Biomaterials

Source: STANDARD HANDBOOK OF BIOMEDICAL ENGINEERING AND DESIGN

P•A•R•T•3

BIOMATERIALS

Downloaded from Digital Engineering Library @ McGraw-Hill (www.digitalengineeringlibrary.com) Copyright © 2004 The McGraw-Hill Companies. All rights reserved. Any use is subject to the Terms of Use as given at the website. BIOMATERIALS

CHAPTER 11 BIOPOLYMERS

Christopher Batich and Patrick Leamy University of Florida, Gainesville, Florida

11.1INTRODUCTION 11.3 11.2POLYMER SCIENCE 11.4 11.3SPECIFIC POLYMERS 11.12 REFERENCES 11.30

11.1 INTRODUCTION

Polymers are large molecules synthesized from smaller molecules called monomers. Most polymers are organic compounds with carbon as the base element. Plastics are polymers that are rigid solids at room temperature and generally contain additional additives. Some common plastics used in biomedical applications are polymethyl methacrylate for intraocular lenses, braided polyethylene terephthalate for vascular grafts, and ultrahigh-molecular-weight polyethylene for the articulating surfaces of orthopedic implants. Polymers and biopolymers in particular encompass a much broader spectrum than plastics alone. Biopolymers include synthetic polymers and natural polymers such as proteins, polysaccharides, and polynucleotides. This chapter will only cover the most commonly used examples in each class but will provide references to more specific sources. Many useful polymers are water-soluble and are used as solutions. Hyaluronic acid is a naturally occurring high-molecular-weight polymer found in connective tissues and is used to protect the iris and cornea during ophthalmic surgery. Polyvinyl pyrrolidinone is a synthetic polymer used as a binder or additive in 25 percent of all Pharmaceuticals.1 Hydrogels are another class of polymers that has many biomedical applications. Hydrogels are polymers that swell in water but retain their overall shape. They are therefore soft and moist and mimic many natural tissues. The most wellknown hydrogel series is poly(hydroxyethyl methacrylate) (PHEMA) and PHEMA copolymers, which are used in soft contact lenses. Gelling polymers are hydrogels that can be formed in situ using chemical or physical bonding of polymers in solution. Alginates, for instance, are acidic polysaccharides that can be cross-linked using divalent cations such as calcium. Other examples of gelling polymers are the poloxamers that can gel with an increase in temperature. Alginates are widely used in cell immobilization, and poloxamers are used as coatings to prevent postsurgical adhesions. Elastomers are low-modulus polymers that can reversibly deform up to many times (some over 500 percent) their original size. Silicones and polyurethanes are common elastomeric biopolymers. Polyurethane is used as a coating for pacemaker leads and for angioplasty balloons. Silicones are used for a variety of catheters, soft contact lenses, and foldable intraocular lenses.

11.3 Downloaded from Digital Engineering Library @ McGraw-Hill (www.digitalengineeringlibrary.com) Copyright © 2004 The McGraw-Hill Companies. All rights reserved. Any use is subject to the Terms of Use as given at the website. BIOPOLYMERS

11.4 BIOMATERIALS

The next section begins with an overview of polymer science topics, including synthesis, structure, and mechanical properties. The remainder of this chapter (Sec. 11.3) will discuss individual polymers, including their applications and properties. The polymers are presented in the following order: water-soluble polymers, gelling polymers, hydrogels, elastomers, and finally, rigid polymers. These five categories are roughly ordered from low to high modulus (i.e., high to low compliance). Water-soluble polymers in solution do not have an elastic modulus since they are fluids, so these are presented first. In fact, most polymers do not have a true elastic modulus since they are viscoelastic and exhibit solid and viscous mechanical behavior depending on the polymer structure, strain rate, and temperature. Natural tissues are continuously repaired and remodeled to adjust to changes in the physiologic environment. No current synthetic biomaterial or biopolymer can mimic these properties effectively. Consequently, the ideal biomaterial or biopolymer performs the desired function, eventually disappears, and is replaced by natural tissue. Therefore, degradable polymers are of great interest to the biomedical engineering community. Polylactides and their copolymers are currently used as bone screws and sutures since they have good mechanical properties and degrade by hydrolysis so that they can, under optimum conditions, be replaced by natural tissue. In addition to classification as water-soluble polymers, gelling polymers, hydrogels, elastomers, and rigid polymers, polymers can also be classified as bioinert, bioerodable, and biodegradable. Bioinert polymers are nontoxic in vivo and do not degrade significantly even over many years. Polymers can degrade by simple chemical means or under the action of enzymes. For the purposes of this chapter, bioerodable polymers such as polylactide are those that degrade by simple chemical means, and biodegradable polymers are those that degrade with the help of enzymes. Most natural polymers (proteins, polysaccharides, and polynucleotides) are biodegradable, whereas most synthetic degradable polymers are bioerodable. The most common degradation reactions for bioerodable polymers are hydrolysis and oxidation.

