Conque. 15th Judicial District Court, Lafayette Parish, Louisiana. Criminal Docket 73313. 1997.

Further Reading

Erlich HA, Gelfand D, Sninsky JJ. Recent advances in the polymerase chain reaction. Science 1991; 252: 1643–1650.

Innis MA, Gelfand DH, Sninsky JJ, White TJ, editors. PCR Protocols: A Guide to Methods and Applications. Academic; San Diego: 1990.

Mullis KB, Ferre´ F, Gibbs RA, editors. The Polymerase Chain Reaction. Birkha¨user; Boston: 1994.

See also ANALYTICAL METHODS, AUTOMATED; DNA SEQUENCE;

MICROARRAYS.

POLYMERIC MATERIALS

XIAOHUA LIU

The University of Michigan

Ann Arbor, Michigan

SHOBANA SHANMUGASUNDARAM

TREENA LIVINGSTON ARINZEH

New Jersey Institute of

Technology

Newark, New Jersey

INTRODUCTION

This article aims to provide basic and contemporary information on polymeric materials used in medical devices and instrumentation. The fundamental concepts and features of polymeric materials are introduced in the first section. In the second section, the major commodity polymers used in medicine are reviewed in terms of their basic chemical and physical properties. The main part of this article, however, is devoted to polymers in biomedical engineering applications, including tissue engineering and drug delivery systems.

Polymers are a very important class of materials. A polymer can be defined as a long-chain molecule that is composed of a large number of repeating units of identical structure. Some polymers, (e.g., proteins, cellulose, and starch) are found in Nature, while many others, including polyethylene, polystyrene, and polycarbonate, are produced only by synthetic routes. Hundreds of thousands of polymers have been synthesized since the birth of polymer science. Today, polymeric materials are used in nearly all areas of daily life.

Polymers can simply be divided into two distinct groups based on their thermal processing behavior: thermoplastics and thermosets. Thermoplastics are linear or branched polymers, and they soften or melt when heated, so that they can be molded and remolded by heating. This property allows for easy processing and recycling. In comparison, thermosets are three-dimensional (3D) network polymers, and cannot be remelted. Once these polymers are formed, reheating will cause the material to scorch.

In addition to classification based on processing characteristics, polymers may also be grouped based on the chemical structure of their backbone. Polymers with one

identical repeating unit in their chains are called homopolymers. The term copolymer is often used to describe a polymer with two or more repeating units. The sequence of repeating units along the polymer chain can form different structures, and copolymers can be further classified as random copolymers, alternating copolymers, block copolymers, and graft copolymers. In random copolymers, the sequence distribution of the repeating units is random, while in alternating copolymers the repeating unit are arranged alternately along the polymer chain. A block copolymer is one in which identical repeating units are clustered in blocks along the chain. In graft copolymers, the blocks of one type of repeating unit are attached as side chains to the backbone chains.

Unlike simple pure compounds, most polymers are not composed of identical molecules. A typical synthetic polymer sample contains chains with a wide distribution of chain lengths. Therefore, polymer molecular weights are usually given as averages. The number average molecular weight (Mn), which is calculated from the mole fraction distribution of different sized molecules in a sample, and the weight average molecular weight (Mw), which is calculated from the weight fraction distribution of different sized molecules, are two commonly used values. The statistical nature of polymerization reaction makes it impossible to characterize a polymer by a single molecular wˇ eight. A measure of the breadth of the molecular weight distribution is given by the ratios of molecular weight averages. The most commonly used ratio is Mw/Mn. As the weight dispersion of molecules in a sample narrows, Mw approaches Mn, and in the unlikely case that all the polymer molecules have identical weights, the ratio Mw/Mn becomes unity. Most commercial polymers have the molecular weight distribution of 1.5–10. In general, increasing molecular weight corresponds to increasing physical properties and decreasing polymer processability.

In many cases, individual polymer chains are randomly coiled and interviewed with no molecular order or structure. Such a physical state is termed amorphous. Amorphous polymers exhibit two distinctly different types of mechanical behavior. Some, like poly(methyl methacrylate, PMMA) and polystyrene are hard, rigid, glassy plastics at room temperature, while others, like polybutadiene and poly(ethyl acrylate), are soft, flexible, rubbery materials at room temperature. There is a temperature, or range of temperatures, below which an amorphous polymer is in a glassy state, and above which it is rubbery. This temperature is called the glass transition temperature (Tg). The value of Tg for a specific polymer will depend on the structure of the polymer. Side groups attached to the polymer chain will generally hinder rotation in the polymer backbone, necessitating higher temperatures to give enough energy to enable rotation to occur.

