Polymeric Nanoparticles

Encyclopedia of Nanoscience and Nanotechnology

www.aspbs.com/enn

Polymeric Nanoparticles Bobby G. Sumpter, Donald W. Noid, Michael D. Barnes Oak Ridge National Laboratory, Oak Ridge, Tennessee, USA

Joshua U. Otaigbe University of Southern Mississippi, Hattiesburg, Mississippi, USA

CONTENTS 1. Introduction 2. Synthetic Routes for Polymeric Nanoparticles 3. Supercritical Fluid-Based Particle Production 4. Droplet and Aerosol Techniques 5. Gas Atomization Approaches 6. Dendrimers, Hyperbranched Polymers, or Star Polymers 7. Molecular Imprint Polymers 8. Simulation and Modeling of Polymer Particles 9. Applications of Polymer Particles 10. Polymer Particle Patent Review 11. Conclusions Glossary References

1. INTRODUCTION Science and technology continue to witness enormous attention focused on the production of new materials on the micrometer and nanometer scale that have tunable material, electrical, and optical properties. Polymer particles, polymer particle alloys, or polymeric composites provide one viable avenue for the production of these highly desired systems. Currently, polymer particles can be produced in a variety of ways, some of which allow easily controllable particle size and composition as well as a number of crucial physical properties [1–12]. In addition, recent results have shown that polymeric particles in the micro- to submicrometer range can be formed such that dynamical confinement effects result in interesting nanostructures and properties that cannot be produced using conventional methods [2]. ISBN: 1-58883-064-0/$35.00 Copyright © 2004 by American Scientific Publishers All rights of reproduction in any form reserved.

Polymer particle wires and arrays, “supramolecular particle structures,” have also been produced which offer another set of exciting possibilities [4]. These combined capabilities open the door to a variety of novel uses, such as electrooptic and luminescent devices, magnetic coatings, thermoplastics and conducting materials, hybrid inorganic–organic polymer alloys, polymer-supported heterogeneous catalysis, high-energy-density materials, information materials, and a whole host of applications in the biomedical field [6–16]. In this chapter we review some of the recent progress in the production and characterization of polymer particles and provide examples of a number of relevant applications. Our intent is to provide a general overview of the various areas and methods relevant to polymeric particles. Since there is a very large literature base for each of the topics discussed in the following sections, we have tried to provide some general references where more extensive literature citations can be found.

2. SYNTHETIC ROUTES FOR POLYMERIC NANOPARTICLES The synthesis of polymeric nanoparticles in large and homogeneous quantities has received considerable attention in polymer and materials science [17–73]. Much of the motivation has been derived from the incredibly broad and often unique applications of polymeric particles (see later sections for details). To date most of the synthetic production of polymer particles generally falls within two primary approaches. The first approach is based on the emulsification of the water-immiscible organic solution of the polymer by an aqueous phase containing a surfactant, followed by evaporation of the solvent. The second approach is based on the precipitation of a polymer after addition of a nonsolvent of the polymer. On the other hand, nanoparticles formed of natural macromolecules are generally obtained by thermal denaturing proteins (such as albumin) or by a gelification process, as in the case of alginates. Encyclopedia of Nanoscience and Nanotechnology Edited by H. S. Nalwa Volume 8: Pages (873–903)

874 In the past, polymer latexes (suspensions or dispersions of polymer particles) were largely made by conventional emulsion polymerization but this method is mostly suitable for only radical homopolymerization of a narrow set of barely water-soluble monomers. To broaden the range of possible polymeric systems a number of new techniques for generating micro- and miniemulsions, phase inversions, secondary dispersions, and suspension polymerizations have been developed and successfully implemented. Figure 1 illustrates some of the types of polymerization methods available for producing polymer particles and the corresponding particle size range. We discuss a number of these techniques and their applicability to the production of polymeric nanoparticles. Our discussion is only meant to give a flavor of the various polymerization routes for producing polymer particles. There are a number of reviews and books dedicated to these methods and more complete details are better obtained from those references and references cited therein [17–26].

2.1. Emulsion Polymerization Emulsion polymerization as a conventional preparation method can make polymeric particles in the size range of 100–1000 nm, a range that has been gradually broadened [17, 18, 27–39]. For example, the seeded emulsion polymerization technique was developed to make latexes larger than 1000 nm, while the miniemulsion and microemulsion polymerizations were designed to prepare particles in the ranges 50–200 and 20–50 nm, respectively (see Fig. 1). Emulsion polymerization is a widely used industrial process for making coatings, paints, adhesives, and resins. Monomers used in emulsion polymerization are typically only sparingly soluble in water although a few percent of water-soluble co-monomers are often added to enhance stability. Both ionic, such as sodium dodecyl sulfate or sodium dodecyl benzene sulfonate, and nonionic surfactants are used to produce the emulsions. A typical polymer emulsion

Polymeric Nanoparticles

formulation contains a water-soluble initiator such as potassium persulfate, an organic phase consisting of monomers dispersed in 1–20 micrometer droplets, and a surfactant that is above its critical micelle concentration. The surfactant causes a high concentration of monomer-swollen micelles to form in the aqueous phase. As the system is heated, the initiator decomposes to give aqueous phase radicals that propagate with small amounts of monomer dissolved in the aqueous phase. The newly forming radicals become hydrophobic very quickly and enter the micelles where they initiate polymerization of particles. Particle nucleation continues until all of the micelles either have been nucleated to form polymer particles or have been dispersed. As long as there are monomer droplets in the system, homogeneous nucleation can continue to take place. Once the micelles have been depleted, the polymer particles continue to grow by using monomer diffusing through the aqueous phase. Particle growth is continued until all of the monomers in the aqueous phase have been depleted. One of the critical elements of emulsion polymerization is the formation of micelles which act as compartmentalized reaction chambers. This is how emulsion polymerization can produce reasonably small particles. Polymerization conducted in dispersed aqueous systems, such as suspension polymerization, produces relatively large polymer particles (20–1000
m).

2.1.1. Soap-Free Emulsion Polymerization In emulsion polymerization, surfactants play important roles such as maintaining the polymer particle stability, controlling the particle size, distribution, latex surface tension, and latex rheological properties. Clearly the choice and amount of surfactants significantly affect the polymer latex performance. For example, improper surfactant choice may lead to foaming, which in turn causes surface defects and decreased water resistance. Also the amount of the surfactants is the key factor to control new particle generation in the case of seeded polymerization. Unfortunately, surfactant molecules used in emulsion polymerization do not always stay tightly on the surface of particles but repetitively undergo desorption and absorption. These molecules are not easily removed from the final latex product and can often interfere with applications to systems that are not compatible with this type of latex contaminant. To overcome this type of problem, two techniques were developed, soap-free emulsion polymerization or the use of polymerizable surfactants [30, 31]. Soap-free emulsion polymerization can produce functional polymer particles in the submicrometer size range. Water is usually used as the continuous phase in soap-free polymerization. The polymer particles formed during soap-free emulsion polymerization retain their stability by electrorepulsive forces between ionic fragments on the particle surfaces or sequences.

2.1.2. Miniemulsion Polymerization

Figure 1. Particle size range achieved for different synthetic polymerization techniques.

Miniemulsion polymerization shares many of the fundamental principles with emulsion polymerization, most importantly compartmentalization [19, 32, 33]. Miniemulsions are specially formulated heterophase systems where stable nanodroplets of one phase are dispersed in a second

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continuous phase (see Fig. 2). This system is created by using an appropriate combination of high shear treatment, surfactants, and the presence of an osmotic pressure agent that is insoluble in the continuous phase. Nanodroplet stability is obtained by adding an agent that dissolves in the dispersed phase but that is not soluble in the continuous phase. A simple example is a typical oil–water miniemulsion, where oil, a hydrophobic agent, an emulsifier, and water are homogenized by high shear to obtain homogenous and monodisperse droplets in the size range of 30 to 500 nm. The generality and potential of the miniemulsion method lay in the fact that since each of the droplets is basically an individual batch reactor, a whole variety of polymerization reactions can be performed, thus significantly extending the profile of classical emulsion polymerization. Radical homopolymerization, copolymerization, catalytic chain transfer, controlled free radical polymerization, polyaddition reactions, metal catalyzed reaction, among others have all been utilized to produce polymer particles using the miniemulsion technique. Due to this large range of possible polymerization reactions and the nearly unlimited number of possible monomers that can be used for the formation of particles, a wide variety of polymeric particles have been produced using miniemulsion technology. Examples include numerous homopolymers, in particular polystyrene, poly(methyl methacrylate), poly(vinyl chloride), poly(acrylic acid), poly(n-methylol acrylamide), polyacrylonitrile, etc., polymer–polymer hybrids, encapsulated pigments, carbon black, and liquid, silica, and composite particles. A useful list of characteristics for determining if a system represents a miniemulsion has been compiled by Antonietti and Landfester [19]. They discuss seven items that should be present. (1) Dispersed miniemulsions in a steady state are stable against diffusional degradation but critically stabilized with respect to colloidal stability. (2) The interfacial energy between the oil and water phase is significantly greater than zero and the surface coverage of the droplets by surfactant molecules is incomplete.

(3) The formation of a miniemulsion requires high mechanical agitation to reach a steady state. (4) The stability of droplets against diffusional degredation originates from an osmotic pressure within the droplets that controls the solvent or monomer evaporation. (5) Polymerization occurs by droplet nucleation only. (6) The growth of droplets during polymerization can be suppressed. (7) The amount of surfactant or inherent surface stabilizing groups required to form a polymerizable miniemulsion is small compared to other polymerizations.

2.1.3. Microemulsion Polymerization Miniemulsions are defined by the mode of operation instead of a size range and are fairly easy to distinguish among most other heterophase polymerization methods. However, it can be confusing to find in the literature another method called microemulsion polymerization. Microemulsions are formed by mixing water, a hydrophobic compound, and suitable emulsifiers [20, 34, 35]. The medium is a multicomponent liquid that exhibits long-term stability, has low viscosity, and is optically transparent and isotropic. In microemulsions, the polymerization starts from a thermodynamically stable state that is spontaneously formed. This is generally achieved by using large amounts of specialized surfactants or mixtures that have an interfacial tension at the oil–water interface that is near zero. The microdroplets formed consist of a spherical organic core surrounded by a monomolecular shell of emulsifier molecules whose polar groups are in contact with the continuous aqueous phase. Initiation of polymerization is not simultaneously obtained in all of the microdroplets and therefore only some of the droplets contain the first polymer chains formed. These chains influence the stability of the microemulsion and can lead to an increase in the particle size and secondary nucleation. Latexes formed via microemulsions typically consist of relatively small polymer particles in the range of 5–50 nm but the particles are often mixed among numerous empty micelles. However, a variety of elaborate surfactants (mixtures of cationic and anionic salts) have been utilized to significantly alter the final polymer particle size, surfactant content, and distribution. The essential features of microemulsion polymerization are: (1) polymerization proceeds under nonstationary state conditions; (2) size and particle concentration increase throughout polymerization; (3) chain transfer to monomer/exit of transferred monomeric radical–radical reentry events are operative; and (4) molecular weight is independent of conversion and distribution of the resulting polymer broad. Microemulsion and inverse microemulsion polymerization have been used to produce a variety of polyacrylate latex particles, water-soluble nanoparticles, and conductive polymeric particles.

2.1.4. Inverse Emulsions Figure 2. Fundamental principles involved in miniemulsion polymerizations.

The advantage gained by emulsion stabilization is not restricted to only direct micro- and miniemulsions but can easily be extended to inverse emulsions [21, 36, 37]. Polymer

876 spheres in the nanometer range, below 200 nm in diameter, can be produced through this standard technique that involves the use of an inverse emulsion—a clear mixture of water in oil also containing a surfactant. The water-in-oil inverse emulsion contains pools of water surrounded by oil molecules. These water droplets can be used as miniature nanoreactors to produce nanoparticles by adding the right amount of monomer into the solution. The chemical thermodynamics governing the emulsion drives the monomer molecules added into the solution directly into the water droplets. The polymerization reaction occurs inside the water droplets, triggered by the addition of an appropriate initiator substance into the system. The microscopic polymerization process inside the tiny water droplet is similar to macroscopic polymerization. One advantage at this stage of particle formation is that drug molecules can be taken up and effectively encapsulated. The nanoparticles formed assume the spherical shape of the water droplet with the size of the resulting nanoparticle being restricted by the diameter of the water droplet. Applications of the inverse emulsion polymerization to micro- and miniemulsions are the most common. For miniemulsions, osmotic pressure is built up by an insoluble agent such as an ionic compound, in the continuous phase. The droplet size finds an equilibrium state which is characterized by a dynamic equilibrium rate between fusion and fission of the droplets and the droplet size seems to be only dependent on the quantity of the osmotic agent. There appears to be a zero effective droplet pressure that results from a balance between the osmotic pressure and the Laplace pressure. As such, inverse miniemulsions do not appear to be as critically stabilized as that for direct miniemulsions but instead are stable systems. Nevertheless, surfactants can be used in a relatively efficient manner for inverse miniemulsion polymerization, especially when compared to inverse microemulsion and inverse suspension polymerizations.

Polymeric Nanoparticles

miniemulsion and suspension polymerization is that suspension polymerization utilizes much larger monomer droplets dispersed in the continuous phase.

2.3. Precipitation and Dispersion Polymerization Dispersion polymerization can be considered an intermediate technique between homogenous and heterogenous polymerizations [24, 39–43]. All reagents are initially soluble in the medium and produce an insoluble polymer which precipitates out as the polymerization proceeds. By using soluble polymer stabilizers, polymer particles can be produced. The particle stability is primarily controlled by steric effects. A good example of successful dispersion polymerization is the preparation of polyphenol particles. In this work, peroxidase-catalyzed dispersion polymerization was performed by using a water-soluble polymer stabilizer in aqueous 1,4-dioxane and poly(vinyl methyl ether) in a 40% phosphate buffer solution as a steric stabilizer. This work produced relatively monodisperse particles in the submicrometer range. Similar particles of m- and p-cresols and p-phenylphenol have also been produced using the same type of synthetic procedure. In precipitation polymerization, a polymer is generally precipitated out of solution by adding a nonsolvent of the polymer [25]. The primary polymer particles do not form into colloids but remain in a loose slurrylike form. This occurs since no stabilizer or block copolymer is added to the medium and therefore no steric barrier for particle stability is formed. Polymerization can occur in both the continuous and dispersed phase. Careful control of the kinetics can give polymer materials with a wide range of particle sizes (see Fig. 1). For example polymeric spherical particles with an average size of 160 nm have been prepared by precipitation of the particles which was facilitated by the increasing molecular weight of the polymer or from increased cross-linking.

2.2. Suspension Polymerization

2.4. Seeded Polymerization

Another polymerization method that has many similarities to the emulsion methods is suspension polymerization [22, 38]. In this synthetic method a water-insoluble monomer is dispersed in the continuous phase as liquid droplets via vigorous stirring. An oil-soluble initiator is used to begin polymerization inside the monomer droplets. Droplets are kept from adhesion and coalescence by the presence of a small amount of stabilizer. Nearly all of the nucleation occurs in the droplets which act as isolated batch polymerization reactors. The larger droplet size causes the droplet pressures to be much smaller which leads to Ostwald ripening at a considerably slower rate than in miniemulsions. The final polymer particle size has been found to depend on the stirring speed, volume ratio of the monomer to water, concentration of the stabilizer, the viscosity of both phases, and the design of the reaction vessel. When a properly designed reactor and well-stabilized suspension is used, monodisperse polymer particles can be produced. The final product is generally limited to polymeric particles in the size range of 20–2000
m. The main difference between

Polymerization based on using a previously formed polymer particle or one that is created during the process but altered by swelling followed by chemical reactions is usually referred to as seeded polymerization. Seeded polymerization can be accomplished using many of the previously discussed synthesis techniques, in particular emulsion and dispersion polymerization [23, 34–42]. Synthesis based on seeded polymerization can be used to produce porous polymer particles as well as composite, core–shell, and hollow structures. The porosity of the particles produced by a seeded polymerization technique has been found to be dependent on the molecular weight of the seed polymer. As the molecular weight of the seed increases, the porous particles produced can become macroporous. One drawback of seeded polymerization is that the final particle diameter is limited by the size of the initial polymer particle seed. Monodisperse submicrometer polymer particles are not easily obtained using seeded polymerization but particles from 1 to several hundreds of micrometers appear to be readily producible. For example, extremely uniform

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polymeric particles have been successfully produced using the seeded polymerization techniques. In a rather elaborate study, a repeated seeded emulsion polymerization in a nongravitational field was used to generate uniform polymeric microspheres up to 100
m in size. Ugelstad et al. performed a two-step swelling technique and achieved similar results [42, 43]. This method is characterized by the use of an oligomer of extremely low solubility in water as an effective swelling agent. In order to produce larger particles, from 0.5 to 100
m, which have applications in areas such as polymer coating emulsions that are resistant to shear thinning, Ito et al. used a seeded emulsion polymerization procedure [47]. Controlled coagulation induced by the formation of secondary polymers with opposite charge to the surface of the seed particles was achieved. They studied and characterized the effects of agitation rate, size of the polymer seed particles, and the pH or the reaction mixture. A variety of seeded polymerization methods have been used to produce monodisperse micrometer-sized polymeric particles. Many of these studies were based on using a swelling stage during the overall process. For example, a dynamic selling method makes the seed polymer absorb a large amount of swelling monomers by treating the monomer soluble in the medium with slow, continuous, dropwise addition of water. Many of the conventional emulsion and dispersion seeded polymerization techniques use seed particles consisting of linear polymers for the initial swelling stage. This is due to difficulty associated with preparing micrometer-sized seed particles with a crosslinked network structure. Some success has been reported in using a two-stage swelling process of cross-linked seed particles. The effect of seed cross-linking on monomer swelling and final particle morphology reveals a strong dependence. Core–shell composite polymer particles can also be efficiently produced using seeded polymerization. A seeded dispersion polymerization method was reported to yield micrometer-sized monodisperse polymethyl methacrylate (PMMA)/polystyrene (PS) composite particles consisting of a PMMA core and a PS shell. This study suggested that seeded dispersion polymerization, in which almost all monomers and initiators exist in the medium with seed particles having higher glass transition temperature than polymerization temperature, has an advantage for producing core–shell polymer particles. In particular, polymer layers tend to accumulate in their order of formation, even if the morphology is unstable thermodynamically.

2.5. Self-Assembly of Block and Ionic Polymers Surfactant-free polymeric nanoparticles, something that is extremely difficult to achieve via most synthetic routes, can be produced by taking advantage of the self-assembly of block copolymers and ionomers in a selective solvent [26, 53–73]. Self-assembly of block copolymers can be successfully induced by a variety of methods including chemical reaction, polymer–polymer complexation, microphase inversion, temperature control, and a microwave method. Most of these techniques produce core–shell nanoparticles

but have the advantage that nanoparticles are surfactantfree. In addition, core–shell structures are often desirable for many uses in biomedicine (see later sections). Poly(styrene-block-(2,-bis-[4-methoxyphenyl]oxycarbonyl) styrene) nanoparticles have been prepared via self-assembly by using temperature control. The particles are formed with a core–shell structure by using temperature and p-xylene as a solvent. The temperature-induced self-organization is achieved due to the solubility of the rod-shaped poly([4methoxyphenyl]oxycarbonyl)styrene block in p-xylene (soluble above 100
C). Temperature controlled selforganization was also used to produce nanoparticles of poly(N -isopropylacrylamide) (PNIPAM) grafted with short poly(ethylene oxide) chains. Both of these polymers are soluble in water at room temperature, but at higher than 32
C, PNIPAM becomes hydrophobic and undergoes an intrachain coil-to-globule transition and an interchain aggregation to form nanoparticles. By controlling the formation conditions, interchain association can be completely suppressed and a single-chain core–shell nanoparticles are formed. -- -caprolactone) Core–shell poly(ethylene oxide-block-C (PEO-b-PCL) diblock copolymer nanoparticles that are stable in water have also been produced using a microphase inversion technique. In this work, tetrahydrofurane was used as the primary solvent which was suddenly replaced by a nonsolvent, water. This leads to the aggregation of the water insoluble polymeric block, PCL, and to the formation of a core, while the soluble block, PEO, formed a protective corona. Since these core–shell nanoparticles have been shown to be biodegradable in the presence of Lipase PS, they have important applicability to drug delivery. Complexation between multiple polymer blocks has been used to generate stable core–shell nanoparticles. Polyacrylate and PMMA can be complexed with hydroxyl-containing polystyrene [PS–(OH)] in toluene to form insoluble particles. Successful implementation of this concept was achieved by using poly(styrene–block–methyl methacrylate) diblock copolymer complexed with hydroxyl containing polystyrene. Complexation of the PMMA block and the PS–(OH) led to an insoluble core, while the soluble PS blocks prevent macroscopic precipitation. The final product was stable nanoparticles whose particle size could be regulated by the initial concentrations of the two components and by the mixing order. Microwave irradiation can also be used to facilitate the formation of polymeric nanoparticles. Stable polystyrene nanoparticles were formed by using microwave radiation in the presence of potassium persulfate in water. This method substantially reduces the reaction time (factor of 20) and produces narrowly distributed nanoparticles. Particle size can be controlled by varying the monomer-to-initiator weight ratio.