11.2 POLYMER SCIENCE

11.2.1 Polymer Synthesis and Structure

Polymers are frequently classified by their synthesis mechanism as either step or chain polymers. Step polymers are formed by step wise reactions between functional groups. Linear polymers are formed when each monomer has two functional groups (functionality = 2). The second type of polymerization is chain polymerization, where monomers are added one at a time to the growing polymer chain. Most polymerization techniques yield polymers with a distribution of polymer molecular weights. Polymer molecular weight is of great interest since it affects mechanical, solution, and melt properties of the polymer. Figure 11.1 shows a schematic diagram for a polymer molecular weight distribution.

Number average molecular weight Mn averages the molecular weight over the number of molecules,

whereas weight average molecular weight Mw averages over the weight of each polymer chain.

Equations (11.1) and (11.2) defined Mw and Mn.

(11.1)

(11.2)

where Ni is the number of polymer chains with molecular weight Mi. The polymerization mechanism is a useful classification because it indicates the likely low- molecular-weight contaminants present. Chain-growth polymers frequently contain unreacted monomers, whereas step-growth polymers have low-molecular-weight oligomers (short chains) present.

BIOPOLYMERS 11.5

FIGURE 11.1 Typical polymer molecular weight distribution.

These low-molecular-weight species are more mobile or soluble than polymers and hence more likely to have physiologic effects. For instance, the monomer of PMMA causes a lowering of blood pressure and has been associated with life-threatening consequences when present (e.g., in some bone cements). Furthermore, the same polymer can be prepared by both mechanisms, leading to different impurities. For instance, polylactide is usually prepared by a chain-growth mechanism involving ring opening of a cyclic dimer (lactide) rather than the condensation of lactic acid. As with all materials, a polymer’s properties can be predicted and explained by understanding the polymer’s structure on the atomic, microscopic, and macroscopic scales. Polymers can be roughly classified into two different classes, thermoplastic and thermoset. Thermoplastic polymers are made of individual polymer chains that are held together by relatively weak van der Waals and dipole-dipole forces. Thermoplastic polymers can be processed into useful products by melt processing, namely, injection molding and extrusion. They can also be dissolved in solvents and cast to form films and other devices. Although they often degrade or denature before melting, most proteins and polysaccharides can be considered thermoplastics since they are made of individual chains and can be dissolved in solvents. Finally, thermoplastics can be linear or branched. Thermosetting polymers contain cross-links between polymer chains. Cross-links are covalent bonds between chains and can be formed using monomers with functionalities of greater than 2 during synthesis. Some polyurethanes and many silicones are formed using monomers with functionalities greater than 2. Cross-links also can be created after the polymer is formed. An example of this is vulcanization, which was discovered by Charles Goodyear in 1839 to toughen natural rubber. Vulcanization uses sulfur as a cross-linking agent. Thermosets are, in essence, one giant molecule since all the polymer chains are connected through the cross-links. Thermosets cannot be melted after they are formed and cannot be dissolved in solvents. Depending on the cross-link density, thermosets can swell in certain solvents. When a cross- linked polymer solidifies or gels, it usually has some linear or unconnected polymer present, which sometimes can be extracted after implanation. Figure 11.2 shows a schematic diagram for linear, branched, and cross-linked polymers. Polymers in the solid state have varying degrees of crystallinity. No polymer is truly 100 percent crystalline, but some are purely amorphous. Figure 11.3 is a simple model depicting a crystalline polymer. Polymer chains folding over themselves form crystalline regions. Amorphous regions of disordered polymer connect the crystals. Polymer chains are packed tighter in crystalline regions, leading to higher intermolecular forces. This means that mechanical properties such as modulus and