For most polymers, the Tg constitutes their most important mechanical properties. At low temperatures (< Tg), an amorphous polymer is glass-like, with a value of Young’s modulus in the range of 109–1010 Pa, and it will break or yield at strains greater than a few percent. When the temperature is > Tg, the polymer becomes rubber-like, with a modulus in the range of 105–106 Pa, and it may withstand large extensions with no permanent deformation. At even

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higher temperatures, the polymer may undergo permanent deformation under load and behave like a highly viscous liquid. In the Tg range, the polymer is neither glassy nor rubber-like. It has an intermediate modulus and has viscoelastic properties.

CHEMICAL AND PHYSICAL PROPERTIES OF MAJOR COMMODITY POLYMERS

This section reviews the major polymers used in medical applications, with a brief discussion of chemical as well as physical properties and their application. They are grouped as homopolymers or copolymers.

Homopolymers

Polyacrylates (e.g., PMMA) and poly(hydryoxyethyl methacrylate) (PHEMA), are used for hard and soft contact lenses because of their excellent physical, coloring properties, and ease in fabrication. The PMMA polymer is a hydrophobic, linear chain polymer that is glassy at room temperature. It has very good light transmittance, toughness, and stability, making it an excellent material for intraocular lenses and hard contact lenses. The PHEMA polymer is used for soft contact lenses. With the addition of a –CH2OH group to the methyl methacrylate side group of the PMMA structure, the polymer becomes hydrophilic. Typically, PHEMA is cross-linked with elthylene glycol dimethylacrylate (EGDM) to prevent the polymer from dissolving when hydrated. When fully hydrated, PHEMA is a hydrogel with potential use in advanced technology applications (e.g., biomedical separation and biomedical devices).

Polyolefins, which include polyethylene (PE) and polypropylene (PP), are linear chain polymers. Polyethylene is a highly crystalline polymer that is used in its high density form for biomedical applications because low density forms cannot withstand sterilization temperatures. The high density form is used for drains and catheters. The ultrahigh molecular weight form (UHMWPE) is used in orthopedic implants for load-bearing surfaces in total hip and knee joints. The material has good toughness, creep properties, resistance to environmental attack, and relatively low cost. The PP is related to PE by the addition of a methyl group along the polymer chain. It has similar properties to PE (e.g., high rigidity, good chemical resistance, and tensile strength) and is used for many of the same applications. It also has a high flex life, which is superior to PE and is therefore used for finger joint prostheses.

Polytetrafluoroethylene (PTFE), commonly known as Teflon, is similar in structure to PE except that the hydrogen in PE is substituted with fluorine. This polymer has a high crystallinity (> 94%), high density, low modulus of elasticity, and tensile strength. It is a very stable polymer and difficult to process. The material also has very low surface tension and friction coefficient. It is used for vascular graft applications due to the lack of adherence of blood components.

Poly(vinyl chloride) (PVC) is typically used for tubing for blood transfusions, feeding, and dialysis. Pure PVC is hard and brittle. However, for these applications, the addition of

plasticizers makes it soft and flexible. Issues concerning these plasticizers exist because they can be extracted during long-term use, making PVC less flexible over time.

Poly(dimethyl siloxane) (PDMS), or silicone rubber, is a versatile material. Low molecular weight polymers have low viscosity and can be cross-linked to make a higher molecular weight rubber-like material. It has a silicon– oxygen backbone instead of a carbon backbone. The material is less temperature sensitive than other rubbers because of its lower Tg. It also has excellent flexibility and stability. The applications of PDMS are widespread (e.g., catheter and drainage tubing, insulation for pacemaker leads, a component in some vascular graft systems, prostheses for finger joints, blood vessels, breast implants, outer ears, chin and nose implants). Since its oxygen permeability is very high, PDMS is also used in membrane oxygenators.

Polyamides, commonly known as nylons, are linearchain polymers containing –CONH– groups. With the presence of these groups, the chains attract strongly to one another by hydrogen bonding. Increasing numbers of

–CONH– groups and a high degree of crystallinity improves physical properties (e.g., strength and fiber forming ability). They are used for surgical sutures.

Polycarbonates are tough, amorphous, clear materials produced by the polymerization of biphenol A and phosgene. It is used as lenses for eyeglasses and safety glasses, and housings for oxygenators and heart–lung bypass machines.