2.6. Polyanionic Solution-Based Both continuous and batch processes have been developed which use a polyanionic solution that is atomized into a swirling polycationic solution to form polymeric nanoparticles [74–81]. This method of production is often referred to as titration since a sequential addition of one polymer into another is performed. By varying the ratios of

878 polyanion to polycation, a variety of nanoparticle compositions can be produced. One advantage of this method is that all solutions are made using water as a solvent which eliminates the possibility of having trace amounts of organic solvents of surfactants within the nanoparticles (a serious problem for medical applications). The polyanionic method is intimately effective for generating core–shell nanoparticles. In a typical process, the anionic solution (droplet-forming) forms the core and the cationic solution (receiving solution) forms the corona or shell. This is the most common setup and is often referred to as the standardized system; however, there are examples of the reverse where a droplet-forming cationic solution is mixed with an anionic receiving solution. A typical batch system is composed of a needle connected to a syringe that is inserted into an ultrasonic hollow titanium probe with a conical tip. The probe is connected to a transducer and power generator which is used for nebulizing the solution. An anionic polymer solution is introduced into the syringe and slowly extruded through the needle and the probe tip where it is atomized by the transducer. The atomized anionic mist is released into air above a container of the cationic solution which is vigorously swirled during the reaction (1–2 min). As mentioned previously the anionic solution is generally used as the droplet-forming internal phase mixture (core polymer) and the cationic solution is used as the receiving batch mixture (corona or shell polymer). A reverse system simply uses the same setup but introduces a cationic mixture into the syringe to form the mist that is received by an anionic solution. The batch system described can be modified into a continuous system by using two inflow lines, one for the anionic solution and one for the cationic solution, and one overflow line to keep the receiving bath volume constant. This mode of operation produces nanoparticles of similar quality to the batch system.

2.7. Polyelectrolyte Complexes Polymeric nanoparticles formed from macroscopic homogeneous colloidal systems can be prepared by aggregates of a high molar mass polyion species of weak charge density (called the host) with a much shorter lower mass macromolecular counterion (called guest) [82, 83]. Through continuous addition of the guest reactant, polymer nanoparticles form as colloidal particles that aggregated and precipitate. By altering the ratio of the host to guest, a variety of compositions can be produced. This technique is similar to the polyanionic solution based methods described previously and share similar advantages. In particular, multipolymeric water-soluble mixtures of two interacting pairs enable a template assembly of the nanoparticles. There is no use of organic solvents or surfactants and the process offers a high flexibility in choosing reacting pairs.

3. SUPERCRITICAL FLUID-BASED PARTICLE PRODUCTION Supercritical fluids (SCFs) are substances that are above their critical temperature and critical pressure [84]. These substances often have densities and solvating capabilities

Polymeric Nanoparticles

similar to those of a typical liquid but have diffusivity and viscosity comparable to that of gases, making them ideal solvents. These unique properties provide great promise as a versatile, environmentally acceptable replacement for conventional solvents. Indeed SCFs have been used fairly extensively for extractions, in particular for coffee and tea decaffeination, natural product extraction, and chromatography. More recent applications of SCF technology have been in the area of processing such as mixing, impregnation, encapsulation, reaction, crystal growth, etc. [85–97]. The most used SCF has been carbon dioxide (CO2 . This is primarily because supercritical carbon dioxide (scCO2  has an easily achievable critical point of 31.1
C and 73.8 bars and is nontoxic, cheap, nonflammable, and environmentally acceptable and may be recycled. The use of SCFs in polymer science has begun to witness an increase in popularity and a number of successful production techniques for polymeric particles have been reported [75–87]. Recently polymer-based nanoparticles have been produced by these alternative methods using supercritical fluid technology. Particles that have been produced using SCF technology tend to have characteristics that are strongly influenced by the properties of the solute, the type of SCF used, and the processing parameters (such as flow rate of solute and solvent phase, temperature and pressure of the SCF, pre-expansion temperature, nozzle geometry, and the use of coaxial nozzles). For example, polymer properties such as polymer concentration, crystallinity, glass transition temperature, and polymer composition are important factors that determine the final morphology of the particles. An increase in the polymer concentration can lead to the formation of less spherical and fiberlike particles. In an antisolvent process, the rate of diffusion of antisolvent gas is higher in a crystalline polymer compared to an amorphous polymer leading to high mass transfer rates in crystalline polymers that produces high supersaturation ratios and small particles with a narrow size distribution. Since SCFs act as plasticizers for polymers by lowering their glass transition temperatures Tg, polymers with a low Tg tend to form particles that become sticky and aggregate together. A change in polymer chain length, chain number, chain composition, and branching ratio can alter polymer crystallinity and thus the particle morphology. Core–shell particle structures can be produced by using an intimate mixture under pressure of the polymer material with a core material either before or after SCF solvation of the polymer, followed by an abrupt release of pressure which leads to solidification of the polymeric material around the core material. This technique has been successfully used to microencapsulate infectious Bursal Disease virus vaccine in a polycaprolactone or a poly(lactic-co-glycolic acid) matrix. There have been a reasonable number of drug and polymeric microparticles prepared using SCFs as both solvents and antisolvents. Particles from 5 to 100
m were the first to be produced using an array of solutes including lovastatin, polyhydroxy acids, and mevinolin. Further work in the past decade has lead to the simultaneous co-precipitation of two solutes, a drug, an excipient, and poly(lactic acid) (PLA) particles of lovastatin and naproxen. In these studies, supercritical CO2 was passed through an extraction vessel containing a mixture of drug and polymer, and the CO2

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containing the drug and the polymer was then expanded through a capillary tube. In another process, PLA and clonidine were dissolved in methylene chloride, and the mixture was expanded by supercritical carbon dioxide to precipitate polymeric drug particles. Similar to polymeric particles produced using SCF technology, the properties of the drugs such as solubility and partitioning of the drug into SCF determine the properties of the particles formed. For example, if the drug is soluble in a SCF under the operating conditions, it will then be extracted into the SCF and will not precipitate out. It has been observed that steroids with log P (the log of the partition coefficient) values between 1.6 to 3.9 formed spherical nonporous particles, whereas steroids with log P of 4.2 or 4.3 were extracted out into the SCF. The properties of the drugs also play an important role during encapsulation of a drug in a polymer matrix. There are strong influences of the properties of the drug on the drug loading. PLA-microparticle formation using an antisolvent process with supercritical CO2 indicated that an increase in log P decreases the loading efficiency as well as release rate, possibly because lipophilic drugs can be entrained by supercritical CO2 during SCF precipitation. Nucleation and growth rate influence the effective encapsulation and morphology of the particles. If the initial nucleation and growth rate of the drug is rapid and the polymer precipitation rate is relatively slow, then the drugs can form needles encapsulated in polymeric coat. SCF technology is currently claimed to be useful in producing particles in the 5 to 2000 nm range. U.S. Patent 6, 177, 103 describes a process that rapidly expands a solution of the compound and phospholipid surface modifiers in a liquefied gas into an aqueous medium, which may contain the phospholipid. By expanding into an aqueous medium, particle agglomeration and growth are prevented, thereby producing particles of a narrow size distribution. An additional step may be required to remove the aqueous phase if the final product is a dry powder. To achieve commercial success, the methods or techniques developed need to be scaled up to produce batch quantities for conducting further research or for marketing the product. The advances in the understanding of the mechanism of supercritical particle formation and SCF mass transfer are forming the basis for efficient scale-up of the laboratory-scale processes. While many laboratory investigators were only able to produce milligrams of the product, a scaled process that was capable of producing 200 g of biodegradable PLA particles in the size range of 6 to 50
m has been developed. Cost of manufacturing at the pilot scale with SCF technology has been claimed to be comparable to several conventional techniques, such as single-stage spray drying, micronization, crystallization, and milling batch operations. Thus from the perspective of scale-up, SCF technology appears to offer some advantages. The processing equipment can be a single stage, totally enclosed process that is free of moving parts and constructed from highgrade stainless steel, allowing easy maintenance. It offers reduced solvent requirements and particle formation occurs in a light-, oxygen-, and possibly moisture-free atmosphere, minimizing these often confounding factors.

4. DROPLET AND AEROSOL TECHNIQUES Many nonsynthetic methods for producing polymeric particles are based on nebulization or piezoelectric droplet generation of very dilute polymer solutions [98–111]. Over the last several years, advances in microdroplet production technology for work in single-molecule detection and spectroscopy in droplet streams has resulted in generation of droplets as small as 2–3
m with a size dispersity of better than 1%. In the context of polymer particle generation, droplet techniques are attractive since particles of essentially arbitrary size (down to the single polymer molecule limit) can be produced by adjusting the size of the droplet of polymer solution, or the weight fraction of the polymer in solution. While droplet production in the size range of 20–30
m (diameter) is more or less routine (several different ondemand droplet generators are now available commercially), generation of droplets smaller than 10
m remains nontrivial especially under the added constraint of high monodispersity. Small droplets (<10
m) are especially attractive as a means for producing multicomponent polymer-blend and polymer-composite particles from solution since solvent evaporation can be made to occur on a millisecond time scale, thus inhibiting phase separation in these systems. The primary condition for suppression of phase separation in these systems is that solvent evaporation must occur on a time scale that is faster than the self-organization times of the polymers. This implies time scales for particle drying on the order of a few milliseconds implying droplet sizes <10
m (depending on solvent, droplet environment, etc.). It was shown recently that a microdroplet approach can be used to form homogeneous composites of co-dissolved bulk immiscible polymers using instrumentation developed in our laboratory for probing single fluorescent molecules in droplet streams. In addition to a new route to forming nanoscale polymer composites, a microparticle format offers a new tool for studying multicomponent polymer blend systems confined to femtoliter and attoliter volumes, where high surface area-to-volume ratios play a significant role in phase separation dynamics. Several different choices exist for producing micrometer and submicrometer droplets of solution–each with certain trade-offs in terms of volume throughput, nominal size, and size dispersity. There are additional trade-offs associated with sampling and interrogation facility that should be considered as well. Two familiar methods of droplet production include electrospray generation and aerosol generation using a vibrating orifice coupled to a high-pressure liquid stream. In electrospray generation, a liquid stream is forced through a needle biased at approximately 1 kV (nom.). Charge carriers induced on the surface of the liquid stream eventually come close enough during solvent evaporation for Coulomb repulsion to occur (the Taylor cone), resulting in fragmentation, or explosion, of the liquid stream. This results in a cloud of charged liquid droplets whose size can be made quite small (<1
m). The obvious drawback is that it is difficult to isolate individual particles for study, and size dispersity tends to be highly sensitive to experimental parameters. Another common method of

880 producing liquid droplets is the technique of vibrating orifice aerosol generation (VOAG). Invented by Berglund and Liu back in the 1970s, the VOAG is unmatched in terms of volume throughput (>100 nanoliters per second) and size dispersity (<0.1% depending on experimental conditions). This technique works by introducing a high-frequency (10 to 100 kHz) instability in a high-pressure liquid stream applied by a piezoelectric transducer (PZT). The resulting fragmentation of the stream produces highly monodisperse droplets that are ultimately limited by the purity of the radio frequency (rf) signal applied to the PZT. Some disadvantages of this mode of production are that the droplets travel at high speeds (several meters/second) and are quite close together (typically no more than 3 droplet diameters apart). This makes isolation and spectroscopic interrogation of individual droplets difficult. A more serious problem is in the significant particle size limitations associated with this technique. A VOAG works best at a size range of 30–50
m but can function down to about 12–15
m. Because of the way droplets are produced, however, there is a concomitant increase in the rf frequency that can be problematic. The method we have chosen in our experiments is an “on-demand” or droplet ejection device. Like a VOAG, it also uses piezoelectric transduction but at much lower frequencies. The physics of droplet production is completely different for the two methods: The VOAG operates by generating a high (and fixed) frequency instability in a liquid stream; the on-demand droplet generator functions by the application of a acoustic wave to a static solution, which forces (ejects) a droplet out of a micrometer sized orifice. We use Pyrex or quartz tubing that is heated, drawn, cut, and polished to produce a tapered orifice that can range in size from 1 to 50
m. The droplet sizes are comparable (usually slightly larger) to the orifice diameter and, depending on the quality of the orifice, size dispersity less than 1% can be achieved. Droplet production rates tend to be significantly lower than the aforementioned techniques. Ultimately, droplet rates are limited by piezoelectric relaxation times (10 kHz); practically, however, under conditions of high monodispersity, droplet rates are typically much lower (20–100 Hz). The advantages of this technique are small size and on-demand production that makes single droplet/particle manipulation and interrogation straightforward.

Polymeric Nanoparticles

Recently some interest has focused on trying to suppress phase separation in mixed polymer systems by very rapid solvent evaporation from small (≤10
m diameter) droplets of dilute polymer solution. Using instrumentation developed for probing single fluorescent molecules in 1–10
m diameter droplet streams [117], detailed exploration of microdroplets to form homogeneous polymer composites without compatibilizers as a possible route to new materials with tunable properties has been accomplished [118]. From these studies it has been shown the primary condition for suppression of phase separation in such systems is that solvent evaporation must occur on a time scale that is fast compared to selforganization times of the polymers. This implies time scales for particle drying on the order of a few milliseconds which would require droplet sizes ≤10
m (depending on solvent, droplet environment, etc.). In addition to this new route to forming nanoscale polymer particle composites, a microparticle format offers a new tool for studying multicomponent polymer blend systems confined to femtoliter and attoliter volumes where high surface area-to-volume ratios play a significant role in phase separation dynamics. Figure 3a illustrates qualitatively the effect of phase separation on optical diffraction fringe contrast and definition for two polymer-blend particles prepared from different sized droplets of co-dissolved polymers (polyvinyl chloride and polystyrene) in tetrahydrofuran. The particle on the left is homogeneous as evidenced by uniform fringe intensity, and high-fringe contrast and definition. Moreover, the scattering data can be matched quantitatively to Mie theory calculations that assume a homogeneous and spherical particle. The particle on the left has no discernible fringe structure but does display interesting periodic “island” structure implying some order and uniformity of phase-separated domains.

4.1. Tailoring the Properties of Polymer Particles Composite polymer particles, or polymer alloys, with specifically tailored properties could find many novel uses in a number of fields. However, the problem of phase separation from bulk-immiscible components in solution often poses a significant barrier to producing many commercially and scientifically relevant homogeneous polymer blends [112–114]. The typical route taken in trying to form homogeneous blends of immiscible polymers is to use compatibilizers to reduce interfacial tension. A number of different groups have examined phase separation in copolymer systems to fabricate fascinating and intricate meso- and microphase separated structures with a rich variety of morphologies [115, 116].

Figure 3. (a) See [118, 119]. (b) See [119].

Polymeric Nanoparticles

Figure 3b shows molecular dynamics simulations of a stable polymer-blend particle (10 nm diameter) composed of immiscible components. The leftmost particle remains homogeneous throughout a broad temperature range. For phase separation to occur (right), an enormous amount of thermal energy must be supplied in order to overcome the surface energy barrier. This result agrees qualitatively with the observation that homogeneous blends of bulk-immiscible polymers can be formed in spherical microparticles. The composite particle was calculated to have a single melting temperature of 190 K and glass transition temperature of 90 K which is different than either of the polymer components (Tm 218 K, Tg 111 K for light and Tm 162 K, Tg 81 K for dark). The segregated particle has two melting points and glass transition temperatures that correspond to within 10 K of the individual components. Formation of homogeneous polymer-blend composites from bulk-immiscible co-dissolved components using droplet techniques has two requirements. First, solvent evaporation must occur on a relatively short time scale compared to polymer translational diffusion. Second, the polymer mobility must be low enough so that, once the solvent has evaporated, the polymers cannot overcome the surface energy barrier and phase-separate. It was previously shown definitively the effects of droplet size and solvent evaporation, and the second requirement is almost always satisfied even for modest molecular weight polymers. To explore effects of polymer mobility in detail, composite particles of poly(ethylene glychol) (PEG) oligomers (MW 200, 400, 1000, and 3400) with medium molecular weight (14 K) atactic poly(vinyl alcohol) (PVA) were produced [120]. This type of system allowed systematic examination of the phase separation behavior where one component (PEG) had substantially different viscosities (specified as 4.3, 7.3, and 90 cSt at room temperature, respectively). Higher molecular weight PEG polymer-blend particles were shown to be homogeneous by utilizing bright-field microscopy, optical diffraction, and fluorescence imaging. Blend particles prepared with the 200 molecular weight PEG were observed to form sphere-within-a-sphere particles with a PVA central core. Figure 4 shows diffraction data acquired from particles at successive 10 min intervals from a 10
m diameter PEG[200]/PVA[14 K] (80:20 w/w) particle. As shown in the first frame, the particle is initially homogeneous. The second and third frames indicate that the composite particle undergoes phase separation into an inhomogeneous particle as evidenced by the fringe distortion. Interestingly, the structure in the twodimensional (2D) diffraction data for this system is much different than those observed for large phase-separated

Figure 4. See [119].

881 PVC/PS particles that presumably coalesce into submicrometer spheroidal domains. On the basis of fluorescence and phase-contrast imaging data, PEG[200]/PVA[14 K] particles form spherically symmetric (sphere-within-a-sphere) heterogeneous structures, which should also produce welldefined diffraction fringes. The interpretation of these data was that diffusional motion of the PVA core in the PEG host particle, combined with rotational diffusion of the particle, breaks the spherical symmetry and thereby introduces distortion in the diffraction pattern. This observation is entirely consistent with our model of polymer-composite formation where heterogeneous particles may be formed provided that the mobility of one of the polymers is low enough to overcome the surface energy barrier. From the 20 min time scale for phase separation in the low molecular weight PEG system, we estimate a diffusion coefficient of 10−10 cm2 /s, which is consistent with recent molecular modeling results. For a diffusion coefficient, D, of 10−10 cm2 /s and 1200 s time scale, the average diffusion distance r = 6Dt1/2 = 85
m, which is comparable to the particle diameter. Composite particles formed from the higher molecular weight PEG (>1000) form homogeneous composite particles with PVA. Another interesting aspect of this work comes from Mie analysis of the scattering data for homogeneous composite particles. Observations for several different polymer blend systems reveal that the material dielectric constant (manifested in both the real and imaginary parts of the refractive index) can be tuned by adjusting the relative weight fractions of the polymers in the mixture. Both Ren and Imn for the polymer-blend microparticles are intermediate between the values determined for pure single-component particles and can be controlled by adjusting the weight fractions of polymers. For both miscible and (bulk) immiscble polymers that have been combined in homogeneous microparticles, the measured refractive index was observed to be very close to estimates obtained from a simple mass-weighted average of the two species. Although the microdroplet technique is well suited for producing nearly arbitrarily small particles (down to a single molecule limit), optical diffraction is obviously not suitable for probing particles smaller than a few hundred nanometers. To complement experimental effort on polymeric particles, investigation of various dynamical and steady-state properties of smaller polymer and polymer blend nanoparticles (1–10 nm diameter) has been examined using molecular dynamics tools. These traditionally reliable and accurate simulations allow development of considerable insight into the structure, and properties of polymer-blend particles, as well as aiding in interpretation of experimental results and guiding future experiments. Results have been reported from classical molecular dynamics techniques; polymer nanoparticles of varying size (up to 300,000 atoms), chain lengths (between 1 and 200 monomers), and intermolecular interaction energy have been examined which allows the systematic study of size-dependent physical properties and time dependence of segregation/equilibration of these particles [119]. Some of these studies are discussed in more detail in later sections of this chapter.

882

5. GAS ATOMIZATION APPROACHES The production of micro- and nanometer-sized polymer powders from molten polymers is an attractive, facile, low energy, and economic process. Polymer powders with tailored characteristics such as particle shape, size distribution, and purity can be directly prepared from the molten state of polymers such as polyethylene-based waxes that cannot be ground using conventional methods [121–126]. The gas atomization process (GAP) for mass-producing high quality spherical polymer powders involves using high pressure (approximately 7.6 MPa maximum) nitrogen gas and a specifically designed nozzle to atomize a molten stream of polymer into fine droplets that cool to form spherical powders. Powders with properties tailored to varying applications can be efficiently produced in short cycles by changing a few process control variables in a contamination-free environment, making the GAP a useful alternative to conventional grinding processes. These benefits of the process together with its flexibility, high throughput, and facile nature should make it highly attractive to industrial processes that must be capable of mass production and safe, environmentally benign operation. The targeted applications of the powders include uses as powder spray coatings [1], formulating ingredients for functional coatings, and as raw materials for solid-state compacting of polymer alloys and composites [1, 127]. For these applications, the required properties of the powders include purity, uniform micrometer-sized particles with uniform size distribution, and spherical shape. These properties are essential for free-flowing powders with optimal surface area, leading to products with improved handling and performance capabilities. Commercial organic polymer powders are produced by conventionally grinding extruded polymer pellets, often under cryogenic temperature conditions. Grinding is undesirable because it is expensive, highly energy-intensive, and susceptible to contamination from the grinding equipment and environmental pollution. Because of the erratic nature of the grinding process, it is almost impossible to control the quality and distribution of the powders and the size and shape of the particles. The GAP method is an alternative route to mass producing polymer powders that eliminates most of the problems of conventional grinding operations. In addition, the simplicity and versatility of the GAP means that the equipment can be constructed from readily available construction materials such as steel (used in the crucible) and impact-resistant crystal-clear polycarbonate (used in the atomization chamber). The optical clarity of the latter allows direct real time visualization of the atomization of the molten polymer as it exits the crucible. This process involves heating the material in a crucible until the desired atomization temperature is reached. Once the material reaches this temperature, it is forced out of the crucible through a circular channel (the pour tube) into the atomization nozzle, where it is atomized into fine particles by the high pressure nitrogen gas. The particles cool as they fall through the atomization chamber, forming micrometer-sized powders that collect in a vented chamber. Additional details of the GAP process has been reported [121–126].