11.6 BIOMATERIALS

FIGURE 11.2 Schematic diagram showing different polymer structures.

strength increase with crystallinity. Ductility decreases with crystallinity since polymer chains have less room to slide past each other. The primary requirement for crystallinity is an ordered repeating chain structure. This is why stereoregular polymers are often crystalline and their irregular counterparts are amorphous. Stereoregular polymers have an ordered stereostructure, either isotactic or syndiotactic. Isotactic polymers have the same configuration at each stereo center, whereas configuration alternates for syndiotactic polymers (Fig. 11.4). Atactic polymers have no pattern to their stereostructure. Polypropylene (PP) is a classic example of a polymer whose crystallinity and properties change drastically depending on stereostructure. Syndiotactic and isotactic PP have a high degree of crystallinity, whereas atactic polypropylene is completely amorphous. Isotactic PP has excellent strength and flexibility due to this regular structure and makes excellent sutures. Atactic PP is a weak, gumlike material. Recent advances in polymer synthesis have made available new polymers with well-controlled tacticity based on olefins. It is likely that they will find use as biomaterials in the future.

BIOPOLYMERS 11.7

FIGURE 11.3 Simple model showing crystalline and amorphous polymer regions. (Reproduced from Fundamental Principles of Polymeric Materials, ed. by Stephen L. Rosen. New York: Wiley, 1993, p. 43.)

Crystallinity plays a large role in the physical behavior of polymers. The amorphous regions play perhaps an even greater role. Some amorphous polymers such as poly methyl methacrylate (PMMA) are stiff, hard plastics at room temperature, whereas polymers such as polybutadiene are soft and flexible at room temperature. If PMMA is heated to 105°C, it will soften, and its modulus will be reduced by orders of magnitude. If polybutadiene is cooled at to -73°C, it will become stiff and hard. The temperature at which this hard-to-soft transformation takes place is called the glass transition

temperature Tg. Differential thermal analysis (DTA) or a similar technique called differential scanning calorimetry (DSC) can be used to determine the temperature at which phase transitions such as glass transition

temperature and melting temperature Tm occur. DTA involves heating a polymer sample along with a

11.8 BIOMATERIALS

FIGURE 11.4 Stereoisomerism in polypropylene

standard that has no phase transitions in the temperature range of interest. The ambient temperature is increased at a regular rate, and the difference in temperature between the polymer and the standard is measured. The glass transition is endothermic; therefore, the polymer sample will be cooler

compared with the standard at Tg. Similarly, melting is endothermic and will be detected as a negative temperature compared with the standard. If the polymer were quenched from melt prior to DTA analysis, it would be amorphous, even though it would have the potential to crystallize. In this case,

the sample will crystallize during the DTA run at a temperature between Tg and Tm. Figure 11.5 shows a schematic DTA curve for a crystalline polymer quenched for melt. A polymer that does not crystallize would show a glass transition only, and the crystallization and melting peaks would be absent. These measurements can be made to identify an unknown plastic or to aid in the synthesis of new polymers with desired changes in mechanical properties at certain temperatures. Random copolymers have no pattern to the sequence of monomers. A random copolymer using repeat units A and B would be called poly(A-co-B). The term alternating copolymer is fairly selfexplanatory with an alternating pattern of repeat units. Block copolymers consist of long-chain segments (blocks) of single-repeat units attached to each other. Block polymers most commonly employ two different repeat units and contain two or three blocks. Block copolymers are named poly(A-b-B) or simply AB for polymers with two blocks (diblock polymer). A triblock copolymer would be named poly(A-b-B-b-A) or simply ABA. Graft copolymers consist of a backbone with side chains of a different repeat unit and are named poly(A-g-B). (See Fig. 11.6.) Block and random copolymers are the most common copolymers. An example of a random copolymer is poly(lactide-co-glycolide), also known as poly(lactic-co-glycolic acid) depending on the synthesis route. Note that the structure for poly(lactide-co-glycolide) does not specify the type (random, alternating, block, or graft) and must be accompanied by the structure name to specify copolymer type.

