-to-manage complications have been reported with these products. With the explosion of new substances coming on to the market for softtissue augmentation, it is essential that physicians be aware of both shortand long-term effects of new materials. Industry must also recognize the potential complications and problems with products, and disclose reported complications in their literature.24 Globalization of the cosmetic surgery market presents unique challenges to physicians. It is important for physicians to be aware of potential presentations and complications of new and less commonly used cosmetic treatments, including those used primarily outside the United States.23

References 1. Karim RB, Hage JJ, Van Rozelaar L, Lange CAH, Raaijmakers J. Complications of polyalkylimide 4% injections (Bio-Alcamid™): a report of 18 cases. J Plast Recontruct Aesthetic Surg 2006;59:1409–14.

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2. Exon JH. A review of the toxicology of acrylamide. J Toxicol Environ Health B Crit Rev 2006;9:397–412. 3. Smith EA, Oehme FW. Acrylamide and polyacrylamide: a review of production, use, environmental fate and neurotoxicity. Rev Environ Health 1991;9:215–28. 4. Shaw I, Thomson B. Acrylamide food risk. Lancet 2003;361:434. 5. Claoue BL, Rabineau P. The polyalkylimide gel: experience with Bio-Alcamid. Semin Cutan Med Surg 2004;23:236–40. 6. Cheng NX, Xu SL, Deng H, et al. Migration of implants: a problem with injectable polyacrylamide gel in aesthetic plastic surgery. Aesth Plast Surg 2006;30:215–25. 7. Amin SP, Marmur ES, Goldberg DJ. Complications from injectable polyacrylamide gel, a new nonbiodegradable soft tissue filler. Dermatol Surg 2004;30(12 Pt 2): 1507–9. 8. Alijotas-Reig J, Garcia-Gimenez V, Miro-Mur F, Vilardell-Tarres M. Delayed immune-mediated adverse effects related to polyacrylamide dermal fillers: clinical findings, management and follow-up. Arch Dermatol 2009;35:360–6. 9. Honig JF. Cheek augmentation with bio-alcamid in facial lipoatrophy in HIV seropositive patients. Journal Craniofac Surg 2008;19:1085–8. 10. Formigli L, Zecchi S, Protopapa C, et al. Bio-Alcamid: an electron microscopic study after skin implantation. Plast Reconstr Surg 2005;113:1104–6. 11. Lemperle G, Morhenn V, Charrier U. Human histology and persistence of various injectable filler substances for soft tissue augmentation. Aesth Plast Surg 2003;115: 337–8. 12. Christensen LH, Nielsen JB, Mouritsen L, Sorensen M, Lose G. Tissue integration of polyacrylamide hydrogel: an experimental study of periurethral, perivesical, and mammary gland tissue in the pig. Dermatol Surg 2008;34:S68–77. 13. Lotti T, Cammarota N, Protopapa C. Immunohistochemical and ultrastructural evaluation of human tissue after subcutaneous injection of new filler Bio-Alcamid. Polymekon Science Dosier 2001;1:28–31. 14. Goldman MP. Pressure-induced migration of a permanent soft tissue filler. Dermatol Surg 2009;35(suppl 1):403–6. 15. Wolters M, Lampe H. Prospective multicenter study for evaluation of safety, efficacy, and esthetic results of cross-linked polyacrylamide hydrogel in 81 patients. Dermatol Surg 2009;35(suppl 1):338–43. 16. Narins R. A 12-month Controlled Study in the United States of the Safety and Efficacy of Hydrogel, A Permanent Soft-Tissue Filler. [Abstract]. American Society of Dermatologic Surgery Meeting, October 1–4, 2009. 17. El-Sayed Ibrahim El-Shafey. Complications from repeated injection or puncture of old polyacrylamide gel implant sites: case reports. Aesth Plast Surg 2008;32:162–5. 18. Goldan O, Georgiou I, Grabov-Nardini G, et al. Early and late complications after a nonabsorbable hydrogel polymer injection: a series of 14 patients and novel management. Dermatol Surg 2007;33;S199–206. 19. Jones DH, Carruthers A, Fitzgerald R, Sarantopoulos P, Binder S. Late-appearing abscesses after injections of nonabsorbable hydrogel polymer for HIV-associated facial lipoatrophy. Dermatol Surg 2007;33:S193–8. 20. Gomez-de la Fuente E, Alvarez-Fernandez JG, Pinedo F, et al. Cutaneous adverse reaction to Bio-Alcamid Implant. Acta Dermosifiliogr 2007;98:271–5. 21. Pacini S, Ruggiero M, Morucci G, et al. Bio-Alcamid: a novelty for reconstructive and cosmetic surgery. Ital J Anat Embryol 2002;107:209–14. 22. Ji J, Zhang W. Bacterial behaviors on polymer surfaces with organic and inorganic antimicrobial compounds. J Biomed Mater Res A 2009;88:448–53.

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23. Alijotas-Reig J, Garcia Gimenez V. Delayed immune-mediated adverse effects related to hyaluronic acid and acrylic hydrogel dermal fillers: clinical findings, longterm follow-up and review of the literature. J Eur Acad Dermatol Venereol 2008; 22:150–61. 24. LaTowsky BC, Wesley NO, MacGregor JL, Kaminer MS, Arndt KA. Delayed inflammatory reaction to 4% polyacrylamide gel (Bio-Alcamid) used for soft tissue augmentation. Arch Dermatol in press (December 2009). 25. Karim RB, de Lint CA, van Galen SR, et al. Long-term effect of polyalkylamide gel injections on severity of facial lipoatrophy and quality of life of HIV-positive patients. Aesthetic Plast Surg 2008;32:873–8.

C H APTER 9

Artefill: the First to Last Adam M. Rotunda Division of Dermatology, David Geffen School of Medicine, University of California, Los Angeles, USA

Rhoda S. Narins Division of Dermatology, New York University School of Medicine, New York, USA

Conventional approaches to facial folds are surgical augmentation or minimally invasive injectables, which until recently have been limited to resorbable fillers. Although medical-grade silicone has been used as a dermal filler for years, widespread acceptance has been limited primarily due to its nonapproval for this indication. Artefill, smartly marketed with the tagline, “The First to Last,” is the first to break conventions. It is the only soft-tissue filler cleared by the US Food and Drug Administration (FDA) in 2006 to address the unmet need for a nonresorbable filler indicated for the correction of nasolabial folds. Artefill is composed of polymethylmethacrylate (PMMA) microspheres suspended in bovine collagen containing lidocaine. The unique durability of the product presents safety concerns that are not germane to the conventional, nonpermanent products discussed in this textbook. We wish to examine Artefill’s history and evolution, pivotal trial efficacy and safety data, and its uses and limitations in clinical practice.

History Since Judet introduced PMMA in 1947 as the first hip prosthesis,1 the chemical inertness and biocompatibility of the material has been well accepted. Methylmethacrylate polymers are nontoxic, noncarcinogenic, and have a melting temperature of 101°C.2 Further investigation in animals revealed that a key factor of the biocompatibility of dermally implanted PMMA is the round, smooth shape and size of the microspheres.3 Dr Gottfreid Lemperle of Germany developed PMMA microsphere technology for permanent soft-tissue dermal augmentation that was first used in clinical trials in 1989.4, 5 Arteplast, the original formulation, was composed of 32–42 μm PMMA beads suspended in a rapidly resorbed gelatin vehicle, which was thought to promote intradermal clumping after injection. In

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Figure 9.1 Erythema and atrophy demonstrated at the site of PMMA (polymethylmethacrylate) microsphere granuloma due to intralesional triamcinolone injections. (Reproduced from Gelfer A, Carruthers A, Carruthers J, Jang F, Bernstein SC. The natural history of polymethylmethacrylate microspheres granulomas. Dermatol Surg 2007;33:614–20 with permission of Blackwell Publishing.)

1994, Artecoll was developed using a new purification process that reduced the irregular particle surface contours and disparate PMMA particle size originally evident in Arteplast. Moreover, the reformulation was intended to eliminate nanoparticle elements and electrical surface charges found on the beads by implementing a novel sieving process during manufacturing. A high rate of Arteplast granulomas (up to 2.5% of the 400 individuals injected with the original formulation) was likely due to these irregularities.4 Non-resorbable particles less than 20 μm can be phagocytosed and not degraded, leading histologically3 to a collection of inflammatory cells, collagen and “frustrated macrophages” (giant cells), which may give rise clinically to inflamed nodules at the site of product placement (Figure 9.1). Since 1994, Artecoll was marketed in Europe by Rofil Medical International (Breda, the Netherlands) and has subsequently been used in more than 200 000 patients.4 The reported complication rate of that product was <0.1%.4 In 2001, Artecoll was modified so that bovine collagen sourced from a restricted, closed cattle herd in the USA could be used to reduce risks of prion contamination. Initial investigations of Artecoll revealed that PMMA particle size with a diameter less than 20 μm was <1% of the formulation.4 However, subsequent testing by Artes Medical revealed that particle size with a diameter less than 20 μm in the Artecoll distributed in Canada was actually >30%.6 These particles are the most likely reason for numerous reports of Artecoll granulomas reported in Canada,6 where the product has been approved since 1998. Therefore, in 2003, despite previous failed attempts aimed at eliminating nanosized particles, a second-generation Artecoll was produced to ensure that particles smaller than 20 μm were <1% of the PMMA in the formulation. The proportion of particles smaller than 20 μm is considered undetectable in the Artefill available in the USA.7 In addition to a history of reformulations and product refinements, all of which had not inspired confidence in this filler technology, over a

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period of about 6 years multiple versions of PMMA (with similar sounding names) have been manufactured.8 PMMA bead suspensions have been available for use at various locations across the globe for about a decade. Numerous manufacturers, producing slightly different products, have sold to licensed practitioners most commonly in Brazil, the European Union (EU), Canada and the USA. A study sponsored by Artes Medical using scanning electron microscopy (SEM) demonstrated the varied particle shapes, surface finishes, particle size anomalies and gross size distributions of related PMMA products available worldwide at different time points.8 Table 9.1 summarizes their findings. Table 9.1 Summary of scanning electron microscopy (SEM) findings

Product

Country of Origin

ArteFill (Year 2007)

USA

Artecoll (Year 2005)

Canada

Artecoll (circa 2001)

Europe

Metacrill (circa 2006)

Brazil

NewPlastic (circa 2006)

Brazil

SEM Analysis (Particle shape, surface finish, size, gross size distribution, and anomalies) • Size: 30 to 50 microns, with negligible small sizes. • Shape: Smooth surfaced microspheres with scant if any sediment. • Size: 30 to 50 microns, with negligible small sizes. • Shape: Smooth surfaced microspheres with slight surface irregularity, scant if any sediment. • Size: 32 to 40 microns, but with larger variation in particle sizes. • Shape: presence of nanoparticles on the surface of mincrospheres. • There are sub-20 micron particles and some sub 5 micron particles noted with some sediment. • Size: 0.2 to 60 microns. Many sub-20 micron particles exist, and many are sub-5 micron. • Shape: Many irregular shapes, some non spherical, jagged edges, poor surface. • Size: 0.2 to 70 microns. Some large spheres over 70 microns and some very small particles. • Shape: Some are non spherical, and conjoined, may small spheres and particles exist.

Reproduced from Piacquadio D, Smith S, Anderson R. A comparison of commercially available polymethylmethacrylate-based soft tissue fillers. Dermatol Surg 2008;34:S48–52 with permission of Blackwell Publishing.

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Figure 9.2 Upper two images: SEM (scanning electron microscopy) findings of PMMA (polymethylmethacrylate) from Brazil, circa 2006 (Metacrill). Lower two images: SEM findings of PMMA from Brazil, circa 2006 (NewPlastic). (Reproduced from Piacquadio D, Smith S, Anderson R. A comparison of commercially available polymethylmethacrylate-based soft tissue fillers. Dermatol Surg 2008;34:S48–52 with permission of Blackwell Publishing.)

It is apparent that the diversity and inconsistency of the PMMA beads synthesized over the past decade could induce marked differences in safety profiles and performance of these products. Although the nonuniformity in the non-US products has been documented to adversely impact biocompatibility and migration,3 the direct impact of the PMMA characteristics in one specific version of the product has not been compared with those of another version in well-controlled clinical trials. The PMMA available in Brazil as Metacrill and NewPlastic has a significantly varied particle size and surface characteristics relative to the 2007 Artefill now available in the USA.8 A survey of SEM findings reveal the progressively uniform particle size and surface regularity as one contrasts PMMA products from Brazil (Figure 9.2), Artecoll and Artefill from Canada (Figure 9.3), and, lastly, Artefill available in

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Figure 9.3 Upper two images: SEM findings of PMMA (polymethylmethacrylate)

from Canada, year 2005 (Artecoll). Lower two images: SEM findings of PMMA from Canada, year 2007 (Artefill). (Reproduced from Piacquadio D, Smith S, Anderson R. A comparison of commercially available polymethylmethacrylate-based soft tissue fillers. Dermatol Surg 2008;34:S48–52 with permission of Blackwell Publishing.)

the USA (Figure 9.4). The pivotal trial submitted to review by the FDA used Artecoll, with differences from Artefill that are highlighted in Table 9.2. It is likely that a history of reformulations, name changes and varied manufacturers have led to great confusion and skepticism about the safety of Artefill among clinicians already wary of permanent fillers. Unfortunately, the disrepute of non-US PMMA deriving primarily from reports of granulomas6,9–13 has led to a similar sentiment towards PMMA manufactured in the USA. However, potentially positive outcomes from a large (1000 patient), long-term, prospective study investigating the safety and efficacy of Artefill, initiated in August 2008, may reinvigorate interest in the product and provide momentum for

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Figure 9.4 SEM (scanning electron microscopy) images of PMMA (polymethylmethacrylate) from the USA, year 2007 (Artefill). (Reproduced from Piacquadio D, Smith S, Anderson R. A comparison of commercially available polymethylmethacrylate-based soft tissue fillers. Dermatol Surg 2008;34:S48–52 with permission of Blackwell Publishing.)

Table 9.2 Third-generation PMMA enhancements compared with second-generation

ones 3rd Generation Distributor/Manufacturer

Composition PMMA Characteristics

Regulatory Status

2nd Generation

Artes Medical Rofil Medical (Netherlands) Dedicated U.S. GMP European Medical Contract manufacturing facility Manufacturing 20% PMMA suspended in 80% bovine collagen gel, 0.3% lidocaine Round & smooth surface Round & smooth surface Uniform size Non-uniform size

Removal of PMMA microsphers <20 microns FDA approved (October 2003)

Not FDA approved, not in U.S. clinical trials

Reproduced from Cohen SR, Berner CF, Busso M, et al. Five-year safety and efficacy of a novel polymethylmethacrylate aesthetic soft tissue filler for the correction of nasolabial folds. Dermatol Surg 2007;33:S222–30 with permission of Blackwell Publishing.

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manufacture and use in the USA in the future. Artes Medical, Inc. (San Diego, CA) filed for Chapter 7 Bankruptcy on December 1, 2008, yet Artefill was recently acquired by Suneva Medical, Inc. (San Diego, CA). We anticipate that the company will rejuvenate Artefill and in doing so seek additional data to alleviate safety concerns and support the efficacy of its product.

Mechanism Artefill consists of a 20% (by vol) semisolid blend of smooth-surfaced PMMA microspheres ranging in size from 30 μm to 50 μm suspended in an 80% (by vol) gel matrix of partially denatured bovine collagen gel, with 0.3% lidocaine hydrochloride. In accordance with FDA requirements, <1% of the PMMA particles are <20 μm, with the rest consisting of 32- to 40-μm beads.7 The proposed mechanism of action of the device is based on the PMMA microsphere’s ability to stimulate the host’s immune response to induce fibroblast neocollagenesis on and in between the microspheres. Over a period of 1–3 months, new collagen serves to replace the short-lived bovine collagen composing most of the injected material. This sequence of events leads, in turn, to a composite of the patient’s own collagen interspersed with the nonresorbable PMMA microspheres, thereby preventing bead migration.3 Therefore, tissue augmentation is expected to be permanent, consisting of 80% (by vol) host connective tissue. Correction of volume deficits occurs gradually, over the two or three injection sessions spanning several months, rather than after one injection session typical of most resorbable fillers. This stepwise treatment avoids permanent overcorrection. In all cases of injection, the material is injected into the deep, reticular dermis in order to avoid the nodularity and irregularity commonly seen with superficial placement.