Polymeric Nanoparticles

GAP feasibility studies and process development efforts focused on using commercial polyethylenes (e.g., Hoechst Celanese’s PE130 and PE520) [128] as the model material because they are presently the largest volume commodity plastics used in the United States (over 9 × 109 kg are produced annually). The high consumption, low toxicity, low molecular weights (2000 to 10,000 g/mol), and low melting temperatures (approximately 200
C) of the PE130 and PE520 make them ideal materials for atomization. Thus far, only the low molecular weight polyethylenes have been atomized into fine powders with changeable particle shapes and size distributions (0–250
m). The studies conducted to date show that the quality and properties of the product powders depend on three key processing variables: (1) polymer melt temperature, (2) gas atomization pressure, and (3) melt stream size or pour tube diameter. Unlike particles produced by conventional grinding, the particles in gasatomized powders are spherical with smooth surfaces and near uniform sizes. Other particle shapes—such as whiskers and elongated spheres—can be produced under specific processing conditions such as using low atomization pressures (approximately 2 MPa). Typically, the whiskers have diameters of about 100 nm and lengths of a few millimeters. To expand the GAP method to produce powders from other polymers with tailored powdered characteristics for wide applications, computer simulations of the process are needed. As mentioned, potential applications of the product powders include use as formulation ingredients for functional coatings tailored to specific biochemical engineering application areas, such as personal hygiene and beauty care products, packaging, and other disposable and/or recyclable plastic products. Other applications include polymer dispersions or emulsions in environmentally friendly solvents, feedstock for solid-state compacting of polymer alloys, and powder spray coatings. As an example, the PE520 is designed for use in paints to increase matting effects and to mar resistance of the painted surface. Other advantages of using polymer powder additives in paints are improved sanding ability smoothness, and rheological properties; prevention of pigment settling and metal marking; and water repellence. Because of the flexibility, versatility, and economy offered by GAP, it should be attractive to polymer manufacturers, processors, and end-users. Because the polymers (PE130 and PE520) can be atomized in a relatively narrow temperature range (190–220
C), temperature control in GAP must be precise to avoid potential thermal degradation of the molten polymer prior to atomization. This can be achieved by heating the polymer in the crucible under a blanket of nitrogen gas using precisely controlled band heaters with thermocouples strategically placed in the melt. Obviously, polymers that show different rheological properties under conditions that they are likely to encounter during atomization can be expected to atomize differently. At low pressures (approximately 2 MPa), for example, the shear induced by the gas jets on the molten polymer at the instant of melt disintegration is not enough to completely overcome the internal elastic stresses present in the molten polymer. This leads to the formation of whiskers and elongated spheres rather than absolute spheres. For the polyethylenes studied thus far, it has been found that the formation of whiskers and elongated spheres can be

Polymeric Nanoparticles

avoided by using high gas atomization pressures (approximately 7.6 MPa). It appears that a mixture of whiskers and spheres would be ideal for making self-reinforced polymer powders that can be used for applications requiring improved mechanical properties. Investigations on expanding the use of GAP to other polymers with vastly different thermal and rheological properties are needed. More recently, 50/50 blends of PE130 and ultralow melting phosphate glass composition have been successfully atomized under conditions that were used to atomize the pure PE130 polymer. This result confirms the expectation of the broad application of GAP to many fields, such as producing polymer alloys, glass–polymer alloys, in-situ composites, and related products with tailored properties. These products could be used in many areas, such as for decorative or protective coatings, for polymer-supported heterogeneous catalysts, and in producing lightweight structural composites. The structural composites can be easily fabricated by applying established solid-state powder compaction methods to the gas-atomized composite powders to form compacts with varying shapes and sizes. The research conducted thus far has provided valuable insight into GAP diagnostic control systems, dynamics, and mechanisms of powder formation. This knowledge can be used to expand the method to include the production of other kinds of materials with desirable properties for beneficial uses. The desirable properties of the powders include the following: purity, particle shape, particle size, and size distribution. The many initial problems of GAP when applied to polymers and composites are now understood and can be controlled and managed in order to produce powders with tailored characteristics. The technology of GAP has now advanced to a stage of finding more applications in the areas of polymer engineering and composite engineering and of scaling up to mass production of the fine polymer powders.

6. DENDRIMERS, HYPERBRANCHED POLYMERS, OR STAR POLYMERS Dendrimers, hyperbranched polymers, or star polymers offer capabilities similar to polymeric nanoparticles since they generally form relatively small spherical materials, often with core–shell structures (generally a hollow core) [129–173]. As such it is important to recognize this new class of macromolecular materials in a chapter on polymeric nanoparticles. The interest in dendrimers and hyperbranched polymers has substantially increased since the pioneering work of Vogtel, Tomalia, and Newkome [132–136]. A broad range of dendrimers and hyperbranched polymers are now available and there has been enormous interest in their uses and applications. Many of these applications, such as the development of selfassemblies, electroactive and electroluminescent devices, sensors, molecular devices, catalysts, pharmaceuticals and biochemicals, analytical chemical applications, nanoscale building blocks, micelle mimics, and performance materials are synergistic with those of polymeric particles. This is due to the similarities in fundamental size and shape as well as compositions.

883 Dendrimers and hyperbranched polymers represent a novel class of structurally controlled macromolecules derived from a branch-upon-branch structural motif. Dendrimers are well defined, highly branched macromolecules that radiate from a central core and are synthesized through a stepwise, repetitive reaction sequence that guarantees complete shells for each generation, leading to polymers that are highly monodisperse. The synthetic procedures developed for dendrimer preparation permit nearly complete control over the critical molecular design parameters, such as size, shape, surface/interior chemistry, flexibility, and topology. These synthetic methods are more closely related to organic chemistry than to traditional polymer synthesis. There are basically two different synthetic strategies for the synthesis of dendrimers: a divergent and a convergent approach to construct dendridritc frameworks. Both methods use step-by-step synthesis (activation or protection of monomers, condensation reactions, purification) and require quantitative coupling reactions to construct high generation dendrimers. More recently, a number of methods have been developed that reduce the number of synthetic steps for producing dendrimers in high yields: a double-stage convergent growth approach; a hypercore monomer approach; double-exponential dendrimer growth; orthogonal coupling strategies. Hyperbranched polymers offer an advantage over dendrimers in their ease of synthesis. On the other hand the degree of branching and the structure is less controllable than for dendrimers. The simplest branched material is a star polymer in which several linear polymer chains are attached to only one branching point. These polymers can contain chemically the same or different arms linked to a core. Star-block copolymers have also been made in which the arms consist of block or triblock copolymers. Various types of hyperbranched polymers, with multiple branching points, have been synthesized, including polyesters, poly(ether ketones), polyuretanes, polyamides, polycarbosilanes, etc. Many properties of dendrimers have been found to differ from their linear polymer analogs. In general, dendrimers are more soluble in common solvents and less viscous compared to analogous linear polymers. The solubility depends predominantly on the properties of their surface groups which can to a large degree be controlled. Dendrimers with hydrophobic interiors such as polyethers and polycarbosilanes can be made water soluble by introducing hydrophilic groups into their surface groups. The opposite can also be achieved, that is, changing a water soluble dendrimer into an insoluble material by converting the hydrophilic surface groups into hydrophobic surface groups. Another interesting and useful feature of dendrimers is the intrinsic viscosity in solution, and melt is lower than linear analogs. The main reason for this difference appears to be due to the lack of chain entanglements. Results have shown that intrinsic viscosity of a dendrimer does not obey the well known Mark–Houwink–Sakurada behavior. This has been associated to a transition from an extended structure for lower generation dendrimers to a globular shape at higher generations. Similar trends are also found for hyperbranched polymers, where the viscosity depends on the degree of branching: polymers having high branching

884 display behavior similar to dendrimers while those with low branching can have chain entanglements and behave more like linear polymers. Other properties that differ are hydrodynamic volume which is larger for dendrimers, the degree of crystallinity (dendrimers are amorphous), and the glass transition temperature. The glass transition temperature has been found to be a function of the backbone depending on the structure, the number of end-groups, and the number of crosslinks or branching points. The glass transition temperature decreases with an increase in the number of end-groups but it increases with increasing number of branch points and the polarity of the end-groups. For hyperbranched polymers, the glass transition temperature appears to depend more on the chain length between the branching points. This means that systems with short chain lengths will have low glass transition temperatures even though the total molecular weight may be quite large. The rich source of possible surface functionality for dendrimers makes them very attractive for nanometer building blocks and carrier molecules. They are also important in technologies such as coatings and inks where their unusual viscosity characteristics play an important role. Xerox has a number of patents which use dendrimers in ink and toner applications. Dendrimers have also found an increasing role as additives to commodity plastics where they improve the drying of plastic fibers.

7. MOLECULAR IMPRINT POLYMERS With the increased interest in chemical and biosensors within the field of modern analytical chemistry as well as medical and environmental science, methods for generating materials suitable for these applications based on biomimics have been introduced. Systems with large surface areas populated by large numbers of reactive or binding sites are optimal. Polymeric particles offer such possibilities due to their inherent large surface area and the possibility of functionalization. Dendrimers, hyperbranched polymers, or star polymers also provide numerous advantages for this area of interest. Another possibility has come from using synthetic polymers as templates for imprinting an image of a molecule, a technique known as molecular imprinting (an antibody mimic) [174–191]. The final product generally consists of a bulk polymer which is then processed into a fine powder, the smaller the particles comprising the powder the better. There are basically two distinct approaches to molecular imprinting. A prepolymerization complex between imprint molecule and functional monomers can be formed via noncovalent interactions or they can be covalently coupled. The covalent imprint method offers more homogeneous population of binding sites and a higher yield of binding sites relative to the amount of imprint molecule utilized. Noncovalent imprinting is somewhat more flexible when it comes to selecting the functional monomers, possible target molecules, and the use of the imprinted materials. Hybrid methods have also been suggested which attempt to combine the advantages of covalent and noncovalent molecular imprinting methods.

Polymeric Nanoparticles

A common method for preparing molecular imprint polymers is by using solution polymerization followed by mechanical grinding of the polymeric solid to give small particles with diameters generally in the micrometer range. Particles can also be prepared directly in the form of spherical beads by using, for example, a two-phase system using perflurocarbons instead of water as the continuous phase. Polymeric particles synthesized in this way can also be made magnetic by inclusion of iron oxide particles. Another method for synthesizing molecular imprint polymer particles without requiring mechanical grinding is based on using dispersion polymerization. This method can generate aggregates of spherical particles and if the system is sufficiently dilute one can get reasonably controllable and uniform sized particles. Other methods have been reported where the polymeric particles that are imprinted are formed in-situ, inside a chromatography column or in a capillary.

8. SIMULATION AND MODELING OF POLYMER PARTICLES Molecular modeling provides a way of visualizing processes at a submacromolecular level that also connects theory and experiment. Particularly attractive from a computational point of view is that many polymer particles are very close to the size scale where a complete atomistic model can be studied without using artificial constraints such as periodic boundary conditions. Yet these particles are often too small for traditional experimental structure/property determination. Polymeric particles in the micro- and nanometer size range show many new and interesting properties due to size reduction to the point where critical length scales of physical phenomena become comparable to or larger than the size of the structure itself. This size-scale mediation of the properties (mechanical, physical, electrical, etc.) opens a facile avenue for the production of materials with predesigned properties. The primary computational tool used to date for the study of polymeric nanoparticles, in particular, their atomisticbased structure and dynamics, has been molecular-dynamicsbased algorithms for generating and modeling polymer nanoparticles [192–208]. Some efforts using Monte Carlo techniques have also been pursued [209]. Structural and dynamical details of polymer processes at the atomic or molecular level have been studied and linked to experimentally accessible macroscopic properties of materials. A number of these studies will be discussed. Since the smaller sized particles have more surface atoms than the larger ones (larger surface area to volume ratio), a decrease of the diameter increases the ratio. The large ratio of surface atoms to the total number of atoms leads to a reduction of the nonbonded interactions between the polymer chains on the surface layer; hence the cohesive energy is dramatically dependent on the size. In addition, the ratio of surface chain ends to total number of chain ends for the particles is much larger than that of the bulk system, leading to enrichment of chain ends at surface. This observation is consistent with analysis of thin films. With regard to an effect of the side chain atoms, the increase in these atoms corresponds to a decrease in the ratio of surface atoms and therefore represents an increase of cohesive energy of the system.

885

Polymeric Nanoparticles

The increase in cohesive energy is due to the increase in the number of atoms that are inside the spherical particle versus on the surface. This phenomenon is a result of the finite sized spherical confinement of the particle and is different than what is observed in the corresponding bulk systems (side chains tend to lower the cohesive energy). The large proportional surface area leads to large surface free energy, which is described by per unit of surface area (J/nm2 ). The surface is irregular and has many cavities that may introduce unique (catalytic or interpenetrating) properties of polymer fine particles. The free volume (cavities) and molecular packing can be important in a diffusion rate of a small molecule trapped in the particles. It also suggests that nanoscale polymer particles are loosely packed and can show dynamical flexibility (e.g., compressive modulus of the particles is much smaller than that of the bulk system). Simulations have also been performed on models for bulk polyethylene (PE). The radial distribution function for the simulated bulk PE, which provides information on the intraand intermolecular structure, was in very good agreement with experimental data. Comparing a bulk system with the nanoscale spherical particles reveals the effects of conformational changes of the particles due to the size reduction and the shape. The most notable difference was in the amount of gauche conformations as signified by the magnitude of a peak at 3.2 Å. For the smaller particles this peak was almost entirely missing. The larger particles tended to have a somewhat higher concentration of gauche conformations but were still significantly less than the bulk. This reduction in the conformational disorder as the diameter of the particle decreases is a surface induced phenomenon. As the particle diameter decreases the surface area to volume ratio increases and the polymer chains are forced to lie mostly on the surface of the spherical particle. The surface tends to cause the polymer chains to form a pseudocrystalline layer; that is, the polymers fold in a nearly all-trans configuration. Several simulations have been applied to study the morphology of single or multiple chains with different chain lengths and compositions. The surface chains of the polymer nanoparticles tend to straighten and align at temperatures below the melting point; the preferential morphology for the small polymer particle with a long chain length is a rodlike shape. This stretching of the chains leads to a reduction of the cohesive energy and an increase in volume. Studies on the effects of chain length show that the particles with the shortest chain length (see Fig. 5) have the most spherical shape. For a transition from the amorphous (solid) to the melt phase (liquid) and a glass–rubber transition, the volume increases owing to conformational disorder of the polymer particles. Energy, temperature, and volume are calculated while annealing the system gradually by scaling the momenta with a constant scaling factor. Thermal analysis has provided a great deal of practical and important information about the molecular and material world relating to equations of state, critical points, and other thermodynamics quantities. Figure 6a shows the dependence of the melting point and glass transition temperature on the diameter of the particle. The dramatic reduction of the melting point for the polymer particles is an important example of surface effects and

Figure 5. See [206].

shows the importance of size. Since the large ratio of surface atoms to the total number leads to a significant reduction of the nonbonded interactions (lower cohesive energy), the melting point decreases with decreasing size. Figure 6b

Figure 6. See [194].

886 shows the effect of chain length on these transition temperatures. A strong dependence of the melting point and the glass transition temperature on chain length is attributed to molecular weight and nonbonded energy of each chain. From an atomistic thermodynamic analysis, the melting point of a polymer particle (6000 atoms) with chain lengths of 50 and 100 beads was found to be 186 and 232 K, respectively. The melting point was higher than the temperature at which the surface chains experienced a significant change in mobility. There appear to be two steps in the melting transition. The first step (mechanical melting) is at a temperature of 200 K and the second (thermodynamic melting) is 230 K. The first step is an early melting stage at which all chains in the particle start moving. The second step is the fusion stage of a solid. There is a plateau region between the first and second stages. The mobility of the chains in the outer layers increases rapidly after this region. In contrast, the chains in the core layer do not have the second step and increase linearly. In the past, numerous calculations have been performed for the mechanical property of bulklike crystalline PE polymer using force field semiempirical, ab initio calculation, and ab initio molecular dynamics (MD) methods. The compressive (bulk) modulus for the amorphous polymer particles was calculated in order to get an idea of their stiffness and strength. The compressive modulus and yield point for the PE particles were investigated by applying an external force in MD simulations. It is known that values of the tensile modulus of bulk polyethylene are between 210 and 340 GPa and the compressive modulus is generally higher than the tensile modulus. In addition, the bulk and tensile strength or yield point are always much smaller than the modulus for a thermoplastic such as polyethylene. In a MD study of polymer nanoparticles, a compressive modulus was found to be several magnitudes of order smaller than the bulk values, and a yield point that was much larger than the modulus. The stress–strain curve actually looked more like a curve for an elastomer. However, the initial deformation caused by the compression (that which gives the modulus) is not reversible. What occurs during this phase is the deformation of a spherical particle to an oblate top. This structure is stable but it lies at a slightly higher energy than that for a spherical particle. Thus, the modulus for compression in this region is actually more a measure of the force required to deform the spherical polymer particle into an oblate top (pancakelike structure). Further deformation tends to be reversible up to the point of rupture. This deformation is actually more closely related to the bulk modulus since the stress is due to the cohesive energy and not a microstructure. This leads to a yield point that is significantly larger than the modulus.

9. APPLICATIONS OF POLYMER PARTICLES Polymeric particles offer a number of unique properties that make their range of possible applications quite broad: small size and volume; large and specific surface area; high

Polymeric Nanoparticles

diffusibility and mobility; stable dispersions; uniform size, shape, morphology, surface chemistry; and the fact that they can be produced in various sizes, shapes, and compositions. To date many of the applications include examples from the biomedical, optical and optoelectrical, chemical, and rheological fluid fields. We briefly discuss some of these applications and provide extensive references for anyone interested in further details.

9.1. Biomedical Applications Dramatic progress in biomedical engineering has recently led to the development of new macromolecular drugs which hold great promise for successful therapeutics. Medicinal uses of polymeric materials have been fairly broad and continue to grow. For example, biodegradable polymers have been used for sutures, artificial skin, and materials for covering wounds. Other medical and biochemical applications have included the use of polymer particles in absorbents, latex diagnostics, affinity bioseparators, and drug and enzyme carriers. In particular, the use of nanoparticles as drug delivery vehicles has enjoyed significant activity and research. Drugs or other biologically active molecules have been dissolved, entrapped, encapsulated, absorbed onto surfaces, and chemically attached to polymeric particles as a means for delivery [14–16, 210–239]. Controlled drug release formulations have been tried in various forms depending on the specific end use. Controlled drug release offers many advantages over other types of delivery including the ability to supply more constant drug levels, to enable more efficient utilization of the drug, and to locally deliver the agent to a confined area. In addition, decreased costs and frequency of administration add to the attractive features of these types of drug delivery systems. To date, polymer microand nanoparticles have been the most extensively utilized system for these purposes. When suitably encapsulated, a pharmaceutical can be delivered to the appropriate site, its concentration can be maintained at proper levels for long periods of time, and it can be prevented from undergoing premature degradation. Nanoparticles offer the advantage that they provide a better penetration into the body and are small enough that they can be injected into the circulatory system or delivered via the respiratory system or through traditional oral intake.

9.1.1. Drug Delivery Modern pharmaceutical development makes extensive use of high-throughput screening, genomics, combinatorial chemistry, and other techniques. This has led to the synthesis of new chemical compounds that are bringing new challenges and opportunities to pharmaceutical development. One of the largest new set of drugs being developed is proteins and peptides, macromolecules which are often poorly permeable, poorly soluble, and unstable in physiological fluids and have unfavorable pharmacokinetics. These drugs generally need special care and require specific delivery systems. One of the most common degradation pathways is physical damage to proteins in the form of aggregation or precipitation. Unfortunately protein aggregates can form during the formulation process, long-term storage, or shipping and delivery. This can have dramatic impact on the final efficacy of the drug.

