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Introduction
Hydrogels are hydrophilic polymers that absorb water and are insoluble in water at physiologic temperature, pH, and ionic strength because of the presence of a three-dimensional network. The cross-links can be formed by covalent bonds, or electrostatic, hydrophobic, or dipoledipole interactions. The hydrophilicity is due to the presence of hydrophilic groups, such as hydroxyl, carboxyl, amide, and sulfonic groups along the polymer chain. The area of hydrogel research has expanded dramatically in the last 10 years, primarily because hydrogels perform well for biomedical applications. This is true for both the synthetic and natural hydrogels. Hydrogels work well in the body because they mimic the natural structure of the bodys cellular makeup. Recent advances in the use of hydrogels for tissue engineering, drug delivery, and contact lens application, to name but a few of the many biomedical applications of hydrogels, have led to (for the rst time) the potential to design articial organs in a controlled fashion, to deliver drugs to specic sites in the body, and to fabricate the rst true extended wear contact lenses. This article focuses on the biomedical applications of hydrogels. Several areas of nonbiomedical applications are also discussed. Hydrogels can be classied as synthetic, natural, smart, and biodegradable hydrogels. There may be many more classes of hydrogels, but this class division is based on the current focus of hydrogel research. Hydrogels which are interpenetrating polymer networks (IPNs) and block copolymers, for example, are discussed throughout the article. The preparation of hydrogels focuses on the details of free-radical cross-linking polymerization, chemical cross-linking, irradiation cross-linking, and physical interaction cross-linking techniques.
Encyclopedia of Polymer Science and Technology. Copyright John Wiley & Sons, Inc. All rights reserved.

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Properties
A hydrogel is a cross-linked polymer that swells in water to an equilibrium value. The dry hydrogel is called a xerogel or dry gel. When the hydrogel is dried, water evaporates from the gel and causes collapse of the gel structure. If water is removed without disturbing the network, either by freeze-drying or by organic solvent extraction techniques, the resultant hydrogel is extremely porous. These materials are referred to as aerogels (1). The amount of water a material needs to absorb to be classied as a hydrogel remains undened, but most researchers generally agree that if a material absorbs at least 10% water and is insoluble in water, it can be classied as a hydrogel. The swollen equilibrated state of a hydrogel results from a balance between the osmotic driving forces that cause the water to enter the hydrophilic polymer and the cohesive forces exerted by the polymer chains in resisting expansion (2,3). They attain an equilibrium swelling state that depends on the osmotic driving forces and the cross-link density. An equilibrated state is reached quickly following immersion of the dry (xero) gel in water. Most hydrogels, in fact, reach an equilibrium concentration of water within 15 min of hydration time. The degree of hydration (water content) can be expressed using the following equation: %Water(weight) = [(hydrated weight dry weight)hydrated weight]100 The degree of water absorption related to the dry state of the polymer is called percent hydration. This is calculated using the following equation: %Hydration = [(hydrated weight dry weight)dry weight]100 The more hydrophilic the polymer and/or monomers used to prepare the hydrogel, the higher the degree of hydration. This hydration can also, to some extent, be controlled through cross-link density. The higher the degree of crosslinking for a given polymer system will result in a corresponding decrease in water content. An expression for polymer swelling is found in the FloryHuggins equation where the volume fraction of the polymer in the swollen gel is expressed as
1 V2 = mp dp 1 1 mp dp + mw dw

where mp and mw are the weights of dry polymer and solvent, respectively, and dp and dw are the densities of dry polymer and solvent at 25 C (4,5). The hydrophilicity of the hydrogel system can also be expressed by means of an interaction parameter ( ). This parameter denes the interaction energy during the process of hydration. The parameter is determined experimentally from stressstrain curves and the swelling characteristics of the hydrogel using the FloryHuggins equation,
1/3 2 = e v1 2 v2 /2 + ln(1 v2 ) + v2 v2 0 (v2 )

where e is the concentration of elastically effective chains in a volume unit of

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unswollen polymer, v1 is the molar volume of solvent, and the isotropic dilation factor. One can approximate 2 0 to equal (v0 )2/3 if the polymerization is performed in a solvent (v0 in this case is the volume fraction of the monomer in the original mixture or the volume fraction of the polymer at network formation), and e can be approximated from stressstrain curve. The water that is contained in hydrogels is believed to consist of a bound water and free water (6). When the dry hydrogel polymer is placed in water, the hydrophilic groups along the polymer chain are hydrated rst. Water will form a hydration sphere around these hydrophilic groups. This type of water is called bound water. The bound water molecules are believed to be tightly held in the hydrogel matrix through a series of chemical interactions, such as hydrogen bonding. As the hydrogel continues to hydrate, additional water that is absorbed by the hydrogel is referred to as unbound or free water. This water lls the voids and pores of the hydrogel. The water in this hydration sphere has less structure and higher mobility than does bound water. Higher water content hydrogels contain more free water. It is the free water that is believed to be responsible for the end of day dehydration characteristics of high water content hydrogel contact lenses. These types of water are determined experimentally using dsc (differential scanning calorimetry) and nmr (nuclear magnetic resonance) techniques. It is important to note, however, that not all researchers believe that free and bound water exists. From heat-capacity measurements in the hydrogel poly(HEMA) [poly(2hydroxyethyl methacrylate)] and a study of the thermodynamics from mixing water with poly(HEMA), researchers have indicated that strong interactions of water with the polar groups along the polymer chain does not occur. Evidence as determined by pulsed gradient nmr indicates that all of the water in poly(HEMA) hydrogels diffuses as a homogeneous water phase (7). The amount and type of water that is contained in the hydrogels determines the diffusion and transport characteristics of the hydrogel. This is important for drug delivery and contact lens application. It has been shown that the low water transport characteristics of some contact lens hydrogel system is the major factor responsible for contact lens adhesion. The oxygen permeability and water transport characteristics of conventional hydrogels increase with increasing levels of hydration. Details of the diffusion and dynamic transport behavior or hydrogels can be found in excellent reviews (8). The design of a high water content hydrogels for biomedical application where mechanical integrity is required can be a serious problem because of the fact that high water content hydrogels typically possess very poor tear strengths.

Classes of Hydrogels
Hydrogels can be classied as either synthetic or natural according to their origin, degradable or stable depending on their stability characteristics, and intelligent or conventional depending on their ability to exhibit signicant dimensional changes with variations in pH, temperature, or electric eld. Conventional Synthetic Hydrogels. The class of conventional synthetic hydrogels is prepared by free-radical polymerization of vinyl-activated monomers. These monomers can be classied according to type and charge. The water content

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of the resultant hydrogel can vary widely, depending on the hydrophilicity of the monomer and degree of cross-linking. A difunctional monomer is added to crosslink the polymer chains. One of the most important classes of monomers used to prepare synthetic hydrophilic polymers and hydrogels are the methacrylates and acrylates. The principal monomer is shown in (1) where R H (acrylate) and R CH3 (methacrylate). A wide variety of commercially available hydrophilic acrylates and methacrylates exist. A huge advantage of this class of monomers is their relative ease of polymerization and low cost. The monomer 2-hydroxyethyl methacrylate (HEMA) (2) has been used extensively in the contact lens industry. Poly(HEMA) possesses a water content of 38% and has excellent mechanical strength. The monomer glyceryl methacrylate (3) when polymerized and cross-linked results in a hydrogel of approximately 70% water, depending on its purity and degree of cross-linking.