Block copolymers often phase segregate into an A-rich phase and a B-rich phase. If one repeat unit (or phase) is a soft phase and the other is a hard glassy or crystalline phase, the result can be a thermoplastic elastomer. The crystalline or hard glassy phase acts as a physical cross-link. The

BIOPOLYMERS 11.9

FIGURE 11.5 Schematic representation of a DTA curve for crystalline polymer quenched from melt prior to analysis.

FIGURE 11.6 Schematic diagram showing classes of copolymer.

11.10 BIOMATERIALS

advantage of thermoplastic elastomers, unlike chemically cross-linked elastomers, is that they can be melt or solution processed. Many polyurethanes are thermoplastic elastomers. They consist of soft segments, either a polyester or a poly ether, bonded to hard segments. The hard segments are ordinarily synthesized by polymerizing diisocyanates with glycols. Similarly, thermoplastic hydrogels can be synthesized by using a hydrophilic A block and a hydrophobic B block. Poly(ethylene oxide-b-lactides) (PEO-b-PLA) are biodegradable hydrogel polymers that are being developed for drug-delivery applications. 2–6 PEO is a water-soluble polymer that promotes swelling in water, and PLA is a hard, degradable polymer that acts as a physical cross- linker.

11.2.2 Polymer Mechanical Properties

Solid polymer mechanical properties can be classified into three categories: brittle, ductile, and

elastomeric (Fig. 11.7). Brittle polymers are polymers with a Tg that is much higher than room temperature, such as PMMA. These polymers have a high modulus and high ultimate tensile strength but low ductility and toughness. Ductile polymers are semicrystalline polymers such as polyethylene

and PTFE that have a Tg below room temperature for the amorphous polymer content. The crystals lend strength, but the rubbery amorphous regions offer toughness. These polymers have lower strength and modulus but greater toughness than brittle polymers. Elastomers have low moduli since

they have a Tg well below room temperature, but they can return to their original shape following high extensions since cross-links prevent significant polymer chain translations.

FIGURE 11.7 Mechanical behavior of polymers. (Reproduced from Encyclopedia of Materials Science and Engi- neering, ed. by M. B. Bever. Cambridge, MA: MIT Press, 1986, p. 2917.)

Mechanical properties of polymers, unlike those of other engineering materials, are highly strain rate and temperature dependent. Modulus increases with increasing strain rate and decreasing temperature (Fig. 11.8). The strain-rate dependence for mechanical properties shows that polymers exhibit viscous behavior in addition to solid or elastic behavior.

BIOPOLYMERS 11.11

FIGURE 11.8 Schematic diagram showing strain rate and temperature dependence of polymer mechanical properties. (Reproduced from Ency- clopedia of Materials Science and Engineering, ed. by M. B. Bever. Cam- bridge, MA: MIT Press, 1986, p. 2917.)

For an elastic solid, stress σ is a linear function of the applied strain , and there is no strain-rate dependence. Elastic modulus E is the slope of the stress versus strain curve. An elastic material can be modeled as a spring, whereas viscous materials can be modeled as a dashpot. For a fluid (viscous material), stress is proportional to strain rate and unrelated to strain. Viscosity η is the slope of the stress versus strain rate curve. Figure 11.9 shows the stress/strain relationship for elastic solids and the stress/strain-rate relationships for viscous liquids. Polymers can exhibit both viscous and solid mechanical behavior; this phenomenon is called viscoelasticity. For a given polymer, the degree of viscous behavior depends on temperature. Below

Tg, polymers will behave more or less as elastic solids with very little viscous behavior. Above Tg,

FIGURE 11.9 Stress/strain relationship for elastic solids and the stress/strain rate relationships for viscous liquids.