Polymeric Nanoparticles

Currently some of the largest challenges, are in improving solubility, enhancing the chemical/enzymatic stability, reducing adsorption to containers, minimizing aggregation, assisting with refolding of proteins, and improving absorption. Presently, there are at least 75 protein or peptide-based products approved for marketing in the United States alone that can be used in the treatment of cancer, diabetes, multiple sclerosis, and growth deficiencies. With more than 100 other such drugs in human clinical trials, the market for proteinbased drugs will continue to grow clearly defining the importance of designing appropriate drug delivery vehicles. Polymeric nanoparticles offer promising technologies that overcome many of the problems presented for protein/peptide delivery and stability [14–16, 210–239]. Compared to other colloidal carriers, polymeric particles have a higher stability when in contact with biological fluids, and their polymeric nature (system of very large molecules) allows for the desired controlled and sustained drug release. Polymeric particles also represent drug delivery systems suitable for most of the administration routes (inhalation, oral, circulatory system), even if a rapid recognition by the immune system may limit their use as injectable carriers. Indeed there has already been some success in using polymeric-based particles for peptide drug delivery. The first microparticle extended-release formulation of a peptide to be approved by the U.S. Food and Drug Administration consists of poly(lactic-co-glycolic) acid microparticles that encapsulate the leuteinizing-hormone-releasing hormone agonist, leuprorelin acetate. This particular formulation is used for diseases such as endometriosis and prostate cancer. Another approved formulation used the same microparticle to encapsulate recombinant human growth hormone for the treatment of growth hormone disorders. A substantial amount of research has focused on using polymeric nanoparticles, in particular PEG derivatives, for drug delivery. PEG is a simple, water-soluble, nontoxic polymer that is nonimmunogenic (the immune system does not recognize it and it is not metabolized) and has been approved in a number of products for human administration by mouth, injection, and topical application. PEG-based systems have been shown to entrap up to 45% by weight of a drug within the nanoparticle and to have extended circulation times due to decreased uptake by the mononuclear phagocyte system. A controlled release system that uses an injectable polymer vehicle has been employed by a number of researchers and has also been commercialized by Schering-Plough and Roche. The polymer protects the protein from rapid hydrolysis or degradation within the body thereby prolonging its action. Pioneering research on systems where PEG polymer chains were chemically attached to drug substances showed that by increasing their size there was an associated improvement in their delivery. When PEG is attached to a drug it can often extend the length of action in the body from minutes to hours or days depending on the molecular weight of the PEG molecules. Further advances using PEG in conjunction with other polymers are already in development to improve injectable polymer systems. In one technique, a low-molecular-weight biodegradable polymer that is a viscous liquid at room temperature is prepared. This is then mixed with the therapeutic protein and injected. PLA-PEG and poly(orthoester) have

887 been used in this system. Low-molecular-weight PLA-PEG has delivered bone morphogenetic protein (a bone growth factor used in the regeneration of bone tissue) into rats, with the polymer being degraded within three weeks and replaced by bone. Simply varying the viscosity of the polymer by changing either polymer concentration or polymer molecular weight may control the release of protein from this system. These polymers break down by hydrolysis, and further studies need to be undertaken to assess protein stability in this system and possible inflammatory responses in target tissues. In a second technique, a biodegradable polymer is dissolved in a physiologically acceptable solvent, suspending the protein particles, and this suspension is then injected into the tissue or patient. On entering the tissue, the solvent diffuses in the aqueous environment while the polymer precipitates out and entraps the protein particles. This injectable polymer depot has been explored using poly(lactic co-glycolic acid) with N -methyl pyrrolidone or glycofurol as the solvent. The rate of release may be adjusted by such parameters as the weight percentage of polymer in solution, the ratio of polylactide to polyglycolide, molecular weight, and protein loading. The release kinetics from this system was found to be favorable and there has been no reported loss in activity of human soluble tumor factor receptor. Some other applications in the research sector of the drug delivery arena have included: the use of chitosan particles as a cancer chemotherapeutic carrier for adriamycin; chitosan particles used for oral substained delivery of nefedipin, ampicillin, and various steroids; ocular drug delivery via a suspension composed of hydrogels and particles which enhances the bioavailability of ocular drugs; a particle gel for extending precorneal residence time of ocular drugs; treatment of infiltrating brain tumors such as oligodendrogliomas by using IdUrd loaded poly(d,l-lactide-co-glycolide) particles and intracranial implantation via sterotactic injection; use of alginate-poly-l-lysine particles for possible treatments of insulin-dependent diabetes mellitus; polyalkycyanoacytate nanocapsules for the delivery of insulin and indomethacin; biodegradable particles for drug delivery based on 1,5-diozepan-2-one and d,l-diactide; glutamate and the tripeptide TRH-impregnated polyanhydride-based particles for stimulation of trigeminal motoneurons; a simple, cost effective, and scalable method that is based on albumin microparticles (biodegradable, nontoxic, and nonimmunogenic) for drug release (such as chlorothiazide); microcapsules of polyelectrolyte complexes for PH controlled release; chitosan/gelatin network polymer particles for controlled release of cimetidine; block copolymers of biodegradable poly(l-lactic acid) and poly(dl-lactide-coglycolide) with poly(ethylene glycol) for controlled drug delivery and targeting; polymer-based gene delivery systems; drug deliver platforms based on synthetic polypetides; aliphatic polyanhydrides for drug carriers; biodegradable gelatin particles for treatment of kidney disease. Clearly there has been intensive research into the use of polymer-based systems for controlled drug delivery and release [14–16, 210–239]. While there are currently only a

888 few clinically approved polymeric systems, the use of polymeric systems for oral extended release has a relatively large research base. Nano- and microparticle systems have been the most extensively used/studied formulations for controlled drug release and the field is primed for technology development for moving these bench studies into the clinical arena. Nanoparticle delivery systems have been demonstrated to provide a better penetration of the particles inside the body. Owing to their size, delivery via intravenous injection is possible and therefore they can be used for intramuscular or subcutaneous applications. In addition, the nanoscale of these systems also can minimize irritant reactions at the injection site. Nanoparticle systems also exhibit greater stability, in both longer shelf storage lives and uptake times. These synthetic systems are extremely versatile and can be designed to elicit the desired kinetics, uptake, and response from the body. Nanoparticulate drug deliver systems have even been recommended for the broad application of vaccination. Currently, immunization often requires multiple injections (MMR, hepatitis, tetanus, etc.) and there may be a high preponderance of people to put off or to miss these boosters, leading to limitations in the efficacy of the immunization. A more efficacious vaccine that would only require a single dosage or an oral controlled release system is highly desired and some success has been reported by using nanoparticulate drug delivery systems [16, 232]. In summary, extensive research has shown that polymeric particles offer enormous advantages to drug delivery systems due to: (1) there is the possibility to functionalize the particle; (2) the large size of the polymer molecule(s) making up the particle make it possible for them to remain at delivery site for longer time (protection against premature metabolism and reduced immungenicity); (3) drugs can be released slowly and/or in a controlled manner by (a) diffusion of a carrier polymer, (b) deposition of the carrier itself, (c) osmotic force, (d) swelling of the carrier/delivery system, and (e) chemical reaction; (4) multiple administration routes, such as inhalation, injection, or oral, are feasible.

9.1.2. Immunoassays Since the first demonstration in 1979 that proteins could be transferred to microporous nitrocellulose membranes and detected using antibodies, development of rapid immunoassays using these high-surface-area materials has proliferated [16, 240–265]. Initially much investigation centered on understanding the interactions between proteins and polymers and the requirements for blocking nonspecific interactions on the membrane and on developing a series of detection methodologies and strategies. This work has led to a variety of immunoassay delivery systems for detecting a large menu of analytes. The determination of antigens in biofluids is generally accomplished though heterogeneous immunoassays. The most common methods require the separation of the antigen–antibody complexes from the medium, followed by measurement of the quantity of antigen. One technique, called the sandwich method, uses an immobilized antibody and a labeled antibody. The carriers of the antibodies require large surface areas in order to allow the formation of the desired antigen–antibody complex. Polymer particles have been found to be very applicable in this regard

Polymeric Nanoparticles

and plates with immobilized polyacrolein particles have been developed and used to covalently bind antibodies. In addition, polymer particle dispersions offer similar capabilities. Latex agglutination tests are the quickest, easiest methods among immunoassays. They can be sensitive, depending on the method of determination, and are comparable to other methods. Some of the first latex particles to be used were based on poly(styrene) derivatives. The ability of polystyrene to bind protein molecules without significantly changing the biochemical activities is the basis for most polymer particle immunoassays. Polystyrene can be used as the backbone of these particles and is crucial for the easy assimilation of these particles into most binding protocols. Other studies have used poly(hydroxyethyl methacrylate) and poly(glycidyl methacrylate) particles. Results have shown that in addition to the biospecific attractive force between the antigen and antibody, the electrostatic interactions between antibody– polymer particle and antigen–polymer particle have strong influence on agglutination rate. New latex designs consist of particles having a heterogeneous surface in a microdomain structure. By doping magnetic materials, such as iron oxides, into polymer particles, the resulting particles retain some magnetic properties and can be used as solid supports for immunoassays in single use or automated assays. Automated assays using magnetic particles can quickly wash or separate the reaction components to reduce assay time or increase performance. Sorting of cells or cellular isolation has also been accomplished using these types of magnetic particles. Immunoglobulins targeting the desired material can be attached to the surface of the particles for directed isolation. A suspension of magnetic particles is mixed with a preparation of the target molecule or cell. Once the target has bound to the affinity group, a magnet is used to separate the target-bound particles from the solution. The unbound material can then be washed away from the particles. Depending on the application, the target molecules or cells can then, if needed, be detached from the magnetic particles. Some of the biomedical applications of these types of magnetic particles are: cell separation, mRNA separation, protein purification, immunoassays, afinity purification, ion exchange, PCR clean-up, solid-phase cDNA library construction, isolation of single or double stranded DNA, solidphase DNA sequencing, hybridization procedures, charcoal trapping, sequence-specific magnetic particle probes, plasmid purification, and genomic DNA separation. Biochemicals such as DNA, hormones, proteins, and ligands are also immobilized for diagnostics. DNA diagnosis uses DNA-carrying particles, composed of single stranded DNA, which subsequently binds to its complementary DNA or RNA. Research has shown some enhanced capabilities for 20-mer DNA on latex particles. These systems were capable of binding to complementary DNA faster than free DNA, presumably due to the restriction of dynamic motion of the chains (DNA attached to a particle is difficult to hybridize). The interactions between proteins, DNA, enzymes, antibodies, and substrates such as polymer particles have been an active area of research, driven by the desire for rapid and accurate diagnostics and for the development of ultrasensitive biosensors.

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9.1.3. Polymeric Particles for In Vivo and In Vitro Analysis Labeled polymer particles have been used to determine cardiac output and regional blood flow [266–284]. This has been achieved in mice by radioactively labeling the polymer particles and detecting the amount deposited by the blood into body tissues. Alternatives to this procedure that offer better safety included using polystyrene impregnated with dyes which could be measured with spectrometry, fluorescence labeling of the particles, and using air filled albumin particles that can be determined by ultrasound contrast. Some interesting trends on the effects of particle size on tissue distribution have been observed. Particles larger than 10
m can be targeted to lung tissues and those smaller than a micrometer are typically engulfed by Kupffer cells in the liver. A fascinating application of polymeric particles is their use in preoperative embolization. Such procedures can facilitate surgical removal of tumors by reducing their volume and vascularity as well as decreasing blood loss during surgery. Biodegradable particles composed of starch and poly(d,l) lactide have shown some success in emboluses. Other candidates come from thermosensitve polymers such as poly(N -isoproplyacrylamide) which precipitates out at certain temperatures and occludes capillary vessels. Polymeric particles have also been utilized for the analysis of activity of phagocytes such as macrophages and leukocytes. These assessments were performed by using latex particles as inert invaders which the phagocytes would ultimately engulf. The latex particles were fluorescently labeled and were easily detectable inside of the phagocytes. The susceptibility of polymeric particles to phagocytosis is a crucial aspect to understand since drug delivery via these particles must reach its intended site. Research has mapped out a number of the influences of polymer particle size, composition, morphology, and surface chemistry.

9.2. Optical and Optoelectronic Applications For many years, researchers in materials and photonics have been interested in the design and fabrication of structures that confine and manipulate electromagnetic fields on length scales comparable to optical wavelengths. The ultimate goal is an all-optical information processing and computation platform using photons in ways analogous to electrons in silicon devices on similar length scales. Specific focus areas such as wafer-scale integration, parallel processing, and frequency management (e.g., add-drop filters) on micro- or submicrometer length scales are active areas of photonics research. While a great deal of progress has been made in the burgeoning field of microphotonics, we are still a long way off from realizing important goals such as the optical transistor and all-optical integrated circuits [285]. One of the critical issues faced by researchers trying to engineer high-density photonic device and optical computing/information processing structures is the problem of “turning” the path of the photon. Waveguide structures work well as long as the path is straight; however, including turns with bend radii comparable to propagation wavelength is seriously problematic since the losses tend to be unacceptably high. Typically, minimum bend radii in such structures

are on the order of several tens of micrometers (at least) to avoid scattering and retroreflection losses at the turn.

9.2.1. Photonic Molecules A new strategy has recently emerged for confining and manipulating electromagnetic fields with precise frequency and spatial control. Based on coupled optical microcavities, these new photonic structures have been called photonic molecules (PMs) by virtue of the similarity between the field eigenmodes and electronic structure in real molecules [286]. In contrast with waveguides in photonic bandgap (PBG) crystals (fabricated by introducing line defects) where a broad range of frequencies are allowed to propagate within the band gap, PM structures permit transmission only at cavity resonance frequencies. Furthermore because the resonance Q’s (energy storage factors) can be made quite high (>104 ), it is conceivable that these kinds of structures can function as amplifiers, switches, and add-drop filters. A recent discovery that lends fascinating and interesting materials properties describes the use of a simple watersoluble polymer blend to generate a new kind of polymer microsphere-based structure which was called a photonic polymer [287]. In the course of screening different watersoluble polymer blends for high-density ordered microsphere array applications [288], it was discovered that particles made from polyethylene glycol (≈10 k MW) and polyvinyl alcohol (14 k MW) in a 41 mass ratio had a tendency to stick together in clumps of two, three, or multiple particles. Under higher magnification, we observed that the “sticking” was in fact a partial merging of the particle surfaces shown in Figure 7. The particle binding was so robust that under high-precision particle focusing conditions, we were able to “stack” particles in nearly perfect columnar structures up to ≈20 particles high. Other types of two- and threedimensional architectures were explored using an electric quadrupole and computer-controlled 2D translation stage for particle positioning. One of the most surprising aspects of this work was the observation of sharp resonance features (distinct from “monomer” resonances) in fluorescence from dye doped

Figure 7. Electron micrograph of a photonic polymer structure made from merged polymer-blend microspheres [287]. There are about 30 individual spheres in the vertical chain that has folded near the top.

890 into the particles. Interestingly, the optical properties of merged-sphere systems were considered theoretically several years earlier by Videen and co-workers [289]. Resonance features in emission were also observed in transient merging-droplet experiments by Moon et al. [290]. What is surprising about the observation of shared optical resonances from merged spheres (especially with the large solid angle of intersection) is that a large segment of the dielectric boundary which confines the electromagnetic wave has been removed. Geometric optics calculations of long-lived trajectories in merged spheres show clearly that high-Q resonances are not supported for (plane) angles of intersection exceeding more than a few degrees. Calculations on bispheres of differing sizes have shown an interesting antinodal structure that includes an interaction between states with significantly different angular momenta, but with very low Q. Only in the special case where the contact angle is very small—similar to the physisorbed sphere case— are high-Q coupled resonances in the equatorial plane supported. In the experimental case, typical plane angles of intersection can be more than 50 degrees; yet the structures clearly support high-Q resonances. Using a combination of threedimensional ray optics and surface-of-section techniques [291], robust periodic trajectories that make a quasi-helical path around the particle chain axis have been demonstrated. These coupled resonances were highly robust with respect to overlap angle, deviations from collinearity, and size along the axis of the polymer structure.

9.2.2. Light Scattering Devices and Lenses Light scattering by polymeric particles dispersed in different polymeric matrices can be used for the fabrication of a high efficiency back-light for liquid crystalline displays. Multimode scattering depends on the correlation length of the heterogeneous domains. The brightness of the back-light has been increased by a factor of 1.5 over conventional designs by using particles in a polymer film. Light diffusers, blinds, and shades can be developed if the polymer particles have a refractive index differing from the polymer matrix [292–294]. Lens effects have also been observed from polymer particles [292–294]. Amorphous polymer particles are generally transparent and the spherical texture can give a lens effect at the microscopic level. Polymer particles having a radial graded refractive index can be prepared by a dynamic seeded polymerization technique. These particles have a composition gradient decreasing toward the center of the particle which causes an increasing refractive index. Excellent light focusing properties have been observed. Other reports on lens effects of polymer particles have focused on using a close-packed structure of polystyrene microparticles on a glass slide. With this arrangement, standard optical microscopy was used to clearly view the insides of the particles.

9.2.3. Electroluminescent Devices Organic electroluminescent devices based on polymer layers have attracted much attention because of low operating voltages, the ability to tune the color of the emitting light, and

Polymeric Nanoparticles

ease of fabrication. The phenomenon known as electroluminescence (EL) is caused by the emission of light generated from the recombination of electrons and holes electrically injected into a semiconductor. Traditionally most conventional and marketable electroluminescent devices have been inorganic semiconductors but developments dating back to the late 1990s have opened the door to a broad range of organic materials [295–306]. One of the most exciting developments in the field of conducting polymers occurred in the early 1990s with the discovery that conducting polymers such as poly(phenylene vinylene) (PPV) could be used as the emissive layer in light emitting diodes (LEDs). High-efficiency surface emission across the whole visible spectral range could be obtained relatively easily and researchers were able to achieve the emission of many different colors of light using these devices. The first polymer LEDs used PPV as the emitting layer [306]. Many different polymers have now been shown to emit light under the application of an electric field (EL). PPV and its derivatives are still the most commonly used materials, but polythiophenes, polypyridines, and polyphenylenes are now being tested for higher efficiency, longer lifetime, and lower power requirements. Despite the extensive studies in this field, the quantum efficiency and brightness of polymeric LEDs still remain modest. In addition, one of the problems associated with such devices is that the lifetime of the cell is too short to use for many practical purposes, due to degradation of the cell caused by the gradual crystallization. Polymeric nanoparticles and nanoparticle composites may provide new possibilities for optimizing quantum efficiency and brightness as well as the LED lifetime [302]. Enhancement of current densities, radiances, and power efficiencies in polymer light emitting devices have been observed from using polymers mixed with oxide nanoparticles. The semiconducting polymer PPV has attracted the most attention as an electroactive material. In general compounds with shorter conjugation lengths have a higher photoluminescence quantum yield. Precise control of the conjugated chain lengths could lead to very useful organic structures. Recently, research into semiconducting polymeric nanoparticles, in this case (poly[2-methoxy-5-(2 -ethyl-hexyloxy)-1,4phenylene vinylene]) (MEH-PPV), has demonstrated the capability of possible control of the chain length and therefore the fluorescence emission spectra. This research is beginning to shed some light on the structural characteristics and luminescence properties which point toward many promising possibilities. An organic analog of inorganic quantum rods has been produced using droplet techniques and results indicate linearly polarized fluorescence with a narrow Gaussian-like emission spectra having a discrete distribution of center frequencies. The luminescence dynamics of these particles were found to be qualitatively similar to those of thin films but had a significantly higher photostability. The luminescence properties of these newly discovered organic quantum rods might have important applications to biomedical imaging. For in vitro studies, a fluorescent microscope could be used to follow the time dependent activities of proteins, enzymes, or cells that have been tagged with organic quantum rods of different lengths. Rods that have different lengths are composed of polymer molecules that

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Polymeric Nanoparticles

differ in the number of monomeric repeat units which cause them to have different fluorescent emission. Currently visualization of proteins and cells is achieved by labeling them with organic fluorescent dyes, or fluorophores, such as the popular green fluorescent protein (GFP). But this approach has some rather significant limitations. To make GFP produce green light, a laser of a shorter wavelength, such as blue light, must be used. But if another dye that fluoresces in the blue wavelength were being used at the same time, then its signal would be lost in the blue light needed to trigger the first dye. This type of spectral overlap limits the use of fluorophores to two, or perhaps three, for any given experiment. Another major limitation of fluorophores is that their emission does not last long enough. The unique physical properties of organic quantum rods should be able to overcome these obstacles. Simply by altering their size, they can be engineered to produce light at many different wavelengths. Spectral overlap is not such an issue because the rods can have very similar light absorption/excitation profiles and there should not be a limit to the number of quantum rods one could use in an experiment. In addition, quantum rods should not stop fluorescence even after being visualized for very long periods of time. While traditional inorganic quantum dots or rods also exhibit these properties and provide similar capabilities, they have serious limitations concerning their hydrophobic nature. For inorganic quantum dots to mix with the aqueous contents of a cell, they have to possess a hydrophilic coat. Organic quantum rods are made of semiconducting polymers that can have numerous side groups (ethers, methoxyls, hydroxyls, etc.) which can be hydrophilic and therefore may not suffer this problem to the extent of the inorganic quantum dots. The side groups also provide chemical sites for attaching protein specific antibodies or aptamers which can be used as targeting molecules for specific delivery. In addition it is relatively easy to produce composites or blends of the semiconducting polymers without loss of the fluorescence properties.