Another very important class of monomers used to prepare synthetic hydrogels is the acrylamide/methacrylamide (4) (R CH3 or H) based monomers. These include the monomers acrylamide (AA), N -methacrylamide (MAA), N ,N dimethylacrylamide (DMA), and diacetone acrylamide (DAA). The polymers prepared from AA, MAA, and DMA are all super water absorbent polymers, each capable of absorbing several times their weight in water. DMA is a particularly useful monomer for biomedical application in that it possesses excellent hydrolytic and thermal stability characteristics and moderately low levels of toxicity, unlike AA, which is extremely toxic. The polymerization of the monomer 2-hydroxyethylmethacrylamide (5) also results in a super water absorbent polymer. Despite its similar structure to the methacrylate analogue HEMA, this polymer is capable of water contents as high as 85%, simply because of substitution of the ester for an amide linkage.

The class of hydrophilic monomers based on the cyclic lactams is also an important class of monomers. The most widely used lactam monomer is N -vinyl pyrrolidinone (NVP) (6). This is also a super absorber. Hydrogels prepared from

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this monomer absorb several times their weight in water, despite the hydrophobic aliphatic ring structure. Cross-linking agents for NVP and NVP-based copolymerizations include N ,N -methylenebisacrylamide and allyl methacrylate. The monomer NVP is widely used for contact lens application, and in fact, most commercial contact lens materials contain NVP.

Monomers that contain ionic functionality are also widely used for the preparation of hydrogels. These include methacrylate, methacrylamide, and styrenebased monomers that contain acidic or basic functionality. In this class of monomers is included methacrylic acid, acrylamidomethylpropylsulfonic acid (7), and p-styrene sulfonate. These are typically used as comonomers at low concentration. The ionic functionality in a buffered saline environment dramatically increases the water content of the resultant hydrogel. For example, copolymerization of 2 wt% methacrylic acid with HEMA results in a hydrogel having a water content of 60% (compared with a 38% water content for HEMA alone). In a similar fashion, the cationic monomer methacryloyloxyethyltrimethylammonium chloride (MAC) is extremely hydrophilic. A hydrogel containing 60% NVP, 10% MAC, and 30% HEMA results in a material having an equilibrium water content of 87% (9).

The copolymerization of MAC with methacrylic acid results in ampholytic hydrogels. These are hydrogels that contain both anionic and cationic characteristics (10). These materials exhibit interesting pH-dependent behavior. Zwitterionic hydrogels, based on 2-(methacryloyloxy)ethyl-2 -(trimethylammonium)ethyl phosphate inner salt (8), have also been designed for improved biocompatibility. These hydrogels mimic the zwitterionic structure of phospholipids such as phosphatidylcholine, which is a major component of the outer membrane of all living cells (11). Zwitterionic monomers contain both a cationic and anionic charge on the same molecule.

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It is important to note that almost all high water content hydrogels possess poor mechanical properties. This is a huge disadvantage of hydrogels, especially when one needs to design a material for an application that requires some mechanical integrity. A homopolymer of poly(NVP), for example, resembles a hydrated gelatin. In order to overcome the poor strength of these materials, it is necessary to copolymerize these super absorbent monomers with monomers that are capable of improving the overall tear strength of the material. Several monomers have been successfully used. One such monomer is methyl methacrylate (MMA). Low concentrations of MMA in a copolymer formulation typically result in a reduction in water content, but a dramatic improvement in mechanical integrity is also observed. Monomers such as cyclohexyl methacrylate and t-butylcyclohexyl methacrylate also work well (12). These monomers improve the mechanical properties of hydrogel formulations by imparting rigidity to the polymer network. This approach, however, is seriously limited in that phase separation often occurs before acceptable properties are achieved. One approach to overcome this phase separation issue, while improving the overall hydrogel strength, is through the use of hydrophilic-bulky strengthening agents, such as 4-t-butyl2-hydroxycyclohexyl methacrylate (TBE) (9) (13). Excellent mechanical characteristics and optical clarity have been achieved through the use of TBE. A 80/20 (w/w) copolymer of NVP and TBE results in an 85% water-containing hydrogel that possesses a tear strength equivalent to the 38% water-containing hydrogel poly(HEMA).

Silicone Hydrogels. A new class of hydrogels based on silicone has been developed (14). These materials were developed in an attempt to combine the high oxygen permeability of polydimethylsiloxane and the excellent water absorption characteristics of conventional non-silicone hydrogels. This new class of hydrogels was developed primarily for contact lens application. These silicone hydrogels are also prepared by free-radical polymerization techniques. The biggest limitation in the design of silicone hydrogels is that siliconebased monomers are hydrophobic and insoluble in hydrophilic monomers. The copolymerization of methacrylate-functionalized silicones with hydrophilic monomers generally results in opaque, phase-separated materials. There have been essentially three approaches in the design of transparent silicone hydrogels, ie, in minimizing the phase separation that occurs during polymerization of methacrylate-functionalized silicones with hydrophilic monomers. One approach has involved a protectiondeprotection procedure (15). This involves the protection of a hydrophilic monomer with a hydrophobic protecting group. Copolymerization of the protected monomer with a methacrylate-functionalized silicone, followed by removal of the protecting group, results in a transparent silicone hydrogel. For example, trimethylsilyl-protected 2-hydroxyethyl methacrylate is

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readily soluble in silicone-based monomers. Copolymerization of the protected HEMA with the monomer methacryloyloxyethyl tris(trimethylsilyloxy)silane forms a transparent, hydrophobic material that, following immersion in a mild basic or acidic deprotecting solution and extraction to remove hexamethyldisiloxane, gives a transparent silicone-based hydrogel (10). This is a good approach in principle; however, it is extremely expensive because of the large number of processing steps and length of time required for complete deprotection.

Another approach has been the use of a solubilizing co-solvent. For example, the addition of a co-solvent that is capable of solubilizing an incompatible mixture of silicone and a hydrophilic monomer, in many cases, results in transparent materials following cure. Examples of co-solvents include isopropyl alcohol, hexanol, and methyl dodecanoate. This approach has the additional advantage of controlling the glass-transition temperature of the material. The addition of higher concentrations of co-solvent results in a lower glass-transition temperature as a result of a higher polymer chain exibility (higher free volume). It is imperative that the glass transition of the material is below the cure temperature in order to effect a complete cure. The third and most successful approach has been the preparation of siloxanes containing hydrophilic groups to improve the solubility of siliconebased materials with hydrophilic monomers. In this approach several synthetic avenues have been pursued including the synthesis of hydrophilicTRIS [tris(trimethylsiloxysilyl)propyl methacrylate] derivatives, siloxanes containing hydrophilic blocks, and siloxanes containing hydrophilic grafts, such as polyethyleneglycol-grafted silicones (11) (1619).

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Natural Hydrogels. Naturally occurring water-soluble polymers include polynucleotides, polypeptides, and polysaccharides. These polymers are derived from a variety of naturally occurring sources such as plants, animals, and humans, or are synthesized. The polymer collagen, for example, is obtained from cows, pigs, and humans, depending on the type of collagen required. Polypeptides can be synthesized by a protection/solid support scheme or through recombinant DNA techniques. Hydrogels of naturally occurring polymers are prepared by the chemical or physical cross-linking of these polymers. The chemical crosslinking reaction of polysaccharides (alginate, chitin, chitosan, cellulose, oligopeptides, and hyaluronic acid (12)) and proteins (albumin, gelatin) leads to a variety of well-dened hydrogels (2022). Hydrogels prepared from these polymers exhibit excellent biocompatibility, primarily because they mimic the structural components of the body. In humans, glycoaminoglycans are hydrogels that exist in the connective tissue, such as skin, tendon, and bone (23,24). Additional information on the naturally occurring polymers can be found in excellent reviews (25,26).