Safety and efficacy Efficacy The pivotal trial submitted to the FDA using the second-generation predecessor to Artefill, named Artecoll, was completed in September 2001.4 It was a randomized, double-blind, controlled study at eight US treatment centers which included 251 individuals using PMMA (n = 128) compared with a collagen control (Zyderm II/Zyplast, Inamed Aesthetics, Santa Barbara, CA, n = 123). Product efficacy was determined using a validated six-point, facial fold assessment (FFA), photonumeric grading

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scale at four anatomical sites. Either a control substance or Artecoll was injected in the glabellar folds, nasolabial folds, vertical lip lines, and marionette lines (corner of the mouth). The FFA, a photometric index rating wrinkle severity ranging from 0 (none) to 5 (severe), was determined in a randomized manner and raters were not informed of the evaluation period (pre- or post-treatment). The mean score of the FFA of all the facial sites, graded by three blinded, independent graders using standardized photographs, was designated as the primary endpoint. At all times, for those patients treated bilaterally, such as in the nasolabial folds, scores were averaged yielding one score per patient used for analysis. At the end of the study, the number of patients receiving treatment to each of the facial areas was not significantly different between the Artecoll and the control group. Most patients (108 vs 104 of the Artecoll and collagen groups, respectively) received treatment to the nasolabial folds. At 1 month, there were no significant differences for any site except for the control group, where the glabellar wrinkles appeared more improved compared with Artecoll. However, at 3 months, nasolabial fold and marionette lines were significantly better than for the controls, but the overall FFA was not significant between the two treatments. At 6 months, Artecoll was significantly better than the control substance at the nasolabial folds and overall. Individuals receiving the PMMA filler displayed significant nasolabial fold correction at 3, 6, and 12 months relative to the collagen control at similar time points (p < 0.001). This was observed despite smaller quantities of the filler utilized than in the collagen controls patients (0.82 mL/ fold vs 1.46 mL/fold, p < 0.001, respectively). In fact, the efficacy of the collagen filler disappeared by 6 months. Further, the PMMA filler demonstrated nasolabial fold correction for both the primary and secondary measures at 12 months (p < 0.001). Given the underlying long-term safety concern for this novel filler, of interest is a 5-year safety study conducted by the sponsor, Artes Medical, to better define product safety.7 Using the cohort of patients treated in the original pivotal trial, the primary objective of this study was to determine efficacy for nasolabial folds based on the blinded FFA evaluations, as well as safety using unanticipated event evaluations. Study candidates were those patients initially treated with PMMA (n = 128) plus those in the collagen control group who elected at 6 months to crossover into the PMMA filler therapy (n = 106) for a total of 234 potential participants. The eight original investigators contacted these individuals 5 years from their last treatment by telephone or certified letter who were asked to participate in a single follow-up visit, where numerous assessments were

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performed. Although the photos at 6 months were previously evaluated at the time of the clinical trial, they were graded once again by three independent physicians (dermatologists or plastic surgeons) to minimize drift bias. Photographs used for the FFA at the 6-month time point were evaluated and compared with photos of the nasolabial folds at the new 5-year follow-up (performed under similar conditions) and provided in random order to the assessing physicians in the same session. These evaluations were performed blinded to the time point and treatment of the participants and averaged. Change from pre-treatment to 6 months was computed using the original (pivotal trial) set of 6-month photograph ratings. Change from 6 months to 5 years was computed using the new set of 6-month photograph ratings and the cumulative improvement was computed by summing these two changes. Investigators were asked at the visit to determine on a 5-point scale the success of the PMMA filler treatment, using an ordinal scale ranging from “not at all successful” to “completely successful.” In addition, patients were requested to rate themselves as “very dissatisfied” to “very satisfied.” From the original study, 62% or 145 individuals responded to the inquiries for their participation, of whom 142 were eligible for evaluation (15 men, 127 women, mean age 52.4 years). Most individuals were from their original PMMA treatment group (82) and 60 from the crossover group. The mean follow-up period was 5.4 years from their last treatment (range 4.5–6.3 [excluded from analysis] years). Although multiple anatomical sites were treated during the original pivotal trial, this longterm study focused only on the nasolabial folds, for which 124 of the 142 participants had treated. Most treatments were bilateral. This long-term efficacy study determined convincingly that PMMA filler is indeed permanent (Figures 9.5 and 9.6). The mean clinical

Figure 9.5 Male patient, before and after photos – baseline to year 5. This man had no additional cosmetic procedure during the 5-year follow-up period. (Reproduced from Cohen SR, Berner CF, Busso M, et al. Five-year safety and efficacy of a novel polymethylmethacrylate aesthetic soft tissue filler for the correction of nasolabial folds. Dermatol Surg 2007;33:S222–30 with permission of Blackwell Publishing.)

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Figure 9.6 Female patient, before and after photos – baseline to year 5. This woman had no additional cosmetic procedure during the 5-year follow-up period. (Reproduced from Cohen SR, Berner CF, Busso M, et al. Five-year safety and efficacy of a novel polymethylmethacrylate aesthetic soft tissue filler for the correction of nasolabial folds. Dermatol Surg 2007;33:S222–30 with permission of Blackwell Publishing.)

Somewhat Successful Moderately N=3 Successful N=8

Very Successful N=50

Not at All Successful N=1

Dissatisfied N=3 Somewhat Satisfied N=9

Completely Successful N=61

Very Dissatisfied N=0

Satisfied N=31

Very Satisfied N=80 Investigators’ Ratings N=123

Subjects’ Ratings N=123

Figure 9.7 Investigators’ success ratings at Year 5 (left) and Subjects’ satisfaction

ratings at year 5 (right). (Reproduced from Cohen SR, Berner CF, Busso M, et al. Five-year safety and efficacy of a novel polymethylmethacrylate aesthetic soft tissue filler for the correction of nasolabial folds. Dermatol Surg 2007;33:S222–30 with permission of Blackwell Publishing.)

improvement, as graded by live assessment by the live (unblinded) investigator, was 1.67 (on the 5-point FFA scale) and 1.01 by the blinded evaluations of the photographs. The PMMA maintained significant improvement in all evaluated patients (n = 119) at 5 years compared with baseline (note that five patients were excluded due to missing photographs). Ninety percent of the investigators reported “completely successful” or “very successful” and, similarly, 90% of patients were “very satisfied” or “satisfied” with the treatment (Figure 9.7).

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1

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rs Ye a

s th on m 5

on m 3

1

m

on

th

th

s

0

5

0.2

PMMA Control

r

0.4

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Masked Observer Rated FFA Scale Improvement

1.2

Figure 9.8 (a) PMMA (polymethylmethacrylate) filler shows marked improvements over collagen control at 6 months (p < 0.001). (b) Continuous improvement of PMMA filler ratings between 6 months (0.71) and 5 years (1.01, p < 0.001). (Reproduced from Cohen SR, Berner CF, Busso M, et al. Five-year safety and efficacy of a novel polymethylmethacrylate aesthetic soft tissue filler for the correction of nasolabial folds. Dermatol Surg 2007;33:S222–30 with permission of Blackwell Publishing.)

There is evidence that, over time, the filler improves in performance (Figure 9.8). Blinded observer improvement in the FFA was 0.2 point higher at the 5-year photograph assessments than at the 6-month FFA assessments of the nasolabial folds (p < 0.002).

Safety It is generally agreed that permanent fillers expose patients to certain potential long-term risks that are not encountered with the use of resorbable fillers. Artes Medical has investigated the product characteristics of nonstandardized, less stringently regulated products containing PMMA, and it has acknowledged that these disparities from the current USproduced Artefill are likely responsible for the generally unfavorable opinion that clinicians have for its product.8 As is true for pharmaceutical drugs, devices such as fillers are subject to varied regulatory standards and requirements across the globe. The most stringent preclinical, clinical, and manufacturing standards are upheld in the USA. In the EU, on the other hand, referenced data and relatively small human safety and efficacy trials are required for device approval and, in countries outside the EU and the USA, the pathway to drug and/or device approval is generally less stringent.

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Figure 9.9 PMMA (polymethylmethacrylate) microsphere granulomas in the upper lip. (Reproduced from Gelfer A, Carruthers A, Carruthers J, Jang F, Bernstein SC. The natural history of polymethylmethacrylate microspheres granulomas. Dermatol Surg 2007;33:614–20 with permission of Blackwell Publishing.)

Granulomas can occur after any injectable filler,12 and their incidence been estimated to be 1:100–1:5000 injected patients.9 The time period between injection and granulomas reported with Artecoll has ranged anywhere between 6 months and 10 years.9 They are characterized by rapid-onset, swollen, erythematous, typically tender nodules at one or more of the injected sites. These should be distinguished clinically from true lumps and nodularity, which may occur at sites injected “overenthusiastically”6 (too much volume) or too superficially. The development of a biofilm should also be considered with any injectable, and an antibiotic should be tried as the first line of treatment. The lips are particularly prone to nodules and perhaps granulomas6,13 (Figure 9.9). This may be due to the intense power of the lip muscle which forces the material into lumps. Impurities and irregularities in the filler are thought to be responsible for noninfectious PMMA granulomas. The pivotal trial submitted to the FDA cited above revealed a comparable, statistically insignificant, adverse event profile between the collagen control and Artecoll.4 There were a total of 27 adverse events (of 128 individuals) in the Artecoll groups versus 38 events (of 123 individuals) in the control group. In general, there was more redness, lumpiness, and swelling in the control group. Serum immunoglobin G levels, used to detect allergy to the bovine collagen in both products, was elevated in one person using Artecoll after 1 month only, and in one person in the collagen control after 1, 3, and 6 months. The 5-year safety study revealed no serious or unanticipated adverse events, yet 28 cases of adverse events (in 21 individuals) among the 145 participants were recorded.7 Of these, 20 treatment-related events were experienced by 15 participants. Most events (80%) were mild in nature and consisted of “lumpiness” in 10 of the 15 treatment-related adverse events. Most notable were two cases of “granuloma or enlargement of the implant” based on clinical, not histological, observation. One of these cases

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was someone who reported both moderate severe lumps in the melolabial fold and lip 6 months after the last injection. Excision was required for final resolution. In another patient, who had a nodule in each of the nasolabial folds 5 years after PMMA injection, intralesional steroid injection was only moderately effective at reducing these “severely” inflamed reactions. However, we do not know the concentration of triamcinolone used. The concentration of intralesional steroid needed to treat these lumps is usually high (40 mg/mL triamcinolone). The patient has to be warned of possible temporary atrophy which can then be treated with a temporary filler. In sum, the short- and long-term data available from well-controlled clinical trials do not suggest any prevailing safety concern. Nevertheless, it may be some time before clinicians are comfortable with the fact that Artefill represents a new class of durable, permanent fillers that satisfies an unmet need, rather than a source of needless, potentially permanent adverse events. The safety data reviewed reveal that Artefill shares a comparable safety profile with that of the other soft-tissue dermal fillers (i.e. specifically hyaluronic acids and calcium hydroxylapatite). Moreover, granulomatous and localized inflammatory nodules have been documented with these other nonpermanent fillers.9,12 The caveat to this discussion, however, is that experience with Artefill in the USA is relatively limited. With continued use, the refined, third-generation PMMA product (Artefill) may reveal an even lower risk profile than that observed in the long-term studies with Artecoll. Nevertheless, as with the other fillers, resorbable or not, and the broadened use to other anatomical sites and to a diverse injector population (presenting varied training and techniques), we may perhaps learn of additional adverse events anecdotally and in the peer-reviewed scientific literature.

Practical applications Although the FDA has approved Artefill for correction of nasolabial folds, unlike some of the other resorbable fillers, the pivotal trial submitted to the FDA has demonstrated that Artefill can also be used safely and effectively in other locations, yet these anatomical areas are still considered off-label. Clinicians are using Artefill to augment volume deficits in the malar and submalar areas as a result of HIV or senescence, as well as placing Artefill in acne scars and along the nasal dorsum as a minimally invasive means to shape the nasal profile. Truth be told, Artefill is being used in a manner similar to other dermal fillers; however, it is prudent to avoid injecting the product in the tear troughs and vermillion lip.

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Ideal patients are those who have used dermal fillers in the past. In our experience, patients who are very comfortable conceptually with facial augmentation, and those who have experienced localized reactions common to all injectables, are the most suitable for permanent fillers. Otherwise, the concern about any local response may be compounded with an additional fear resulting from the filler’s permanence. Whether there are localized anticipated reactions such as transient redness and swelling common to all fillers, or a more serious problem as a result of treatment, the ‘experienced’ filler patient will generally be better equipped to manage the situation with the physician. Furthermore, the authors believe that Artefill is best used by experienced physician injectors only, such as those who have previously treated several hundreds of patients with nonpermanent fillers. Although the approach to injection with Artefill is similar to other dermal fillers, unlike the more “forgiving” collagen-based, or even hyaluronic acid-based, fillers for that matter, it is particularly technique sensitive. Before treatment with the currently available product, patients should be tested for allergy to bovine collagen, although, in the future, additional product refinements may eliminate the need for allergy testing in the product. Localized redness and swelling after placement of the product on the volar aspect of the forearm, or other easily visualized site, 2 weeks before facial injection will determine pre-existing allergy. If the patient is not allergic, the following steps are used: 1. The facial site is first gently cleansed with isopropyl alcohol or hydrogen peroxide. 2. A topical anesthetic, such as EMLA (2.5% lidocaine and 2.5% prilocaine, AstraZeneca, Wilmington, Delaware) or other topical anesthetic formulation can be applied to the skin for 20–30 minutes. This will be wiped off immediately before injection only into the facial side to be treated. The other side can be left covered until immediately before injection. Some clinicians prefer the use of an icepack directly on the skin for several seconds before injection. Should the white roll (where the vermillion [red] lip meets the cutaneous upper lip) be treated, local mental and infraorbital nerve block may be used. The red part (vermillion) or body of the lips, as well as the tear troughs, should not be injected. 3. The desired depth is deep dermis (reticular dermis)/upper subcutaneous fat layer (Figure 9.10) using a tunneling method, where the product is continuously injected while the needle is moved back and forth beneath the wrinkle at a fixed level (Figure 9.11). Injection technique preferences vary between clinicians, but in general the tunneling method, rather than serial injection or the depot technique,

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Figure 9.10 The recommended

method of Artefill injection. The product is placed in the deep dermis/ subcutaneous fat interface and tunneled proximally. (Reproduced with permission from Artes Medical.)

Figure 9.11 Before and after Artefill placement. Tunneling rather than serial

injection or depot injection is recommended for facial lines. (Reproduced with permission from Artes Medical.)

is recommended. Crosshatching and fanning, common techniques used with the other fillers, are employed. 4. As the viscosity of Artefill is several times higher than collagen and other hyaluronic acid fillers used for dermal fold augmentation, a 27G or even a 26G half-inch needle is used. Some clinicians test the patency of the needle by injecting a small quantity of product from the tip before implantation. 5. As with other fillers, blanching of the skin means that injection was too superficial and therefore the needle should be withdrawn and the blanched area immediately massaged. Deep placement at the subcutaneous/deep dermal junction appears to avert lumps and other surface irregularities seen using more superficial placement. 6. At the end of the injection, the skin should be gently massaged. Patients are advised not to massage the area at home, but they can be instructed

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to apply a cold pack on the injected sites for 10 minutes every hour for several hours at home. 7. Mild-to-moderate swelling will be apparent for 12–24 hours and mild erythema or pink color will be present for up to 5 days after injection. Bruising is variable (and may occur more often and with greater severity in patients who use over-the-counter herbal products, NSAIDs, fish oil, vitamin E, and aspirin or other blood thinners), but patients should be forewarned. The bruising is certainly less than with hyaluronic acid and more similar to that seen with collagen products. 8. Patients are best seen at 4 weeks after the initial treatment (some clinicians recommend a 2-week follow-up) to allow for additional adjustments and filling. Additional follow-up and treatment may occur over a span of several months to allow for gradual filling and correction as the patient’s collagen scaffolds the PMMA bead.

Approach to granulomas Numerous techniques have been described to treat PMMA-induced, noninfectious granulomas,9–13 a testament to the fact that none of these methods has been deemed most effective, although high-dose intralesional steroids appear to be the most reasonable first-line therapy. Steroids such as triamcinolone acetonide (Kenalog), methylprednisolone acetonide (Depo-Medrol), and betamethasone diproprionate (Diprosone) have been used. Dermal and fat atrophy (see Figure 9.1) after intralesional steroid injection is a treatment risk that should be discussed, but atrophy risk can be mitigated by relatively deep injection (should the granuloma similarly appear deep) along with using low volumes of high-dose steroids. It is our experience that very high doses if triamcinolone acetonide, as noted above – up to 40 mg/mL – are most effective. Other injectable therapy consists of combinations of steroids, Diprosone and 5-fluorouracil (5FU), and lidocaine.10 Alternatively, intralesional bleomycin is a theoretical therapy,6 and intralesional allopurinol has been reported to be effective for Arteplast granulomas.11 Systemic use of NSAIDs such as ibuprofen, antibiotics such as minocycline or cephalexin, and corticosteroids have also been used, as have tacrolimus, imiquimod, and antihistamine creams.6 A recent report describes resolution of Metacrillinduced lip and hand nodules after melting them with a high-frequency 100-watt probe, but this has not been met with enthusiasm.13 Multiple hard nodules of Metacrill treated by one of the authors (RN) responded only to 40 mg/mL triamcinolone, suggesting that indeed perhaps small aliquots of high-dose intralesional steroids could be considered the most effective first-line therapy for PMMA-induced granulomas.

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Although PMMA granulomas are relatively uncommon, it is a major concern for both clinicians and patients. It has been conjectured that these reactions are self-limited and eventually self-resolving.6 It is not agreed whether excision causes more harm (scarring) than good (removal).6,13 Regardless, close follow-up is a prudent and ethical medical practice, as careful attention and involvement by the physician to the care of a dissatisfied aesthetic patient build trust and reassurance, and avert medicolegal consequences in most cases.

Summary There is an increasing desire for facial augmentation with injectable dermal soft-tissue fillers. With this interest is a vocal minority of patients who express desire for permanent tissue augmentation. Artefill currently fills this need and delivers an overwhelmingly satisfactory outcome for patients willing to use it, and physicians trained to inject it. Nevertheless, the relatively limited experience with Artefill in the USA and its permanence mandate meticulous technique and an experienced hand. Despite a relatively tarnished past, one complicated by reports of granulomas and variable manufacturing standards, the FDA-approved product has met rigorous safety standards and has thus far delivered on its promise of a safe and efficacious permanent filler. Over time, we feel that clinicians and patients will feel more comfortable with the concept of “permanence.” And further, we will come to appreciate that aging will not leave these or any other permanent “implants” apparent for the world to see. Although the future of Artefill’s availability in the USA is ambiguous, it may prove, in the long run, the benchmark standard in this novel class of fillers.

References 1. Judet J. Prostheses en resins acrylic. Mem Acad Chir 1997;73:561. 2. Polymers and Monomers. Material safety data sheet (MSDS) Poly(methylmethacrylate) MW6000 to MX 350000. Obtained online at www.polymersciences.com/shop/ product/asp?dept%5Fid=300107&pf%5Fid=04552 3. Lemperle G, Morhenn VB, Pestonjamasp V, Gallo RL. Migration studies and histology of injectable microspheres of different sizes in mice. Plast Reconstr Surg 2004;113:1380–90 4. Cohen SR, Holmes RE. Artecoll: a long-lasting injectable wrinkle filler material: Report of a controlled, randomized, multicenter clinical trial of 251 subjects. Plast Reconstr Surg 2004;114:964–76. 5. Lemperle G, Romano JJ, Busso M. Soft tissue augmentation with Artecoll: 10-year history, indications, techniques, and complications. Dermatol Surg 2003;29:573–87.