9.3. Chemical Applications Ion exchange resins, polymer supported transition metal catalysts, and phase transfer catalysts are the most common chemical use of polymeric particles [307–316]. Increasing applications can be found in enzyme immobilization where polymer particles can be used to absorb, entrap, or chemically bind enzymes [307, 308]. This procedure appears to improve the durability of some enzymes. Other applications are related to batchwise separation and some column chromatography (particles > 3
m). In addition, polymeric particles have also found some applications in xerographic toners and as expandable beads for commodity materials. Polymeric particles are also one of the main constituents of polymer colloids, a class of polymers manufactured in the form of fine dispersions of polymer particles in aqueous or nonaqueous media. This class of polymers has found wide commercial applications in synthetic rubber (for tires, running shoes, and so on; Teflon, neoprene for fan belts and wet suits), surface coatings, paints, adhesives, impact modifiers, soil conditioners, toners for image development,

and the biomedical and biotechnical fields. Polymer colloids is one of the largest areas of polymer research and includes emulsion polymerization of acrylic monomers to form latex paints, suspension polymerization of divinylbenzene and comonomers to form ion-exchange and other porous resins, and micro- and miniemulsion polymerization to form submicrometer spheres for biodiagnostic uses. We have not included a specific section on polymeric or functional polymer colloids but have discussed many of the applications and synthetic production methods relevant to this field. A good source to get a more complete view on functional polymer colloids is provided in [309].

9.3.1. Supported Catalysts Supported homogeneous and heterogeneous catalysts are used extensively in industrial manufacturing of fine chemicals such as drugs, perfumes, pesticides, food additives, petrochemicals, etc. [309–312]. The use of inorganic catalyst supports such as activated carbon, silica, silica gel, alumina, etc. unfortunately provide little flexibility for tailoring which often leads to catalysts that do not have satisfactory selectivity. Organic polymer supports, on the other hand, provide a much larger degree of flexibility for tailoring. Cross-linked polymers with specific properties are widely used as catalyst supports since they are inert, nontoxic, nonvolatile, and often recyclable. Specific control over catalytic and complexing ability of ligands can be induced and the amount of metal present on the surface of such catalysts is very small, which is of economic significance in the case of expensive catalytic metals such as Ru and Pd. For these reasons, polymer supported catalysts have generated a considerable amount of interest in research. Examples can be found in selective hydrogenation of polyunsaturated cycloolefines and unsaturated carbonyl compounds where a functional polystyrene-supported metal (Ru, Rh, Pd) catalyst was successfully produced. In addition a number of applications have used commercially available resins as supports and ligands to produce effective polymer-supported catalysts. Again, the advantage of using polymer supports is the possibility to influence product selectivity by support and ligand composition. This applies to both homogeneous and heterogeneous catalyst systems. Clearly, polymeric particles offer notable advantages for catalyst supports due to their high surface area to volume ratio, a crucial element for efficient catalysis. In addition, the intimate control of particle size and composition provides flexible parameters for tailoring the selectivity of the supported catalyst.

9.3.2. Ion Exchange Resins Ion exchange is a process whereby anions or cations from solution replace anions or cations held on a solid sorbent [313]. The exchange process is reversible in that the exchanged ions can be released by treating the sorbent with a suitable stripping reagent. Natural soils contain solids with charged sites that exchange ions, and certain minerals called zeolites are quite good exchangers. Ion exchange also takes place in living materials because cell walls, cell membranes, and other structures have charges. Ion exchange materials

892 include silicates, phosphates, flourides, humus, wool, proteins, cellulose, alumina, glass, and many others. The first industrial ion exchangers were inorganic aluminum silicates, used for softening water and treating sugar solutions. Later it was discovered that sulfonated coal was a relatively effective ion exchange material, but these types of materials are fragile and useful only under restricted operating conditions. Now nearly all ion exchange applications use synthetic polymer resins. Ion exchange resins are polymers with electrically charged sites where ions may replace others [313]. These synthetic ion exchange resins are usually cast as porous beads with considerable external and pore surface where ions can attach. Absorption plays an important role whenever there is a large surface area and if a substance is adsorbed to an ion exchange resin, no ion is liberated. Polystyrene-based ion exchange resins are the most common. These are generally insoluble spherical or irregular porous particles grafted with negatively (sulfonic or carboxylic) or positively (quarternary, tertiary, secondary, or primary amino) charged groups and the particles generally have excellent chemical, mechanical, and in most cases thermal stability. Typical applications of polymer particle-based ion exchange resins have included: water treatment, sugar refinement, preparation and purification of pharmaceuticals, catalysts, etc.

9.3.3. Calibration Standards and Chromatography Polymer particles, in particular, polystyrene particles, which can be produced with quality size standards are often used for calibration of flow cytometers, particle and hematology analyzers, confocal laser scanning microscopes, and zetapotential measuring instruments. In addition, monodisperse polymer particles provide advantages for support materials in high performance liquid chromatography [314–317]. By using precise sized polymer particles, uniform packing of the chromatographic columns can be achieved and allows operation under lower pressures with an associated high efficiency of separation capacity. Another example of the advantage of using monodisperse polymer particles is in size exclusion chromatography. Size exclusion chromatography (SEC), is commonly used to obtain molecular weight distributions of polymers. Many biopolymers, including a large number of polysaccharides, have very large hydrodynamic sizes that may prevent an efficient use of SEC. By using macroporous, highly monodisperse polymer particles the range of molecular sizes accessible for aqueous SEC has been extended toward larger values.

9.4. Rheological Fluids Viscosity control can be achieved by using particles whose volume changes with environmental conditions [318–333]. For example, the volume of carboxylated latex particles increases with increasing pH so that the viscosity of the dispersion increases [318]. Ethyl acrylate-methacacrylic acid copolymer latex is one of the most popular thickeners. Other variables used to influence viscosity have been temperature, poly(N -isopropylacrylamide) particles, and electric fields [318, 319].

Polymeric Nanoparticles

9.4.1. Electrorhelogical Fluids The use of electric fields to control viscosity of polymer particle-based fluids is known as electrorhelogical fluids [318]. These fluids are composed of particles from 1 to 100
m in diameter that are suspended in a nonconducting liquid. The particles align themselves into structures along the direction of an applied electric field which dramatically changes its rheological properties. This is similar to a sol–gel transition but one that is controlled with an electric field. The extent of the alignment of polymeric particles has been found to depend mainly on the difference in dielectric constants of the liquid medium and the particle. Poly(methacrylic acid) particles in various media, paraffin oil, poly(dimethyl siloxane), chlorinated paraffin, and transformer oil, were also found to give increasing yield stress as a function of increasing particle diameter up to 900 nm. Applications of these fluids are expected to be mainly in the area of mechanical devices such as novel switches, actuators, clutches, etc.

9.4.2. Magnetorheological Fluids Magnetorheological (MR) fluids are considerably less well known than electrorheological (ER) fluids. Both fluids are noncolloidal suspensions of polarizable particles having a size on the order of a few micrometers that respond to external MR or ER fields with a change in rheological behavior [318–333]. Typically, this change is manifested by the development of a yield stress that monotonically increases with applied field. Interest in magnetorheological fluids originates from their ability to provide simple, quiet, rapid-response interfaces between electronic controls and mechanical systems [318–333]. Many researchers believe magnetorheological fluids have the potential to radically change the way electromechanical devices are designed and operated. The magnetorheological response of MR fluids results from the polarization induced in the suspended particles by application of an external field. The interaction between the resulting induced dipoles causes the particles to form columnar structures, parallel to the applied field. These chainlike structures restrict the motion of the fluid, thereby increasing the viscous characteristics of the suspension. The mechanical energy needed to yield these chainlike structures increases as the applied field increases resulting in a field dependent yield stress. In the absence of an applied field, MR fluids exhibit Newtonian-like behavior. While the commercial success of ER fluids has remained relatively elusive, MR fluids have seen an increasing commercial success. A number of MR fluids and various MR fluid-based systems have been commercialized including an MR fluid brake for use in the exercise industry (stationary bikes), a controllable MR fluid damper for use in truck seat suspensions, and an MR fluid shock absorber for oval track automobile racing.

10. POLYMER PARTICLE PATENT REVIEW There has been a relatively large number of patents on production methods and applications of polymer micro- and nanoparticles (on the order of 400 from 1996 to 2002).

Polymeric Nanoparticles

A similar trend has been witnessed in the dendrimer and hyperbranched polymer area: approx. 433 patents issued during 1996–2000 on uses and production of dendrimers with an incredible growth rate giving a projection of well over 1000 patents before 2005. Such vibrant activity is clear evidence of the importance and applicability these materials to a broad range of fields. We provide a brief overview of some relevant patents in the area of polymer particles. The purpose is to give a brief overview of the various types of patent disclosures issued, not to discuss all of the various patents. Intricate details of the patents we discuss can best be obtained from the actual patent disclosures and supporting literature contained therein. A continuous process for the preparation of inorganic and organic bead polymers using a static micromixer was disclosed by Eisenbeiss et al. [334]. According to this invention the bead polymers obtainable by the process have a very uniform particle size distribution, which can be set in a range of between 0.1 and 300
m. The process is based on the mixing of liquid streams of suitable, usually immiscible component solutions in a micromixer, giving spherical particles in a continuous procedure with extremely improved volume yield, large particle yield with particle size range which can be set to a specific value, simplified temperature program, and reduced consumption of chemicals. A composite paramagnetic particle and method for production was recently disclosed [335]. In one aspect of the invention, a particle comprised of a multitude of submicrometer polymer bead aggregates covalently cross-linked to each other to form larger diameter particles is presented. Distributed throughout the composite paramagnetic particle are vacuous cavities. Each submicrometer polymer bead has distributed throughout its interior and surface submicrometer magnetite crystals. In another aspect of the invention, composite particles are produced by using high energy ultrasound during polymerization of one or more vinyl monomers. In one embodiment, high energy ultrasound is used during an emulsification step and during the early stages of the polymerization process to produce micrometer sized composite paramagnetic particles. The particles according to the invention exhibit a high percent magnetite incorporation and water and organic solvent stability. A method reported for the preparation of polymer particles includes: (a) forming an organic phase by dissolving a polymer material in a solvent; (b) dispersing the organic phase in an aqueous phase comprising a particulate stabilizer and homogenizing the resultant dispersion, thereby forming spherical particles having a selected particle and uniform particle size distribution; (c) following the homogenizing, adding a particle shape-modifying surface active material to the spherical particles; and (d) removing the solvent, thereby producing irregularly shaped polymer particles having mainly the same selected particle size and distribution as the spherical particles [336]. A process has been reported for the preparation of polyvinylarene polymer particles by suspension polymerization, where (a) vinylarene monomers are suspended in an aqueous medium to yield a suspension; (b) the temperature of the suspension is adjusted to a temperature above 50
C, at which temperature an initiator is added; (c) subsequently, the reaction temperature is increased by 5 to 30
C

893 per hour until a temperature of at least 120
C is reached; and (d) the temperature is retained at least 120
C until the polymerization is complete [337]. Wu describes polymer particles made from copolymers of multifunctional (meth)acrylate monomer and multifunctional aromatics [338]. He also described methods of improving the compression characteristics of (meth)acrylate polymer particles by copolymerizing with a multifunctional (meth)acrylate monomer a multifunctional aromatic monomer. The particles are of a size, are of a uniformity, and contain physical characteristics that make them ideally suitable for use as spacers in liquid crystal display devices. Particles of a copolymer of a vinyl arene and a copolymerizable compound containing a polar moiety and a vinyl moiety containing water may be prepared by forming a mixture of monomers and small amounts of water and polymerizing under agitation to 20 to 70% conversion and then suspending the mass in water and finishing the polymerization. The resulting polymer beads contain finely dispersed water which is useful as an environmentally acceptable blowing agent [339]. An aqueous microemulsion polymerization procedure is described in which very small colloidal polymer particles are produced from tetrafluoroethylene monomer. The polymerization procedure involves adding a free radical initiator to a mixture of a microemulsion of at least one liquid saturated organic compound, and tetrafluoroalkyl ethylene [340]. A composition that includes a plurality of microcapsules each with one to five particles in a liquid droplet, and a complex coacervation induced shell encapsulating the liquid droplet and the one to five particles, has been reported [341]. There is also a composition comprised of a plurality of microcapsules each including a single particle in a liquid droplet, and a complex coacervation induced shell encapsulating the liquid droplet and the single particle. The authors also describe an encapsulation process [342] that includes (a) forming an emulsion composed of a continuous phase comprising a liquid, a cationic material, and an anionic material, and a disperse phase composed of a plurality of droplets of a second liquid, wherein a number of the droplets includes therein one to five particles; and (b) inducing complex coacervation of the cationic material and the anionic material. A polymer packing material suitable for liquid chromatography and a method for producing it was described by Kimura et al. [343]. The polymer packing material was based on polymer particles with a styrene skeleton and had a monodispersed particle distribution that could be obtained by hydrophilic treatment of an inner surface of a micropore existing in a fine pore of the polymer packing material, or subsequent introduction of a hydrophobic group into the inner hydrophilic surface by chemical modification. A method for producing the polymer packing material suitable for liquid chromatography includes the step of polymerizing glycerol dimethacrylate as a cross-linking agent and 2-ethylhexl methacrylate as a monomer according to a two-step swelling polymerization process. Alternatively, the producing method includes the step of cross-linking and polymerizing only glycerol dimethacrylate to form a polymer and introducing the hydrophobic group into the polymer by

894 chemical modification to form a shell around each of the droplets [343]. An inorganic dispersant having a high specific surface area and a high surface activity which comprises a calcium phosphate type compound having a specific particle composition, particle shape, particle size and dispersibility, and specific surface area was recently disclosed. When used as a suspension polymerization stabilizer, it provides polymer particles having a uniform and sharp particle size distribution, and when the polymer particles are contained in an unsaturated polyester resin composition and a toner composition, the obtained compositions have excellent quality [344]. A seeded microemulsion polymerization procedure in which colloidal polymer particles are produced from tetrafluoroethylene or tetrafluoroethylene/comonomer or other polymerizable monomers was described by Wu. The particles have an average diameter between 1 to 100 nm. A microemulsion is formed of a liquid monomer in water and a gaseous monomer is added either before or after polymerization is initiated [345]. An efficient method was disclosed for obtaining polymer particles by evaporating an organic solvent while maintaining a solution of a polymer in the organic solvent in contact with polymer particles, using a simple apparatus and a simple procedure. The polymer particles (powder) produced by the method have a small particle diameter, a high bulk density, and a small amount of residual solvent. The method includes introducing the organic solvent solution of the polymer into a particle producing zone which does not substantially contain steam, wherein an atmosphere is maintained in which the organic solvent is vaporizable and the particles are stirred. The organic solvent is evaporated, while maintaining the solution in contact with the polymer particles [346]. A phase inversion process for preparing nanoparticles and microparticles has been reported. The process involves forming a mixture of a polymer and a solvent, wherein the solvent is present in a continuous phase, and introducing the mixture into an effective amount of a nonsolvent to cause the spontaneous formation of microparticles [347]. Microspheres have been prepared by providing a solution of the polymer and of the active principal in a waterimmiscible solvent which is more volatile than water and mixing with an aqueous solution of the surface-active agent, followed by evaporation of the solvent [348]. Biocompatible microspheres containing one or more active principals, a biodegradable and biocompatible polymer and a surfaceactive agent which is also biodegradable and biocompatible, contain less than 10 ppm of heavy metals. A method of making polymeric particles having a predetermined and controlled size and size distribution is described by M. Nair, Z. R. Pierce, and C. Sreekumar (U.S. Patent 4, 833, 060, 1989). This disclosure describes a process which comprises dissolving a polymer in a solvent immiscible in water to form a solution, forming a suspension of small droplets of said solution in water containing a promoter which is water soluble and silica particles having an average particle size of from 0.001 to 1
m by high shear agitation. The promoter affects the hydrophilic/hydrophobic balance of the silica particles in the water suspension, removing the

Polymeric Nanoparticles

solvent from the droplets and separating the solidified polymer particles from the water. Otaigbe et al. [349] described a method for making polymer microparticles, such as spherical powder and whiskers (a whisker is defined here as a polymer microfiber of <100
m in length and with a diameter of <10
m). The method involves melting a polymer under conditions that avoid thermal degradation of the polymer, atomizing the melt in a special gas atomization nozzle assembly in a manner to form atomized droplets, and cooling the droplets to form polymer microparticles. The gas atomization parameters can be controlled to produce polymer microparticles with desired particle shape, size, and distribution. Handyside and Morgan [350] used rotary, two-fluid, or ultrasonic wave melt atomization processes to prepare thermosetting polymer powder compositions suitable for powder coating processes. The thermosetting resin may consist of polyester or epoxy polymer containing a curing agent and one or more coloring agents. The melt-atomized powder is characterized by improved particle size distribution and by a generally rounded particle shape. Noid et al. [351] used a new device called a microdropletson-demand generator (MODG) to produce polymer microand nanoparticles from solution. The proof of concept was demonstrated using poly(ethylene glycol) microparticles generated with the MODG and captured in a microparticle levitation device. The potential application of the MODG in materials science and technology was eluded to in the previous sections. There are several key advantages to this method for polymeric particle production: (1) It is relatively simple to produce particles of nearly any size and composition, including composites and novel blends. Many of these compositions are not obtainable by more conventional methods. (2) The technique lends itself to clean and efficient operation. There are no synthetic procedures requiring specialized knowledge or experience and there are generally no chemical by-products. (3) The technique is very controllable and arrays of particles or even intricate nanostructures can be quickly produced on any surface. (4) Encapsulation of chemicals, drugs, or other particles into a polymer particle is also relatively straightforward. Aoki et al. [352] developed a method for making aqueous dispersions of ultrafine cross-linked diallyl phthalate polymer particles with average diameter 10–300 nm by polymerizing aqueous solutions containing up to 15% diallyl phthalates in the presence of 7–30% (on diallyl phthalate) water-soluble polymerization initiators without the presence of surfactants. The dispersions are useful as modifiers for rubbers and plastics. Organic monomers such as MMA or oligomers, optionally containing polymerization initiators, can be sublimed into reactors in vacuo in inert atmospheres and irradiated with ultraviolet (UV) light to give ultrafine PMMA particles (3000 to 5000 Å particle sizes) with good purity [353]. A method for manufacturing spherical and uniformsize polyolefin ultrafine particles is reported by Yamazaki and Takebe [354]. In this method, the ultrafine particles (approximately 1.5
m particle size), useful for supports of absorbents, antiblocking agents, etc., are prepared by blending polyolefins in liquid organic compounds, melting the

Polymeric Nanoparticles

blends, cooling to form spherical polyolefin particles, and removing the organic compounds by extraction. In another method [355], electrically conductive polymer ultrafine particles (0.5 to 10
m particle size) are prepared by mixing an organic solvent solution of a metal salt with another organic solvent solution of a thermoplastic polymer, cooling or pouring this mixed solution into water or a poor solvent of the thermoplastic polymer to separate the metal salt-containing thermoplastic polymer particles, and conducting the precipitation of metal from the metal salt by the difference of ionization or by the addition of a reducing agent. Powdered poly(tetrafluoroethylene) (PTFE) with a specific surface area of 2 to 4 m2 /g and a low pressure molding coefficient of 20–150 is ultrasonically ground to give powdered PTFE that has a specific surface area of 4 to 9 m2 /g and a low pressure molding coefficient of <20 [356]. The PTFE powders are useful for moldings having high density (e.g., 2.1872) and good surface smoothness. Polymeric ultrafine particle-adsorbed structures with antistatic, low-friction, and abrasion-resistant properties were prepared by Akaishi et al. [357]. The structures are comprised of various substrates laminated with charged polymeric thin films on which charged polymer ultrafine particles, prepared by a macromonomer method, are adsorbed. The structures are manufactured by immersing charged polymeric thin-film-laminated substrates into a solution containing dispersed charged polymeric ultrafine particles prepared by the macromonomer method to adsorb the particles on the thin films. As an example of this invention by Akaishi et al. [357], a quartz oscillator microbalance as a substrate was alternately immersed 10 times into solutions of polyallylamine hydrochloride and Na styrenesulfonate homopolymer to form multilayer films having the homopolymer layer as the outermost layer. This was immersed in a solution containing dispersed N -vinylacetamide-grafted styrene polymer ultrafine particles in the presence of NaCl to give a polymeric particle-adsorbed structure in which the adsorption of particles depended on the concentration of NaCl. For a review of the macromonomer method for preparing polymer particles, the reader is referred to the classic, elegant review by Ito and Seigou [358, 359]. Printing inks and products made from them employ polymer and inorganic ultrafine particles. In one method, Yamada [360] mixed UV-curable resins with ultrafine Fe-based strong magnetic powders to give ink that could be printed on flexible films, fabrics, or paper to form electromagnetic shields. Polyester acrylate, epoxy acrylate, or urethane acrylate resins were used as the UV-curable binder and the ultrafine magnetic powder was mixed at 80–100 vol% (based on the binder resins) [360]. In a second method, Suwabe et al. [361] prepared aqueous inkjet inks, with good anticlogging ability and smudge prevention, by mixing aqueous dispersion of non-film-forming ultrafine inorganic or synthetic polymer particles (e.g., PMMA particles) with pigments and film-forming resin fine particles. In a third method, Uraki et al. [362, 363] prepared inkjet aqueous dispersion inks containing dispersed colored resin particles with an average diameter of 50–300 nm that were prepared by kneading organic pigments with water-soluble inorganic salts and water-soluble solvents in water and mixing with aqueous dispersions containing fine resin particles. The inks were easily