Smart Hydrogels. A truly amazing class of hydrogels that has found potential use for a wide variety of applications is the class of smart or intelligent hydrogels. Smart hydrogels are, in most respects, very much similar to conventional hydrogels. They are synthesized using similar methods and absorb water. Smart hydrogels, however, deserve to be in their own class. The uniqueness of this class is due to the unusual volume changes that these polymers exhibit under the application of very specic stimuli. Smart hydrogels exhibit signicant volume changes in response to stimuli such as changes in pH, temperature, electric eld, and light (2729). The major reason for the interest in these polymer systems

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is that the smart polymers, in most respects, behave like biopolymers in nature; small changes of some specic stimuli dictate most of the biochemical response in the body. The desire to form hydrogel systems that can mimic biological systems drives a huge area of research. This volume change is abrupt and occurs with only a small change in stimuli. In solution these changes are referred to as the lower critical solution temperature (LCST), where at a specied temperature the polymer precipitates from solution. For a hydrogel system, these changes are marked by an order of magnitude change in the size, shape, and water content of the hydrogel. The hydrogel returns to its original state when the stimuli is removed. These shifts are triggered by changes in the physical state of the hydrogel as a result of changes in the hydrophilic/hydrophobic microstructure of the hydrogel. In designing such systems, the goal is to control the balance of the hydrophobic/hydrophilic nature of the hydrogel system. The driving force behind these transitions varies, with common stimuli including (1) the neutralization of charged groups by either pH shift, (2) the addition of an oppositely charged polymer, and (3) change in the efciency of hydrogen bonding with an increase in temperature or ionic strength (30). Biodegradable Hydrogels. Biodegradable hydrogels, much similar to that of the smart hydrogels category, has expanded at such a fast pace that it now deserves to be in its own class. The uses of biodegradable hydrogels now encompass a wide variety of applications, for both biomedical and nonbiomedical uses. In the design of biomedical products, the basic objective is to fabricate materials that resorb or degrade in a physiological environment so that the device ultimately disappears with no adverse reaction (31,32). Degradable polymers undergo chain scission to form low molecular weight oligomers or monomers. Ultimately, the oligomers and monomers are either fully degraded to biosubstances or are eliminated by the body. Degradation is characterized by loss of molecular weight, loss of mass and mechanical strength. The denition of biodegradation is broad and includes a variety of degradative mechanisms, depending on whether the degradation follows (33). Degradation hydrolytic, thermal, or enzymatic degradation pathways (see BIODEGRADABLE POLYMERS, MEDICAL APPLICATIONS).

Methods of Preparation Free-Radical Polymerization. Free-radical polymerization cross-linking is the preferred route used to prepare hydrogels from the class of acrylates, amides, and vinyl lactams. It can also be used to prepare hydrogels from the naturally occurring polymers if the polymer backbone or chain end of the natural polymer has been functionalized with a radically polymerizable group. It is also the preferred route to prepare interpenetrating network hydrogels (IPNs) using either synthetic monomers or natural polymers (again funtionalized with a radically polymerizable group). The IPNs hydrogels are networks that contain two polymer systems, each in its own cross-link network. To form a hydrogel by free-radical polymerization, a difunctional crosslinking agent must be added to the polymerization. The classical gelation

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theory can be applied to most of these polymerizations, especially for methacrylatedimethacrylate monomer combinations that have similar reactivity (34). This theory allows for a fairly precise determination of the overall kinetics of the system, which includes estimates of the gelation and vitrication point. There are a variety of cross-linkers one can choose from. For methacrylate polymerizations, a common cross-linker is ethylene glycol dimethacrylate (13) that is added at a concentration of 0.11.0%. For acrylamide systems, methylene bisacrylamide is very common. For lactam-based systems, ethylene divinylurea works extremely well. Problems arise when one attempts to copolymerize monomers of unlike reactivity, such as the copolymerization of HEMA with the vinyl lactam NVP. For this type of polymerization, a block-type copolymer possessing high levels of unreacted NVP results. This is due to the slow kinetics of NVP polymerization and unsuitable reactivity ratio of this comonomer system. The reactivity ratios (r1 and r2 values) result in a blocky backbone. This high level of unreacted NVP can be overcome by designing cross-linkers that are capable of polymerizing with both lactam and methacrylate functionality. For example, the crosslinker methacryloxyethyl vinyl carbonate (14) (MEVC) is an excellent example of a cross-linker that possesses reactivity for both a methacrylate and vinyl lactam functionality. The vinyl carbonate group has the same reactivity as the vinyl bond in NVP (35). The copolymerization of NVP and HEMA with MEVC results in a signicant increase in water content (when compared with conventional methacrylate cross-linkers) because of the higher incorporation of NVP in the copolymer.

The chemistry of typical free-radical polymerizations involves an initiation, propagation, chain transfer, and termination step leading to the formation of a cross-linked polymer system (36). The initiation step (radical formation step) utilizes chemistries that when subjected to thermal or ultraviolet radiation form radicals that react with activated monomers, such as a methacrylate. A wide variety of thermal, ultraviolet, visible, and redox initiators are commercially available. Typical thermal initiators include the class of azo compounds, such as azobisisobutylonitrile (AIBN), and peroxide initiators, such as the peroxydicarbonates and the hindered peroctoates. Polymerization conditions vary

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widely depending on the type of initiator and its half-life. For example, the respective 10-h half-life data of AIBN is 64 C, and for cumylperoxydecanoate the 10-h half-life is 38 C. This is extremely helpful in controlling polymerization exotherms, reactivity ratios, and monomer solubility. Typical commercially available ultraviolet and visible light initiators include the benzoin methyl ethers, acetophenones, and benzoyl phenyl phosphine oxides, to name but only a few. The polymerizations can be performed either in solution or neat. There are advantages to both methods depending on the product end use. Solution polymerizations can be helpful when the preparation of large quantities of hydrogel are required. The solvent for most reactions is water; however, a wide variety of polar solvents can be used with the only requirement that they can be exchanged for water in the hydration step. The polymerization exotherm can be controlled by choice of solvent. For many copolymerizations, the addition of a suitable solubilizing solvent is necessary to solubilize monomers of widely varying hydrophilicity. Also, a solvent can aid in the molecular weight control. By use of a chain-transfer solvent such as an alkyl mercaptan, molecular weight and end-group functionality can be controlled (37). Neat polymerizations, also sometimes referred to as bulk polymerizations, are typically performed between metal or glass plates utilizing a exible spacer to accommodate shrinkage. Clamps are used to assure a complete seal. The metal plates are many times treated with a uoro polymer, and the glass plates are treated with a chloromethylsilane to facilitate plate separation and to eliminate adhesion of the polymer lm. The lled plates are cured in an oven or under ultraviolet or visible lights, depending on the desired initiation mode. Following the cure, the lms are removed and extracted with an appropriate solvent. Neat polymerizations are very fast, usually requiring only minutes for total monomer conversion. This, however, limits the reaction size in that exotherms are difcult to control. A big advantage of neat polymerizations is that there is no need for solvent removal. Solvent removal can be very time-consuming, requiring either extensive thermal devolatilization or solution extraction steps. Emulsion and suspension polymerizations are also an important route to obtain hydrogels by free-radical polymerization (38). For some applications, this is the preferred route, particularly when droplets or spheres of the hydrogel are desired. This is an important route to prepare hydrogels for drug delivery application. For these polymerizations, the initiator, solvent, and monomer are added together with a suspending agent and/or emulsier. The cross-linker can be added but is not necessary, depending on whether one desires a soluble polymer. A major disadvantage of this route is that the emulsier and/or suspending agent is sometimes difcult to remove. Chemical Cross-Linking of Polymers. Another important method used to prepare hydrogels is by the cross-linking of hydrophilic polymers (39). This route can be employed for both the synthetic and naturally occurring polymers. In this reaction, a bifunctional cross-linking agent is added to a dilute solution of the hydrophilic polymer. The hydrophilic polymer contains functionality that is capable of reacting with the cross-linking agent. The reaction is typically in solution,