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6. Gelfer A, Carruthers A, Carruthers J, Jang F, Bernstein SC. The natural history of polymethylmethacrylate microspheres granulomas. Dermatol Surg 2007;33:614–20. 7. Cohen SR, Berner CF, Busso M, et al. Five-year safety and efficacy of a novel polymethylmethacrylate aesthetic soft tissue filler for the correction of nasolabial folds. Dermatol Surg 2007;33:S222–30. 8. Piacquadio D, Smith S, Anderson R. A comparison of commercially available polymethylmethacrylate-based soft tissue fillers. Dermatol Surg 2008;34:S48–52. 9. Lemperle G, Rullan PP, Gauthier-Hazan N. Avoiding and treating dermal filler complications. Plast Reconstr Surg 2006;118:92S–107S. 10. Conejo-Mir JS, Sanz Guirado S, Angel Muñoz M. Adverse granulomatous reaction to Artecoll treated by intralesional 5-fluorouracil and triamcinolone injections. Dermatol Surg 2006;32:1079–81 11. Reisberger EM, Landthaler M, Wiest L, Schröder J, Stolz W. Foreign body granulomas caused by polymethylmethacrylate microspheres: successful treatment with allopurinol. Arch Dermatol 2003;139:17–20. 12. Carruthers A, Carruthers JD. Polymethylmethacrylate microspheres/collagen as a tissue augmenting agent: personal experience over 5 years. Dermatol Surg 2005;31:1561–4. 13. Odo MEY, Odo LM, Nemoto NCF, Cucè LC. Treatment of nodules caused by polymethylmethacrylate. A pilot study. Dermatol Surg 2008;34:1746–9.

C H APTER 1 0

Complications from Soft-Tissue Augmentation of the Face: A Guide to Understanding, Avoiding, and Managing Periprocedural Issues Marc D. Glashofer Island Dermatology, Long Beach, New York, USA

Joel L. Cohen AboutSkin Dermatology and DermSurgery, and Department of Dermatology, University of Colorado, Englewood, Colorado, USA

The use of soft-tissue augmentation agents has increased in popularity as more individuals are seeking nonsurgical procedures for age-related rejuvenation. This has been driven by an aging population looking for aesthetic results that are minimally invasive and with little down time. It has been over 20 years since the approval of the first dermal filler, with the majority of the currently marketed filler agents approved in the last 5–18 years. According to a survey conducted in 2007 by the American Society for Dermatologic Surgery, over 1 million injections of dermal fillers were administered in 2007, representing a significant increase over previous years.1 These agents are increasingly being utilized in our practices due in large part to their effectiveness and versatility, and the availability of multiple new options. Their favorable safety profiles also contribute to the popularity of these products.2,3 Despite their impressive safety record, complications and adverse events can occur. The number of complications is likely to increase as new products become available, more people begin seeking this type of intervention, and more injectors begin providing these services. In particular, there has recently been an alarming trend of increasing numbers of untrained physicians and practitioners who do not have an MD using these products.4 In November 2008 an executive summary from the Food and Administration’s (FDA’s) Office of Device Evaluation expressed their concern over growing reports being filed to their office about “adverse

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events with dermal filler agents, with a number that are serious and unexpected.” Some of these adverse events included facial, lip, and eye palsy, disfigurement, retinal vascular occlusion, as well as rare, but life-threatening, events such as severe allergic reactions and anaphylactic shock.5 One of the reasons why the FDA is concerned about an increase in complications is as a result of consumer demand for fillers that are being used outside of approved indications. The exact incidence of complications is unclear to the FDA, as clinical trials are usually designed to continue for only 6 months, whereas some adverse events, which typically occur and resolve shortly after injection, were found to have a delayed onset and long-lasting serious effects. As a result, the FDA is considering that warnings on product labels for dermal fillers be strengthened, and require manufacturers to conduct longer and larger studies to be submitted as part of product approval application. Another concern that dermatologists need to be aware of is the use of counterfeit filler agents. It cannot be emphasized enough that acquiring these agents from sources outside their approved US distributors can lead to an adulterated product with the potential for serious complications. To ensure the best possible outcomes and greatest patient satisfaction, the aesthetic physician who injects dermal fillers must have proper training in their use, be aware of the types of complications, be able to anticipate adverse effects, and know how to treat them if they do occur. When a filler is being used in an off-label manner, it is of even greater significance that this be disclosed and associated risks discussed with the patient. The types of materials approved as soft-tissue augmentation agents vary from biologic to synthetic materials. Currently available filler products can be categorized by duration of effect: temporary (approximately 4–9 months), temporary-plus (duration up to 18 months), and permanent options (Box 10.1). All fillers are associated with the risk of both early and late complications (Box 10.2). The treating physician and patient need to be aware of these before their implementation.

Injection site reactions The most common adverse events associated with fillers are local injection site reactions. These are usually manifested by pain, erythema, and edema. In one study comparing hyaluronic acid (Restylane) with collagen (Zyplast) for the treatment of nasolabial folds on contralateral sides, injection site reactions occurred at 93.5% and 90.6% of the hyaluronic acid- and collagen-treated sites, respectively.6 These reactions were predominantly mild or moderate in intensity, lasted less than 7 days, and were generally similar between treatments.

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Box 10.1 Common dermal fillers Temporary Bovine collagen (Zyderm, Zyplast, Allergan, Inc., Santa Barbara, CA) Human collagen (CosmoDerm, CosmoPlast, Allergan, Inc., Santa Barbara, CA) Porcine collagen (Evolence) Hyaluronic acid (Restylane, Medicis Aesthetics, Inc., Scottsdale, AZ; Juvéderm, Allergan, Inc., Santa Barbara, CA; Prevelle Silk, Genzyme, Inc., Ridgefield, NJ) Calcium hydroxylapatite (Radiesse, BioForm Medical, Inc., San Mateo, CA) Autologous fat Temporary-Plus Poly-L-lactic acid (Sculptra, Dermik Laboratories, Berwyn, PA) Permanent Collagen + polymethylmethacrylate (Artecoll/ArteFill, Suneva Medical, Inc., San Diego, CA) Silicone (Adatosil 5000, Bausch & Lomb, Rochester, NY; Silikon 1000, Alcon Laboratories, Fort Worth, TX)

Box 10.2 Onset of adverse events Early (occurring up to several days post treatment) • Injection site reactions: erythema, edema, ecchymosis, pruritus, tenderness • Skin discoloration: erythema, blue appearing papules, blanching of skin • Infection: erythema, edema, pain, fluctuant masses, possible systemic symptoms • Hypersensitivity: erythema, angioedema, nonfluctuant nodules • Nodularities: caused by inappropriate placement of product • Tissue necrosis and venous congestion: secondary to vascular compromise Delayed (occurring from weeks to years post-treatment) • Infection: erythema, edema, pain, systemic symptoms • Granuloma formation: persistent palpable or visible nodules • Migration of product or product clumping • Aseptic abscess or biofilm reaction • Persistent discoloration and hyperpigmentation • Persistent scarring Adapted from Lowe, NJ, et al. Adverse reactions to dermal fillers: Review. Dermatol Surg 2005;31:1616–25.

Pain is often one of the commonly reported adverse events associated with filler agents. Certain anatomical sites such as the lips, perioral region, and infraorbital skin are more sensitive as a result of increased sensory innervation of these sites. There are a variety of techniques that can be

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used to minimize pain associated with injections. These include the use of topical anesthetics, application of ice before and after the injection, local nerve blocks, and vibratory distraction.7 In addition, it is known that larger needles cause more tissue injury and thus cause a greater degree of injection discomfort. Utilizing the smallest diameter needle recommended in the product insert (usually a 30G for many products) to properly place the product is advocated. When writing this chapter, Prevelle Silk had recently been introduced to the US market with the goal of minimizing the pain associated with injection because it has been formulated with a local anesthetic. Several other products that contain anesthetic are likely coming to the USA, including Juvéderm plus lidocaine. As these injection site reactions are fairly common and somewhat predictable, patients should be informed of them in consultation so that they can plan their treatments in advance. Most fillers often result in some degree of injection site reactions, which may last for 4–7 days. There are some measures that can be taken before and after treatment to reduce the amount of ecchymosis that patients may experience. In general, bruising can be minimized by choosing the injectable filler least likely to cause this problem, e.g. it is believed that collagen-containing fillers are less likely to cause ecchymosis compared with hyaluronic fillers, although they have been found to have a shorter duration of effect. This is secondary to the platelet-aggregating effects of collagen.8 Within the hyaluronic acid category of products, some experts believe that some products result in less swelling than others related to several factors, including extrusion forces, particulate matter, and equilibrium hydration. Swelling and bruising can also often be minimized by avoidance of agents that inhibit coagulation, such as aspirin and nonsteroidal antiinflammatory drugs. Vitamin supplements such as garlic and ginkgo biloba are also known for their inhibitory effects on platelets.9 Other supplements such as vitamin E, St John’s wort, ginger, ginseng, green tea, kava-kava, celery root, and fish oil can inhibit coagulation pathways and further increase bleeding and bruising.10 It is best to withhold these exogenous substances 7–10 days before the procedure. With respect to aspirin specifically, although preventive daily dosing can usually be avoided during this timeframe, the use of “therapeutic” aspirin for patients who have had a history of a heart attack, stroke, or blood clot should not be discontinued. Some practitioners advocate the role of homeopathic medications such as bromelain and arnica in reducing post-treatment ecchymosis. Bromelain is a substance naturally present in mature pineapple stems (Ananas comosus). It has been shown to decrease vascular permeability in animal models by lowering the levels of bradykinin, thereby potentially resulting in less edema, pain, and inflammation.11 Some clinical studies with bromelain were performed over 30 years ago, and have

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shown conflicting results. One study of 53 patients undergoing rhinoplasty revealed decreased swelling and ecchymosis associated with bromelain use.12 However, a further study of 154 plastic surgery patients demonstrated no statistically significant difference in edema between the bromelain and the placebo groups.13 Arnica, Arnica montana, is an extract derived from several mountain plants. The exact mechanism of action of arnica in the treatment of bruises remains unknown; however, it is thought that a compound derived from the extract contains helenalin, a molecule that has been shown to posses antiinflammatory effects.14 In addition, it has been proposed that arnica inhibits platelet function in vitro.15 There have been conflicting results derived from clinical trials of both topical and oral arnica formulations for the treatment of ecchymosis, with some revealing a decrease in posttreatment bruising, whereas others show no statistical difference. Further investigations are needed to substantiate this effect.

Nodules and papules Most subcutaneous nodules and papules, as manifested by palpable and/ or visible bumps under the skin, are frequently a result of inappropriate placement of product. Injecting too superficially can lead to lumps of visible product, or bluish bumps under the skin, specifically with hyaluronic acid fillers (Tyndall’s effect) (Figure 10.1). Such reactions can, for the most part, be prevented by use of the correct technique. Papules and nodules related to superficial placement can sometimes be treated simply by digital pressure, aspiration, or incision and drainage.16,17 Their occurrence can, however, result in anxiety and dissatisfaction for patients. Injection of a filler product too superficially may result in a persistent nodule. Correction of visible papules and nodules can often be accomplished by puncturing the site with a 25G or 27G needle and expressing

Figure 10.1 Inappropriate placement of

fillers can lead to product visibility under the skin.

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the product. When lumps and nodules are secondary to the use of a hyaluronic acid filler, the enzyme hyaluronidase can be utilized to treat them.17 A preliminary skin test should be performed before its use because there have been reports of sensitivity to animal-derived hyaluronidase.18 The incidence of injection site nodules appears to be higher in patients receiving poly-L-lactic acid (PLLA, Sculptra), particularly in the human immunodeficiency virus (HIV)-infected population. In clinical studies, subcutaneous papules, defined as lesions ≤5 mm, typically palpable, asymptomatic, and nonvisible, were seen in 52% and 31% of patients in two separate European HIV-related lipoatrophy studies, each with a 2-year follow-up period. Nodule onset occurred at an average of 7 months posttreatment (range 0.3–25 months) and resolved spontaneously over the course of the study in 23% of the patients. Lower incidences of PLLA nodules were seen in two American HIV-related lipoatrophy studies and in an immunocompetent patient study with 1-year follow-up periods.21,22 In the American HIV-related lipoatrophy studies, nodules occurred in 6–13% of patients.19,20 In a more recent study, comparing PLLA with collagen for the correction of nasolabial fold rhytids in non-HIV-infected patients, nodules <5 mm in diameter occurred in 8.6% of patients receiving PLLA and 3.4% of those receiving collagen. Nodules >5 mm diameter occurred in 6.9% of individuals receiving PLLA and 6.0% receiving collagen.20 It is believed that modifications to the initial European injection protocol and improvements in technique helped minimize the occurrence of subcutaneous papules seen in these later studies. It is important to note that differences in regional thickness of skin can increase chances of injection site nodules, e.g. superficial placement in the infraorbital hollow may result from inexperienced injectors not realizing the change in thickness of the skin between the cheek and lower lid, thus increasing the possibility of noticeable papules23 (Figure 10.2).

Figure 10.2 Noticeable papules of the

infraorbital region.

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Box 10.3 Minimizing adverse events associated with poly-L-lactic acid injection • Product should be reconstituted with at least 5 mL of sterile water for injection, with 1 mL lidocaine added before injection • Allow reconstituted poly-L-lactic acid to stand for ≥24 hours (preferentially 72 hours) before use • Do not refrigerate or freeze; keep at room temperature before injection • Use a needle with a large enough bore (25–26G) so that it does not clog. Care should also be taken not to inject the precipitate at the end of the syringe • Inject into the upper subcutis in a crosshatch manner • Massage the injected area after treatment and instruct the patient do this twice daily for approximately 1 week Adapted from Narins, RS. Minimizing adverse events associated with poly-L-lactic acid injection. Dermatol Surg 2008;34,:S100–4.

It is now known that the efficacy and safety of PLLA can be influenced by correct product reconstitution, dilution, and administration. Recent reports by experts in the field provide insight to how administration of PLLA with optimal techniques can help enhance treatment effect while simultaneously minimizing undesired events24 (NJ Lowe and CA Maxwell, personal observations, 2002–2005) (Box 10.3). Collagen plus polymethylmethacrylate (Artecoll/ArteFill, Suneva Medical, San Diego, CA), is categorized as a permanent filler and as such is less forgiving of complications. Indeed, the most common issues seen with Artecoll involved superficial placement. There have been reports of long-lasting itching and persistent erythema. This may be permanent, but responds to topical or intralesional corticosteroids.26 In addition, the use of this product is contraindicated in certain areas such as the lips, as there may be nodularities and uneven distribution as a result of product migration secondary to the action of the orbicularis oris muscle.25 If calcium hydroxylapatite (Radiesse) is placed too superficially in the mid- or papillary dermis, visible white nodules may occur. These can usually be treated by puncturing the nodules with a number 11 blade or needle, and then expressing the contents.26 A higher incidence of nodule formation may occur when treating the nasojugal sulcus. As a result of the thin skin in the tear trough, injection of calcium hydroxylapatite too superficially in this area can result in visibility of the filler. Rejuvenation of this region should be attempted only by those with considerable

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experience. As with Artecoll, superficial migration of product may occur when this is used in the lips so it is thus not recommended. Fat transplantation is a relatively safe procedure with a low complication rate. The most common complication of fat transplantation is overcorrection, which may result in visible nodules, especially in the infraorbital region. Superficial nodules can also result from the injection of an extremely large bolus of fat too superficially. Overcorrection may be difficult to treat. Low-dose intralesional steroids, local massage, and excision have been attempted as treatments with variable success.27

Granulomas Granulomatous foreign body reactions, manifested as persistent nodules, are usually seen as a later complication of filler agents. These granulomas are secondary to an inflammatory response to a specific product. There is speculation that the composition and size of the filler agent can be associated with the risk of developing this type of reaction. As collagen is usually resorbed in approximately 3–4 months, the risk of delayed or persistent granulomas is quite low. Hyaluronic acid products have been rarely associated with granuloma formation, as evidenced by delayed erythema and either painful or nontender swollen lumps.16 Based on the collective experience of several well-known aesthetic physicians, an algorithm was designed to help manage these inflammatory nodules, which were informally characterized as delayed-onset “angry red bumps” (Figures 10.3). In a specific case, a patient received a hyaluronic acid product in the vermillion and subsequently developed discrete nodules initially associated with eczematous changes in the overlying skin 6 weeks after injection.28 Histological analysis revealed the presence of a sharply demarcated nodule in the subcutaneous fat which was consistent with a granulomatous foreign body reaction to the filler. These granulomas have been shown to sometimes respond to intralesional steroids and calcineurin inhibitors (Protopic, Astellas Pharma US, Inc., Deerfield, IL). In cases of hyaluronic acid-related granulomatous foreign body reactions that do not respond to initial treatment with topical antiinflammatory drugs, hyaluronidase can be employed to resolve the problem.17 There have been reports of foreign body reactions to PLLA as well. One paper reported three cases with significant visible deformity as a result of foreign body-induced giant-cell granulomatous reactions after skin augmentation. These reactions were attributed to the aberrant reactivity of the recipient to the material.29 Treatment with intralesional steroids and 5% imiquimod cream (Aldara), Graceway Pharmaceuticals Exton PA,

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Delayed Onset Angry Red Bumps

Yes Is the lesion fluctuant?

Needle aspiration or incision and drainage; gram /acid-fast stain; culture and sensitivity (aerobic, anaerobic, AFSB) Antibiotics; BIAXIN Rx*

No Antibiotics with coverage for acid-fast bacteria for 7 days BIAXIN Rx*

Re-evaluate for fluctuance. Results of stains and C&S. Improvement or worsening. Continue for antibiotics for total of 14 days

Day 14 Re-evaluate of fluctuance (Improvement or worsening)

Intralesional steroids? Yes/No Nonfluctuant: YES Consider a calcineurin inhibitor

Fluctuant: YES

Worse/ Fluctuant? NO

Consider biopsy for pathological confirmation

Continue Rx to resolution

May need chronic antibiotic suppression and intralesional steroids p.r.n. until NASHA is resorbed Discourage hyaluronidase injection

Figure 10.3 Algorithm for the management of angry red bumps. Asterisk

indicates Biaxin (clarithromycin, Abbott Laboratories, Abbott Park, IL). AFB, acidfast bacilli; C&S, culture and sensitivity; NASHA, nonanimal-stabilized hyaluronic acid. (Reprinted from Narins RS, Jewell M, Rubin M, Cohen J, Strobos J. Clinical conference: management of rare events following dermal fillers – focal necrosis and angry red bumps. Dermatol Surg 2006;32:426–34.)