Copolymers

Poly(glycolide lactide) (PGL) are random copolymers used in resorbable surgical sutures. The PGL is polymerized by a ring-opening reaction of glycolide and lactide and is gradually resorbed in the body due to the ester linkages in the polymer backbone via hydrolysis.

A copolymer of tetrafluoroethylene and hexafluoropropylene (FEP) is used similarly to PTFE. The advantage of FEP is that it is easier to process than PTFE, but still retains excellent chemical inertness and a low coefficient of friction. The FEP has a crystalline melting temperature of 265 8C, whereas PTFE is 375 8C.

Polyurethanes are copolymers, which contain ‘‘hard’’ and ‘‘soft’’ blocks. The ‘‘hard’’ blocks are composed of a diisocyanate and a chain extender, with a Tg above room temperature, and has a glassy or semi-crystalline character. The ‘‘soft’’ blocks are typically polyether or polyester polyols with a Tg below room temperature. Thus, the material also has rubbery characteristics. Polyurethanes are tough elastomers with good fatigue and bloodcontaining properties. They are typically used for pacemaker lead insulation, vascular grafts, heart assist balloon pumps, and artificial heart bladders.

POLYMERS IN BIOMEDICAL ENGINEERING APPLICATIONS

Polymers Used in Tissue Engineering

Synthetic Polymers. The most widely used synthetic polymers for tissue engineering products, either under

development or on the market, are poly(lactic acid) (PLA), poly(glylic acid) (PGA), and their copolymers PLGA. Both PLA and PGA are linear aliphatic polyesters formed by ring-opening polymerization with a metal catalyst. The PLA can also be obtained from the renewable agricultural source, corn and degrades in two phases: hydrolysis and metabolization. The PLA and PGA polymers have similar chemical structures except that the PLA has a methyl pendant group. Both degrade by simple hydrolysis of their ester linkages. The PGA can also be broken down by nonspecific esterases and carboxypeptidases. The degradation rate is dependent on initial molecular weight, exposed surface area, crystallinity, and, in the case of copolymers, the PLA/PGA ratio present. PGA is highly crystalline, having a high melting point, and a low solubility in organic solvents. It is also hydrophilic in nature, losing its mechanical strength over a period of 2–4 weeks in the body.

The PLGA was developed to achieve a wider range of possible applications for PGA. Due to the extra methyl group in lactic acid, PLA is more hydrophobic and has a slower rate of backbone hydrolysis than PGA. The PLA is also more soluble in organic solvents. The copolymer PLGA degradation depends on the exact ratio of PLA and PGA present in the polymer. The PLGA polymer is less crystalline and tends to degrade more rapidly than either PGA or PLA. Lactic acid is a chiral molecule that exists in two stereoisomeric forms that yield four morphologically distinct polymers. Both d-PLA and l-PLA are two stereoregular polymers d,l-PLA is the racemic polymer and mesoPLA can be obtained from d,l-lactide.The amorphous polymer is d,l-PLA and is used typically for drug delivery applications where it is important to have a homogenous dispersion of the active agents within a monobasic matrix. The l-PLA polymer is semi-crystalline and most commonly used because the degradation product of l(þ)-lactic acid is the naturally occurring steroisomer of lactic acid. It is typically used for high mechanical strength and toughness applications (e.g., orthopaedics).

Some of the other synthetic polymers currently under investigation for tissue engineering applications are described briefly. Polycaprolactone (PCL) is a synthetic aliphatic polyester with a melting point (Tm) of 55– 65 8C. Degradation of PCL is a slow process that occurs either by hydrolysis or enzymatic degradation in vivo. The slow degradation rate of PCL is particularly interesting for long-term implants and controlled release application. Poly(hydroxy butyrate) (PHB) and its copolymers are semi-crystalline thermoplastic polyester made from renewable natural sources. In vivo, PHB degrades into hydroxybutyric acid that is a normal constituent of human blood. The PHB homopolymer is highly crystalline and has a high degradation rate. Its biodegradation and biocompatibility properties have led to research on its prospective use as a material for coronary stents, wound dressings, and drug delivery. Poly(propylene fumarate) (PPF) is an unsaturated linear polyester formed by the copolymerization of fumaric acid and propylene glycol. These polymer networks degrade by hydrolysis of the ester linkage to water-soluble products, namely, propylene glycol, poly(acrylic acid-co-fumaric acid), and fumaric acid. Due to its unsaturated sites along the polymer backbone, which