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but may also be performed through a suspension reaction where microparticles or spheres are desired. Most of the naturally occurring polymers can be cross-linked in this fashion. For example, the polymers albumin and gelatin can be cross-linked with formaldehyde or a difunctional dialdehyde (40,41). The aldehyde reacts with the amino group along the albumin polymer backbone (15). Also, using a similar approach, chrondroitin sulfate can be cross-linked with diaminododecane catalyzed by dicyclohexycarbodiimide (42). In this example, increasing the concentration of diaminododecane increased the degree of cross-linking. Cystein-bearing polypeptides can be cross-linked through cystein bonds (43,44). Another example is the cross-linking of poly(vinyl alcohol) using a diisocyanate-terminated poly(ethylene oxide). Hydrogels have also been prepared from functionalized poly(ethylene glycol) (PEG) through enzymatic cross-linking. PEG functionalized with a glutaminamide and a lysine-containing polypeptide were cross-linked by the reaction of a natural tissue enzyme, transglutaminase (16). Transparent gels of water contents as high as 90% have been prepared by this route (45).

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Irradiation Cross-Linking of Polymers. Hydrogels can also be obtained by ionizing-radiation techniques. This route can be employed for both the synthetic and naturally occurring polymers. Ionizing radiation is a radiation that possesses enough energy to ionize simple molecules either in air or water (46). The radiation can be in the form of an electron beam irradiation or radiation. This cross-linking reaction can be accomplished by irradiation of a hydrophilic polymer in bulk or in solution. These reactions are usually performed in water. The preferred method, however, is irradiation of a polymer solution. The solution method is preferred because it requires less energy for formation of a macroradical, and radical efciency is increased because of the reduced viscosity of the reaction mixture. When a polymer solution is irradiated, reactive sites along the polymer backbone are formed. The main reactive species (when water is used as the reactive solvent) are hydrated electrons, hydroxyl radicals, and hydrogen atoms. It is the hydroxy radicals, however, that lead to abstraction of hydrogen atoms along the polymer chain with formation of a multisite radical functionalized macromolecule. When these radicals combine, a cross-link is formed. This is not true for all polymer systems; some polymers, in fact, will degrade under ionizing radiation (47). Many polymers in solution will undergo simultaneous cross-linking and degradation reactions. Each polymer system is unique and the optimum irradiation conditions need to be determined experimentally to minimize chain degradation and maximize cross-linking reactions. Gels through Physical Interactions. Hydrogels can also be formed through a series of physical interactions. It is this type of reaction that, in fact, provides most of the cellular network in the body. These physical interactions include polyelectrolyte complexation, hydrogen bonding, hydrophobic association, and crystalline entanglements. Typical methods to prepare lms utilizing physical interactions involves solvent casting or precipitation techniques. Polyelectrolyte Complexation. Hydrogels can be easily formed through the formation of polyelectrolyte complexes (48). The bonds formed through polyelectrolytic complexation occur between pairs of charged sites along the polymer backbone. The hydrogels formed through electrolytic complexation are insoluble in water, and the electrolytic bonds can be very stable depending on the pH of the system (710 kcal). Polyelectrolyte complexes are divided into four subclasses depending on the basicity and acidity of the polyelectrolytes. These include strong acidstrong base, strong acidweak base, weak acidstrong base, and weak acidweak base subclasses. The composition of these complexes is dictated by the degree of dissociation of the electrolytic components. The complexation of poly(sodium styrene sulfonate) and poly(4vinylbenzyltrimethylammonium chloride) is easy to form (17) (49). By combining two water-based solutions of each polymer at equimolar concentration, the complex forms immediately as evident by the formation of white precipitate. Another example is the polyelectrolyte complexation of an amino group containing chitosan with the polymer sodium alginate (50). Sodium alginate also forms a strong complex through the association of calcium ions (51).

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Hydrogen Bonding. Hydrogels can also be formed through the hydrogen bonding of macromolecular chains. A hydrogen bond is formed through the association of electron-decient hydrogen and a functional group of high electron density. Similar to the polyelectrolytic complexes described above, hydrogen-bonded complexes occur in many biological systems. The hydrogen-bonded complex (18) of poly(acrylic acid) and poly(NVP) is one of the more common (52,53). This complex is affected by a variety of factors, such as the molar ratio of each polymer, the solution temperature, polymer concentration, type of solvent, and polymer structure (degree of association between complexing functionalities). This complex will not form a gel at neutral pH.

Hydrophobic Association. Hydrogels can also be formed through hydrophobic associations (5458). Polymer systems such as block copolymers, graft copolymers, and polymer blends form microphase/microdomain separated structures. The hydrophobic domains in these structures behave as associated crosslink sites. These polymers combine hydrophobic segments that form unique hydrophobic phases dispersed (or surrounded) by hydrophilic water absorbing regions. These hydrophobic-associated polymer blends typically possess poor mechanical properties because of poor interfacial adhesion, and lms are usually opaque because of macrophase polymer separation. Control of the size of the hydrophobic phase tends to improve the optical transparency and mechanical integrity. A precise balance needs to be established. One of the major advantages of this approach is the resultant low cost economics of the system. Commercially available polymers can be used to generate a wide variety of high strength, low cost hydrogels. This is particularly true of polymer blends. The hydrophobic phases of blend hydrogels form multicross-link sites along the polymer backbone and, so loss of the water-soluble polymer is

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minimized. This is extremely important for biomaterials where polymer leaching cannot be tolerated. Another advantage of this approach is that these polymer blends are soluble in organic solvents and ow at elevated temperatures. This allows for the processing of these hydrophobic blends by injection molding. Covalently cross-linked systems are insoluble in organic solvents and do not ow even at elevated temperatures. An excellent example of a hydrophobically associated hydrogel is the copolymer of poly(butyl methacrylate-co-methacrylamide-coacrylic acid) with a blend of poly(N ,N -dimethylacrylamide-co-N -vinylpyrrolidone) (59,60). Hydrophobic association is the predominant associated force holding this polymer blend together. It is reported that this polymer is stable in water at a pH range of 111.

Biomedical Applications of Hydrogels

One of the rst areas of commercial application for hydrogels was contact lenses (61). In the 1950s and 1960s Otto Wichterle in Prague discovered the hydrogel poly(HEMA), and a very simple process to prepare contact lenses (62). The process consisted of spinning a monomer solution in a preformed optical quality mold. This ingenious work was completed on an old-fashioned erector set in the early morning hours of Christmas. Since that time the area of hydrogel research has expanded rapidly. Hydrogels have been used for a wide variety of nonbiomedical applications, but the primary area of hydrogel research has focused on biomedical applications. This is the result of the generally excellent biocompatibility exhibited by hydrogels. Hydrogels have been successfully used for a wide variety of biomedical applications including contact lenses, intraocular lenses, drug delivery devices, implants, and scaffolds for living cell encapsulations.