Northridge, CA) resulted in no visible clinical improvement. Treatment in one of the cases involved excision of the largest nodules, with a “satisfactory” result (Figures 10.4). The physicians recommend that, if feasible, surgical excision is the best option for this type of reaction; however, this would result in at least some degree of clinical scarring. Although some US physicians report success with PLLA using the modifications mentioned previously, many physicians still have concerns when using this product, especially in patients with an intact immune system. The concern of a vigorous granulomatous response to this product has been evidenced in patients who have had immune reconstitution,

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Figure 10.4 Sterile abscess after

incision and drainage of angry red bump three weeks after hyaluronic acid filler injections.

where a previously immunodeficient patient became relatively immunocompetent while being treated for HIV. The hypothesis is that these patients may develop an overactive response to infectious or foreign substances. At present, the risk of immune response to PLLA among immunocompetent patients is still an unresolved concern of several key opinion leaders.30 Bovine collagen plus polymethylmethacrylate (PMMA; Artecoll, ArteFill) can also be associated with the formation of delayed granulomas, although the rate is low. Between 1995 and 2000, these complications occurred in just 0.01% (15/200 000) of Artecoll patients.25 Granulomas in those receiving bovine collagen plus PMMA have generally occurred 6–24 months post-treatment. These enlarging granulomas often appeared after the second or third implantation of the product. The specific cause of these reactions is unknown; however, half the patients experiencing them reported an associated severe infection (influenza) or some type of facial injury. Treatment usually consists of intralesional injections of corticosteroids. It is important to note that the ArteFill is not the same as the Artecoll. ArteFill is derived from a closed US bovine herd, and has a smaller particle size, so there is believed to be a significantly lower risk of immunogenicity. Granulomas seen after silicone gel injections can occur years after injection. It is not yet completely understood why delayed granuloma formations occur.31 Treatment of these is usually accomplished with intralesional steroids and/or excision when possible. Successful amelioration of these granulomas has been reported with the use of the immunomodulatory cream Aldara.32

Hypertrophic scarring Excessive scar formation is a rare complication that can be encountered when injecting filler agents. This is usually as a result of too superficial a

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placement of the filler in the upper dermis. African–American individuals have an inherently higher incidence of developing hypertrophic scars and keloids after trauma. There had been concern that this population was at increased risk of developing excessive scarring after augmentation with filler agents. This speculation was recently dispelled by a study revealing that the use of hyaluronic acid in people with darker skin was as safe and effective as in people with fair skin.33 It is noted, however, that it is of importance to minimize the number of needle punctures, in order to limit the risk of hyperpigmentation in patients with Fitzpatrick types IV–VI. When hypertrophic scars do occur they can often be successfully managed with intralesional triamcinolone injections, 10-40 mg/mL at 1-month intervals. The use of the pulse-dye laser has also been successful in treating post-injection hypertrophic scars. Ultimately, the most critical point in minimizing this potential event is to place the product in the proper plane, which is not too superficial.

Infection As the skin is pierced during injections, infection after soft-tissue augmentation can occur. The injecting physician needs to screen for, and if necessary treat, active, chronic, or recurrent regional infections before any injections. Potential infectious etiologies may be bacterial or viral in nature. It is possible that fillers may trigger recurrent herpetic (herpes simplex virus or HSV) lesions.16 Therefore, in patients with a history of herpes outbreaks, prophylactic antiviral treatment is often recommended if the filler is to be used for the purpose of lip augmentation. In patients with active herpes lesions, facial injections should not be performed until the lesions have completely resolved. To minimize the risk of infection, appropriate skin preparation with either isopropyl alcohol or chlorhexidine should be performed. Commonly recovered bacterial microorganisms associated with injections of dermal fillers include staphylococci and streptococci. When an infection is suspected, as manifested by single or multiple erythematous and/or fluctuant nodules, it is best to culture the exudate and initiate empirical treatment with an antibiotic such as clarithromycin for at least 2 weeks until the more specific culture results become available.16 There have also been reports of infections from mycobacteria after facial augmentation using autologous fat.34 When a new lesion appears at the site of injection more than 2 weeks post-procedure, it may be suggestive of an atypical infection, such as a mycobacterial organism.35 In this setting patients usually present with a firm, mildly tender nodule, and may have systemic

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symptoms such as fever and fatigue. When suspected, the lesion should be cultured or biopsied, and the specimens sent for bacterial, fungal, and acid-fast stains. Biofilm reactions are a new concern regarding culture negative infections (so-called sterile abscesses) at the sites of prior filler injections.36 Some of these reactions have been reported years after injection of the product. Biofilm reactions have been reported more frequently when a permanent nondegradable gel such as silicone or polyacrylamide gel is injected. It is hypothesized that a low-grade chronic infection can occur and thrive in a biofilm – a film comprising bacteria, their nutrients, and their waste products. As silicone does not interact with host tissue, the biofilm serves as a barrier to inflammatory cells and cytokines that would normally be able to quell this infection.30 The use of intralesional corticosteroids in this setting is contraindicated. If this infection is treated initially with steroids, intralesionally or systemically, NSAIDs, a weak antibiotic, or a broad-spectrum antibiotic in a low dosage, then these measures can actually aggravate and prolong the infectious process. This type of biofilm infection requires treatment with a broad-spectrum antibiotic in high dose for an extended treatment period.37–39 Contamination of filler agents is another concern, especially when there are individuals who may utilize non-FDA-approved products or illegally import products outside of approved US distributors. Specifically, in 2002, there was an outbreak of Mycobacterium abscessus infection in New York after soft-tissue augmentation with an unapproved hyaluronic acid product, Hyacell, which was performed by a nonphysician in a New York City hotel room.40 Empirical treatment with clarithromycin and prednisone resulted in clearance of these infections. With the increase in nonphysicians and untrained personnel performing aesthetic procedures, and with the possibility that non-FDA-approved agents or even counterfeit products are being used, it is possible that we may see an increase in these types of complications.

Hypersensitivity reactions All soft-tissue augmentation agents, with the exception of autologous fat, are composed of foreign body material. As a result, varying degrees of immune system reactivity can occur. Severe reactions are rare, but can have important medical and aesthetic implications. In addition to productspecific sensitivity reactions, the introduction of a foreign substance other than the filler, such as residual lipstick incompletely removed from the patient’s lips before injection, could potentially cause an immunologic reaction.

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Given its animal source, bovine collagen, in the form of Zyderm I, Zyderm II, and Zyplast, can be immunogenic, resulting in allergic reactions. The incidence of foreign body reactions reaches 1.3% in some series.6 Before bovine collagen injection, two skin tests are recommended to test for sensitivity. As a result of the availability of newer filler agents that are not engineered from an animal source, bovine collagen has fallen out of favor. A new porcine-derived collagen, Evolence (OrthoNuetorgena), was FDA approved in the summer of 2008 for use in the correction of rhytids of the nasolabial folds. Porcine-derived collagen is very genetically similar to human collagen.41 In addition, this specific product has been engineered with the goal of eliminating crossantigenic portions of the collagen molecule which could elicit an immune response.42 Therefore, no skin test is needed. The availability of human collagen as a filler agent several years ago (Cosmoderm and Cosmoplast) significantly reduced concerns about the risk of hypersensitivity reactions to the collagen class of fillers, after so many years of there simply being bovine collagen on the market. However, one must be aware that a sensitivity-type reaction with human collagen may still rarely be possible.43 Hypersensitivity has also been very rarely reported with hyaluronic acid products. Injectable hyaluronic acid has been derived either from avian sources or via fermentation using streptococci, but the latter nonanimalsourced bacterial fermentation processing has prevailed in acceptance. It has been postulated that residual proteins resulting from the manufacturing process can potentially lead to hypersensitivity reactions in certain patients. One rare, but dramatic, type of reaction was an angioedema-type hypersensitivity to a nonanimal-stabilized hyaluronic acid gel after injection into the upper lip.44 In this case, the patient received 1 mL of Restylane for lip augmentation. One hour after injection, the patient returned to the treating physician with an angioedema-type swelling of the upper lip (Figure 10.5), without systemic complaints. The patient was treated with

Figure 10.5 Angioedema-type swelling

and early vertical and horizontal fissures 1 hour post-procedure in a patient treated with 1 mL hyaluronic acid per side. (Photograph courtesy of Naomi Lawrence, MD.)

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8 mg dexamethasone intramuscularly and was observed for 2 hours. Stabilization of swelling occurred, and she was subsequently treated with an oral steroid taper with complete resolution of edema within 5 days. Protocols in the manufacturing of Restylane were instituted in 2000 to reduce the amount of trace protein present. Safety data of the product used before 1999 revealed a rate of adverse events 5.9 times greater compared with use of the product after this date.45 Similar modifications have been implemented with other filler agents in this class to further decrease rates of hypersensitivity reactions.

Necrosis Judicious injection of fillers requires an appreciation of normal facial anatomy, with consideration given to location and course of major arteries and nerves, and differences between regional properties and thickness. Injection necrosis is a rare but important complication associated with dermal fillers.46 Inadvertent injection of filler product directly into a vessel or placing too much volume around a vessel can lead to an immediate reticulated violaceous discoloration of the skin, which can be a sign of impending necrosis such as along the course of the angular artery (Figure 10.6) (nasolabial fold area) or supratrochlear artery (glabellar area) (Figure 10.7). Necrosis can be attributed to one of two factors: an interruption of vascular supply due to compression, or frank obstruction, of vessels by direct injection of the material into a vessel itself. This can manifest clinically as a violaceous bluish-grey discoloration, pain, erosion, and/or ulceration (Figure 10.8). The glabellar region is the injection site commonly believed to be at greater risk, as small-caliber vessels branch from the supratrochlear arteries to supply this watershed region with minimal collateral circulation.47

Figure 10.6 The anatomic location of

the angular artery giving rise to the lateral nasal artery at the level of the alar groove (intra-operative photo during Mohs surgery).

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Figure 10.7 Necrosis of the glabella.

Figure 10.8 Impending necrosis.

According to a recent treatment algorithm, a number of precautions can be taken to avoid necrosis.48 In the glabella, these precautions include: injecting superficially and medially (away from the eye); aspirating before injecting; and injecting slowly, avoiding overcorrection, and using only a small amount of product divided over multiple treatment sessions. Selection

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of appropriate agents that are small in particle size and intended for superficial use is vital. If impending necrosis is suspected, treatment options include immediately applying warm gauze and tapping the area to facilitate vasodilation and blood flow. The application of nitroglycerin paste to further promote vasodilation is also believed to be of potential benefit. For cases in which a hyaluronic acid filler is used, there have recently been two reports of impending necrosis where hyaluronidase was successfully used along the distribution of the underlying vessel and the adjacent patchy violaceous skin to remove some of the product and seemingly decompress the vessel.48,49 For more severe or unresponsive cases of necrosis, Schanz and colleagues described their success using deep subcutaneous injections of low-molecular-weight heparin into the affected area.50 Development of emboli are serious complications that have not been seen with hyaluronic acids, but have been seen in association with fat transplantation and earlier forms of collagen.51 A rare case of occlusion of the middle cerebral artery and ocular fat embolism with blindness has occurred after the use of autologous fat for augmentation of the senescent face.52,53 There has even been a report in the literature of an acute fatal stroke immediately after injection of autologous fat.54

Conclusion Injectable filling agents offer the promise of facial rejuvenation while offering reduced risks compared with more invasive procedures. The use of fillers for cosmetic dermatology indications is increasing rapidly, and will likely continue to do so in the foreseeable future. Although usually safe as a class, complications can and do occur. To ensure the best possible outcomes and greatest patient satisfaction, the physician who injects softtissue augmentation agents must have proper training in their use. A thorough understanding of facial anatomy, as well as proper product selection and injection techniques, is required to minimize avoidable adverse events. A detailed understanding of the potential pitfalls, and how best to avoid and manage them when they occur, is of paramount importance to all those who utilize these agents.

References 1. Physician Practice Survey. American Society for Dermatologic Surgery, Rolling Meadows, Illinois. 2007. 2. Andre P. Evaluation of the safety of a non-animal stabilized hyaluronic acid (NASHA—Q-Medical, Sweden) in European countries: a retrospective study from 1997 to 2001. J Eur Acad Dermatol Venereol 2004;18:422–5.

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3. Godin MS, Majmundar MV, Chrzanowski DS, Dodson KM. Use of Radiesse in combination with Restylane for facial augmentation. Arch Facial Plast Surg 2006;8:92–7. 4. Brody HJ, Geronemus R, Farris P. Beauty Versus Medicine: The Nonphysician Practice of Dermatologic Surgery. Dermatol Surg 2003;29:319–24. 5. Executive Summary Dermal Filler Devices General and Plastic Surgery Devices Panel, Food and Drug Administration. November 2008. (www.fda.gov/OHRMS/ DOCKETS/ac/08/briefing/2008-4391b1-01%20-%20FDA%20Executive%20 Summary%20Dermal%20Fillers.pdf) 6. Narins RS, Brandt F, Leyden J, et al. A randomized, double-blind, multicenter comparison of the efficacy and tolerability of Restylane versus Zyplast for the correction of nasolabial folds. Dermatol Surg 2003;29:588–95. 7. Niamtu J, Smith K, Carruthers J. Pain control in cosmetic facial surgery. In: Dover JS, Alam, M, eds. Procedures in Cosmetic Dermatology. Philadelphia: Saunders Elsevier, 2008: pp. 127–41 8. Bauman, L. Minimizing bruising. Skin Aging 2007;15(10):48–9. 9. Ang-Lee MK, Moss J, Yuan CS. Herbal medicines and perioperative care. JAMA 2000;286:208–16. 10. Dinehart SM, Henry L. Dietary supplements: altered coagulation and effects on bruising. Dermatol Surg 2005;31:819–26. 11. Kumakura S, Yamashita M, Tsurufuji S. Effect of bromelain on kaolin-induced inflammation in rats. Eur J Pharmacol 1988;150:295–301. 12. Seltzer AP. Minimizing post-operative edema and ecchymosis by the use of an oral enzyme preparation (bromelain). A controlled study of 53 rhinoplasty cases. Eye Ear Nose Throat Mon 1962;41:813–7 13. Gylling U, Rintala A, Taipale S, et al. The effect of a proteolytic enzyme combinate (bromelain) on the postoperative edema by oral application. A clinical and experimental study. Acta Chir Scand 1966;131:193–6. 14. Lyss G, Schmidt TJ, Merfort I, Pahl HL. Helenalin, an anti-inflammatory sesquiterpene lactone from Arnica, selectively inhibits transcription factor NF-κB. Biol Chem 1997;378:951–61. 15. Schroder H, Losche W, Strobach H, et al. Helenalin and 11alpha,13-dihydrohelenalin, two constituents from Arnica montana L., inhibit human platelet function via thiol-dependent pathways. Thromb Res 1990;57:839–45. 16. Narins RS, Jewell M, Rubin M, et al. Clinical conference: management of rare events following dermal fillers – focal necrosis and angry red bumps. Dermatol Surg 2006;32:426–34. 17. Brody HJ. Use of hyaluronidase in the treatment of granulomatous hyaluronic acid reactions or unwanted hyaluronic acid misplacement. Dermatol Surg 2005;31:893–7. 18. Hirsch RJ, Cohen JL. Surgical insights: challenge: correcting superficially placed hyaluronic acid. Skin Aging 2007;15:36–8. 19. Sculptra. Prescribing information. Bridgewater, NJ: Dermik Laboratories, 2006. 20. Werschler P. The Cosmetic Study Investigator Group. Efficacy of injectable poly-Llactic acid versus human collagen for the correction of nasolabial fold wrinkles. Presented at the American Society for Dermatologic Surgery. October 28, 2006; Palm Desert, CA, Abstract CS359. 21. Burgess CM, Quiroga RM. Assessment of the safety and efficacy of poly-L-lactic acid for the treatment of HIV-associated facial lipoatrophy. J Am Acad Dermatol 2005;52:233–9. 22. Engelhard P, Knies M. Safety and efficacy of New-Fill® (polylactic acid) in the treatment of HIV-associated lipoatrophy of the face (HALF). XIV International AIDS Conference; 2002 Jul 7–12; Barcelona, Spain.

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23. Stewart D, Gladstone H, Mooney M, et al. Visible papules after periorbital injection of poly-L-lactic acid. Ophthal Plast Reconstr Surg 2007;23:298–301. 24. Narins, RS. Minimizing adverse events associated with poly-L-lactic acid injection. Dermatol Surg 2008;34(suppl 1):S100–4. 25. Lemperle G, Romano JJ, Busso M. Soft tissue augmentation with Artecoll: 10-year history, indications, techniques, and complications. Dermatol Surg 2003;29:573–87. 26. Berlin A, Cohen JL, Goldberg DJ. Calcium hydroxylapatite for facial rejuvenation. Semin Cutan Med Surg 2006;25:132–7. 27. Donofrio L. Technique of periorbital lipoaugmentation. Dermatol Surg 2003;29:92–98. 28. Fernández-Aceñero MJ, Zamora E, Borbujo J. Granulomatous foreign body reaction against hyaluronic acid: report of a case after lip augmentation. Dermatol Surg 2003;29:1225–6. 29. Beljaards RC, de Roos K-P, Bruins FG. NewFill for skin augmentation: A new filler or failure? Dermatol Surg 2005;31:772–6. 30. Newburger AE. Cosmetic medical devices and their FDA regulation. Arch Dermatol 2006;142:225–8. 31. Christensen, L. Normal and pathologic tissue reactions to soft tissue gel fillers. Dermatol Surg 2007;33(suppl 2):S168–75. 32. Baumann LS, Halem ML. Lip silicone granulomatous foreign body reaction treated with aldara (imiquimod 5%). Dermatol Surg 2003;29:429–32. 33. Odunze M, Cohn A, Few JW. Restylane and people of color. Plast Reconstr Surg 2007;120:2011–16. 34. Obagi S. Autologous fat augmentation and periorbital laser resurfacing complicated by abscess formation. Am J Cosmet Surg 2003;20:155–7. 35. Klein AW. Injectable bovine collagen. In: Klein AW, ed. Tissue Augmentation in Clinical Practice: Procedures and techniques. New York: Marcel Dekker, 1998: pp. 269–91. 36. Narins RS, Monheit G. Editorial Comment. Dermatol Surg 2008;34:S1. 37. Christensen L, Breiting V, Vuust J, Hogdall E. Adverse reactions following injection with a permanent facial filler polyacrylamide hydrogel (Aquamid): causes and treatment. Eur J Plast Surg 2006;28:464–71. 38. Lowe NJ, Maxwell CA, Patnaik R. Adverse reactions to dermal fillers: review. Dermatol Surg 2005;31:1616–25. 39. Zarini E, Supino R, Pratesi G, et al. Biocompatibility and tissue interactions of a new filler material for medical use. Plast Reconstr Surg 2004;15:934–42. 40. Toy BR, Frank PJ. Outbreak of Mycobacterium abscessus infection after soft tissue augmentation. Dermatol Surg 2003;29:971–3. 41. Shoshani D, Markovitz E, Cohen Y, et al. Skin test hypersensitivity study of a crosslinked, porcine collagen implant for aesthetic surgery. Dermatol Surg 2007;33: S152–8. 42. Narins R, Monheit G. Evolence – a new collagen filler. Presentation at the World Congress of Dermatology, Buenos Aires, October 2, 2007 43. Stolman LP. To the editor: human collagen reactions. Dermatol Surg 2005;31: 1634. 44. Leonhardt JM, Lawrence N, Narins RS. Angioedema acute hypersensitivity reaction to injectable hyaluronic acid. Dermatol Surg 2005;31:577–9. 45. Friedman PM, Mafong EA, Kauvar AN, et al. Safety data of injectable nonanimal stabilized hyaluronic acid gel for soft tissue augmentation. Dermatol Surg 2002;28: 491–4.