are labile and can be cross-linked in situ, PPF is currently being evaluated for filling skeletal defects of varying shapes and sizes. Polyphosphoesters (PPE) are biodegradable polymers with physicochemical properties that can be altered by the manipulation of either the backbone or the side-chain structure. This property of PPE makes them potential drug delivery vehicles for low molecular drugs, proteins, deoxyribonucleic acid DNA plasmids, and as tissue engineering scaffolds. Since the phosphoester bond in a PPE backbone is cleaved by water, the more readily water penetrates, with greater bond cleavage and faster degradation rate. The products of hydrolytic breakdown of PPE are phosphate, alcohol, and diol. Polyphosphazenes are inorganic polymers having a phosphorus–nitrogen alternating backbone and each phosphorus atom is attached to two organic or organometallic side groups. They degrade by hydrolysis into phosphate, amino acid, and ammonia. The potential application is in low molecular weight drug release and in formulation of proteins and peptides. Polyanhydrides are a class of degradable polymers synthesized from photopolymerizable multimethacrylate monomers. Many polyanhydrides degrade from the surface by hydrolysis of the anhydride linkages. The rate of hydrolysis is controlled by the polymer backbone chemistry. They are useful for controlled drug delivery as they degrade uniformly into nontoxic metabolites. Polyorthoesters (POE), another class of biodegradable and biocompatible polymers, can be designed to possess a sur- face-dominant erosion mechanism. Acidic byproducts autocatalyzed the degradation process resulting in increased degradation rates than nonacidic byproducts. The POE, which is susceptible to acid-catalysed hydrolysis, has attracted considerable interest for the controlled delivery of therapeutic agents within biodegradable matrices.

Natural Polymers. Collagen is a widely used natural polymer in tissue engineering. It is a structural protein, being a significant constituent of the natural extracellular matrix. It has a triple-helical molecular structure that arises from the repetitious amino acid (glycine, proline, and hydroxyproline) sequence. In vivo, collagen in healthy tissues is resistant to attack by most proteases except specialized enzymes called collagenases that degrade the collagen molecules. Collagen can be used alone or in combination with other extracellular matrix components (e.g., glycosaminoglycan and growth factors) to improve cell attachment and proliferation. It has been tested as a carrier material in tissue engineering applications.

Other natural polymers under investigation for tissue engineering applications are described briefly. Gelatin, denatured collagen, is obtained by the partial hydrolysis of collagen. It can form a specific triple-stranded helical structure. The rate of the formation of a helical structure depends on many factors (e.g., the presence of covalent cross-bonds, gelatin molecular weight, the presence of amino acids, and the gelatin concentration in the solution). Gelatin is used in pharmaceuticals, wound dressings, and bioadhesives due to its good cell viability and lack of antigenicity. It has some potential for use in tissue engineering applications. Silk is a fibrous protein characterized by a highly repetitive primary sequence of glycine and

390 POLYMERIC MATERIALS

alanine that leads to significant homogeneity in secondary structure, b-sheets in the case of many of the silks. Silk is biodegradable due to its susceptibility to proteolytic enzymes. Silk studies in vitro have demonstrated that protease cocktails and chymotrypsin are capable of enzymatically degrading silk. The mechanical properties of silk provide an important set of material options in the fields of controlled release, biomaterials, and scaffolds for tissue engineering. Alginate is a straight-chain polysaccharide composed of two monomers, mannuronic acid and guluronic acid residues, in varying proportions. Alginate forms stable gels on contact with certain divalent cations, such as calcium, barium, and strontium. Alginate is widely used as an instant gel for bone tissue engineering. Chitosan, a copolymer of glucosamine and N-acetylglucosamine is a crystalline polysaccharide. It is synthesized by the deacetylation of chitin. Chitosan degrades mainly through lysozyme-mediated hydrolysis, with the degradation rate being inversely related to the degree of crystallinity. Chitosan has excellent potential as a structural base material for a variety of tissue engineering application, wound dressings, drug delivery systems, and space-filling implants. Hyaluronate, a glycosaminoglycan is a straightchain polymer composed of glucuronic acid and acetylglucosamine. It contributes to tissue hydrodynamics, movement, and proliferation of cells in vivo. Hyaluronan is enzymatically degraded into monosaccharides. It has been used in the treatment of osteoarthritis, dermal implants, and prevention of postsurgical adhesions.