Contact Lenses. Conventional Hydrogels. With the discovery of poly(HEMA), the contact
lens industry began to ourish. This is because HEMA is a transparent, soft material that, when hydrated, absorbs 38% water, and as a result is very comfortable to wear. The HEMA lens also has excellent wetting characteristics and biocompatibility. Within a few years following this discovery, a number of companies began to market their own version of the HEMA lens. A multitude of new hydrogel contact lenses emerged (6366). Most were based on copolymers of HEMA, NVP, and glyceryl methacrylate, together with cross-linkers and initiators. These materials were marketed as daily wear lenses, ie, wear the lens for one day, remove it at night for cleaning, and again wear the lens the next day. With the huge success of the daily wear contact lens market, researchers began to look for ways to increase the contact lens wearing time. This started a huge research effort to design contact lens materials for extended wear application, with the primary goal to simplify the patients cleaning and wearing schedule. Such design was not a trivial task. The design of a new contact lens material for extended wear application requires a material to satisfy a number of very strict design requirements. The material must be optically transparent, possess chemical and thermal stability, biocompatibility, and be wettable to tears. It must also have suitable mechanical properties. This requires a material to have a low modulus for patient comfort and high tear strength for lens handling

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durability. In addition, it is important that the material can be processed through free-radical polymerization techniques. Finally, the material must be permeable to oxygen. There is a lack of blood vessels in the corneal network, and so the cornea obtains almost all of its oxygen requirements from the atmosphere. Placing a contact lens over the eye that does not breathe may result in a number of physiological problems (microcysts, inammation, infections, and corneal ulcers) (67). There have been several approaches in the design of high oxygen permeable hydrogels for extended wear contact lens application. The rst and simplest approach reduces the lens thickness to increase the oxygen transmissibility. The key intrinsic material properties that are a measure of oxygen diffusion are oxygen permeability (Dk), where D is the diffusion coefcient and k is a proportionality coefcient called the Henrys law coefcient, and oxygen transmissibility (DkL 1 ), where the actual amount of oxygen reaching the cornea is inversely proportional to the lens thickness L. Several thin-lens designed contact lenses were introduced to the market with, however, limited success. These lenses were extremely difcult to handle, and most thin-lens designs did not provide enough oxygen permeability for extended lens wear application. The second approach consists of designing hydrogels with a high water content. A direct correlation exists between water content and oxygen permeability, and so the higher the water content, the higher the hydrogels oxygen permeability (Fig. 1, ). There are two methods of designing high water hydrogels. The rst involves the polymerization of highly hydrophilic monomers, such as NVP. The second utilizes the use of ionic monomers. The polymerization of HEMA with small concentrations of methacrylic acid, in a buffered saline environment results in a signicant increase in water content. For example, with the addition of 2 wt% of methacrylic acid to HEMA, a 60% water content is realized (as compared with 38% for pure HEMA). Both methods require the use of cross-linkers and initiators and may need strengthening agents.

140 120 100 80 Dk 60 40 20 0 0 20 40 60 % Water 80 100 120

Fig. 1. Relationship between Dk and percent water for conventional hydrogels ( ) and TPVC-based silicone hydrogels () (Dk in units of Barrers).

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At the time of the discovery of high water content hydrogels, these materials were considered a huge breakthrough with the potential, many practitioners believed, to be the ultimate contact lens material. This promise, however, was short-lived. There are several limitations of high water content hydrogels. The rst is that high water content hydrogels typically possess poor tear strengths and often exhibit a high afnity for protein, particularly for hydrogels possessing an ionic functionality (68). Deposits can affect material wetting, patient comfort, visual acuity, and may even cause inammatory responses. In addition, in dry environments, high water content hydrogels can induce a clinical response known as epithelial dehydration (a dehydration of the corneal epithelial cells) (69). This results in damage to the corneal epithelial cells. This phenomenon is a result of the high rate of water evaporation that occurs with the high water content hydrogels. Silicone Hydrogels. Another approach in the design of an extended wear contact lens consisted of the development of materials based on polydimethylsiloxane elastomers (PDMS). PDMS appeared to be an ideal polymer for use in an extended wear lens because it possessed a low modulus of elasticity, excellent transparency, and high oxygen permeability (70). The major drawback is that PDMS is completely nonwettable to tears, thus requiring surface treatment to impart wettability. These surface treatments were typically ineffective, resulting in surfaces that possessed marginal wetting characteristics and a high afnity for lipids. Another signicant drawback was that silicone lenses under normal wear conditions adhered to the cornea. This was attributed to the low water transport and high recovery characteristics of silicone (See SILICONES). In an attempt to combine the high oxygen permeability of PDMS and the excellent comfort, wetting, and deposit resistance of conventional hydrogels, the design of silicone-based hydrogels for contact lens application has been studied. This approach was also an attempt to design materials that did not adhere to the cornea. But most of all, it would provide lenses possessing levels of oxygen permeability high enough for extended wear application with minimal physiological impact. One simple, yet elegant approach in the design of a transparent silicone hydrogel has been reported (71,72). This material has been introduced commercially under the trade name Balalcon. This new silicone hydrogel system is based on a vinyl carbamate substituted TRIS derivative: (Tris(trimethylsiloxy)silylpropylvinylcarbamate) (TPVC, (19)). The TPVC molecule contains the hydrophobic silicone portion, and attached to this silicone is a hydrophilic vinyl carbamate group. This direct hydrophilic attachment now gives the silicone signicant hydrophilic character. The TPVC molecule is soluble in all proportions with hydrophilic monomers, such as HEMA and NVP. In addition, the vinyl carbamate group provides a polymerization link for copolymerization with hydrophilic monomers. The polymerization reaction of TPVC with NVP (and a suitable cross-linker) cast using uv initiation methods, results in transparent, high Dk, low modulus gels that are insoluble in water. Figure 1 () shows the relationship between oxygen permeability (Dk) versus percent water for the TPVC-based silicone hydrogels. This is an important relationship in that it clearly shows the Dk advantage in designing hydrogels based on silicone. In contrast to conventional non-silicone-based hydrogels, the Dk decreases with increasing

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water content because of the lower concentration of TPVC in the higher water content copolymers.

Intraocular Lenses. An intraocular lens (IOL) is an implant that is used to replace the diseased or damaged natural lens of the eye (7377). The lens is supported in the eye through the use of haptics or loops that are attached directly to the IOL optics. There have been a wide variety of materials that have been successfully used as IOLs, ranging from the rigid poly(methyl methacrylate) to the soft elastomer silicone. The current trend in IOL research is to design materials that can be folded and inserted through a small corneal incision. The natural lens is removed using emulsication techniques, and the IOL lens is placed in the original capsule bag that held the lens. Once the IOL is inserted, the lens recovers to its original shape. The small incision is desirable to reduce the degree of induced astigmatism (loss of sphericity) in the operated eye and to minimize corneal trauma. Hydrogels have also been successfully used for small incision IOLs. There are a number of commercially available hydrogel IOLs based predominately on HEMA, that range in water content from 17 to 28%. Aromatic-based methacrylates, such as phenylethyl methacrylate, are added to increase the refractive index of the lens. A higher refractive index will allow for a thinner IOL design (for power considerations) and result in an IOL that can be inserted through a smaller opening and recover its shape faster. A recent research effort has focused on an expandable IOL hydrogel where the lens is inserted in a dehydrated state and allowed to hydrate in the eye. This allows for the insertion of IOLs with reduced dimensions that make insertion through a small opening possible (78). Once the lens is implanted in the eye, it quickly hydrates, expands, and reaches its nal dimensions within minutes. Drug Delivery. The goal of drug delivery is to maintain the drug concentration in the body (plasma) within therapeutic limits for long periods of time. A constant drug release rate (zero-order) is desired. Conventional drug administration (oral delivery, injection) usually results in poor control of the plasma drug concentration. The controlled release of drugs from polymeric matrices has, however, been very successful. Many polymeric devices that deliver drugs at a