895 filtered through a 0.45-
m membrane to form ink showing good discharge ability and transparency. Composite structures consisting of metallic nanoparticles coated with organic polymers or organic polymer blend nanoparticles have been reported [364–369]. Funaki et al. [364] prepared a metal–organic polymer composite (especially porous) structure composed of a microphaseseparated structure from a block copolymer in which a metalphilic polymer chain and a metalphobic polymer chain are bonded together at each end, and ultrafine metal particles (<10 nm) were contained in the metalphilic polymer phase of the microphase-separated structure. Preferred polymers are a poly(2-vinylpyridine) and 2-vinylpyridineisoprene block copolymer. The composite structures just mentioned are useful as functional material (e.g., catalyst) in heterogeneous catalysis. Ehrat and Watriner [365] prepared thermoplastic polyolefin or olefin copolymer powders with average particle size of 80 to120
m by grinding in an impact mill together with fillers, such as Al, Mg, and/or Ca hydroxides, carbonates, or oxides. The composite mixtures are useful as highly filled molding compositions for battery electrodes or as powder coatings. Tamura [366] developed anisotropic magnetic-permeable composites. The composite contains ultrafine particles of ferromagnetic Fe oxide that are smaller than single domain sizes dispersed in a solid organic polymer as oriented in the domain direction of the particles and substantially separated from each other. The composites are prepared by dispersing the particles in a monomer and polymerizing the monomer in a magnetic field. Far-infrared (IR) radiation-emitting bodies from polymer microparticles and inorganic compounds have been reported [367]. The bodies are prepared from polymer particles with ultrafine inorganic particles (e.g., Al2 O3 or SiO2  bonded to their surfaces. The bodies are useful for accelerating fermentation, preserving fresh food, and promoting plant growth. A typical method for producing the radiation-emitting bodies involves mixing an aqueous dispersion of PVC particles (2
m) with AlCl3 and NH4 OH to give polyvinylchloride (PVC) particles with adhering alumina hydrate particles (0.01
m). The product can be extruded to give a film that is capable of farIR radiation emission. The preparation of composite ultrafine organic polymer mixture particles has been reported by Kagawa [368]. The composite particles were prepared by dissolving two different organic polymers in a solvent with a boiling point higher than the melting point of the polymers and collision crushing with pressure to give particles with diameter <005
m. The composite particles have good film-forming property (e.g., formed 5–10
m film on Al foil that can be readily peeled off from the foil). Ultrafine polystyrene particles and their composites with other materials can be prepared by adding dropwise polystyrene (weightaverage molecular weight 3,840,000) solution (approximately 0.0002% in C6 H6 ) to the surface of H2 O and the solvent evaporated to give a thin layer of ultrafine particles which could be collected by moving barriers. The particles are cumulated on a chrome plate at a surface pressure of 1 to 50 dyne/cm2 to give composite materials having area occupied with the particles ranging from 11 to 90%. Hayashi et al. [370] and Suda et al. [371] developed low-temperature, glass coloring agents containing ultrafine

896 noble metal particle—polymer composite and ultrafine colored polymer particles, respectively. The former coloring agents contain a composite of ultrafine Au, Pt, Pd, Rh, or Ag particles dispersed in a polymer without coagulation, an organometallic compound for fixing the ultrafine particles in glass, a printing binder, glass powder, and an organic solvent [370]. The low-coloring temperature decreases strain in the colored glass and improves its cutting property. The ultrafine colored polymer particles developed by Suda et al. [371] are useful for electrostatic photographic image developing agents or cosmetics. The particles are prepared by mixing the pigments with COOH (or ester)-containing polyolefins and nonaqueous solvents and precipitating. Stirring the pigment-coated carbon black, Zn naphthenate, and saponified EVA polymer in organic solvents, evaporating, and precipitating resulted in particles with a median diameter of 1.564
m. Superparamagnetic composites have been developed by Tamura [372]. The superparamagnetic composite material consists of ultrafine particles of ferromagnetic Fe oxide smaller than sizes of single domain structures dispersed as substantially separated in an organic polymer and prepared by dispersing the particles in a monomer and polymerizing the monomer. An aqueous dispersion of the ultrafine particles is prepared by a chemical reaction, hydrophobic coating of the particles by adding a surfactant to the dispersion, separating the particles, and adding the mixture to the monomer. The resulting composite has an extremely low residual magnetization and coercive force [372]. Ultrafine polymer particles can be prepared from vinyl polymers [373, 374], polyisocyanates and acrylates [375], polystyrene [376], and polyacrylates [377–379] by graft copolymerization [373], spreading and curing [375], dispersion polymerization [376], and emulsion polymerization [374–379]. The resulting particles are useful for waterresistant coatings and films [373, 375, 377], adhesives [376, 378, 379], and freeze–thaw cycle resistant films [374]. Ultrafine particle polymer latex is obtained by emulsion polymerization using a redox-type polymerization initiator in the presence of a compound serving as polymerization inhibitor solution in the monomer [380]. Coagulation of rubbermodified polymer latexes has been reported by Kitayama et al. [381]. In [381], a 30% acrylonitrile-butadiene-Me methacrylate-styrene graft copolymer (melting temperature 90
C) latex was coagulated with an aqueous solution of CaCl2 (11 mmol/L) at a concentration of 12 mmol/L and 95
C, separated, water washed, dewatered, and dried to form a powdered polymer without any particles. Ultrafine, particulate polymer latex based on unsaturated monomers with an average size <100 nm, a cross-linked structure, and glass transition temperature lower than that calculated by weight fraction method can be used to give a film excellent transparency, smoothness, tack, water resistance, and mechanical strength [382]. The polymer particle properties are dependent on the surfactant used. The latex is useful as a component in paints, adhesives, binder, additive for hydraulic inorganic material, fiber processing, reinforcement for optical glass fiber, electroconductive film, paper making, and photosensitive compositions [382]. Stable, aqueous colorants, useful in cosmetics, writing inks, and textiles, are prepared by encapsulating ultrafine, primary particles with

Polymeric Nanoparticles

polymers which are not substantially altered in the process [383]. Artificial stone compositions for high-gloss products resistant to chemicals, water, and weathering can be prepared by mixing: (1) hydraulic inorganic material, (2) SiO2 -based by ash with an average particle size 1–20
m, (3) waterdispersible ultrafine granular acrylic polymer with an average particle size 50–2000 nm, and (4) pigment [384]. The ultrafine granular acrylic polymer was prepared by emulsion polymerization. Ultrafine particles can be dispersed in organic polymers to form composites that exhibit good transparency and stability, making the composites useful for selective wavelength-shielding optical filters and nonlinear optical materials [385, 386]. Yao and Hayashi [385] prepared ultrafine particle-dispersing polymer compositions from the reaction (which forms ultrafine particles) of metal compounds and chalcogenation agents in an organic solution of polymer bearing pyrrolidone groups and stabilizer, followed by removal of the solvent. A typical preparation of the ultrafine particle-dispersing polymer compositions consists of injecting 0.5 ml H2 S (g) into a tube containing 3.08 mg Cd(NO3 ) · 24H2 O and 0.01 g polyvinylpyrrolidone in 5 ml MeOH. Displacing the H2 S with nitrogen gave a product containing dispersed CdS with size 60 Å, which showed absorbency at 510 nm. In another patent, Yao and Hayashi [386] reported cuprous halide-dispersed polymer compositions and manufacture of polymer compositions dispersed with ultrafine cuprous halide powders to give a transparent film containing ultrafine CuBr particles with average diameter of 8.5 nm. Giannelis et al. [387] have published a comprehensive review covering recent references on polymer–silicate nanocomposites. Recently, considerable attention has been paid to this type of nanocomposite to afford model systems to study confined polymers or polymer brushes and because of various applications in technical and biomedical fields.

11. CONCLUSIONS In this chapter, we have reviewed recent progress and discussed new insights into generating, characterizing, and modeling polymer micro- and nanoparticles. A wide range of electronic, optical, physical, chemical, and mechanical properties of single and multicomponent polymer particles have been used to fulfill needs for a broad spectrum of applications. Even with the large amount of work done in the past and currently occurring, there still remains tremendous potential in the future development of multicomponent polymer particles with tailored properties and particles for controlled release and delivery of pharmaceuticals. One exciting area is in the observation that polymer particle structures suggest the capability of manipulation of optical waves in a wide variety of 2D and 3D photonic wire structures that can be tailored to a particular application. We anticipate a number of interesting applications of these type of structures including 3D conductive vertical wires/supports and sensor technologies. By tuning the particle intersection (via adjustment of polymer blend composition), one can turn on (or off) coupling between orthogonal particle chain segments where the bend radius is close to the particle radius

897

Polymeric Nanoparticles

(e.g., 1 to 4
m). Losses should be comparable to single (linear) chain coupling which has already been shown to be low. From a purely scientific point of view, photonic molecules represent a new field of study that incorporates a variety of disciplines including materials science, optics, and electronic structure. A number of challenges remain, however. Most polymeric materials are strongly absorbing at near infrared (i.e., telecommunications) frequencies so it remains a nontrivial task to find polymer-blend systems that are transmissive in this important frequency range but also retain the material properties similar to the PEG:PVA blend used in the studies summarized here. Further challenges include engineering an optical (or electronic) interface to the photonic molecule or polymer structure with specific frequency input–output requirements. This new class of structures may ultimately complement photonic bandgap crystal technology and add a new component to the toolbox for microphotonics. Another developing and extremely important area that can benefit enormously from polymeric particle technology is that of drug delivery. More than 80% of all drugs are currently delivered in a powder format. Although tablets and capsules clearly play key roles in drug delivery, they can often be quite unsuitable for effective processing and delivery of macromolecules, especially proteins, peptides, monoclonal antibodies, antisense drugs, interleukins, cytokines, enzymes, and gene medicines. Preparation of fine powders of these types of macromolecules presents a significant problem to drug manufacturers since formation directly by precipitation from solution can cause numerous difficulties in filtering and drying the minute particles. Currently processors harvest larger particles from crystallizers and then dry and mill them to the desired size. This frequently damages the structure and surface of the drug and can also generate highly charged particles that stick to each other, making further processing very difficult. These types of difficulties in using conventional manufacturing processes to prepare fine particles with specific, preferred characteristics could also significantly constrain the design of new, promising drug delivery systems. Use of polymeric particles and the associated production technology can offer solutions to many of these current difficulties. In addition, the unique capabilities of nanoparticle delivery systems to protect drugs from degredation, prolong their residence time, withstand heat sterilization, have better storage life, remain stable in harsh conditions, and provide controlled release make this technology very attractive. It is clear that micro- and nanoparticlulate systems have the potential to have a revolutionary impact on drug delivery and several other areas in the biomedical field. Already proof-of-concept studies have yielded some very encouraging results but further improvements are needed in order to employ a larger range of the available therapeutic macromolecules (gene therapy agents and sensitive proteins). Other biomedical applications that may depend/benefit on new advances in polymer particle technology are medical imaging, bioassays, and biosensors. The incorporation of functional nanoparticles can be highly advantageous for the performance of numerous bioassays. The tremendous increase in surface area offers the ultimate ability for binding to target molecules such as proteins and enzymes. These

same particles offer complementary advantages for the production of highly sensitive biosensors. In addition, polymer particles can be produced out of conjugated molecules that fluoresce. With future advances in the functionalization of these so-called organic quantum rods, noninvasive biomedical imaging could be substantially improved. Finally, in the ultimate search for new and improved materials, polymeric particles offer the unique possibility of producing new alloys of polymers that do not typically mix. This capability opens the door to a nearly unlimited number of polymer blend and composite molecular systems of which the properties and dynamic behavior remain to be explored.

GLOSSARY Biomedical engineering An integration of physical, chemical, mathematical, and computational sciences and engineering principles to study biology, medicine, behavior and health. Catalysis A substance that increases the rate of a chemical reaction without being consumed. Colloidal dispersion A system in which particles (solid, liquid, or gas) of colloidal size are dispersed in a continuous phase of a different composition or state. Drug delivery The method and route used for administration of medicinal therapeutics. Electroluminescence The nonthermal conversion of electrical energy into light in a liquid or solid substance. Emulsion A system in which liquid droplets and/or liquid crystals are dispersed in a liquid. Fluorescence The emission of light or other electromagnetic radiation of longer wavelengths by a substance as a result of the absorption of some other radiation of shorter wavelength. Fluorescent emission continues only as long as the stimulus producing it is maintained. Immunoassay A process that measures and identifies a specific biological substance such as an antigen. Latex An emulsion or sol in which each colloidal particle contains a number of macromolecules. Molecular modeling Computational methods used to simulate and model simple and complex systems. Nanoparticle A particle that has size dimensions on the nanometer scale. Optoelectronic Any device that functions as an electricalto-optical or optical-to-electrical transducer. Photonics The technology of generating and harnessing light and other forms of radiant energy whose quantum unit is the photon. Polyelectrolytes A polymeric substance which, on dissolving in an ionizing solvent, dissociates to give polyions together with an equivalent amount of ions of small charge and opposite sign. Polymer Long-chain molecules of high molecular weight consisting of many repeating monomer units. Polymerization A synthetic technique for producing polymers.

898 Semiconducting polymers Polymers that are semiconductors (typically having conductivities in the range of 10−7 to 10−3 S/cm). Suspension A system in which solid particles are dispersed in a liquid. Supercritical fluid Substances that are above their critical temperature and pressure.

ACKNOWLEDGMENTS This work was sponsored by the Division of Materials Science, Office of Basic Energy Sciences, U.S. Department of Energy, under contract DE-AC05-00OR22725 with Oak Ridge National Laboratory, managed and operated by UT-Battelle, LLC. Financial support of J.U.O.’s research from the U.S. National Science Foundation (through grants 992088 and 0242754) and Huntsman Chemical Corporation and the research of work of his former students are gratefully acknowledged.

REFERENCES 1. J. Otaigbe, M. D. Barnes, K. Fukui, B. G. Sumpter, and D. W. Noid, Adv. Polym. Sci. 154, 1 (2000). 2. M. D. Barnes, K. C. Ng, K. Fukui, B. G. Sumpter, and D. W. Noid, Mater. Today 2, 25 (1999). 3. B. G. Sumpter, K. Fukui, M. D. Barnes, and D. W. Noid, Mater. Today 2, 3 (1999). 4. M. D. Barnes, K. Runge, B. Hathorn, S. Mahurin, B. G. Sumpter, and D. W. Noid, Mater. Today 5, 20 (2002). 5. “Polymer Powder Technology” (M. Narkis and N. Rosenzweig, Eds.). Wiley, New York, 1999. 6. T. A. Misev, “Powder Coatings Chemistry and Technology.” Wiley, New York, 1991. 7. “Polymeric Reagents and Catalysts” (W. T. Ford, Ed.). Am. Chem. Soc., Washington, DC, 1986. 8. W. T. Ford et al., Pure Appl. Chem. 60, 395 (1988). 9. J. M. J. Frechet et al., Pure Appl. Chem. 60, 353 (1998). 10. “Preparative Chemistry Using Supported Reagents” (P. Laszlo, Ed.). Academic Press, New York, 1987, and pertinent references contained therein. 11. C. Adachi, S. Hibino, T. Koyama, and Y. Taniguchi, J. Appl. Phys. 2, L827 (1997). 12. M. Granstrom and O. Inganas, Appl. Phys. Lett. 68, 147 (1996). 13. J. Hanes, J. L. Cleland, and R. Langer, Adv. Drug Delivery Rev. 28, 97 (1997). 14. H. Kawaguchi, Progr. Polym. Sci. 25, 1171 (2000). 15. M. N. V. Ravi Kumar, N. Kumar, A. J. Domb, and M. Arora, Adv. Polym. Sci. 160, 45 (2002). 16. A. Prokop, E. Kozlov, G. Carlesso, and J. M. Davidson, Adv. Polym. Sci. 160, 119 (2002). 17. D. C. Blackley, “Polymer Lattices,” 2nd ed. Chapman & Hall, London, 1997. 18. “Emulsion Polymerization and Emulsion Polymers” (P. A. Lovell and M. S. El-Aasser, Eds.), Wiley, New York, 1997. 19. M. Antonietti and K. Landferster, Progr. Polym. Sci. 27, 689 (2002). 20. I. Capek, Adv. Col. Int. Sci. 92, 195 (2001). 21. D. J. Hunkeler and J. Hernandez-Barajas, “Inverse-Emulsion/ Suspension Polymerization in Organized Media.” Gordon & Breach, Philadelphia, 1992. 22. J. V. Dawkins, Comprehensive Polym. Sci. 4, 231 (1989). 23. I. Fuminori, M. Guanghui, N. Masatoshi, and O. Shinzo, Col. Sur. 201, 131 (2002).

Polymeric Nanoparticles 24. “Dispersion Polymerization in Organic Media” (K. E. J. Barrett, Ed.), Wiley, 1974. 25. C. Bunyakan and D. Hunkeler, Polymer 40, 6213 (1999). 26. G. Zhang, A. Niu, S. Peng, M. Jiang, Y. Tu, M. Li, and C. Wu, Acc. Chem. Res. 34, 249 (2001). 27. R. Arshady, Polym. Engn. Sci. 33, 865 (1993). 28. R. G. Gilbert, “Emulsion Polymerization: A Mechanistic Approach.” Academic Press, New York, 1995. 29. G. Odian, “Principles of Polymerization,” 3rd ed. Wiley, New York, 1991. 30. M. B. Urquiola, E. D. Sudol, V. L. Dimonie, and M. S. El-Aasser, J. Polym. Chem. 31, 1403 (1993). 31. D. Cochin and F. Candau, Macromolecules 26, 5755 (1993). 32. K. Landfester, Adv. Mater. 13, 765 (2001). 33. F. J. Schork, G. W. Poehlein, S. Wang, J. Reimers, J. Rodrigues, and C. Samer, Colloid Surf. A 153, 39 (1999). 34. M. Antonietti, R. Basten, and S. Lohmann, Macromol. Chem. Phys. 195, 441 (1995). 35. F. Candau, M. Pabon, and J.-Y. Anquetil, Colloid Surf. A 153, 47 (1999). 36. K. Landfester, M. Willert, and M. Antonietti, Macromolecules 33, 2370 (2000). 37. F. Candau, Macromol. Symp. 92, 169 (1995). 38. H. G. Yuan, G. Kalfas, and W. H. Ray, J. Macromol. Sci. Rev. Macromol. Chem. Phys. C 31, 215 (1991). 39. M. Okubo and J. Izumi, Col. Sur. 153, 297 (1999). 40. K. Jin-Woong and S. Kyung-Do, Polymer 41, 6181 (2000). 41. J. W. Vanderhoff, M. S. El-Aasser, F. J. Micale, E. D. Sudol, C. M. Tseng, H. R. Scheu, and D. M. Cornfeld, ACS Polym. Preprint 28, 455 (1986). 42. J. Ugelstad, F. K. Kaggerud, F. K. Hansen, and A. Berge, Macromol. Chem. 180, 737 (1979). 43. J. Ugelstad, Makromol. Chem. 179, 815 (1978). 44. M. Okubo, M. Shiozaki, M. Tsujihiro, and Y. Tsukuda, Col. Polym. Sci. 269, 222 (1991). 45. M. Okubo and T. Nakagawa, Col. Polym. Sci. 270, 853 (1992). 46. M. Okubo and M. Shiozaki, Polym. Int. 30, 469 (1993). 47. F. Ito, M. Guanghui, N. Masatoshi, and O. Shinzo, Col. Sur. A 201, 131 (2002). 48. Y. Almong, S. Reich, and M. Levy, Br. Polym. J. 14, 131 (1982). 49. C. K. Ober, K. P. Lok, and M. L. Hair, J. Polym. Sci. Lett. Ed. 23, 103 (1985). 50. C. M. Tseng, Y. Y. Lu, M. S. El-Aasser, and J. W. Vanderhofff, J. Polym. Sci. Polym. Chem. Ed. 24, 2995 (1986). 51. M. Okubo, K. Ikegami, and Y. Yamamoto, Col. Polym. Sci. 267, 193 (1989). 52. H. Uyama, H. Kurioka, and Kobayashi, Col. Sur. A 153, 189 (1999). 53. A. Harada and K. Kataoka, Science 283, 65 (1999). 54. S. A. Jenekhe and X. L. Chen, Science 283, 372 (1999). 55. M. Svensson, P. Alexandridis, and P. Linse, Macromolecules 32, 637 (1999). 56. J. Kritz, J. Plestil, Z. Tuzar, H. Pospisil, J. Brus, J. Jakes, B. Masar, P. Jicek, and D. Doskocilova, Macromolecules 32, 397 (1999). 57. K. Matsumoto, M. Kubota, H. Matsuoka, and H. Uamaoka, Macromolecules 32, 7122 (1999). 58. Z. Zhou, B. Chu, and D. G. Peiffer, Macromolecules 26, 1876 (1993). 59. K. Mortensen and W. Brown, Macromolecules 26, 4128 (1993). 60. R. Nagarajan and K. Ganesh, Macromolecules 22, 4312 (1989). 61. Q. F. Zhou, X. Zhu, and Z. Wen, Macromolecules 22, 491 (1989). 62. Y. X. Liu, D. Zhang, X. H. Wan, and Q. F. Zhou, Chin. J. Polym. Sci. 16, 283 (1998). 63. X. Wan, Y. Tu, D. Zhang, and Q. F. Zhou, Chin. J. Polym. Sci. 16, 377 (1998). 64. R. L. Jones and R. J. Spontak, J. Chem. Phys. 103, 5137 (1995). 65. X. Qui and C. Wu, Macromolecules 30, 7921 (1997). 66. X. Qui and C. Wu, Phys. Rev. Lett. 80, 620 (1998).