Polymeric Scaffold FabricationTechniques (6–8). Scaffolds for tissue engineering, in general, are porous to maximize cell attachment, nutrient transport, and tissue growth. A variety of processing technologies have been developed to fabricate porous 3D polymeric scaffolds for tissue engineering. These techniques mainly include solvent casting and particulate leaching, gas-foaming processing, electrospinning technique, rapid prototyping, and thermally induced phase-separation technique, which are described below.

Solvent casting and particulate leaching is a simple, but commonly used method for fabricating scaffolds. This method involves mixing water soluble salt (e.g., sodium chloride, sodium citrate) particles into a biodegradable polymer solution. The mixture is then cast into the desired shape mold. After the solvent is removed by evaporation or lyophilization, the salt particles are leached out and leave a porous structure. This method has advantages of simple operation and adequate control of pore size and porosity by salt/polymer ratio and particle size of the added salt. However, the interconnectivity between pores inside the scaffold is often low, which seems to be problematic for cell seeding and culture.

Gas foaming is marked by the ability to form highly porous polymer scaffold foams without using organic solvents. In this approach, carbon dioxide is usually used as a foaming agent for the formation of polymer foam. This approach allows the incorporation of heat sensitive pharmaceuticals and biological agents. The disadvantage of this method is that it yields mostly a nonporous surface and closed-pore structure.

Electrospinning is a fabrication process for tissue engineering that use an electric field to control the formation and deposition of polymer fibers onto a target substrate. In electrospinning, a polymer solution or melt is injected with an electrical potential to create a charge imbalance. At a critical voltage, the charge imbalance begins to overcome the surface tension of the polymer source, and forms an electrically charged jet. The jet within the electric field is directed toward the ground target, during which time the solvent evaporates and fibers are formed. This electrospinning technique can fabricate fibrous polymer scaffolds composed of fiber diameters ranging from several microns down to several hundred nanometers.

Rapid prototyping is a technology based on the advanced development of computer science and manufacturing industry. The main advantage of these techniques is their ability to produce complex products rapidly from a computer-aided design (CAD) model. The limitation of this method is that the resolution is determined by the jet size, which makes it difficult to design and fabricate scaffolds with fine microstructure. The controlled thermally induced phase-separation process was first used for the preparation of porous polymer membranes. This technique was recently utilized to fabricate biodegradable 3D polymer scaffolds. In this approach, the polymer is first dissolved in a solvent (e.g., dioxane) at a high temperature. Liquid– liquid or solid–liquid phase separation is induced by lowering the solution temperature. Subsequent removal of the solidified solvent-rich phase by sublimation leaves a porous polymer scaffold. The pore morphology and microstructure of the porous scaffolds varies depending on the polymer, solvent, concentration of the polymer solution, and phase separation temperature. One advantage of this method is that scaffolds fabricated with the technique have higher mechanical strength than those of the same porosity made with the well-documented salt-leaching technique.

Polymers for Drug Delivery. Over the past decade, the use of polymeric materials for the administration of pharmaceuticals and as biomedical devices has dramatically increased (9–11). One important medical application of polymeric materials is in the area of drug delivery systems. There are a few polymer molecules having a drug function, however, in most cases when polymers are used in drug delivery systems, they serve as a carrier of drugs. Table 1 lists some of the important biodegradable and nonbiodegradable polymers used in drug delivery systems.

Table 1. Typical Biodegradable and Nonbiodegradable Polymers Used in Controlled Release Systems

Most of the above biodegradable and nonbiodegradable polymers have been discussed in the previous sections; therefore, they are not described further here.

Stimuli-Responsive Hydrogels for Drug Delivery. Hydrogels have been used as carriers for a variety of drug molecules (10). A hydrogel is a network of hydrophilic polymers that are cross-linked by either covalent or physical bonds. It distinguishes itself from other polymer networks in that it swells dramatically in the presence of abundant water. The physicochemical and mechanical properties can be easily controlled, and hydrogels can be made to respond to changes in external factors.

In recent years, temporal control of drug delivery has been of great interest to achieve improved drug therapies. Stimuli-responsive hydrogels exhibit sharp changes in behavior in response to an external stimulus (e.g., temperature, pH, solvents, salts, chemical or biochemical agents, and electrical field). The stimuli-responsive hydrogels have the ability to sense external environmental changes, judge the degree of external signal, and trigger the release of appropriate amounts of drug. Such properties have made it very useful for temporal control of drug delivery (12,13).