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sustained release rate are now commercially available. Controlled release devices offer the desired therapeutic range of drug dose. Controlled drug delivery applications include sustained delivery (time) and target delivery systems (insertion at the diseased site). The delivery of drugs such as protein-based drugs, eg, insulin and growth factor, and also conventional drugs, eg, steroids and antibiotics, can be achieved. Controlled release systems can generally be divided into three sections depending on their mode of release: diffusion controlled, chemical erosion, and solvent activated (79). In a diffusion-controlled device, the drug is surrounded by an inert barrier and diffuses from a reservoir, or the drug is dispersed throughout a polymer and diffuses from the polymer matrix. In a chemical erosion device, the drug is dispersed in a bioerodible polymer system or is covalently linked to a polymer backbone via a hydrolyzable linkage. As the polymer or hydrolyzable link degrades, the drug is released. In a solvent-activated device, the drug is dispersed within polymeric matrix and the device is swelled with a suitable solvent (usually water). As the device swells, the drug is released. Conventional Hydrogels. Hydrogels have been used extensively in the eld of controlled drug delivery (8085). The advantages of using hydrogels in drug delivery systems are that they can be used at a local level, ie, insertion at the diseased site. This has become important because many of the new protein-based drugs require delivery in this fashion. The release of a growth factor, for example, to a specic site is highly desirable. This is because many biologically active polypeptides have very short half-lives and can not be administered orally (86). The hydrogel can be cross-linked at the diseased site by photopolymerization techniques, complexation, and enzymatic cross-linking. The hydrogel will also conform to the local anatomy (organs, vessels). A wide variety of conventional cross-linked homo- and copolymeric hydrogels have been used for drug delivery application. In most hydrogels, the rate of diffusion through the bulk depends on two primary factors: the extent of cross-linking and water content. The extent of cross-linking determines the extent of swelling and the distance between chains within the hydrogel network. When entrapped drugs are diffusing within the network, the rate of diffusion can depend on the interchain separation and the size of the diffusing drug. The rate of diffusion is also controlled by water content. The general approach is to design hydrogels with very specic levels of hydrophilicity/hydrophobicity. This hydrophilic/hydrophobic balance controls water content and drug diffusion, where each drug will diffuse according to its dissolution prole (87). For water-soluble drugs dispersed in a high water content hydrogel, drug release will be rapid. Hydrogel drug delivery systems can be used in the hydrated or dry states. The drug is incorporated during the polymerization process or through diffusion techniques using preformed lms, tablets, etc (equilibrium absorption from concentrated drug solutions). A major limitation of incorporating the drug during the polymerizing process is that the drug will release during the extraction process (the process used to remove unreacted monomers) and, as a result, this technique is rarely used for biomedical applications. The diffusion method is a viable alternate to disperse and deliver drugs. In this method, the hydrogel is soaked in a drug solution until an equilibrium dispersion is reached. The hydrogel is then dried, packaged, and sterilized before use. Dried hydrogels release the drug as the

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material hydrates (the drug will diffuse very slowly in an unhydrated hydrogel). The release of water-soluble drugs from a dry hydrogel involves the simultaneous absorption of water and desorption of drug through a swelling-controlled diffusion mechanism (88). As water penetrates a glassy hydrogel matrix that contains a dissolved or dispersed drug, the polymer swells and its glass-transition temperature is lowered. As the water enters the material, a water front forms that separates the glassy polymer from the swelled hydrated polymer. In regard to drug distribution and release, the solvent front separates the drug in the unhydrated core from the swollen water phase. As the water phase continues to grow and expand, the drug diffuses and is released. The drug release kinetics during this process can range from a square root of time dependence (Fickian) to a linear time (Case II transport) dependence. The Case II transport is governed by the rate of polymer relaxation. For most cases, the intermediate situation, which is termed non-Fickian (rate of Fickian diffusion and polymer relaxation are comparable), is observed (89). For example, thiamine HCl release from an initial dry poly(HEMA) hydrogel bead, as plotted versus the square root of time, shows an initial non-Fickian behavior with linearity established only after long periods of time. Many conventional hydrogel designs that achieve zero-order drug-release are available. The manufacture of reservoir-based hydrogels (reservoir of drug encapsulated and surrounded by a polymer membrane) and matrix diffusion systems (drug is homogeneously dispersed in the hydrogel matrix) using common hydrogels, such as HEMA and glyceryl methacrylate, are relatively easy. The zero-order release rate can be achieved in many cases using either approach; however, the release rate of drugs from a matrix-type system typically declines continuously proportional to the square root of time. Soaking a poly(HEMA)/progesterone matrix, followed by uv irradiation in the presence of a cross-linker, can result in a rate-controlled membrane that exhibits a fairly steady release rate (90). Another use of a controlled release device makes use of a semicrystalline hydrogel (91). The hydrogels in these examples are based on poly(vinyl alcohol) and poly(ethylene oxide). In these systems, lms are prepared through solution casting techniques. The lms are subjected to an annealing process that creates varying degrees of crystallinity depending on the annealing time and temperature. The degree of crystallinity can be controlled and the degree of crystallinity is the controlling factor of drug release. The rate of crystal dissolution in water controls the rate of drug release. A commercial drug delivery application utilizing hydrogels has been introduced by Geltex pharmaceuticals (92). In this work a nonabsorbed hydrogel based on poly(allylamine) substituted with quaternary amine was designed for hypercholesterolemia (high cholesterol). The quaternary amine binds selectively with cholesterol. This polymer acts in the intestine as a bile acid scavenger to lower serum cholesterol levels in patients with increased risk of vascular disease. Bile acid sequestrants act by binding bile salts in the intestine and prevent them from passing through the intestinal wall and back into the blood stream. A U.S. NDA (new drug application) was led in July 1999 with approval received in May 2000. Degradable Hydrogels. Many research groups have studied the use of degradable hydrogels for drug delivery (93). The encapsulated drug will release at a controlled rate depending on such factors as pH, temperature, and cross-link density. Many examples of degradable drug delivery hydrogels can be found in the literature (39).

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One of the rst successful degradable release systems was based on the polyester hydrogels. These hydrogels are prepared by the copolymerization of malonate-type polyesters (polyesters that contain pendent backbone unsaturation) with monomers, such as NVP and acrylamide. Release of serum albumin occurs from these systems by a bulk erosion process. Other drugs can also be used. As the ester linkage of the polyester backbone hydrolyzes, the entrapped drug is gradually released to the surrounding environment. The release rate depends on the cross-link density. The degradation components of these erodible cross-linked polyesters result in nontoxic, water-soluble by-products. In a similar system, polyester macromers of a poly(ethylene glycol)-co-(lactic acid or glycolic acid) were prepared and evaluated for use as bioerodible hydrogels (94). These gels degrade upon hydrolysis of the oligo( -hydroxy acid) regions and release the by-products poly(ethylene glycol), the hydroxy acid, and oligo( -acrylic acid) (20). The degradation rate can be controlled by tailoring the concentration of -hydroxy acid. If polymerized in contact with tissue, the gels adhere, and if polymerized prior to tissue placement, the gels are nonadhesive. The protein albumin was entrapped within these hydrogels and shown to release at a consistent rate. The release rate was dependent on the cross-link density and the molecular weight of the protein.