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46. Glaich AS, Cohen JL, Goldberg LH. Injection necrosis of the glabella: protocol for prevention and treatment after use of dermal fillers. Dermatol Surg 2006;32: 276–81. 47. Hanke CW, Hingley R, Jolivette DM, et al. Abscess formation and local necrosis after treatment with Zyderm® or Zyplast® collagen implant. J Am Acad Dermatol 1991;25: 319–26. 48. Hirsch RJ, Cohen JL, Carruthers JD. Successful management of an unusual presentation of impending necrosis following a hyaluronic acid injection embolus and a proposed algorithm for management with hyaluronidase. Dermatol Surg 2007;33: 357–60. 49. Hirsch RJ, Lupo M, Cohen JL, Duffy D. Delayed presentation of impending necrosis following soft tissue augmentation with hyaluronic acid and successful management with hyaluronidase. J Drugs Dermatol 2007;6:325–8. 50. Schanz S, Schippert W, Ulmer A, et al. Arterial embolization caused by injection of hyaluronic acid (Restylane). Br J Dermatol 2002;146:928–9. 51. Hanke CW. Adverse reactions to bovine collagen. In: Klein A, ed. Augmentation in Clinical Practice: Procedures and techniques. New York: Marcel Dekker, 1998: p. 145. 52. Dreizen NG, Framm L. Sudden unilateral visual loss after autologous fat injection into the glabellar area. Am J Opthalmol 1989;107:85–87. 53. Feinendegen D, Baumgartner R, Schroth G, Mattle H, Tschopp H. Middle cerebral artery occlusion and ocular fat embolism after autologous fat injection in the face. J Neurol 2009;245:53–4. 54. Yoon SS, Chang DI, Chung KC. Acute fatal stroke immediately following autologous fat injection into the face. Neurology 2003;61:1151–2.

C H AP TER 1 1

The Mathematics of Facial Beauty: A Cheek Enhancement Guide for the Aesthetic Injector Arthur Swift Westmount Institute of Plastic Surgery, and Victoria Park Medical Spa, Montreal, Canada and McGill University, Montreal, Canada

All beauty is mathematics. (Ancient Greek saying)

The recent availability of safe volumizing fillers has provided cosmetic physicians the tools necessary to contour facial features nonsurgically. To this end, it is imperative to have a good understanding of the aesthetic goals necessary to achieve a beautiful and natural result. What should be the preferred facial volume and feature shape? What is the ideal beautiful normal for each individual face, and is there a code to unlock the patient’s potential? Is it unreasonable to have lofty aesthetic goals, or should we be less principled and more moderate? “A thing moderately good is not as good as it ought to be. Moderation in temper is always a virtue; but moderation in principle is always a vice” (Thomas Paine 1737–1809). This chapter focuses on trying to decipher objective parameters in creating a template to maximize each individual’s facial beauty. The technique offered is personal and, as is evidenced below, not a unique concept. It in no way represents the best or sole method to nonsurgically release the patient’s facial beauty potential. Rather the intent is to encourage aesthetic injectors to always be result oriented, to develop methodical and comprehensive approaches to facial enhancement, and to push creativity beyond rejuvenation into the realm of beauty maximization.

Facial beauty A thing of beauty is a joy forever: Its loveliness increases: it will never pass into nothingness. John Keats Injectable Fillers: Principles and Practice. Edited by Derek Jones. © 2010 Blackwell Publishing

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St Thomas Aquinas, known as the “angelic doctor,” was one of the great philosophers of the Catholic Church in the thirteenth century. He proclaimed beauty to be “integras, proportio, et claritas” – harmony, proportion, and clarity. True facial beauty arouses the senses to an emotional level of pleasure and “evokes in the perceiver a high degree of attraction” (Stephen Marquardt, personal communication). It would seem essential that the injection specialist have a deep understanding and a well-cultivated taste for beauty. Otherwise he would be satisfied with a low and common goal rather than the maximization of beauty potential in his patient. Although certain individuals may be endowed with an innate aesthetic sense, it can be learned at least in part by the ardent study of art and the constant observation of facial and body proportions and relationships.1 Regardless of nationality, age, or ethnic background, for the most part people universally share a sense of what is attractive.2 When British researchers asked women from England, China, and India to rate pictures of various Greek men, their choices were identical. When asked to select attractive faces from a diverse collection, whites, Asians and Latinos from a dozen countries also shared the same choices.3 Studies have shown that even babies demonstrate a sense of what is attractive: 3- and 6-monthold infants will gaze longer at a nice-looking face than at one that is not attractive.4 In a large research project on facial attractiveness at several German universities, digitally composed faces were created using a specialized software algorithm based on people’s perception of beauty (see www. beautycheck.de). Using a 7-point Likert scale (1 = very unattractive to 7 = very attractive), results proved that in fact most people, regardless of ethnicity, seem to have similar subjective ideas about what constitutes an attractive face (Figure 11.1). Finding objective answers, however, as to why we regard one face as being more beautiful than another is actually not as easy as it seems. Review of numerous articles on facial beauty has led this author to identify seven key facial features that appear to be subconsciously assessed when determining facial beauty (Figure 11.2). It is interesting to note that four features of these “Magnificent Seven” – facial shape, eyebrow shape, nose and lips – are amenable to injection contouring with fillers (e.g. hyaluronic acids) and neuromodulators (e.g. botulinum toxin A). Skin clarity, texture, and color can be markedly improved with topical agents, present-day energy device technology, and judicial use of make-up; forehead height can be accentuated or camouflaged by hair style; and inter-eye distance can be disguised by creative shadowing when applying eye make-up. All this emphasizes the importance of working closely with skilled aestheticians and experienced hairdressers when offering patients global facial beautification.

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1

4

2

3

5

6

Figure 11.1 Using a morphing software, German researchers created gradually

changing images. Images 5 and 6 consistently scored highest on the seven-point attractive scale when exposed to different large volume cohorts.

I. II. III. IV.

Facial shape (cheeks & chin) Forehead height Eyebrow shape Eye size and inter-eye distance V. Nose shape VI. Lips (length and height) VII. Skin clarity/texture/color

Figure 11.2 The “Magnificent Seven”

facial features that influence our perception of facial beauty.

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Figure 11.3 Artist’s rendition of an

attractive face scaled to five eyewidths’ across.

The story of phi I know not what beauty is, but I know that it touches many things. Dürer

The attractiveness of the female figure is often described in measured numbers (e.g. 36–24–36), so why not the face? The ancient Greeks maintained that all beauty is mathematics. The idea of a mathematical code, formula, relationship, or even a number that can describe facial beauty is not a modern concept. Medieval artists were impressed by the magical number 7. For them, the perfect face was neatly divisible into horizontal sevenths: the hair the top seventh, forehead two-sevenths, nose another two-sevenths, a seventh between nose and mouth, and the final seventh from mouth to chin. Novice artists are often taught that the simplest way to approximate the relative width of facial features is to divide the face into vertical fifths with each fifth being equal to one eye width (Figure 11.3). Only one mathematical relationship has been consistently and repeatedly reported to be present in beautiful things, both living (Figure 11.4) and synthetic (Figure 11.5) – the “Golden Ratio” (also known as the “Divine Proportion”). The Golden Ratio is a mathematical ratio of 1.618:1, and the number 1.618 is called phi (Φ), because it was regularly used by the Greek sculptor

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A

B

C

D

E

F

Figure 11.4 The divine proportion in living things: (a) nautilus shell; (b) sunflower; (c) tiger’s head; (d) phalanges of the hand; (e) human body; (f) butterfly.

B

A

D

C

E

Figure 11.5 The Golden Ratio in architecture, music and art. (a) Venus de Milo; (b)

Stradivarius violin; (c) Notre Dame Cathedral; (d) Parthenon; (e) Leonardo da Vinci’s Vitruvian Man.

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that divides line ab in a ratio of 1.618 (a) to 1 (b); 1 (a) to 0.618 (b); and 1 (a) to 1.618 (a + b).

a

b

⎧ ⎪ ⎪ ⎨ ⎪ ⎪ ⎩

Figure 11.6 The Golden Section is the only point in line ab

145

a+b a+b is to a as a is to b

Phidias.5 Phi with an upper case “P” is 1.6180339887…, whereas phi with a lower case “p” is 0.6180339887…, the reciprocal of phi and also phi − 1. This irrational number is the only one in mathematics that, when subtracted by units (1.0), yields its own reciprocal. Employed since the time of the Egyptians, the Golden Ratio was formulated as one of Euclid’s elements, one of the most beautiful and influential works of science in the history of humankind. This ratio was known to the Greeks as the “Golden Section” and to the Renaissance artists as the “Divine Proportion”. In geometry, it is a linear relationship in which the smaller length is to the larger part as the larger part is to the complete line (Figure 11.6). RM Ricketts noted that the golden calipers applied to the human hand reveals that each phalanx of each finger is golden to the next in all five fingers6 (see Figure 11.4d). Stephen Marquardt, a California-based oral and maxillofacial surgeon, has conducted extensive research on human facial attractiveness.7 His pioneering work on the mathematical construction of facial form led to his controversial (see www.beautyanalysis.com)8 “Golden Mask,” derived from the Golden Ratio (Figure 11.7). Marquardt maintains that the evidence shows that our perception of physical beauty is hardwired into our being and based on how closely one’s features reflect phi in their proportions. His modification of Hungerford’s classic quote that “beauty is in the phi [eye] of the beholder” is quite convincing. Since January 2007, the author has employed the application of the Golden Ratio in his facial injection technique in an attempt to maximize the results obtained (beauti”phi”cation). This was achieved initially by the use of a golden mean caliper – a tool based on an articulated pentagon for dynamically measuring the phi proportion (Figure 11.8). The calipers were first used by Renaissance artists to determine the “divine” proportions for their compositions in stone and on canvas. The calipers initially help the aesthetic injector see phi more as a relationship than as a number. Eventually, a geometric familiarity with the Golden Ratio develops which leads to its intuitive expression in the injection technique. In the absence of disease, the medial canthi remain a constant cutaneous landmark with age for each individual adult face. Measuring the

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Figure 11.7 Marquardt’s female and male golden masks (www.beautyanalysis.com).

intercanthal distance (x) to establish the unit length on which Phi (1.618x) and phi (0.618x) are created, aesthetic goals can now be defined in order to maximize each patient’s “phi” beauty potential. The following sections describe the author’s personal technique for beauti”phi”cation.

The math to the beautiful cheek … beauty’s ensign yet Is crimson in thy lips and in thy cheeks William Shakespeare, Romeo and Juliet

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Figure 11.8 Golden mean caliper: when the gauge is adjusted, the middle arm will

always show the golden section or phi ratio point between the two outer arms.

The single feature that matters time and again in studies on facial beauty is symmetry.9 Many papers have discussed attractiveness in terms of symmetry, balance, and harmony.10–13 Although often referred to as the “first feature of beauty,” symmetry is not absolute.14 Kent Remington, a pioneer in the field of aesthetic dermatology, has eloquently (and rightfully) stated that the left and right sides of the face should be considered more as sisters than as twins. Consensus guidelines point to “an evolving paradigm” in facial rejuvenation with a shift from the two-dimensional approach (focus on correcting dynamic facial lines) to the three-dimensional one including loss of facial volume.15 Youth and beauty are exemplified by a full and wide midface, referred to as the “triangle of youth” (Figure 11.9). Aging changes the three-dimensional topography of the underlying facial structures, resulting in deflation and ptosis of the midface skin and soft tissue16 (Table 11.1). Conventional face lifting without volume replacement is unable to restore facial fullness and fails to address the issue of deteriorating facial shape secondary to facial soft-tissue atrophy. Reasonable goals in both midface rejuvenation and cheek enhancement should involve adequate volume restoration and contouring in the aesthetically appropriate locations.17,18

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Table 11.1 Volume loss staging in the midface Stage 1

Stage 2

Stage 3

Stage 4

Normal

Evidence of early soft-tissue ptosis or atrophy Slightly visible

Visible depression or descent

Severe depression or atrophy

Figure 11.9 The “triangle of youth”. Youth is typified by a full and wide midface.

Aging results in deflation of midface structures and support, tissue deterioration and subsequent descent of the facial envelope, causing a reversal of the triangle.

Figure 11.10 A female model

demonstrating an ovoid, angular cheek mound with eccentric apex (star) as well as the ogee curve of the right cheek contour.

The female cheek mound is ovoid or egg shaped, not circular, and should not extend higher than the limbus of the lower eyelid (Figure 11.10). The cheek axis is not vertical but angled from the lateral commissure to the base of the ear helix. Most importantly, each malar prominence has a defined

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Figure 11.11 Top models demonstrating Phi facial width proportion (i.e. medial

canthus to medial canthus measure x; medial canthus to ipsilateral cheek apex measures 1.618x).

apex, located high on the midface, below and lateral to the lateral canthus, and eccentrically located within the cheek oval. Proportion and harmony are paramount in the midface, so great care should be taken to avoid overjudicious use of filler product in this region in the attempt to reinflate. As a rule of thumb, ideal facial width, for most ethnicities, falls approximately Phi from the medial canthus for each cheek (Figure 11.11).

Technique The technique for midface contour volumization and cheek enhancement should involve a minimum of needle punctures in order to achieve the desired result. A filler product with a high G′ (stiffness factor) or high cohesivity is chosen in order to maximize lifting capacity of the overlying tissue (tentpole effect). Placement of the product is done submuscularly (supraperiosteally) via vertical puncture, and subcutaneously via angulated percutaneous technique, always injecting antegrade. Injection aliquots are usually limited to no more than 0.5 mL and

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negative pressure on the syringe is recommended to check for intravascular needle location in high-risk regions. Depending on the type of product selected for the lift effect, feathering of the cheek contour in a more superficial subdermal plane may be indicated using a softer (lower G′) product to avoid any step-off areas. Massage with ultrasound gel is always performed after treatment to mold and blend the product as discerned by tactile fingertip touch rather than relying on visual observation. A two-step marking approach is used to create the “Fabergé egg” appearance to the cheek along with its eccentric apex. This process can be likened to giving the face what it wants (its volume), and then giving it what it needs (the proper apogee). Step 1: giving the cheek what it wants (restoring the ogee curve) Ogee is an architectural shape consisting of a concave arc flowing into a convex arc, creating an S-shaped curve. In aesthetic facial surgery, the term is used to describe the malar or cheekbone prominence transitioning into the midcheek hollow (Figure 11.11). The aim of cheek enhancement is to restore (or in some cases create) a gentle ogee curve and subtly define the malar prominence’s zenith. Using an eyebrow pencil, the depleted and concave (negative vector) areas of the cheek are marked overlying the anterior cheek, malar– zygomatic and submalar regions (Figure 11.12). The inferior border of the body of the maxilla is outlined to demarcate supraperiosteal and subcutaneous placement of product. Injections overlying the body of the maxilla are layered supraperiosteally (submuscularly) as well as subcutaneously (if necessary to correct any resistant contour irregularities), while those overlying the parotid (preauricular), submalar region, and lower anterior cheek are performed purely in the subcutaneous plane. Any pre-existing irregularities in the skin are addressed by direct intradermal injection of an appropriate lower G′ product. Injections are performed from superior to inferior on the face, as higher placed product will influence the lower zones by lifting the adjacent inferior tissue. This is evidenced by the softening of the nasolabial fold and jowl on the treated side after the cheek mound has been restored. Quite often less product is required for direct correction of whatever deformity may remain along the upper nasolabial fold triangle and prejowl sulcus (Figure 11.13). Step 2: giving the cheek what it needs (the proper apogee) Once the previous step 1 markings have been wiped away and the gel massage completed, the cheek is now ready for the beauti”phi”cation

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Body of Maxilla Line

Parotid line

1 3

2

Figure 11.12 The depleted region of the right cheek is outlined (black dashed line).

Injections overlying the body of the maxilla (zone 1 above the body of maxilla line) are placed supraperiosteally and if necessary subcutaneously. Depth of volume injections for zones 2 and 3 are limited to the subcutaneous plane.

Treated Side Cheek apex defined subtly Positive contour Softening of N/L fold and marionette Softening of jowl

Untreated Side

Blunted malar region Pre-auricular hollow Deflated peau d’orange skin Persistent Jowl

Figure 11.13 Injections of the upper midface affecting lower zones (nasolabial fold

and jowl).