Temperature-Sensitive Hydrogels. Temperature is the most widely used stimulus in environmentally responsive polymer systems. Temperature-sensitive hydrogels can respond to the change of environmental temperature. The change of temperature is not only relatively easy to control, but also easily applicable both in vitro and in vivo. Poly(N-isopropylacrylamide) (PNIPA) is representative of the group of temperature-responsive polymers that have a lower critical solution temperature (LCST), defined as the critical temperature at which a polymer solution undergoes phase transition from a soluble to an insoluble state above the critical temperature. The PNIPA exhibits a sharp phase transition in water at 32 8C, which can be shifted to body temperatures by the presence of hydrophilic monomers (e.g., acrylic acid). Reversely, the introduction of a hydrophobic constituent to PNIPA would lower the LCST of the resulting copolymer.

When PNIPA chains are chemically cross-linked by a cross-linker (e.g., N,N0-methylenebisacrylamide and ethylene glycol dimethacrylate), the PNIPA hydrogel is formed, which swells, but does not dissolve in water. The PNIPA hydrogel undergoes a sharp swelling-shrink- ing transition near the LCST, instead of sol–gel phase separation. The sharp volume decrease of the PNIPA hydrogel above the LCST results in the formation of a dense, shrunken layer on the hydrogel surface, which hinders water permeation from inside the gel into the environment. The PNIPA hydrogels have been studied to the delivery of antithrombotic agents (e.g., heparin), at the site of a blood clot, utilizing biological conditions to trigger drug release. Drug release from the PNIPA hydrogels at temperatures below LCST is governed by diffusion, while above this temperature drug release is stopped, due to the dense layer formation on the hydrogel surface.

Some types of block copolymers made of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) also possess an inverse temperature sensitive property. Because of

their LCST at around body temperature, they have been widely used in the development of controlled drug delivery systems based on the sol–gel phase transition at the body temperature.

pH-Sensitive Hydrogels. Polymers with a large number of ionizable groups are called polyelectrolytes. The pHsensitive hydrogels are cross-linked polyelectrolytes containing either acidic or basic pendent groups, which show sudden changes in their swelling behavior as a result of changing the external pH. The pendant groups in the pHsensitive hydrogels can ionize in aqueous media of appropriate pH value. As the degree of ionization increases (via increasing or decreasing pH value in the aqueous media), the number of fixed charges on the polymer chains increases, resulting in increased electrostatic repulsions between the chains. As a result of the electrostatic repulsions, the uptake of water in the network is increased and thus the hydrogels have higher swelling ratios. The swelling of pH-sensitive hydrogels can also be controlled by ionic strength and copolymerizing neutral comonomers, which provide certain hydrophobicity to the polymer chain. The pH-sensitive hydrogels have been used to develop control release formulations for oral administration. For polycationic hydrogels, the swelling is minimal at neutral pH, thus minimizing drug release from the hydrogels. The drug is released in the stomach as hydrogels swell in the low pH environment. This property has been used to prevent release of foul-tasting drugs into the neutral pH environment of the mouth.

Sometimes, it is desirable that hydrogels with certain compositions can respond to more than one environmental stimulus (e.g., temperature and pH). Hydrogel copolymers of N-isopropylacrylamide and acrylic acid with appropriate compositions have been designed to sense small changes in blood stream pH and temperature to deliver antithrombotic agents (e.g., streptokinase or heparin) to the site of a blood clot.

Electrosensitive Hydrogels. The electrosensitive hydrogels, which are capable of reversible swelling and shrinking under a change in electric potential, are usually made of polyelectrolytes. The electric sensitivity of the polyelectrolyte hydrogels occurs in the presence of ions in solution. In the presence of an applied electric field, the ions (both coions and counterions) move to the positive or negative electrode, while the polyions of the hydrogels cannot move. This results in a change in the ion concentration-depen- dent osmotic pressure, and hydrogels either swell or shrink to reach its new equilibrium. The electrosensitive hydrogels exhibit reversible swelling–shrinking behavior in response to on–off switching of an electric stimulus. Thus, drug molecules within the polyelectrolyte hydrogels might be squeezed out from the electric-induced gel contraction along with the solvent flow.

Other Stimuli-Sensitive Hydrogels. Hydrogels that respond to specific molecules found in the body are especially useful for some drug delivery purposes. One such hydrogel is glucose-sensitive hydrogel, which has potential applications in the development of self-regulating insulin delivery systems.