Drug-delivery devices combining cross-linked conventional hydrogels, where the drug is covalently linked via a degradable oligopeptide side chain, have been designed for targeted anticancer drugs. In this example, hydrogels of N -(2hydroxypropyl)methacrylamide were prepared. The drug was attached synthetically by a degradable oligopeptide linkage. In vitro experiments have shown that these devices target ovarian carcinoma cells with promising results (95). Another interesting example of hydrogels for drug delivery utilizes the concept of degradable natural polymers (96). In this work, the natural oligosaccharide hyaluronic acid (HA) is chemically modied through the use of a pendent hydrazido functional group that is covalently linked to a wide variety of drugs, such as steroids. The covalent link is hydrolytically unstable and under mild conditions it releases the drug. Smart Hydrogels. Research efforts on the design of smart hydrogels for drug delivery application has increased signicantly over the past few years (30,31,97). Such systems show promise as drug-delivery devices because of the rapid release of conventional and protein-based drugs during the expansion/contraction of these hydrogel systems. Efforts have focused primarily on designing systems that make use of change in pH and temperature. The idea behind this approach is that smart hydrogels will both expand and contract, forming a hydrogel switch that releases drug or protein in a controlled fashion. When a drug is incorporated into a smart hydrogel, the diffusion of the polymer is dependent on the gel-state. Smart hydrogels can be designed to release drugs either above or below the lower critical solution temperature (LCST). Smart hydrogels

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have been designed to release drugs at low pH (gastric release application) and at basic pH (intestinal release application). Some brilliant work in this area has been described. Most of this has been based on the polymer poly(isopropyl acrylamide) (IPA) (9799). IPA has a critical solution temperature close to that of body temperature (32 C). A large variety of IPA-based polymers (grafts, block) containing varying concentration of hydrophobic monomers have been synthesized. The concentration of hydrophobic monomer controls the critical solution temperature. Recent examples include the design of thermosensitive hydrogels as heparin-releasing polymers for the prevention of thrombosis. In this system, copolymers such as of N -isopropylacrylamide, butyl methacrylate, and acrylic acid were cross-linked together with heparin. At temperatures below the LCST, the polymer swelled signicantly and solution loading of the drug was performed. Above the LCST, the gel de-swelled and released heparin. Another example makes use of a hydrogel based on an etherurethane isopropylacrylamide IPN for use as a heparin-release system. In this example, the smart polymer was applied as a coating on polyurethane catheters. This heparin-release coating system resulted in a signicant reduction in thrombus formation on test surfaces in contact with venous blood (100). The design of smart polymers as glucose-sensitive systems that release insulin has recently been described (101,102). The ultimate goal in this work is to design an articial pancreas. This is accomplished by incorporating glucose oxidase into a pH- or temperature-sensitive smart polymer. An insulin-releasing drug-delivery system was produced by the incorporation of glucose oxidase, bovine serum albumin, and insulin into a gel of poly(N ,N -dimethylamino)ethyl methacrylate-co-ethylacrylamide)(103,104). Exposure of this system to glucose in the desired physiological concentration range resulted in a reduction in the system pH and swelling of the polymer (as brought about by protonation of the polymer). This swelling causes a release of insulin. Another system based on a polymer complex of poly(N -vinyl-2-pyrrolidinone-co-phenylboronic acid acrylamide-co-dimethylaminopropylacrylamide) and poly(vinyl alcohol) also shows glucose sensitivity. In this system, a stable gel forms at pH 7.4 because of the covalent linkage of the boronatehydroxy groups. The gel contains insulin. Through the addition of glucose, the complex dissociates and transforms the gel to a sol-state (the gel begins to solubilize) resulting in swelling and subsequent insulin release (105). Tissue Engineering. The use of biomedical materials over the last 20 years has, in most respects, been extremely successful. A wide variety of materials have been developed that have been successfully used to replace hips, heart valves, and the natural lens of the eye, to name but a few successful applications. The major drawback in this area of research, however, is that these materials, for almost all cases, can only perform for short periods of time. No long-term replacements have to date been developed. The clinical needs are even greater in the case of organs, where replacement by organ transplantation is the only option. The area of tissue engineering, however, offers some intriguing possibilities. The goal of tissue engineering is to create living, three-dimensional tissue/organs using cells obtained from readily available sources, such as cells obtained directly from the patient (31). The ultimate goal in this work is to grow cells specic to a particular organ and then to direct the cell growth to form the

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actual organ. This theoretically can be accomplished through the attachment of specic cells to a scaffolding matrix that directs cell attachment, differentiation, and growth. In order to do this amazing feat, a physical scaffold is required to allow for the organization of cells to form the specic organ (to simulate cell growth, migration, and differentiation). These scaffolds need to interact with the cells through highly specic bioreactions that control cell adhesion and growth factor responses. The scaffolds are ideally biodegradable. Some fabulous work in this area has recently been reported. The use of biodegradable hydrogels as a temporary-support template for cartilage has been reported (106). Cartilage is a biphasic material made up of collagen as the solid support suspended in a gel of proteoglycans. Within this gel are the chondrocytes that are responsible for maintaining the extracellular matrix of cartilage (glycosaminoglycans and type II collagen). For this work the hydrogel calcium alginate was used as the scaffold. The alginate polymer was prepared by dissolving in water and adding calcium ions to form a complexed cross-link polymer network. The immobilization of chondrocytes in alginate was accomplished simply by soaking the alginate in a solution of chondrocytes. Researchers have demonstrated that the chondrocytes maintained their structure, were capable of proliferating at rates signicantly higher than that of monolayer cultures, maintained their production of glycosaminoglycans and collagen, and formed a mechanically functional matrix in a hydrogel network. This has all led to the rst successful experiments that have shown that new cartilage can be created in vivo using hydrogel scaffolding. In a similar concept, the design of biodegradable hydrogels for bone regeneration through growth factor release has been reported (107). In this research effort, gelatin was cross-linked with either glutaraldehyde or carbodiimide. The growth factor was added by solution adsorption into the preformed gelatin hydrogels. The cationic growth factor was held in the gelatin matrix through complexation with the anionic sites along the gelatin backbone. The gelatin enzymatically degrades in the body to release the growth factor. When implanted into a bone defect, the growth factor resulted in accelerated bone regeneration and closed the bone defect. Wound Dressings. Hydrogels have also been used as wound dressings because most hydrogels are soft, exible, conform to the wound, are biocompatible, and are permeable to water vapor and metabolites. As wound dressings, they absorb the exudate, do not stick to the wound, allow for access of oxygen to the wound site, and accelerate healing. This is actually a very large market with total sales of synthetic wound dressings, as reported in 1999, of $350 million (108). The dressing is usually applied as a thin preformed/prehydrated lm. The hydrogel wound dressings are based on hydrocolloid/hydrogels and alginate dressings. Hydrophilic monomers and polymers used to prepare the hydrogel bandages are based on NVP, poly(ethylene oxide), and poly(vinyl alcohol). Biosensors. A biosensor is a compact device or probe that detects, records, and transmits information regarding a physiological change or the presence of various chemical or biological materials in the environment. A biosensor is a probe that integrates a biological component, such as a biological product (enzyme or antibody), with an electronic component to yield a measurable response. Biosensors are used to monitor changes in the physiological environment (109). The usual