Polymeric Nanoparticles 67. C. Wu, A. Niu, and L. M. Leung, J. Am. Chem. Soc. 121, 1954 (1999). 68. L. M. Leung and K. H. Tan, Polym. Commun. 35, 1556 (1994). 69. M. Jiang, X. Qui, W. Qin, and L. Fei, Macromolecules 28, 730 (1995). 70. Y. Zhang, M. Xiang, M. Jiang, and C. Wu, Macromolecules 30, 2035 (1997). 71. M. Xang, M. Jiang, Y. Zhang, and C. Wu, Macromolecules 16, 3712 (2000). 72. Z. Gan, T. F. Jim, M. Li, Y. Zhao, S. Wang, and C. Wu, Macromolecules 32, 590 (1999). 73. W. Zhang, J. Gao, and C. Wu, Macromolecules 30, 6388 (1997). 74. R. M. Fitch, “Polymer Colloids: A. Comprehensive Introduction.” Academic Press, San Diego, 1997. 75. P. Calvo, C. Remunan-Lopez, J. L. Vila-Jato, and M. J. Alonso, Pharmaceut. Res. 14, 1431 (1997). 76. P. Calvo, C. Remunan-Lopez, J. L. Vila-Jato, and M. J. Alonso, J. Appl. Polym. Sci. 63, 125 (1997). 77. S. Deacon, J. Clin. Pathol. 29, 749 (1976). 78. A. Prokop, C. A. Holland, E. Kozlov, B. Moore, and R. D. Tanner, Biotechnol. Bioeng. 15, 228 (2001). 79. P. K. Smith, R. I. Krohn, G. T. Hermanson, A. K. Mallia, F. H. Gartner, M. D. Provenzano, E. K. Fujimoto, N. M. Goeke, B. J. Olson, and D. C. Klenk, Anal. Biochem. 150, 76 (1985). 80. R. Fagnani, M. S. Hagan, and R. Bartholomew, Cancer Res. 50, 3638 (1990). 81. A. Prokop, U.S. Patent 6, 482, 439, 2002. 82. A. V. Kabanov and V. A. Kabonov, Bioconj. Chem. 6, 7 (1995). 83. G. F. Pierce, J. E. Tarpley, D. Janagihar, T. A. Mustoe, G. M. Fox, and A. Thomason, Amer. J. Pathol. 140, 1375 (1992). 84. A. A. Clifford, “Fundamentals of Supercritical Fluids.” Oxford Univ. Press, London, 1998. 85. P. G. Jessop and W. Leitner, “Chemical Synthesis Using Supercritical Fluids.” Wiley–VCH, Weinheim, 1999. 86. S. G. Kazarian, Polym. Sci. Ser. C 42, 78 (2000). 87. A. I. Cooper and J. M. DeSimone, Curr. Opin. Solid State Mater. Sci. 1, 761 (1996). 88. A. I. Cooper, J. D. Londono, G. Wignall, J. B. McClain, E. T. Samulski, J. S. Lin, and A. Dobrynin, Nature 389, 368 (1997). 89. M. Rubinstein, A. L. C. Burke, J. M. J. Frichet, and J. M. DeSimone, Nature 389, 368 (1997). 90. S. M. Frederick and J. D. Wang, Inorg. Chim. Acta 294, 214 (1999). 91. S.-D. Yeo, G.-B. Lim, P. G. Debenedetti, and H. Bernstein, Biotech. Bioeng. 41, 341 (1993). 92. B. Subramaniam, R. A. Rajewski, and K. Snavely, J. Pharm. Sci. 86, 885 (1997). 93. J. W. Tom and P. G. Debenedetti, J. Aerosol Sci. 22, 555 (1991). 94. B. L. Knutson, P. G. Debenedetti, and J. W. Tom, “Preparation of Microparticulates Using Supercritical Fluids” (S. Cohen, and H. Bernstein, Eds.). Dekker, New York, 1996. 95. L. Benedetti, A. Bertucco, and P. Pallado, Biotech Bioeng. 53, 232 (1997). 96. L. Frederiksen, K. Anton, P. van Hoogevest, H. R. Keller, and H. Leuenberger, J. Pharm. Sci. 86, 921 (1997). 97. R. Chang and E. J. Davis, J. Coll. Inter. Sci. 54, 352 (1976). 98. E. J. Davis and A. K. Ray, J. Coll. Inter. Sci. 75, 566 (1980). 99. A. K. Ray, A. Souyri, E. J. Davis, and T. M. Allen, Appl. Opt. 30, 3974 (1991). 100. J. F. Widmann, C. L. Aardahl, and E. J. Davis, Am. Lab. 28, 35 (1996). 101. See also the review by E. J. Davis, Aer. Sci. Tech. 26, 212 (1997). 102. P. Chylek, V. Ramaswamy, A. Ashkin, and J. M. Dziedzic, Appl. Opt. 22, 2302 (1983). 103. H. C. Van de Hulst and R. T. Wang, Appl. Opt. 30, 4755 (1991). 104. G. Konig, K. Anders, and A. Frohn, J. Aerosol Sci. 17, 157 (1986). 105. A. R. Glover, S. M. Skippon, and R. D. Boyle, Appl. Opt. 34, 8409 (1995).

899 106. J. F. Widmann and E. J. Davis, Colloid Polym. Sci. 274, 525 (1996). 107. T. Kaiser, S. Lange, and G. Schweiger, Appl. Opt. 33, 7789 (1994). 108. S. Holler, Y. Pan, R. K. Chang, J. R. Bottinger, S. C. Hill, and D. B. Hillis, Opt. Lett. 23, 1489 (1998). 109. J. F. Widmann, C. L. Aardahl, T. J. Johnson, and E. J. Davis, J. Coll. Int. Sci. 199, 197 (1998). 110. M. D. Barnes, N. Lermer, W. B. Whitten, and J. M. Ramsey, Rev. Sci. Instrum. 68, 2287 (1997). 111. N. Lermer, M. D. Barnes, C.-Y. Kung, W. B. Whitten, and J. M. Ramsey, Anal. Chem. 69, 2115 (1997). 112. C. Koning, M. van Duin, C. Pagnoulle, and R. Jerome, Progr. Polym. Sci. 23, 707 (1998). 113. J. W. Yu, J. F. Douglas, E. K. Hobbie, S. Kim, and C. C. Han, Phys. Rev. Lett. 78, 2664 (1997). 114. A. H. Marcus, D. M. Hussey, N. A. Diachun, and M. D. Fayer, J. Chem. Phys. 103, 8189 (1996). 115. S. A. Jenekhe and X. L. Chen, Science 279, 1903 (1998); 283, 372 (1999). 116. F. S. Bates and G. H. Fredickson, Phys. Today 52, 32 (1999), and references cited therein. 117. C.-Y. Kung, M. D. Barnes, N. Lermer, W. B. Whitten, and J. M. Ramsey, Appl. Opt. 38, 1481 (1999). 118. M. D. Barnes, C.-Y. Kung, K. Fukui, B. G. Sumpter, D. W. Noid, and J. U. Otaigbe, Opt. Lett. 24, 121 (1999). 119. M. D. Barnes, K. C. Ng, K. Fukui, B. G. Sumpter, and D. Noid, Macromolecules 32, 7183 (1999). 120. K. Fukui, B. G. Sumpter, M. D. Barnes, D. W. Noid, and J. U. Otaigbe, Macromol. Theory Sim. 8, 38 (1999). 121. J. U. Otaigbe, D. W. Noid, and B. G. Sumpter, Adv. Polym. Technol. 17, 161 (1998). 122. J. U. Otaigbe and J. McAvoy, Adv. Polym. Technol. 17, 145 (1998). 123. J. U. Otaigbe and J. McAvoy, Mater. World 5, 383 (1997). 124. J. U. Otaigbe, J. M. McAvoy, A. I. Enderson, J. Ting, J. Mi, and R. Terpstra, U.S. Patent 6, 171, 433, 1997. 125. J. M. McAvoy and J. U. Otaigbe, Gas atomization of polymers, in “SPE 55th ANTEC Papers,” 1997. 126. J. M. McAvoy, M. S. Thesis, Iowa State University, 1997. 127. J. P. Jog, Adv. Polym. Tech. 12, 281 (1993). 128. Hoechst waxes for technical applications technical brochure, Hoechst Celanese Corporation, Summit, NJ, pp. 1–33, 1993. 129. K. Inoue, Progr. Polym Sci. 25, 453 (2000). 130. O. A. Matthews, A. N. Shipway, and J. F. Stoddart, Progr. Polym. Sci. 23, 1 (1998). 131. J. Roovers and B. Comanita, Adv. Polym. Sci. 142, 180 (1999). 132. D. A. Tomalia and H. D. Durst, Top. Curr. Chem. 165, 193 (1993). 133. E. Buhleier, W. Wehner, and F. Vogtle, Synthesis 155 (1978). 134. D. A. Tomalia, H. Barker, J. R. Dewald, M. Hall, G. Kallos, S. Martin, J. Roeck, J. Ryder, and P. Smith, Polym. J. 17, 117 (1985). 135. D. A. Tomalia, H. Barker, J. R. Dewald, M. Hall, G. Kallos, S. Martin, J. Roeck, J. Ryder, and P. Smith, Macromolecules 19, 2466 (1986). 136. G. R. Newkome, Z.-Q. Yao, G. R. Baker, and V. K. Gupta, J. Org. Chem. 50, 2003 (1985). 137. F. Zeng and S. C. Zimmerman, Chem. Rev. 97, 1681 (1997). 138. C. J. Hawker and J. M. J. Frechet, J. Am. Chem. Soc. 112, 7638 (1990). 139. Y. H. Kim, Polym. Chem. Ed. 36, 1685 (1998). 140. E. Malmstrom and A. Hult, JMS Rev. Macromol. Chem. Phys. C 37, 555 (1997). 141. H. Ihre, M. Johansson, E. Malmstrom, and A. Hult, in “Advances in Dendritic Macromolecules” (G. R. Newkome, Ed.), Vol. 3, p 1. JAI Press, Greenwich, CT, 1996. 142. H. Ihre, A. Hult, and E. Soderlind, J. Am. Chem. Soc. 118, 6388 (1996). 143. M. Trollsas, J. Hedrick, D. Mecerreyes, R. Jerome, and P. Dubois, J. Polym. Sci. Polym. Chem. Ed. 36, 3187 (1998).

900 144. C. J. Hawker and F. Chu, Macromolecules 29, 4370 (1996). 145. A. Morikawa, Macromolecules 31, 5999 (1996). 146. A. Kumar and S. J. Ramakrishnan, J. Polym. Sci. Polym. Chem. Ed. 34, 839 (1996); R. Spindler and J. M. J. Frechet, Macromolecules 26, 4809 (1993). 147. H. R. Kricheldorf, O. Bolender, and T. Stukenbrock, Macromol. Chem. Phys. 198, 2651 (1997). 148. M. Ohta and J. M. J. Frechet, J. Mater. Sci. A 34, 2025 (1997). 149. G. Yang, M. Jikei, and M. Kakimoto, Macromolecules 31, 5964 (1998). 150. A. M. Muzafarou, M. Golly, and M. Moller, Macromolecules 28, 8444 (1995). 151. R. A. Gossage, E. M. Martinez, and G. van Koten, Tetrahedron Lett. 39, 2397 (1998). 152. I. L. Rushkin, Q. Shen, S. E. Lehman, and L. V. Interrante, Macromolecules 30, 3141 (1997). 153. C. Lach, P. Muller, H. Frey, and R. Mulhaupt, Macromol. Rapid Commun. 18, 253 (1997). 154. F. Morgenroth and K. Mullen, Tetrahedron 53, 15349 (1997). 155. C. A. Martinez and A. S. Hay, J. Mater. Sci. A 35, 57 (1998). 156. M. Pitsikalis, S. Pispas, J. W. Mays, and N. Hadjichristidis, Adv. Polym. Sci. 135, 1 (1998). 157. C. J. Hawker, R. Lee, and J. M. J. Frechet, J. Am. Chem. Soc. 113, 4583 (1991). 158. P. J. Flory, J. Am. Chem. Soc. 74, 2718 (1952). 159. C. N. Moorefield and G. R. Newkome, in “Advances in Dendritic Macromolecules” (G. R. Newkome, Ed.), Vol. 1, p. 1. JAI Press, Greenwich, CT, 1994. 160. T. H. Mourey, S. R. Turner, M. Rubinstein, J. M. J. Frechet, C. J. Hawker, and K. L. Wooley, Macromolecules 25, 2401 (1992). 161. C. J. Hawker, P. J. Farrington, M. E. Mackay, K. L. Wooley, and J. M. J. Frechet, J. Am. Chem. Soc. 117, 4409 (1995). 162. P. J. Farrington, C. J. Hawker, J. M. J. Frechet, and M. E. Mackay, Macromolecules 31, 5043 (1998). 163. C. J. Hawker, K. L. Wooley, and J. M. J. Frechet, J. Am. Chem. Soc. 115, 4375 (1996). 164. J. K. Young, G. R. Baker, G. R. Newkome, K. F. Morris, and C. S. Johnson, Jr., Macromolecules 27, 3464 (1994). 165. G. R. Newkome, J. K. Young, G. R. Baker, R. L. Potter, L. Audoly, D. Cooper, C. D. Weis, K. Morris, and C. S. Johnson, Jr., Macromolecules 26, 2394 (1993). 166. M. Murat and G. S. Grest, Macromolecules 29, 1278 (1996). 167. S. Stechemesser and W. Eimer, Macromolecules 30, 2204 (1997). 168. V. A. Kabonov, A. B. Zezin, V. B. Rogacheva, Zh G. Gulyaeva, M. F. Zansochova, J. G. H. Joosten, and J. Brackman, Macromolecules 31, 5142 (1998). 169. K. L. Wooley, C. J. Hawker, J. M. Pochan, and J. M. J. Frechet, Macromolecules 26, 1514 (1993). 170. H. Stutz, J. Polym. Sci., Polym. Phys. Ed. 28, 1483 (1990). 171. C. J. Hawker and F. Chu, Macromolecules 29, 4370 (1996). 172. Y. H. Kim and O. W. Webster, Macromolecules 25, 5561 (1992). 173. C. J. Hawker, E. E. Malmstrom, C. W. Frank, and K. P. Kampf, J. Am. Chem. Soc. 119, 9903 (1997). 174. K. Haupt and K. Mosbach, Chem. Rev. 100, 2495 (2000). 175. G. Wulff, Chemtech, November issue, p. 19 (1998). 176. P. A. G. Cormack and K. Mosbach, Reac. Func. Polym. 41, 115 (1999). 177. N. Masque, R. M. Marce, and Borrul, Trends Anal. Chem. 20, 477 (2001). 178. B. Sellergren, Angew. Whcme. Int. Ed. Engl. 39, 1031 (2000). 179. G. Wulf, Angew. Chem. Int. Ed. Engl. 34, 1812 (1995). 180. K. Mosbach and O. Ramstrom, Bio Tech. 14, 163 (1996). 181. M. J. Whitcombe, M. E. Rodriguez, P. Villar, and E. N. Vulfson, J. Am. Chem. Soc. 117, 7105 (1995). 182. J. U. Klein, M. J. Whicombe, F. Mulholland, and E. N. Vulfson, Angew. Chem. Int. Ed. Engl. 38, 2057 (1999).

Polymeric Nanoparticles 183. E. Yilmaz, K. Haupt, and K. Mosbach, Angew. Chem. Int. Ed. Engl. 39, 2115 (2000). 184. K. Hosoya, K. Yoshihako, Y. Shirasu, K. Kimata, T. Araki, N. Tanaka, and J. Haginaka, J. Chromatogr. 728, 139 (1996). 185. M. A. Vorderbruggen, K. Wu, and C. M. Breneman, Chem. Mater. 8, 1106 (1996). 186. A. G. Mayes and K. Mosbach, Anal. Chem. 68, 3769 (1996). 187. R. J. Ansell and K. Mosbach, Analyst 123, 1611 (1998). 188. B. Sellegren, J. Chromatogr. A 673, 133 (1994). 189. L. Ye, P. A. G. Cormack, and K. Mosbach, Anal. Commun. 36, 35 (1999). 190. J. Matsui, T. Kato, T. Takeuchi, M. Suzuki, K. Yokoyama, E. Tamiya, and I. Karube, Anal. Chem. 65, 2223 (1993). 191. L. Schweitz, L. I. Anderson, and S. Nilsson, Anal. Chem. 69, 1179 (1997). 192. K. Fukui, B. G. Sumpter, M. D. Barnes, D. W. Noid, and J. U. Otaigbe, Macromol. Theory Simul. 8, 38 (1999). 193. K. Fukui, B. G. Sumpter, K. Runge, C. Y. Kung, M. D. Barnes, and D. W. Noid, Chem. Phys. 244, 339 (1999). 194. K. Fukui, B. G. Sumpter, M. D. Barnes, and D. W. Noid, Comput. Theor. Polym. Sci. 9, 245 (1999). 195. S. K. Gray, D. W. Noid, and B. G. Sumpter, J. Chem. Phys. 101, 4062 (1994). 196. M. L. Connolly, J. Am. Chem. Soc. 107, 1118 (1985). 197. S. N. Kreitmeier, G. L. Liang, D. W. Noid, and B. G. Sumpter, J. Therm. Anal. 46, 853 (1996). 198. K. Runge, B. G. Sumpter, D. W. Noid, and M. D. Barnes, J. Chem. Phys. 110, 594 (1999). 199. K. Runge, B. G. Sumpter, D. W. Noid, and M. D. Barnes, Chem. Phys. Lett. 299, 352 (1999). 200. B. C. Hathorn, B. G. Sumpter, D. W. Noid, R. E. Tuzun, and C. Yang, J. Phys. Chem. A 106, 9174 (2002). 201. B. C. Hathorn, B. G. Sumpter, M. D. Barnes, and D. W. Noid, Polymer 43, 3115 (2002). 202. B. C. Hathorn, B. G. Sumpter, D. W. Noid, and M. D. Barnes, Macromolecules 35, 1102 (2001). 203. B. C. Hathorn, B. G. Sumpter, M. D. Barnes, and D. W. Noid, J. Phys. Chem. B 105, 11468 (2001). 204. S. K. Gray, B. G. Sumpter, D. W. Noid, and M. D. Barnes, Chem. Phys. Lett. 333, 308 (2001). 205. K. Fukui, B. G. Sumpter, M. D. Barnes, and D. W. Noid, Macromolecules 33, 5982 (2000). 206. K. Fukui, B. G. Sumpter, D. W. Noid, C. Yang, and R. E. Tuzun, J. Polym. Sci. B 38, 1812 (2000). 207. K. Fukui, B. G. Sumpter, D. W. Noid, C. Yang, and R. E. Tuzun, J. Phys. Chem. B 104, 526 (2000). 208. K. Fukui, B. G. Sumpter, M. D. Barnes, and D. W. Noid, Polym. J. 31, 664 (1999). 209. V. Vao-soongnern, R. Ozisik, and W. L. Mattice, Macromol. Theory Simul. 10, 553 (2001). 210. H. Okada, Adv. Drug Deliv. Rev. 28, 43 (1997). 211. D. Luo and W. M. Saltzman, Nature Biotechnol. 18, 33 (2000). 212. N. S. Yang and W. H. Sun, Nature Med. 2, 481 (1995). 213. N. S. Yang, J. Burkholder, B. Roberts, B. Martinell, and D. McCabe, Proc. Nat. Acad. Sci. USA 87, 9568 (1990). 214. J. L. Cleland, O. L. Johnson, S. Putney, and A. J. S. Jones, Adv. Drug Deliv. Rev. 28, 71 (1997). 215. R. A. Jain, R. Hontz, and J. R. Swanson, Proc. Int. Symp. Control. Release Bioact. Mater. 26, 883 (1999). 216. R. Gref, Y. Minamitake, M. T. Peracchia, V. Trubetskoy, V. Torchilin, and R. Langer, Science 263, 1600 (1994). 217. H. Cohen, R. J. Levy, J. Gao, I. Fishbein, V. Kousaev, S. Sosnowski, S. Slomkowski, and G. Golomb, Gene Ther. 7, 1896 (2000). 218. W. F. Anderson, Nature 392, S25 (1996). 219. K. L. Wooley, J. Polym. Sci. A 38, 1397 (2000).