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Figure 11.14 Beauti“phi”cation: the oval cheek mound lies within the triangular markings (see text) with the malar apex located as depicted (star).

markings to delineate the ovoid appearance and define the cheek apex (Figure 11.14). A line is drawn from the lateral commissure to the lateral canthus of the ipsilateral eye. This will establish the anterior extent of the malar prominence (Hinderer’s line). A second line is drawn from the lateral commissure to the inferior tragus of the ipsilateral ear, denoting the lateral and inferior boundaries of the malar prominence (base of the triangle). The highpoint of the cheek is marked by a horizontal line at the level of the limbus of the lower eyelid. The cheek oval is drawn within these boundaries and tangential to the lines drawn. Feathering of the edges of the oval with subcutaneous filler product is done as necessary to create a smooth egg-shaped mound. Lastly, a line is drawn down from the lateral canthus to the base of the triangle, perpendicular to the latter (the height of the triangle). The cheek apex lies Φ (about a third of the way) from the lateral canthus along this line. Note that this defined point is in an eccentric position within the cheek oval. This same apex injection point can be obtained by the intersection of a line drawn from the nasal alar groove (Φ of the nose) to the upper tragus, and a line drawn down vertically from the midpoint of the lateral orbital rim (Figure 11.15). The final injection (between 0.25 and 0.5 mL of product placed on bone by vertical puncture) is performed at this precise point to give the cheek what it needs – a beauti”phi”ed apex. Molding and blending of this apogee are done with ultrasound gel to provide a smooth contour. Facial width can be confirmed with the golden ratio calipers and filler added at this location to “idealize” the facial width proportion.

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Figure 11.15 Beauti“phi”cation: cheek

apex (star) defined by the intersection of a line drawn from the nasal alar groove to the upper tragus and a line drawn vertically down from the midpoint of the lateral orbital rim.

Modifications for the male cheek The male cheek has more anteromedial fullness, a broader-based malar prominence, and an apex that is more medial and subtly defined. The following modifications of the markings are noted: • Hinderer’s line (anteromedial border) is drawn from the lateral commissure towards the ipsilateral lateral iris, stopping at the infraorbital rim. • Due to the lower jaw angle and stronger jaw, the line denoting the inferolateral border of the cheek (base of the triangle) is drawn from the lateral commissure to the base of the ipsilateral infratragal notch. • The apex is modest and more medially located at one-third of the distance along a line drawn from the lateral canthus to the base of the triangle, intersecting the latter at a right angle. • Finally, the Ogee created should be flatter in its lower S curve.

Learn to think in combineese (the language of combination therapy) The doctrine of beauti”phi”cation, or any nonsurgical facial enhancement, is that it be individualized, minimally invasive, result oriented, cost-effective, synergistic, and associated with minimal downtime, anxiety (for both the patient and physician), and pain. The art of bundling products with procedures – of combining fillers, neurotoxin, skin creams, lasers, and energy devices – is where technology and creativity meet.

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Figure 11.16 Beauti“phi”cation: 6-month result with hyaluronic acid filler for tear

troughs, lateral brows, cheek, and chin enhancement.

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Figure 11.17 Beauti“phi”cation: results at 6 months and 1 year follow-up, no

additional treatment.

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Figure 11.18 Beauti“phi”cation: results at 1 year, single treatment with hyaluronic

acid (tear troughs, cheeks, prejowl sulci, chin) and porcine collagen for lip phi proportion. Neuromodulator (botulinum toxin A or BTX-A) given at 18-week intervals for browlift, periorbital dynamic lines, and chin.

Phi relationships can be approached for all facial features, including the nose, chin, lips, and brows, but are beyond the scope of this chapter. The point must be emphasized that having a plan and using pre-treatment markings to achieve desired results are the critical element to volumization in the face. Once goals have been determined and a budget established, a logical syntax is used to create an algorithm for selecting products and procedures. The methodology will lead to consistent and pleasing results with a high rate of patient satisfaction (Figures 11.16–11.20).

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Figure 11.19 Beauti“phi”cation: combination therapy result at 1 year. Hyaluronic

acid filler (midface, superior and inferior orbital rims, nasolabial folds, prejowl sulci), panfacial neuromodulator (browlift, forehead, glabella, crow’s feet, chin, depressor angulae oris), microdermabrasion, and ALA-aminolevulinic acid/IPL-intense pulsed light therapy, home skincare regimen.

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Figure 11.20 Beauti“phi”cation: results at 18 months. Hyaluronic acid filler (cheeks, tear troughs, nose, prejowl sulci, mental crease, lips, philtral columns) and neuromodulator (browlift, glabella, forehead, crow’s feet, chin).

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References 1. Millard DR. Principalization of Plastic Surgery. Baltimore, MD: Lippincott Williams & Wilkins, 1987. 2. Cunningham MR, Roberts AR, Wu C-H, Barbee A, Druen PB. “Their ideas of beauty are, on the whole, the same as ours”: Consistency and variability in the crosscultural perception of female physical attractiveness. J Personality Social Psychol 1995;68:261–79. 3. Jones D, Hill K. Criteria of facial attractiveness in five populations. Human Nature 1993;4:271–96. 4. Langlois JH, Roggman LA, Casey RJ, Ritter JM, Rieser-Danner LA, Jenkins VY. Infant preferences for attractive faces: Rudiments of a stereotype? Dev Psychol 1987;23:363–9. 5. Livio M. The Golden Ratio: The story of phi, the world’s most astonishing number. Broadway Books, 2002. 6. Ricketts R. The biologic significance of the divine proportion and Fibonacci series. Am J Orthod 1982;81:351–70. 7. Bashour, Mounir. Is an Objective Measuring System for Facial Attractiveness Possible? Dissertation.com, 06/28/2007. 8. Safran B. The Mathematics of Beauty: The divine proportion’s effect on facial attractiveness, Brown University, 2007. 9. Rhodes G, Proffitt F, Grady JM, Sumich A. Facial symmetry and the perception of beauty. Psychonomic Bull Rev 1998;5:659–69. 10. Brooks M, Pomiankowski A. Symmetry is in the eye of the beholder. Trends Ecol Evol 1994;9:201–2. 11. Concar D. Sex and the symmetrical body. New Scientist 1995;146:40–4. 12. Enquist M, Arak A. Symmetry, beauty and evolution. Nature 1994;372, 169–72. 13. Grammer K, Thornhill R. Human (Homo sapiens) facial attractiveness and sexual selection: The role of symmetry and averageness. J Compar Psychol 1994;108: 233–42. 14. Swaddle JP, Cuthill IC. Asymmetry and human facial attractiveness: Symmetry may not always be beautiful. Proc R Soc Lond: Series B 1995;261, 111–16. 15. Carruthers J, Glogau RG, Blitzer A. Advances in facial rejuvenation: botulinum toxin type a, hyaluronic acid dermal fillers, and combination therapies – consensus recommendations. Plast Reconstr Surg 2008;121(suppl 5) 5S–30S. 16. Raspaldo H. Volumizing effect of a new hyaluronic acid sub-dermal facial filler: A retrospective analysis based on 102 cases. J Cosmet Laser Ther 2008;10, 134–42. 17. Coleman SR. Structural Fat Grafting. Quality Medical Publishing, 2004. 18. Donafrio LM. Fat distribution: A morphologic study of the aging face. Dermatol Surg 2000;26:1107–12.

C H AP TER 1 2

Hyaluronic Acids: Clinical Applications Derek Jones Department of Medicine, Division of Dermatology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, USA

Timothy C. Flynn Cary Skin Center, Cary, and Department of Dermatology, University of North Carolina, Chapel Hill, North Carolina, USA

In the year 2007 alone, approximately 1.5 million reported filler procedures were performed in the USA,1 with the hyaluronic acid (HA) products Juvéderm and Restylane sharing the top sales in this market. These treatments are effective because, as a person ages, the amount of hyaluronic acid in the skin is reduced, which decreases the skin’s waterbinding capacity and tissue turgor, leading to visible wrinkles and drooping skin. The signs of aging are accelerated with sun exposure, specifically ultraviolet-B (UVB) radiation. A 2007 study reported that UVB radiation decreases the amount of HA in the dermis and upregulates the number of HA degradation products (such as hyaluronidase).2 HA fillers are designed to restore the appearance of youth to the skin by replacing HA and binding water, thus reducing the aged appearance of sagging skin and skin folds. In Chapter 3 we learned that several variables affect the performance of individual HA fillers, including the concentration of HA, degree of crosslinking, cohesivity, G′, and particle size, which all interact to create the unique properties of a particular HA product. Each of these factors may be determined and compared, allowing the physician to have a better appreciation of how to use the various HA products to obtain optimal patient outcomes. At the time of writing there are six FDA-approved HA fillers: Juvéderm Ultra and Ultra Plus (Allergan, Irvine, CA), Restylane/Perlane (Medicis, Scottsdale, AZ), Prevelle Silk (Mentor, Irving, TX), and Hydrelle (Anika Therapeutics, Woburn, MA). The pivotal trial data leading to FDA approval for each filler are reviewed below.

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HA fillers Restylane Restylane is a particle HA product consisting of 100 000 gel particles per milliliter derived from bacterial fermentation. The pivotal trial for Restylane, as performed and reported by Narins et al.,3 randomized 138 patients with prominent nasolabial folds to receive Restylane in one nasolabial fold and bovine collagen (Zyplast) in the contralateral fold. Treatments were repeated at 2-week intervals until optimal cosmetic results were obtained. A blinded investigator evaluated outcomes at 2, 4, and 6 months after baseline. Results proved that less injection volume of Restylane was required to reach optimal cosmetic result compared with Zyplast, and that patients and investigators judged Restylane to be more effective in maintaining the cosmetic correction. The investigatorbased Wrinkle Severity Rating Scale (WRSR) and Global Aesthetic Improvement Scale assessments at 6 months after baseline indicated that Restylane was superior in 56.9% and 62.0% of patients, respectively, whereas Zyplast was superior in 9.5% and 8.0% of patients, respectively. The frequency, intensity, and duration of injection site reactions were similar for the two products. It was concluded that Restylane provides a more durable aesthetic improvement than Zyplast and is well tolerated. A recent study has shown that improvements seen after initial treatment with Restylane persisted for up to 18 months with one retreatment.4 Reasons for persistence after reinjection include the increased production of native collagen which has been shown to be promoted by fibroblast stretching.5

Perlane Perlane, a more viscous form of Restylane containing larger-sized particles of gel, received the approval of the Food and Drug Administration (FDA) in 2007 based on four prospective, randomized clinical studies enrolling 559 patients.6 The largest study enrolled 283 patients who were randomized to receive Restylane in one nasolabial fold and Perlane in the contralateral fold, with the primary efficacy endpoint being the difference in WSRS scores compared with baseline at 12 weeks, with secondary endpoints at 2, 6, and 24 weeks. At 12 weeks, 122 (87%) of the patients in the Perlane group and 108 (77%) in the Restylane group maintained at least a 1-point improvement in the WSRS score. At 24 weeks, 63% of the Perlane patients maintained at least a 1-point improvement, compared with 74% of Restylane patients. The differences between the two products were not statistically significant and therefore Perlane is considered “noninferior” to Restylane.

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Juvéderm Juvéderm, compared with Restylane, is a higher concentration HA (24 mg/ mL), has a higher concentration of crosslinked HA, contains less uncrosslinked HA, and utilizes homogenization in preparation of the final product, which gives the gel a comparatively smoother consistency. Proponents of Juvéderm argue that Juvéderm promotes a smoother result after injection compared with Restylane. However, this has never been proven in well-designed head-to-head trials. The Juvéderm pivotal FDA trial, as studied and reported by Baumann et al., enrolled 439 subjects who were randomized to receive one of three formulations of Juvéderm in one nasolabial fold and Zyplast collagen in the contralateral fold.7 At 24 weeks, all three preparations achieved considerably longerlasting clinical correction than bovine collagen with 81–90% of Juvédermtreated patients maintaining a clinically significant improvement from baseline for 6 months or longer (Figure 12.1).7 Up to 88% of subjects preferred Juvéderm over bovine collagen. All fillers were similarly well tolerated. Currently, Juvéderm and Juvéderm Ultra Plus are available in the USA. Juvéderm Ultra Plus is a robust filler with a higher degree of crosslinking and is indicated where more robust filling is needed (i.e. deeper nasolabial folds). Similar to Restylane, longer-term follow-up has shown persistence of the product for up to a year or longer after repeat treatments.8 Therefore, both Restylane and Juvéderm may be considered semi-permanent fillers.

Prevelle Silk Prevelle Silk is a 5.5 mg/mL HA particle gel containing lidocaine which decreases pain on injection. With the exception of the addition of lidocaine, it is identical to Captique, which is no longer available in the USA. Compared with Restylane and Juvéderm, it contains a much lower concentration of HA, and is considered a “softer” HA filler with less lift capacity. It has a shorter duration of correction (3 months or less). The FDA pivotal trial was a prospective, single-blind, randomized, single-center, split-face study conducted in 45 individuals to evaluate the safety and injection pain during and after the injection procedure with dermal injection with and without lidocaine into contralateral nasolabial folds.9 Pain assessments for the Prevelle Silk-treated sides were lower during injection and for up to 1 hour post-treatment. The majority of patients preferred the Prevelle Silk-treated side because it was less painful. Prevelle Silk is manufactured in the same manner as Hylan B gel (previously available in the USA as Hylaform), except that the HA in Prevelle Silk is derived from a bacterial source rather than from an avian source and includes the addition of 0.3% lidocaine hydrochloride. The FDA pivotal trial for Hylan B enrolled 261 patients who were randomized and treated with either

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Figure 12.1 Effectiveness of Juvéderm Ultra Plus dermal filler in the treatment of

severe nasolabial folds. (From Lupo MP, Smith SR, Thomas JA, Murphy DK, Beddingfield FC 3rd. Plast Reconstr Surg 2008;121:289–97.)

Zyplast or Hylan B in contralateral nasolabial folds. The results showed that per nasolabial fold more volume of Zyplast was required for correction (1.1 mL) compared with Hylan B (0.75 mL), and duration of correction was similar to Zyplast at 12 weeks. Both fillers were equally tolerated.

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Hydrelle Hydrelle (formally Elevess) is a 28 mg/mL HA filler and, like all the other currently FDA-approved fillers, it is derived from bacterial fermentation. Similar to Prevelle Silk, it contains 0.3% lidocaine hydrochloride. It also contains sodium metabisulfite as an antioxidant and is contraindicated in those with sulfite allergies. The FDA pivotal trial was a prospective, randomized, controlled, double-blinded, multi-center study using Hydrelle in one nasolabial fold and Cosmoplast human collagen in the contralateral fold.10 Up to three treatments at 2-week intervals were allowed until optimal correction was achieved. Visits occurred at 1, 4, 6, 9 and 12 months to establish safety and effectiveness. The primary efficacy endpoint was the change in the 6-point wrinkle severity scale (Lemperle Scale) as rated by a blinded, non-treating evaluator. The study randomized and enrolled 141 patients. Results proved that compared to Cosmoplast, less Hydrelle was required to reach optimal correction. Compared with Cosmoplast, Hydrelle achieved a statistically significant greater improvement in correction at 4 months but not at 6 months. Adverse events were similar except that more bruising and swelling occurred with Hydrelle compared to Cosmoplast. The authors have been informed of numerous anecdotal cases of inflammatory reactions after injection of Hydrelle. This may be due to excessive crosslinking of the product or excessive levels of sodium metabisulfite. Further studies are warranted.

Indications It should be noted that all currently FDA-approved HAs have been studied only in nasolabial folds and carry the specific indication on package inserts that they are approved for dermal injection for correction of moderate-tosevere facial wrinkles and folds, such as nasolabial folds. Although not specifically FDA approved, available HAs have been studied off-label for correction of glabellar rhytids, oral commissures (meilolabial folds), lips, midface volumizing, infraorbital, or nasojugal grooves (tear troughs), and augmentation of the dorsal hand. Each off-label indication is considered separately below.

Glabellar rhytids Botulinum toxin A (BTX-A) is the standard treatment for glabellar furrows. However, some individuals have resting glabellar rhytids that are sufficiently deep or “etched-in” that they respond poorly to BTX-A. Carruthers and Carruthers performed a study to retrospectively compare the efficacy of BTX-A combined with intradermal Hylan B with the efficacy of BTX-A alone in 16 individuals with moderate-to-severe glabellar rhytids.11 Their response to Hylan B plus BTX-A was compared

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clinically and photographically to their response with BTX-A alone. Results showed that all subjects had moderate or severe glabellar rhytids at rest before treatment. After BTX-A alone, none (0%) had achieved no or mild rhytids. After BTX-A and Hylan B injection, only 1 of 16 (6%) had moderate glabellar rhytids, with the remainder (94%) being mild. The authors concluded that moderate-to-severe glabellar rhytids were better treated by BTX-A with Hylan B than with BTX-A injection alone. In the author’s opinion, BTX-A works best when combined with about 0.4 mL on average of Restylane or Juvéderm, which contains the ideal volume to achieve optimal correction for most patients with deep etchedin glabellar lines who are unlikely to respond to BTX-A alone. Furthermore, learning to identify patients at baseline who will respond better to a combination of HA and BTX-A will often result in higher patient satisfaction if the patient is informed of that before any treatment is administered. In the glabellar area, HA should be injected into the mid- to deep dermis, using a slow, linear retrograde technique, with small amounts with each linear pass. Caution should be noted with glabellar injections in that the supratrochlear artery runs in the immediate subdermal plane. Inadvertent injection into this artery may cause tissue ischemia and severe tissue necrosis.12 Impending necrosis, manifested as a sudden blanching of tissue in the watershed distribution of the supratrochlear artery, followed by a reticulated purple to blue mottled discoloration of the skin, may be immediately reversed by injection of hyaluronidase into the area.13

Lips and oral commissures Loss of volume and vermillion definition of the lips, combined with loss of the supporting volume of the oral commissures, represent common and significant components of the aging process in the perioral region. Options for approved, lip-enhancement agents are limited, although off-label use of hyaluronic acid-based dermal fillers is frequently employed. A recent multi-center feasibility study for lip enhancement using Juvéderm Ultra was conducted under an Investigational Device Exemption.14 The study was a prospective, open-label, multicenter study treating lips and perioral areas with touch-up treatments allowed at 2 weeks after initial treatment if needed to reach optimal correction. The primary effectiveness analysis was performed by determining “responders,” as defined as the individuals who at 12 weeks increased their lip fullness greater or equal to 1 point on a 4-point-validated lip fullness scale (as rated by a blinded noninjecting expert physician) and who also met their lip fullness scale treatment goals. The primary study phase was 6 months, with additional visits at 6-week intervals for up to an additional 6 months until lip fullness returned to baseline score.