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aim of a biosensor is to produce either discrete or continuous electronic signals that are proportional to a single analyte or a related group of analyte (110). The biosensors typically comprise a biological sensing element, a transducer, a signal conditioner, a data processor, a signal generator, and one or more organic or inorganic membranes. Hydrogels have been used as reactive matrix membranes in biosensors. Hydrogels possess several advantages over other materials in that they exhibit rapid and selective diffusion characteristics of the analyte, as well as provide support. For example, there has been a signicant amount of success in the area of lipid bilayer based biosensor membranes. One of the early disadvantages of these bilayer probes was their poor ion diffusion characteristic. Hydrogels were successfully used to provide both the required ion diffusion and also the support for the thin lipid bilayer membrane (111). Among the various types of biosensors, those that measure glucose have received the most attention, due primarily to the fact that nearly 6% of the population suffers from diabetes (112). In these biosensors, the consumption of oxygen or the formation of hydrogen peroxide is monitored (enzyme glucose oxidase catalyzes the reaction of glucose and oxygen to form gluconic acid and hydrogen peroxide). Hydrogels are used as enzyme immobilization matrices in these type of biosensors. Enzyme entrapped in a hydrogel of poly(HEMA), polyacrylamide, and poly(vinyl alcohol) have been reported (113). Surface Coatings Applications of Hydrogels. The surface treatment of polymeric materials is one of the most active research areas in the eld of biomedical materials. It is generally agreed that the surface of any material is what dictates its cellular response in the body. Attempts to design biocompatible surfaces have been explored with signicant success for many years. This approach, ie, minimization of chemical and physical interactions between the substrate polymer and blood, is the most promising avenue for short-term clinical success. It has been shown that materials functionalized with surfaces consisting of groups such as carboxylate, sulfate, or sulfonate groups act as antithrombogenic agents in that they repel plasma proteins and platelets. The grafting of poly(ethylene oxide) functionalized surfaces onto a variety of material substrate results in an increase in hydrophilicity and provides a reduction of complement activation and platelet adhesion (114). In a similar example, the grafting of poly(HEMA) onto a variety of surfaces has also provided an improvement in antithrombogenic properties. Novel techniques of surface modication, based on molecular imprinting, have led to hydrogel systems with the ability to recognize biological and pharmaceutical compounds. Gel surfaces can be molecularly designed for specic applications (115,116). For example, polyacrylamide gels modied with an adhesion receptor, asioaloglycoprotein, were prepared to study cell adhesion. This work, as well as other similar research efforts, has helped gain an understanding of the required surface functionality for improved receptor response (117,118). Also, in the area of contact lens research, the formation of a hydrogel surface on nonwetting substrates, such as silicone, provides an avenue for a wettable, biocompatible material possessing excellent comfort characteristics. These have all been made possible utilizing techniques such as plasma oxidation, the surface-initiated polymerization of hydrophilic monomers, and the graft functionalization of high molecular hydrophilic polymers through covalent coupling.

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Plasma Surface Modication. One of the earliest approaches to design wettable, hydrogel-like surfaces was by glow discharge plasma and/or corona discharge techniques. Corona treatment of polymer surfaces consists of the reaction of oxygen with the polymer surface under an electric discharge to create polar functionality such as carboxyl, ether, carbonyl, or hydroxyl groups. The formation of polar groups raises the surface free energy and allows for surface wetting. Low pressure glow discharge oxygen plasma has also been used successfully on silicone-based materials. This results in a wettable surface that consists primarily of hydrated cross-linked silicate/silanol functionality. In fact, the SilsightTM silicone elastomer lens, commercialized primarily for pediatric aphakic (loss of natural crystalline lens) patients, is made wettable through oxygen plasma techniques. Since these early efforts to generate wettable surfaces through oxidative treatments, a variety of novel plasma processes have been developed (119). These efforts have focused primarily on plasma polymerization (deposition). This effort is in an attempt to deposit a continuous thin hydrophilic polymer lm layer. In this process, polymerizable gases (monomers) are introduced to the plasma reactor during or after the glow discharge treatment. The plasma conditions initiate polymerization that results in deposition of a thin polymer surface, where the surface chemistry can be manipulated by choice of monomer. This technique results in primarily a covalent polymer attachment. Direct Covalent Coupling. Similar approaches to covalently attached polymers via glow discharge plasma have also been pursued. In these efforts, the polymers were solution-adsorbed and surface-grafted under inert gas plasma. A free-radical mechanism for the grafting has been proposed. This approach has been used to coat a variety of substrates with hydrogels. Upon plasma treatment radicals are formed on the surface that react with oxygen to form hydroperoxy compounds. The homolytic decomposition of the hydroperoxides form radicals that initiate the polymerization (thermal or ultraviolet) of hydrophilic monomers, such as HEMA (120). The adsorption can best be accomplished by using surface-active compounds that preferentially immobilize on the surface before introduction of the plasma. In addition to the conventional plasma polymerization approaches, a signicant number of research programs have focused on the design of wettable surfaces utilizing a combination of glow discharge plasma and polymer grafting through classical chemical reaction techniques (121). One approach demonstrates the successful covalent attachment of a polysaccharide (21). In this process, a silicone surface is aminated using glow discharge ammonia plasma. The aminated surface is then reacted with an oxidized dextran to form a covalently attached (via a Schiff-based linkage) dextran. Following reduction to a stable secondary amine linkage, a highly wettable surface is formed (122). Another approach makes use of covalent grafting utilizing solution techniques only. In this example, the vinyl acetate groups of a medical grade poly(ethylene-covinyl acetate-co-vinyl chloride) was saponied using a solution of methanol and sodium hydroxide and then reacted with hexamethylene diisocyanate to form a highly reactive isocyanate-modied surface. The resultant surface is then reacted, again via solution techniques, with an amine functionalized hydrophilic polymer (123).

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Hydrogel Surfaces through In Situ Polymerization Techniques. Several research groups have reported on efforts to design wettable silicone-based materials through in situ polymerization techniques. These are attempts to design wettable, biocompatible surfaces without the need for surface treatment. The primary driver for this research is cost. Without the need for a secondary surface treatment, a large reduction in lens cost would be achieved. Signicant progress in this area has been made. It has been shown recently that the polarity of the casting substrate may provide an avenue for surface wetting without surface treatment. The casting of silicone-based formulations from polar mold materials results in a surface rich character. For example, a copolymer based on a uorinated silicone and the hydrophilic monomer, DMA was cast against the hydrophilic mold resin Barex (copolymer of acrylonitrile and styrene). X-ray photoelectron spectroscopy analysis of the surface showed a threefold increase in surface nitrogen concentration as compared with the same formulation cast from a hydrophobic polypropylene resin. The Barex cast material resulted in

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a hydrogel-like surface as a result of the preferential polymerizationmigration of DMA at the Barex surface. The use of polymerizable surfactants (surface-active macromer, SAM) in silicone formulations has been explored to form hydrogel-like surfaces without a surface treatment (124). Several surface-active water-soluble macromers were evaluated. The SAMs were prepared using a two-step synthetic procedure. In this procedure, hydrophobic alkylmethacrylates or uoromethacrylates monomers are polymerized with polyoxyethylene methacrylates using a functional mercaptan as a chain-transfer agent. The resultant hydroxyl or carboxylate capped macromer (22) is further functionalized with a polymerizable methacrylate.

The SAMs are surface-active, yet possess signicant hydrophilic character. They are simply added to a silicone formulation, at concentrations of 0.10.5%, and polymerized. It has been shown that the polymerization of SAMs in siliconebased formulations results in a signicant increase in surface polarity. This is due to migration of the SAM to the moldlens interface before polymerization. Clinical performance has also been improved. The incorporation of SAMs has had a positive effect on surface wetting and deposition characteristics.

Nonbiomedical Applications
This article has detailed a variety of biomedical applications of hydrogels. It is important to note, however, that many applications of hydrogels for

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nonbiomedical use have been successfully designed. These include the use of hydrogels for chemical valves, bioseparation devices, biomimetic actuators, thermoresponsive surfaces, afnity precipitation, anodes for bridge-building application, water retention for soil application, and disposable diapers the details of which can be found in other articles (10,31,125128).

BIBLIOGRAPHY
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