Polymeric Nanoparticles 220. G. B. Sukhorukov, E. Donath, S. Moya, A. S. Susha, A. Voigt, J. Hartmann, and H. Mohwald, J. Microencapsulation 17, 177 (2000). 221. S. M. Marinakos, J. Am. Chem. Soc. 121, 8518 (1999). 222. E. Merisko-Liversidge, P. Sarpotdar, J. Bruno, S. Hajj, L. Wei, N. Peltier, J. Rake, J. M. Shaw, S. Pugh, L. Polin, J. Jones, T. Corbett, E. Cooper, and G. G. Liversidge, Pharm. Res. 13, 272 (1996). 223. K. B. Thurmond, E. E. Remsen, T. Kowalewski, and K. L. Wooley, Nucleic Acids Res. 27, 2966 (1999). 224. G. G. Liversidge and K. C. Cundy, Int. J. Pharm. 125, 91 (1995). 225. M. Tobio, R. Gref, A. Sanchez, R. Langer, and M. J. Alonso, Pharm. Res. 15, 270 (1998). 226. L. Dahne, S. Leporatti, E. Donath, and H. Mohwald, J. Am. Chem. Soc. 123, 5431 (2001). 227. C. Allen, D. Maysinger, and A. Eisenberg, Colloid Surf. B 16, 3 (1999). 228. H. Takeuchi, H. Yamamoto, and Y. Kawashima, Adv. Drug Deliv. Rev. 47, 39 (2001). 229. X. Qiu, S. Leporatti, E. Donath, and H. Mohwald, Langmuir 17, 5375 (2001). 230. J. S. Patton, P. Trinchero, and R. M. Platz, J. Control. Release 28, 79 (1994). 231. D. Lemoine and V. Preat, J. Con. Rel. 54, 15 (1998). 232. D. A. Edwards, J. Hanes, G. Caponetti, J. Hrkach, A. Ben-Jebria, M. L. Eskew, J. Mintzes, D. Deaver, N. Lotan, and R. Langer, Science 276, 1868 (1997). 233. S. Dumitriu and M. Dumitrui, “Polymeric Biomaterials.” Dekker, New York, 1994. 234. B. D. Ratner, “Biomaterials Science: An Introduction to Materials in Medicine.” Academic Press, San Diego, 1997. 235. P. Guiot and P. Couvreur, “Polymeric Nanoparticles and Microspheres.” CRC Press, Boca Raton, FL, 1986. 236. J. L. Cleland, A. Daugherty, and R. Mrsny, Curr. Opinion Biotechnol. 12, 212 (2001). 237. D. D. Breimer, Adv. Drug Del. Rev. 33, 265 (1998). 238. P. R. Lockman, R. J. Mumper, M. A. Kahn, and D. D. Allen, Drug Dev. Ind. Pharm. 28, 1 (2002). 239. K. E. Byrd, A. J. Domb, A. J. Sokoloff, and E. L. Hamilton-Byrd, Polym. Adv. Tech. 3, 337 (1992). 240. Y. Dolizky, S. Sturchak, B. Nizan, B. A. Sela, and S. Margel, Anal. Biochem. 220, 257 (1994). 241. D. L. Marshall and G. K. Bush, Am. Biotech. Lab. 5, 48 (1987). 242. J. M. Singer, in “Future Directions in Polymer Colloids” (M. S. El-Aasser, Ed.), p. 315. Nijihoff, Dordrecht, 1987. 243. J. M. Singer and C. M. Plotz, Am. J. Med. 21, 888 (1956). 244. A. Rembaum, S. P. S. Yen, and W. Volksen, Chemtech. March, 182 (1978). 245. S. Hosaka, Y. Murao, S. Masuko, and K. Miura, Immunol. Commun. 12, 509 (1983). 246. A. A. Harchali, P. Montagne, J. Ruf, M. L. Cuilliere, M. C. Bene, G. Faure, and J. Duheile, Clin. Chem. 40, 442 (1994). 247. A. Kondo, S. Uchimura, and K. Higashitani, J. Ferment. Bioeng. 78, 164 (1994). 248. J. Ugelstad, R. Schmid, A. Berge, O. Aune, J. Bjørgum, L. Kilaas, P. Stenstad, A. Skjeltorp, T. Lindmo, and L. Korsnes, in “The Polymer Materials Encyclopedia 6” (J. C. Salamone, Ed.), pp. 4501–4519. CRC Press Inc., Boca Raton, FL, 1996. 249. J. Ugelstad, A. Berge, T. Ellingsen, J. Bjørgum, R. Schmid, P. Stenstad, O. Aune, T. N. Nilsen, S. Funderud, and K. Nustad, NATO ASI Ser. E 138, 355 (1987). 250. M. Uhlem, E. Hornes, and O. Olsvik, “Advances in Biomagnetic Separation.” Biotechnology Press, 1994. 251. M. Okubo and H. Hattori, Colloid Polym. Sci. 271, 1157 (1993). 252. T. Maehara, Y. Eda, K. Mitani, and S. Matsuzawa, Biomaterials 11, 122 (1990). 253. M. Hatakeyama, S. Iwato, K. Fujimoto, H. Handa, and H. Kawaguchi, Colloids Surf. B 10, 171 (1998).

901 254. M. Hatakeyama, S. Iwato, H. Hanashita, K. Nakamura, K. Fujimoto, and H. Kawaguchi, Colloids Surf. A 153, 445 (1999). 255. H. Hakala, E. Maki, and H. Lonnberg, Bioconj. Chem. 9, 316 (1998). 256. A. M. Rudolph and M. A. Heymann, Circ. Res. 21, 163 (1997). 257. U. B. Bruckner and K. Messmer, Biorheology 27, 903 (1990). 258. R. W. Barbee, B. D. Perry, R. N. Re, and J. P. Murgo, Am. J. Physiol. 263, R728 (1992). 259. V. E. Hjortdal, E. S. Hansen, T. B. Henriksen, D. Kjolseth, K. Soballe, and J. C. Djurhuus, Plast. Reconst. Surg. 89, 116 (1992). 260. M. J. Lyon and H. H. Wanamaker, Hearing Res. 67, 157 (1993). 261. D. P. Arnstein, G. S. Berke, T. K. Trapp, T. Bell, and M. Natividad, Otolaryngol. Head Neck Surg. 103, 371 (1990). 262. P. Kowallik, R. Schulz, B. D. Guth, A. Schade, W. Paffhausen, R. Gross, and G. Heusch, Circulation 83, 974 (1991). 263. N. Kobayashi, K. Kobayashi, K. Kondo, S. Horinaka, and S. Yagi, Am. J. Physiol. 266, H1910 (1994). 264. Y. Morita, B. D. Payne, G. S. Aldea, C. McWatters, W. Nusseini, H. Mori, J. I. Hoffman, and L. Kaugfman, Am. J. Physiol. 258, H1573 (1990). 265. F. W. Prinzen and R. W. Glenny, Cardiovasc. Res. 28, 1467 (1994). 266. H. Mori, S. Haruyama, Y. Shinozaki, H. Okino, A. Iida, R. Takanashi, I. Sakuma, W. K. Husseini, B. D. Payne, and J. I. Hoffman, Am. J. Physiol. 263, H1946 (1992). 267. C. Christiansen, H. Kryvi, P. C. Sontum, and T. Skotland, Biotech. Appl. Biochem. 19, 307 (1994). 268. P. Walday, H. Tolleshaug, Y. Gjoen, G. M. Kindberg, T. Berg, and T. Skotland, Biochem. J. 299, 437 (1994). 269. A. Bol, J. A. Melin, J. L. Vanoverschelde, T. Baudhuin, D. Vogelaers, M. DePauw, C. Michel, A. Luxen, D. Laber, and M. Cogneau, Circulation 87, 512 (1993). 270. K. Riggi, M. B. Wood, and D. M. Ilstrup, J. Orthop. Res. 8, 909 (1990). 271. P. Naredi, J. Mattsson, and L. Hafstrom, Int. J. Microcirc. Exp. 10, 169 (1991). 272. R. Sandin, U. Feuk, and J. Modig, Acta Anaesthesiol. Scand. 34, 457 (1990). 273. S. Sanchez, J. C. Bandi, and R. Mastai, Proc. Soc. Exp. Biol. Med. 200, 375 (1992). 274. T. Uchida, T. Takano, and S. Hosaka, J. Immunol. Methods 77, 55 (1985). 275. F. L. Jordan, H. J. Wynder, and W. E. Tomas, J. Neurosci. Res. 26, 74 (1990). 276. H. Kawaguchi, N. Koiwai, Y. Ohtsuka, M. Miyamoto, and S. Sasakawa, Biomaterials 8, 113 (1986). 277. L. Illum, L. O. Jacobsen, R. H. Muller, E. Mak, and S. S. Davis, Biomaterials 8, 113 (1987). 278. S. Yasukawa, H. Oshima, N. Matsumura, and T. Kondo, J. Microencapsul 7, 179 (1990). 279. Y. Tabata and Y. Ikada, Adv. Polym. Sci. 94, 107 (1990). 280. Y. Ishikawa, N. Muramatsu, H. Oshima, and T. Kondo, J. Biomater. Sci. Polym. Ed. 2, 53 (1991). 281. A. G. A. Coombes, P. D. Scoles, M. C. Davies, L. Illum, and S. S. Davis, Biomaterials 15, 673 (1994). 282. Y. Urakami, Y. Kasuya, K. Fujimoto, M. Miyamoto, and H. Kawaguchi, Colloids Surf. B 3, 183 (1994). 283. T. Kasuya, K. Fujimoto, M. Miyamoto, and H. Kawaguchi, Biomaterials 15, 673 (1994). 284. R. S. Hasan, H. M. Dockrell, S. Jamil, T. J. Chiang, and R. Hussain, Infect. Immunol. 61, 3724 (1993). 285. See for example, L. Marshall and G. Kra, The processing power of light, Opt. Photon. News, March 2002. 286. M. Bayer, T. Gutbrod, J. P. Reithmayer, A. Forchel, T. L. Reinecke, P. A. Knipp, A. A. Dremin, and V. D. Kulakovskii, Phys. Rev. Lett. 81, 2582 (1998). 287. M. D. Barnes, S. Mahurin, A. Mehta, B. G. Sumpter, and D. W. Noid, Phys. Rev. Lett. 88, 015508 (2002).

902 288. K. C. Ng, J. V. Ford, S. C. Jacobson, J. M. Ramsey, and M. D. Barnes, Rev. Sci. Instrum. 71, 2497 (2000). 289. G. Videen, D. Ngo, and M. B. Hart, Opt. Comm. 125, 275 (1996). 290. H.-J. Moon, G.-H. Kim, Y.-S. Lim, C.-S. Go, J.-H. Lee, and J.-S. Chang, Opt. Lett. 21, 913 (1996). 291. S. Mahurin, A. Mehta, B. G. Sumpter, D. W. Noid, K. Runge, and M. D. Barnes, Opt. Lett. 27, 610 (2002). 292. Y. Koike and E. Nihei, in “Proc. 3rd IUMRS Int. Conf. Adv. Mat.,” 1993. 293. S. Hayashi, Y. Kumamoto, T. Suzuki, and T. Hirai, J. Colloid Int. Sci. 144, 538 (1991). 294. Y. Koike, Y. Sumi, and Y. Ohtsuka, Appl. Opt. 25, 19 (1986). 295. J. H. Burroughes, D. D. C. Bradley, A. R. Brown, R. N. Marks, K. Mackay, R. H. N. Friend, P. L. Burn, and A. B. Homes, Nature 347, 539 (1990). 296. P. Chandrasekhar, “Conducting Polymers.” Kluwer Academic, Boston, 1999. 297. R. H. Friend, J. H. Burroughes, and T. Shimoda, Phys. World June 1998, p. 35. 298. K. Ziemelis, Nature 399, 408 (1999). 299. A. Kraft, A. C. Grimsdale, and A. B. Holmes, Angew. Chem. Int. Ed. 37, 402 (1998). 300. R. H. Friend, R. W. Gymer, A. B. Holmes, J. H. Burroughes, R. N. Marks, C. Taliani, D. D. C. Bradley, D. A. D. Santos, J. L. Bredas, M. Logdlund, and W. R. Salaneck, Nature 397, 121 (1999). 301. Y. Yang, Mater. Res. Soc. Bull. 22, 31 (1997). 302. S. A. Carter, J. C. Scott, and P. J. Brock, Appl. Phys. Lett. 71, 1145 (1997). 303. G. Yu, J. Gao, J. C. Hummelen, F. Wudl, and A. J. Heeger, Science 270, 1789 (1995). 304. N. C. Greenham, P. Xiaogan, and A. P. Alivisatos, Phys. Rev. B 54, 17628 (1996). 305. J. J. M. Halls, C. A. Walsh, N. C. Greenham, and E. A. Marseglia, Nature 376, 498 (1995). 306. D. Y. Kim, H. N. Cho HN, and C. Y. Kim, Progr. Polym. Sci. 25, 1089 (2000). 307. K. G. I. Nilsson, J. Immunol. Methods 122, 273 (1989). 308. M. Yasui, T. Shiroya, J. Fujimoto, and H. Kawaguchi, Colloids Surf. B 8, 311 (1997). 309. “Functional Polymer Colloid Polymers and Microparticles” (R. Arshady, Ed.), Vol. 4. 1999. 310. H. Li and B. He, Reactive Funct. Polym. 26, 61 (1995). 311. F. Ciardelli, C. Carlini, P. Pertici, and G. Valentini, J. Macromol. Sci. Chem. A 26, 237 (1989). 312. R. Mani, V. Mahadevan, and M. Srinivasan, J. Macromol. Sci. Pure Appl. Chem. A 30, 251 (1993). 313. S. D. Alexandratos, in “Ion Exchange and Solvent Extraction” (A. SenGupta, Ed.), Vol. 14. Dekker, New York, 2000; S. D. Alexandratos and S. Natesan, European Polym. J. 35, 431 (1999); see also Ion exchange, in “Ullmann’s Encyclopedia of Industrial Chemistry,” 6th ed., Wiley–VCH Electronic Release, 2001. 314. E. Meehan, in “Column Handbook for Size Exclusion Chromatography” (C.-S. Wu, Ed.). Academic Press, New York, 1999. 315. “Chromatography of Polymers: Characterization by SEC and FFF.” (T. Provder, Ed.). Am. Chem. Soc., Washington, DC, 1993. 316. “Strategies in Size Exclusion Chromatography” (M. Potschka and P. L. Dublin, Eds.). Am. Chem. Soc., Washington, DC, 1996. 317. J. Ugelstad, L. Söderberg, A. Berge, and J. Bergström, Nature 303, 95 (1983). 318. P. Brrradna, P. Stern, O. Quadrat, and J. Snuparek, Colloid Polym. Sci. 273, 324 (1995). 319. M. J. Garcia-Salinas and F. J. de las Nieves, Progr. Colloid Polym. Sci. 110, 134 (1998). 320. R. Pool, Science 35/36, 327 (1990). 321. T. G. Duclos, Mech. Design 21, 42 (1988). 322. W. M. Winslow, J. Appl. Phys. 1137 (1949). 323. Design News, Dec. 4 (1995).

Polymeric Nanoparticles 324. J. D. Carlson et al., U.S. Patent 5, 277, 282; U.S. Patent 5, 284, 330, 1994. 325. J. D. Carlson and K. D. Weiss, Machine Design Aug. 1994, p. 61. 326. V. D. Chase, Appliance Manuf. May 1996, p. 6. 327. M. R. Jolly, J. D. Carlson, and B. C. Muñoz, Smart Mater. Struct. 5, 607 (1996). 328. W. Kordonsky, J. Magn. Magn. Mater. 122, 395 (1993). 329. Lord Corporation, Rheonetic Linear Damper—RD-1001/RD1004 Product Information Sheet, Lord Corp. Pub. No. PS RD1001/4, 1997. 330. J. Rabinow, AIEE Trans. 67, 1308 (1948). 331. J. Rabinow, Nat. Bureau Standards Tech. News Bull. 32, 54 (1948). 332. E. M. Shtarkman, U.S. Patent 4, 992, 360, 1991, and U.S. Patent 5, 167, 850, 1992. 333. K. D. Weiss, J. D. Carlson, and D. A. Nixon, J. Intell. Mater. Syst. Struct. 5, 72 (1994). 334. F. Eisenbeiss, J. Kinkel, and H.-D.-J. Muller, U.S. Patent 6, 492, 471, 2002. 335. I. Sucholeiki, N.-H. Sung, and J. Y. Lee, U.S. Patent 6, 423, 410, 2002. 336. T. C. Zion, D. E. Smith, H. Yoon, and M. C. Ezenyilimba, U.S. Patent 6, 380, 297, 2002. 337. A. C. Poppelaars and J. M. Zijderveld, U.S. Patent 6, 262, 193, 2001. 338. J.-C. Wu, U.S. Patent 6, 187, 440, 2001. 339. J. J. Crevecoeur, E. W. J. Neijman, L. N. Nelissen, and J. M. Zijderveld, U.S. Patent 6, 242, 540, 2001. 340. H. S. Wu, J. Hegenbarth, X. K. Chen, and J. G. Chen, U.S. Patent 5, 895, 799, 1999. 341. N. Chopra, P. M. Kazmaier, and F. E. Torres, U.S. Patent 6, 492, 025, 2002. 342. N. Chopra, P. M. Kazmaier, and P. J. Gerroir, U.S. Patent 6, 488, 870, 2002. 343. T. Kimura, M. Teramachi, K. Hosoya, and Y. Ohtsu, U.S. Patent 6, 482, 867, 2002. 344. H. Shibata, Y. Takahashi, H. Kasahara, M. Aoyama, and S. Takiyama, U.S. Patent 6, 482, 881, 2002. 345. H. S. Wu, U.S. Patent 5, 523, 346, 1999. 346. M. Okamoto, N. Kunishi, and Y. Koyama, U.S. Patent 5, 583, 166, 1999. 347. E. Mathiowitz, D. Chickering III, Y. S. Jong, and J. S. Jacob, U.S. Patent 6, 235, 224, 2001. 348. G. Spenlehauer, M. Veillard, and T. Verrechia, U.S. Patent 6, 120, 805, 2001. 349. J. U. Otaigbe et al., U.S. Patent 6, 171, 433, 2001. 350. T. M. Handyside and A. R. Morgan, GB Patent 2, 246, 571, 1992. 351. D. W. Noid, J. U. Otaigbe, M. D. Barnes, B. G. Sumpter, and C. Y. Kung, U.S. Patent 6, 461, 546, 1998. 352. K. Aoki, K. Koide, and A. Matsumoto, Jpn Patent 08, 157, 532, 1996. 353. M. Oda and K. Setoguchi, Jpn Patent 02, 097, 501, 1990. 354. M. Yamazaki and K. Takebe, Jpn Patent 01, 198, 634, 1989. 355. M. Shigemitsu, Jpn Patent 01, 006, 035, 1989. 356. Y. Kometani, S. Fumoto, and S. Tanigawa, Ger Patent 2, 063, 635, 1972. 357. M. Akaishi, T. Serizawa, and K. Taniguchi, Jpn Patent 10, 337, 794, 1998. 358. K. Ito, Progr. Polym. Sci. 23, 581 (1998). 359. K. Ito and K. Seigou, Adv. Polym. Sci. 142, 129 (1999). 360. H. Yamada, Jpn Patent 10, 330, 670, 1998. 361. Y. Suwabe, T. Mikami, and M. Fukuda, Jpn Patent 10, 140, 057, 1996. 362. H. Uraki, S. Sawada, Y. Iida, T. Fujigamori, and S. Hazama, Jpn Patent 09, 053, 035, 1997. 363. H. Uraki, J. Satake, Y. Iida, T. Fujigamori, and S. Hazama, Jpn Patent 09, 053, 036, 1997.

Polymeric Nanoparticles 364. Y. Funaki, K. Tsutsumi, T. Hashimoto, and M. Harada, Euro Patent 864, 362, 1998. 365. R. Ehrat and H. Watrinet, Euro Patent 761, 743, 1997. 366. H. Tamura, Jpn Patent 04, 025, 102. 367. H. Nakai and S. Edakawa, Jpn Patent 02, 202, 922, 1990. 368. A. Kagawa, Jpn Patent 63, 120, 740, 1988. 369. J. Kumaki, Euro Patent 197, 461, 1986. 370. S. Hayashi, S. Murakami, K. Goto, T. Noguchi, and Y. Yamaguchi, Jpn Patent 07, 025, 642, 1995. 371. Y. Suda, M. Murakami, and K. Makino, Jpn Patent 06, 287, 313, 1994. 372. H. Tamura, Jpn Patent 03, 163, 805, 1991. 373. K. Kawazu, K. Seike, T. Kawamura, H. Kiyata, and H. Onoyama, Jpn Patent 09, 286, 948, 1997. 374. A. Katsushima, Jpn Patent 06, 073, 334, 1994. 375. T. Fujiwa and S. Urabe, Jpn Patent 09, 255, 914, 1997.

903 376. T. Yoshihara, Jpn Patent 09, 110, 909, 1997. 377. Z. Kishimoto, Jpn Patent 02, 212, 562, 1990. 378. H. Morita, Y. Ishizaki, and J. Azuma, Jpn Patent 01, 170, 677, 1989. 379. S. Myanaga, Y. Doi, and J. Tsunoda, Jpn Patent 08, 259, 846, 1996. 380. A. Shichizawa and Ii-H. Aachi, Jpn Patent 07, 138, 304, 1995. 381. T. Kitayama, N. Takami, K. Urabe, and T. Fukuda, Jpn Patent 06, 256, 405, 1994. 382. H. Morita, E. Hirota, and Y. Ishizaki, Euro Patent 273, 605, 1988. 383. F. J. Micale, U.S. Patent 4, 665, 107, 1987. 384. S. Yamaguchi, T. Takabe, T. Ito, N. Kobayashi, and H. Morita, Jpn Patent 05, 254, 906 1993. 385. H. Yao and T. Hayashi, Jpn Patent 04, 300, 946, 1992. 386. H. Yao and T. Hayashi, Jpn Patent 05, 287, 116, 1993. 387. E. P. Giannelis, R. Krishnamoorti, and E. Manias, Adv. Polym. Sci. 138, 107, 1999, and references therein.