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Fifty individuals were enrolled, and these participants served as their own controls. For eligibility, participants were required to be at least 18 years old, desire enhancement of the lips (vermillion borders, vermilion mucosa, Cupid’s bow, philtral columns, oral commissures), and judged by the evaluating investigator as having attainable treatment goals and a pretreatment lip fullness score of minimal or mild on the 4-point lip fullness scale. Lip fullness goals were established by the treating investigator and participant before treatment. Assessments were made by the participant, treating investigator and an evaluating investigator blinded to the volume, location of treatment, and previous assessment scores. At each visit lip fullness, perioral lines, and oral commissures were assessed using validated photometric scales, and standardized threedimensional images were obtained for measurement of lip changes. Safety evaluations included common treatment site reactions as well as lip sensation and functionality assessments. Results showed that the average treatment volume was 1.6 mL total of Juvéderm Ultra for the upper and lower lip and oral commissures (Figure 12.2).6 Touch-ups were required for 18 of 50 patients at 2 weeks with an average volume of 0.6 mL. At the 12-week primary endpoint, 71%

Figure 12.2 Baseline and weeks 2, 12, and 36: poster presentation at the American

Society of Aesthetic Plastic Surgery, Las Vegas, NV. May 2009. (From Fagien et al.,13 with permission of Allergan.)

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(p < 0.0001) of participants achieved their lip fullness goals and improved greater or equal to 1 point on the lip fullness scale. The agreed endpoint was pre-established as 40% of the cohort being defined as responders at 12 weeks, so clinical effectiveness was established. Participant assessments showed that the vast majority were not adversely affected by treatment in terms of lip function or sensation, whereas investigator assessments demonstrated little change from baseline in lip functionality, both in repose and in animation. The most common treatment reactions were transient swelling (94%), bruising (92%), and tenderness (88%). Aside from these treatment reactions, there were no adverse events related to the Juvéderm injection. The conclusion was that the results of 50 patients demonstrate the utility of Juvéderm Ultra for lip enhancement and improvement of perioral lines and oral commissures with an acceptable safety profile. Both the authors prefer Juvéderm for perioral treatments. When injecting lips with Juvéderm, the author DJ employs an intraoral sulcus block with 2% lidocaine without epinephrine for anesthesia and employs a linear retrograde technique with a 30G 1-inch needle. In addition, a small amount of 1% lidocaine may be mixed with the Juvéderm Ultra just before injection using the female-to-female Luer-Lok transfer technique described below. A demonstration of lip injections performed by this author may be found in the DVD that accompanies this book.

Cheek volumizing Many signs of aging are due to loss of subcutaneous fat in the malar and submalar cheek regions. Fillers, including HAs, may successfully volumize this area when injected appropriately (Figure 12.3). Chapter 12, entitled “The mathematics of facial beauty: a cheek enhancement guide

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Figure 12.3 Before (a) and 2 weeks after (b) Restylane for treatment of facial

lipoatophy.

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for the aesthetic injector”, specifically addresses cheek enhancement using HA fillers. Juvéderm Voluma is a new HA filler that is not yet FDA approved, although FDA studies are underway. It is a 20 mg/mL HA of streptococcal origin with a higher lift capacity. It has a lower molecular weight and higher crosslinking ratio than other available HAs. It will be indicated for subcutaneous/supraperiosteal injection for facial volumizing and contouring. It should be noted that fillers must be injected into the subcutaneous or supraperiosteal plane when volumizing the midface. Intradermal or too superficial injection may create persistent dermal contour irregularities. A recent study performed by Raspaldo2 assessed effectiveness and safety of Voluma in maintaining increased volume in the malar area for up to 18 months post-treatment. Retrospective record data were analyzed for 102 patients (93 women, 9 men; mean age 51.27 years) who received Voluma injected into the midface. All patients were assessed at baseline, 1 month, and 6–18 months post-injection. The Investigator Global Aesthetic Improvement assessment after 1 month and 6–18 months showed that most patients were “much” or “very much” improved. Investigator volume loss assessment confirmed that most patients were either stage 1 or 2 (normal or slight midfacial atrophy) 1 month posttreatment, which was maintained at 6–18 months. Patient efficacy assessment was “very good” or “good” in most cases. It was concluded that Voluma provides aesthetic improvements according to investigator and patient assessment for up to 18 months post-treatment with an excellent safety profile.

Dorsal hand volumizing Most injectable filler procedures have concentrated on the face. Many patients complain of thinning of the skin on the dorsal hand and subsequent increased visibility of the subcutaneous veins. Injection of fillers, including HA, into the subcutaneous skin of the dorsal hand can restore dermal thinning. A recent study compared the use of hyaluronic acid (Restylane, Medicis Aesthetics Inc.) and collagen (Cosmoplast, INAMED Aesthetics) for softtissue augmentation of the dorsal hands.15 Ten female patients who demonstrated dermal thinning of the dorsal hands were randomized to receive 1.4 mL of hyaluronic acid or 2.0 cm collagen to alternate interphalangeal spaces of the dorsal hands. Patients returned at 1 week, 1 month, 3 months, and 6 months for digital photography and completion of a patient/ physician questionnaire. Hands were scored by two separate blinded

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Figure 12.4 Before (left) and after (right) Juvéderm Ultra for prominent tear troughs.

physicians on scales of 1–5 for clearance of veins. Patients scored both tolerability and satisfaction on a scale of 1–5. Hyaluronic acid proved to be superior to collagen in efficacy with analysis showing a mean difference of 0.95 (0.004) and a median difference of 0.9 (0.008) for clearance. The satisfaction difference was not significant with a mean difference of 0.80 (0.070) and median difference of 1.0 (0.117). It was concluded that the use of soft-tissue fillers is a viable tool in hand rejuvenation with hyaluronic acid proving to be superior in efficacy to collagen. As with the cheek, injectable fillers in the dorsal hands should be into the subcutaneous plane. Care should be taken to avoid intravascular injection into the subcutaneous veins, which could lead to pulmonary embolism.

Infraorbital hollows (nasojugal folds, tear troughs) The infraorbital hollow (also termed the ‘nasojugal’ groove or tear trough) is one of the more sought-after indications for HA injection. Performed correctly, patient satisfaction is high (Figure 12.4). However, it is also the most challenging for the injector to master. In the author DJ’s referral practice, it is the most commonly encountered area for patients seeking treatment for an adverse event (overvolumizing, lumpiness, or visible show of material) caused by other injectors. Thankfully, these adverse events are readily treatable with the injection of hyaluronidase.16 In general, only the very experienced injector should attempt correction of this area. The HA should be injected in the immediate epiperiosteal plane deep to the orbicularis oculi using small depot injections with a serial puncture technique. Alternatively linear injection may be used through a 30G needle. Subdermal injection should be assiduously avoided because lumpiness, counter irregularities, and the Tyndall effect are common with subdermal injections. Care should be taken not to damage the infraorbital nerve, which exits in this area, and not to penetrate the nasal sidewall arteries. Treatment of the infraorbital hollow often gives the best results when cheek filling is performed concomitantly.

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Figure 12.5 Before (a–c) and 2 weeks after (d–e) Juvéderm Ultra and Ultra Plus to

the nasolabial folds, lips, and oral commissures. (Details of this treatment performed by the author (DJ) can be viewed on the DVD that accompanies this book.)

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Two excellent manuscripts – by Bosniak and Sadick17 and Hirsch et al.18 have recently been published on proper techniques in this area and should be considered mandatory reading for all physicians interested in treating this area.

Safety The safety profiles of currently FDA-approved HA fillers are strong. The most common procedure- or device-related adverse events are injection site erythema, swelling, pain, and bruising, all of which usually resolve within a few days. More serious complications can sometimes occur and most can be avoided with appropriate injection techniques. Inappropriate or superficial placement is one of the most frequent reasons for patient dissatisfaction. Too superficial placement of HA in the dermis can result in a Tyndall effect, which is a blue discoloration caused by the refraction of light from the clear gel visible superficially in the skin. Although most physicians believe that they are injecting intradermally in the nasolabial fold, a recent study documents that most properly injected HA actually resides in the immediate subcutaneous plane.19 To avoid superficial injection, care should be taken that, when injecting in a linear fashion, the metal hub of the needle should not be visible through the skin in the plane of injection. True hypersensitivity to injectable HA is rare, and occurs about 1/5000 cases. Infection is quite uncommon as well and can usually be managed with either antibiotics or antivirals depending on the clinical features. Injection of HA into the perioral area can potentiate recurrence of herpes simplex virus (HSV) infection, and patients prone to recurrent perioral HSV infection should receive appropriate antiviral prophylaxis before treatment. The most worrisome complication is cutaneous necrosis, which is most commonly caused by occlusion of vascular structures by inadvertent injection of HA intravascularly or by sidewall compression of vascular structures due to overvolumizing of the surrounding soft tissue. The supratrochlear artery in the glabellar area and the angular artery in the superior nasolabial fold are particularly susceptible, and these areas should be considered “high risk.” The injecting physician should have masterful knowledge of vascular structures in areas of injection (Figure 12.6). A protocol to treat the full spectrum of cutaneous necrosis has recently been reviewed by Cohen,12 Hirsch and Carothers.13 Due to the reversibility of hyaluronic acid, complications from these fillers can be easily corrected. The use of ovine testicular hyaluronidase (Vitrase) can dissolve injected HA, which is highly useful if the product

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Figure 12.6 Vascular anatomy of the

midface. The angular artery (a branch of the facial artery) anastomoses with the supratrochlear and dorsal nasal arteries (branches of the ophthalmic artery), joining the external carotid artery network with the internal carotid artery network. Occlusion or embolic events involving this network can lead to extensive tissue necrosis. ST, supratrochlear artery; D, dorsal nasal artery; A, angular artery; SF, superior labial artery; F, facial artery.

is misplaced,4 if there is a complication post-injection (e.g. vascular occlusion or delayed granulomatous reactions),4 or if there is impending vascular necrosis.13 Studies are ongoing to determine the proper dosing of hyaluronidase. In the author DJ’s experience, 10 units of hyaluronidase per 0.1 mL of Juvéderm or 5 units per 0.1 mL of Restylane to be dissolved is the most appropriate dose. The need for the greater amount of hyaluronidase for Juvederm has been proven with in-vitro studies, and is likely because the product is more highly crosslinked, has a higher concentration of HA, and is is non-particulate and more cohesive, allowing for less penetration of hyaluronidase. Further studies are warranted to refine in-vivo dosing recommendations and to determine if this resistance profile confers longer in-vivo residence time of Juvederm compared to other HA fillers.20

Anesthesia A new trend with HA fillers is the addition of lidocaine to the product to decrease the pain of treatment. although Prevelle Silk and Elevess currently have lidocaine preincorporated in the final product, Restylane/ Perlane and Juvéderm do not, although they are the most commonly injected fillers. A Juvéderm product with lidocaine is expected to receive FDA approval in the near future. A recent study has shown that the use of preincorporated lidocaine in Juvéderm greatly increases patient comfort during the procedure.21 This double-blind study at three centers enrolled 60 participants, injected with either Juvéderm with or without lidocaine,

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randomly assigned to left or right nasolabial fold. The injecting physician assessed severity of pain and ease of injection. Participants used a visual analog scale (0–10) for pain assessment. Adverse events were recorded. Physician assessment of injection pain was none or mild in 81% of HA gel injections with preincorporated lidocaine and 36% of HA-alone injections (p < 0.001). Mean pain assessment by participants was 3.6 for HA plus lidocaine and 5.8 for HA alone (p < 0.001). Ninetyfive percent of the injections were considered easy or very easy; a greater percentage of HA plus lidocaine injections was rated very easy. Mild-to-moderate expected treatment-related adverse events were reported for both products. Juvéderm with preincorporated lidocaine increased participant comfort during treatment and improved the injection experience, and does not appear to compromise safety or effectiveness of the product. Although Juvéderm and Restylane are currently sold without preincorporated lidocaine in the USA, these fillers are often used off-label with physician-added lidocaine. In the author DJ’s experience, it is best to use a 1 : 10 dilution of 1% lidocaine with epinephrine:HA filler. The lidocaine is mixed with the filler using a female-to-female adapter, with the product pushed back and forth approximately 20 times. This off-label technique is demonstrated in the DVD that accompanies this book. To further enhance patient comfort, the authors recommend application of topical anesthesia such as EMLA to the injection site for at least 15 minutes before the procedure, and the use of an intraoral sulcus block when injecting the lips.

Injection techniques Patients should be clear in their treatment goals and all risks, benefits, indications, and options of treatment should be discussed. Photographs and written informed consent should be considered mandatory for all patients. Furthermore, patients should be advised to refrain from anticoagulants such as NSAIDs, fish oil, and ginko and other supplements for 7 days before the procedure to limit the potential for bruising. A variety of HA injection techniques may be utilized depending on the indication, including antegrade or retrograde linear threading, serial puncture, crosshatching, and subcutaneous and epiperiosteal injection. Good results are often technique related, and the initial learning curve is steep. Likewise, aesthetic artistic talent is necessary; similar to artists, some injectors will achieve better results than others. Great care must be taken not to inject too superficially, too quickly, or intravascularly. It is the author’s belief that the best learning occurs by observing good injection technique

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and by accumulating experience by performing injections. The author DJ’s favored injection techniques of nasolabial folds, oral commissures, and lips are demonstrated in the DVD that accompanies this textbook (Figure 12.5). Novice injectors should begin by injecting the nasolabial folds, and then progress to off-label areas such as lips and midface volumizing once that has been mastered. One question associated with dermal fillers is whether the rate and variability of local adverse events after treatment are related to injection technique and needle trauma or to the intrinsic chemical composition. Glogau and Kane22 recently performed a study to determine if there is a relationship between dermal filler injection technique and the incidence of local adverse events. A prospective, blinded, controlled study enrolled 283 patients who were randomized to receive midface volume correction of the nasolabial folds and oral commissures with Restylane or Perlane. Data was collected on multiple injection technique variables to assess adverse events. Injection techniques that increase the dissection of the subepidermal plane (e.g. fanlike needle use, rapid injection, rapid flow rates, and higher volumes) increased the incidence of local adverse events. Injection techniques that increase epidermal damage or subcutaneous exposure (e.g. multiple punctures or deep subcutaneous injection) had no effect on adverse events. Furthermore, single injection correction, depth of injection, and Restylane/Perlane injected had no effect on local adverse events. It was concluded that local adverse events after injection with the Restylane/Perlane fillers used in this study were related to investigator technique and not to differences in the intrinsic properties of the HA agents. Helpful tips to decrease adverse events include stopping antiplatelet or anticoagulant medications before injection as appropriate. This will decrease the bruising and local reactions in the skin. The use of topical anesthetics 30 minutes before injection can decrease the pain of the needle stick. Ice or local skin cooling can help decrease the injection pain and post-treatment icing may also decrease bruising. Several other HAs are being used in clinical trials in the USA. They include Puragen Plus (Mentor Corporation, Santa Barbara, CA), which contains lidocaine integrated directly into the formula, Belotero Soft and Belotero Basic (Anteis, Geneva, Switzerland), and Teosyal (Teoxane Laboratories, Geneva, Switzerland). In summary, HA fillers last longer than bovine and human collagen and in general have better patient satisfaction, longer-lasting correction, and similar incidence of adverse events. Practitioners are now using HA fillers in most areas of the face, and are using them at deep and midfacial planes to replace lost facial volumes to give a natural, more beautiful result.

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References 1. http://www.surgery.org/media/news-releases/117-cosmetic-procedures-in-2007-, accessed December 12, 2009. 2. Raspaldo H. Volumizing effect of a new hyaluronic acid sub-dermal filler: a retrospective analysis based on 102 cases. J Cosmet Laser Ther 2008;10:134–42. 3. Narins RS, Brandt F, Leyden J, Lorenc ZP, Rubin M, Smith S. A randomized, doubleblind, multicenter comparison of the efficacy and tolerability of Restylane versus Zyplast for the correction of nasolabial folds. Dermatol Surg 2003;29:588–95. 4. Narins RS, Dayan SH, Brandt FS, Baldwin EK. Persistence and improvement of nasolabial fold correction with nonanimal-stabilized hyaluronic acid 100,000 gel particles/ml filler on two retreatment schedules: results up to 18 months on two retreatment schedules. Dermatol Surg 2008;34(suppl 1):S2–8. 5. Wang F, Garza LA, Kang S, et al. In vivo stimulation of de novo collagen production caused by cross-linked hyaluronic acid dermal filler injections in photodamaged human skin. Arch Dermatol 2007;143:155–63. 6. Perlane Prescribing Information. Medicis Pharmaceutical Corporation. www. medicis.com/products/pi/pi_perlane.pdf. Accessed December 12, 2009. 7. Baumann L, Lupo M, Monheit G, Thomas J, Murphy D, Walker P. Comparison of smooth-gel hyaluronic acid dermal fillers with cross-linked bovine collagen: a multicenter, double-masked, randomized, within-subject study. Dermatol Surg 2007;33 (suppl 2):S128–35. 8. Smith S, Jones D. Poster presentation: Efficacy and safety following repeat treatment for a new family of hyaluronic acid based fillers. American Academy of Dermatology Academy 2006 Meeting, San Diego, CA, 2006. 9. Prevelle Silk. Package insert. Mentor Corporation, 2007. 10. Elevess. Package insert. Anika Therapeutics, Inc, 2006. 11. Carruthers J, Carruthers A. A prospective, randomized, parallel group study analyzing the effect of BTX-A (Botox) and nonanimal sourced hyaluronic acid (NASHA, Restylane) in combination compared with NASHA (Restylane) alone in severe glabellar rhytides in adult female subjects: treatment of severe glabellar rhytides with a hyaluronic acid derivative compared with the derivative and BTX-A. Dermatol Surg 2003;29:802–9. 12. Cohen J. Understanding, avoiding, and managing dermal filler complications. Dermatol Surg 2008;34(suppl 1):S92–9. 13. Hirsch R, Cohen J, Carruthers J, Carruthers A. Successful management of an unusual presentation of impending necrosis following a hyaluronic acid injection embolus and a proposed algorithm for management with hyaluronidase. Dermatol Surg 2007;33:357–60. 14. Fagien S, Mass C, Thomas J, Murphy D, Beddingfield F. Juvederm Ultra for lip enhancement: an open label, multicenter study. Poster presentation at the American Society of Aesthetic Plastic Surgery, Las Vegas, NV, May 2009. 15. Man J, Rao J, Goldman M. A double-blind, comparative study of nonanimalstabilized hyaluronic acid versus human collagen for tissue augmentation of the dorsal hands. Dermatol Surg 2008;34:1026–31. 16. Brody HJ. Use of hyaluronidase in the treatment of granulomatous hyaluronic acid reactions or unwanted hyaluronic acid misplacement. Dermatol Surg 2005;31: 893–7. 17. Bosniak S, Sadick N, Cantisano-Zilkha M, Glavis IP, Roy D. The hyaluronic acid push technique for the nasojugal groove. Dermatol Surg 2008;34:127–31

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18. Hirsch R, Carruthers J, Carruthers A. Infraorbital hollow treatment by dermal fillers. Dermatol Surg 2007;33:1116–19. 19. Arlette JP, Trotter MJ. Anatomic location of hyaluronic acid filler material injected into nasolabial fold: a histologic study. Dermatol Surg 2008;34(suppl 1):S56–63. 20. Jones D, Borell M, Tezel A. In vitro resistance to degradation of hyaluronic acid dermal fillers by ovine testicular hyaluronidase. Dermatologic Surgery, In press. 21. Levy PM, Deboulle K, Raspaldo H. Comparison of injection comfort of a new category of cohesive hyaluronic acid filler with preincorporated lidocaine and a hyaluronic acid filler alone. Dermatol Surg 2009;35(suppl 1):332–7. 22. Glogau R, Kane M. Effect of injection techniques on the rate of local adverse events in patients implanted with nonanimal hyaluronic acid gel dermal fillers. Dermatol Surg 2008;34:S105–9

Index

abscesses, sterile 132 acetaminophen 86 acrylamide 91 Adatosil 83 adverse effects see complications aging process 147 Aldara 128, 130 allopurinol 118 alprazolam 86 Amazing-gel 91, 95 amoxicillin 99 analgesia see pain management anesthesia see local anesthesia Aquamid 91 indications 92–3, 99 injection technique 94 Aquinas, St Thomas 141 Argiform 91, 92 indications 93 injection technique 94 arnica 124, 125 Artecoll complications 127, 128, 130 efficacy 109–13 history 104, 105, 106, 107 safety 114–15 Artefill 103, 119 complications 113, 127, 130 granulomas 118–19 history 104–9 mechanism 109

practical applications 115–18 safety 113, 115 and Sculptra 65 Arteplast 103, 104, 118 Artes Medical, Inc. 109 articaine 50 aspirin 124 assessment 7 Augmentin 99 awareness of cosmetic dermatology practice 3 BCDI (biscarbodi-imide) 21 BDDE (1,4-butanediol diglycidyl ether) 21 beauty 140–3 mathematics 146–9 combination therapy 153–6 phi 143–6 technique 149–53 Belotero Basic 172 Belotero Soft 172 Betacaine 35 betamethasone dipropionate 118 Biaxin 39, 129 Bio-Alcamid complications 95, 96, 97 indications 92, 93, 99 injection technique 93–4 properties 91 biocompatibility 54

175

176

Index

biofilms 132 hydrogel polymers 98, 100 polymethylmethacrylate 114 silicone 87 Bioformacryl 91 biostimulatory agents 54 see also Sculptra bleomycin 118 bone, and aging process 72 botulinum toxin A (BTX-A) 162–3 and Evolence/Evolence Breeze 47, 48, 49, 50 bovine collagen 43 history 43, 44, 78 hypersensitivity reactions 133 polymethylmethacrylate 103, 104, 109, 116 see also Zyderm; Zyplast breastfeeding CaHA microspheres 33–4 Sculptra 64 bromelain 124–5 Caine tips 11 calcium hydroxylapatite (CaHA) microspheres (Radiesse) 37, 40 anesthetic mixed with 8–10 clinical experience 29–31 complications 127–8 considerations 33–40 contraindications 65 duration 31 efficacy 29–30 follow-up treatment 40 injection techniques 32 lower face injections 35–40 midface injections 35–7 nodules 31 pain management 34 pivotal trials 28–9 post-treatment procedures 40 properties and mechanism of action 27–8 radiographic properties 32 safety 31–4 cancelled procedures 7 Candida species 98

Captique 160 celery root 124 cephalexin 96, 118 cheek 146–9 augmentation 149–53 chilling 10, 11, 17 hyaluronic acids 172 chlorhexidine 131 clarithromycin 99, 131, 132 clavulanate potassium 99 clindamycin 96, 99 closing room 4 cohesivity of hyaluronic acids 24–5 collagen bovine 43 history 43, 44, 78 hypersensitivity reactions 133 polymethylmethacrylate 103, 104, 109, 116 see also Zyderm; Zyplast complications emboli 136 granulomas 128 hypersensitivity reactions 133 injection site reactions 122, 124 history 43–4, 78 human 43, 133 history 44 trial 28 see also Cosmoplast porcine see Evolence/Evolence Breeze combination therapy 153–5 complications 121–2 granulomas 128–30 hypersensitivity reactions 132–4 hypertrophic scarring 130–1 infection 131–2 injection site reactions 122–5 necrosis 134–6 nodules and papules 125–8 see also under specific fillers concentration of hyaluronic acids 22 consent 7 hyaluronic acids 171 Sculptra 65 silicone 84

Index consultation see cosmetic patient consultation consultation sheets 6 contaminated fillers 132 cooling 10, 11, 17 hyaluronic acids 172 cosmetic coordinators 6 cosmetic office practice (COP) 1–2 cosmetic patient consultation (CPC) 1 assessment 7 components 2–7 cosmetic office practice 1–2 education 5–7 setting 2–5 Cosmoderm 43, 133 history 44 Cosmoplast 43, 133 efficacy 162, 166–7 history 44 trial 28 cost issues 6–7 counterfeit fillers 122, 132 cranial nerve V 12 crosslinking collagen implants 44, 45 hyaluronic acids 21 Depo-Medrol 118 deposits 6–7 Dermalive 65 dexamethasone 134 Diprosone 118 Divine Proportion 143–6 doxycycline 88 Dürer, Albrecht 143 DVS (divinyl sulfone) 21 education internal 3, 7 patient 4, 5–7 CaHA microspheres 33–4 Sculptra 65 silicone 84 see also training effective hyaluronic acid concentration 22 ELA-Max 10

177

elastic modulus of hyaluronic acids 22–3, 24 Elevess 158, 162 crosslinker 21 lidocaine 162, 170 emboli 136 EMLA cream 10, 11, 116, 171 environmental aids, anesthesia 11 epinephrine 11 CaHA microspheres 33–4 complications 11–12 Evolence/Evolence Breeze 50 hyaluronic acids 171 hydrogel polymers 94 mixed with dermal filler 8, 37 tissue infiltration 16, 17 Escherichia coli 98 etanercept 88 Euclid 145 Evolence/Evolence Breeze 43, 44–5, 51–2, 133 clinical use 47–51 complications 47 contraindications 47, 48, 49–50 duration 46 efficacy 46 injection techniques 50–1 safety 46 Evolution 91 extrusion force CaHA microspheres 9 hyaluronic acids 24 facial analysis and mapping 70 facial beauty 140–3 mathematics 146–9 combination therapy 153–6 phi 143–6 technique 149–53 fat, and aging process 72 fat transplantation 128, 136 fibroplasia hydrogel polymers 92 silicone 76–7, 85, 86, 87 financial issues 6–7 fish oil 124, 171 5-fluorouracil (5FU) 118

178

Index

Food and Drug Administration (FDA) CaHA microspheres 27, 28, 29, 40 collagen implants 43, 44, 133 Evolence/Evolence Breeze 45, 48, 49 complications 121–2 crosslinkers 21, 45 hyaluronic acids 21, 158, 159, 160, 162, 170 hydrogel polymers 93 polymethylmethacrylate 103, 107, 109, 114, 115, 119 Sculptra 56 silicone 77, 78, 79, 80 Formacryl 91, 92 garlic 124 gel hardness 22–3 ginger 124 ginkgo biloba 124, 171 ginseng 1124 Glymatrix technology 45 Golden Mask 145, 146 golden mean caliper 145, 147 Golden Ratio 143–6 Golden Section 145 granulomas 128–30 polymethylmethacrylate 104, 107, 114, 115, 118–19 silicone 87–8 green tea 124 Gross, J. 43 helenalin 125 heparin 136 herpesvirus infection 131 CaHA microspheres 33 hyaluronic acids 169 Hinderer’s line 152, 153 history taking 34 HIV-associated lipoatrophy CaHA microspheres 27, 28–9, 30, 33, 35, 37 complications 96, 126, 130 hydrogel polymers 92–3, 94, 96, 99 Sculptra 55 silicone 80–2, 84–5, 86

homeopathic medications 124–5 homogenization 24 human collagen 43, 133 history 44 trial 28 see also Cosmoplast Hyacell 132 hyaluronic acids (HAs, hyalurons) 19–21, 25, 158 and CaHA microspheres 37, 39 complications 98, 167, 169–70, 172 granulomas 128 hypersensitivity reactions 133–4 hypertrophic scarring 131 infection 132 injection site reactions 122, 124 necrosis 136 nodules and papules 126 concentration 22 crosslinking 21 gel hardness 22–3 indications 162–9 injection techniques 171–2 local anesthesia 170–1 particle size 23–5 safety 169–70 see also Elevess; Juvéderm line; Perlane; Prevelle Silk; Restylane hyaluronidase 126, 128, 136, 163, 167, 169–70 hydrocodone 86 hydrogel polymers 100 complications 95–100 history and science 91–2 indications 92–3, 99 injection technique 93–5 properties 91–2 hydroquinone 87 hydroxychloroquine 99 Hylaform 160 Hylan B 160–1, 162–3 hypersensitivity reactions 132–4 hyaluronic acids 169 hypertrophic scarring 130–1 ibuprofen 118 icing 11, 17, 124

Index Artefill 116 hyaluronic acids 172 Sculptra 65 imiquimod 88, 118, 128 infection 131–2 influenza 130 infraorbital nerve 12, 13 block 12–13, 14 mini-block 13–15 injection site reactions 122–5 Interfall 91, 92 indications 93 injection technique 95 isopropyl alcohol 131 isotretinoin 88 Juvéderm line 158, 160, 161 complications 129, 170 crosslinker 21 indications 163–5, 166, 167, 168 local anesthetic 124, 170–1 particle size 24, 25 kava-kava 124 Keats, John 140 Keflex 39 Kenalog 118 Kirk, D. 43 Knapp, T.R. 44 lactation CaHA microspheres 33 Sculptra 65 Lemperle, Gottfreid 103 lidocaine 11–12 Artefill 103, 109, 116, 118 Betacaine 35 Elevess 162, 170 Evolence/Evolence Breeze 50–1 hydrogel polymers 94 infraorbital nerve block 13 Juvéderm 124, 165, 170–1 mixed with filler 8, 10 CaHA microspheres 8, 9, 33 Evolence/Evolence Breeze 50–1 Juvéderm 165, 171

179

Restylane 171 Sculptra 58 Prevelle Silk 160, 170 Puragen Plus 172 silicone 85, 86 tips 11 tissue infiltration 17 topical anesthetics 10, 11 lidocaine tips 11 lipoatrophy see HIV-associated lipoatrophy liquid injectable silicone (LIS) see silicone LMX-4 10 local anesthesia CaHA microspheres 8–10, 33 hyaluronic acids 170–1 hydrogel polymers 94 local tissue infiltration 16–17 mixed with filler CaHA microspheres 8–10, 33 Evolence/Evolence Breeze 50–1 hyaluronic acids 171 Sculptra 58 pre-treatment 10–11 Sculptra 58, 65 sensory nerve distribution in midand lower face 12–16 silicone 85, 86 see also specific anesthetics local tissue infiltration 10, 16–17 low-molecular-weight heparin 136 Luer-Lok syringe CaHA microspheres 8–9, 33 Evolence/Evolence Breeze 51 hydrogel polymers 93 Juvéderm 165 silicone 83 marionette lines 38–9 marketing 2–3 Marquardt, Stephen 141, 145, 146 massage Artefill 117 CaHA microspheres 9, 35, 39 cheek augmentation 150 Evolence/Evolence Breeze 51

180

Index

local tissue infiltration 17 Sculptra 60, 61 mathematics of facial beauty 146–9 combination therapy 153–6 phi 143–6 technique 149–53 medical records 5 mental nerve 12, 13 block 15–16 Metacrill 105, 106, 118 methylprednisolone acetonide 118 microdroplets 85 minocycline 99, 118 mirrors 4 mucosal swabs 11 muscle, and aging process 67 Mycobacterium abscessus 132 NASHA particles 23 nasolabial folds (NLFs), mini-block 13–15 necrosis 134–6 hyaluronic acids 163, 169, 170 nerve blocks 10, 124 infraorbital 12–15 mental 15–16 mini-block 13–15 nerves 12–16 New-Fill 55 NewPlastic 105, 106 nitroglycerin paste 136 nodules 125–8 CaHA microspheres 31 Evolence/Evolence Breeze 47, 51 hydrogel polymers 94, 99 no-shows 7 nursing mothers CaHA microspheres 33 Sculptra 65 off-label treatments 122 Artefill 115 CaHA microspheres 10, 29 hyaluronic acids 162–9, 171 silicone 78, 82, 83, 84 ogee curve 150, 153 Outline 91

Paine, Thomas 140 pain management 11, 123–4 CaHA microspheres 33 Evolence/Evolence Breeze 50–1 silicone 86 see also local anesthesia papules 125–8 particle size of hyaluronic acids 23–5 patient assessment 7 penicillin 39 Perlane 158, 159 crosslinker 21 injection techniques 172 local anesthesia 170 particle size 23–4 phi/Phi 143–6, 149 physical aids, anesthesia 11 polyacrylamide 91, 92 complications 132 polyalkylimide 92 complications 95 polydimethylsiloxane 76 poly-L-lactic acid (PLLA, Sculptra) 54–5, 56, 72 aging face and volume loss, understanding 66–69 complications 71, 126–7, 128 composition and mechanism of action 56–8 contraindications 59, 65 facial analysis and mapping 70–1 history 55–6 patient preparation 65 patient selection 65 predicting outcomes 61–4 preparation and injection technique 58–61 polymethylmethacrylate (PMMA) 103–7 complications 87, 98, 127, 130 granulomas 104, 107, 114, 118–19 contraindications 60 duration 111–13 efficacy 109–13 mechanism 109

Index practical applications 115–18 safety 113–15 porcine collagen see Evolence/Evolence Breeze prednisone 132 pregnancy CaHA microspheres 34 Sculptra 64 silicone 82 Prevelle Silk 158, 160–1 crosslinker 21 local anesthesia 124, 160, 170 price issues 6–7 prilocaine 10, 35, 50, 116 Propionibacterium acnes 97 Protopic 128 public awareness of cosmetic dermatology practice 3 pulse-dye laser 131 Puragen Plus 172 Radiesse (calcium hydroxylapatite (CaHA) microspheres) 37, 40 anesthetic mixed with 8–10 clinical experience 29–31 complications 127–8 considerations 33–40 contraindications 33, 59 duration 31, 40 efficacy 29–31 follow-up treatment 40 injection techniques 34 lower face injections 37–40 midface injections 35–7 nodules 31 pain management 34 pivotal trials 28–9 post-treatment procedures 40 properties and mechanism of action 27–8 radiographic properties 32–3 safety 31–3 radiographic properties, CaHA microspheres 32–3 record keeping 5 refund policy 7 Remington, Kent 147

181

Restylane 158, 159 complications 122, 133–4, 170 crosslinker 21 duration 46 efficacy 46 injection techniques 172 local anesthesia 170, 171 particle size 23–4 safety 47 Ricketts, R.M. 145 Royamid 91 St John’s wort 124 S-Caine patch 10 scarring, hypertrophic 130–1 scheduling of consultations 3–4, 5 Sculptra (poly-L-lactic acid, PLLA) 54, 72 aging face and volume loss, understanding 66–70 complications 71–2, 126–7, 128 composition and mechanism of action 56–8 contraindications 56, 60, 65 facial analysis and mapping 70–1 history 55–6 patient preparation 65 patient selection 65 predicting outcomes 61–5 preparation and injection technique 58–61 selling, organizational 2–3 sensory nerves 12–16 setting for cosmetic patient consultation 2–5 Shakespeare, William 146 side effects see complications silicone 75, 88 basic science 76 complications 86–8, 130, 132 contraindications 82 controversy 78–80 efficacy 79 history 77–8 indications and patient selection 80–2 injection technique 85–6

182

Index

instrumentation 83–4 mechanism of action 76–7 patient preparation 84–5 safety 78–80 and Sculptra 65 skin aging 66 sodium metabisulfite 162 Staphylococcus aureus 95, 97–8 sterile abscesses 132 St John’s wort 124 Streptococcus viridians 97 Suneva Medical, Inc. 109 symmetry, facial 147 Synera 10 tacrolimus 118 “talkesthesia” 11 Teosyal 172 tetracaine 10 timing of consultations 4, 5 tissue infiltration 10, 16–17 topical anesthetics 10–11, 124 Artefill 116 CaHA microspheres 33–4 hyaluronic acids 172 Sculptra 66 silicone 85, 86 training 122 organizational 3, 7 Sculptra 56 silicone 75 triamcinolone 87, 97, 115, 118, 131

triangle of youth 147, 148 trigeminal nerve 12 Tyndall effect 125, 167, 169 ultraviolet-B (UVB) radiation 158 vascular anatomy of midface 170 vibration 11, 124 viscosity Artefill 117 CaHA microspheres 9, 35 Evolence and Evolence Breeze 45, 48, 49, 50, 51 hyaluronic acids 24 Sculptra 60 silicone 76 Zyplast 45 vitamin supplements 124 Vitrase 169 Voluma 166 volume loss 66–70, 147–8 xylocaine 11 Zimmer Chiller 11 Zyderm 43 complications 133 history 44 Zyplast complications 122, 133 efficacy 46, 159, 160–1 history 44 viscosity 45