11.12 BIOMATERIALS

polymers exhibit viscoelastic behavior until they reach their melting temperature, where they behave as liquids.

(11.3)

When designing with polymers, it is important to keep in mind that many polymers deform over time when they are under a continuous load. This deformation with time of loading is called creep. Ideal elastic solids do not creep since strain (deformation) is proportional to stress, and there is no time dependence. Viscous materials (liquids) deform at a constant rate with a constant applied stress. Equation (11.6) describes the strain in a viscous material under constant load or stress σ.

(11.4)

(11.5)

FIGURE 11.10 Response of elastic model (a) and viscous model (b) to a constant stress applied from t to t . i f (11.6) (Reproduced from Encyclopedia of Materials Science and Engineering, ed. by M. B. Bever. Cambridge, MA: MIT Press, 1986, p. 2919.) Figure 11.10 shows the strain with time of constant stress for a viscous and elastic material. The

stress is applied at t and removed at tf. The elastic model shows an instantaneous deformation when

stress is applied at ti, a constant deformation with time, and then a return to its original length when the load is removed. Therefore, the elastic solid does not creep. The viscous (dashpot) model deforms continu-

ously (creeps) from ti to tf and remains permanently deformed after removal of the load. Adding spring and dashpot models in series and parallel creates viscoelastic models. Several models have been proposed. Figure 11.11 shows the creep behavior for four viscoelastic models. Stress relaxation is a similar phenomenon and is defined as a reduction in stress during a constant deformation. One example of stress relaxation is the use of plastic washers between a nut and bolt. After the screw is secured, the washer deformation is constant, but the stress in the washer diminishes with time (stress relaxation), and the screw is therefore more likely to loosen with time. Therefore, creep and stress relaxation should be accounted for when designing with polymers. The FIGURE 11.11 Creep response for (a) Maxwell model, strain rate for a given application must also be known (b) Voight-Kelvin model, and (c) four-parameter model since modulus, ductility, and strength are strain rate

for constant stress applied at ti and removed at tf. dependent.

BIOPOLYMERS 11.13

11.3 SPECIFIC POLYMERS

11.3.1 Water-Soluble Polymers

Water-soluble polymers are used for a variety of applications. They can be adsorbed or covalently bound to surfaces to make them more hydrophilic, less thrombogenic, and more lubricious. They can be used as protective coatings to prevent damage during surgery. Hyaluronic acid solutions are used in ophthalmic surgery to prevent damage to the cornea and iris. They can be cross-linked to form hydrogels for soft-tissue replacement and for drug-delivery applications. There are numerous water- soluble biopolymers. The polymers discussed below are some of the more common and useful examples.

Poly(N-Vinyl-Pyrrolidinone). Degradation: bioinert.

Poly(N-vinyl-pyrrolidinone) (or PVP) is a widely used water-soluble polymer. Similar to dextran, it has been used as a plasma volume expander to replace lost blood in mass-casualty situations. PVP can also be used as a detoxifying agent many toxic compounds form nontoxic complexes with PVP, which the kidneys eventually excrete. PVP is also used extensively as a binder in the pharmaceutical industry.

Polyethylene Glycol. Degradation: bioinert.

Polyethylene glycol (PEG), also known as polyethylene oxide (PEO), is used primarily to make hydrophobic surfaces more hydrophilic. These hydrophilic coatings are known to drastically reduce bacterial adhesion to substrates, making the surfaces antimicrobial.7–9 PEO also can be coated or grafted onto the surfaces of microparticles to aid in colloidal stability.10–12 Microparticles for drug- delivery applications are quickly recognized and cleared from the circulation by the reticuloendothelial system (RES). PEO coatings help particles elude the RES, thereby increasing their residence time in the circulation.13–16

Hyaluronic Acid. Degradation: biodegradable.

Hyaluronic acid (HA) is a very lubricious high-molecular-weight water-soluble polymer found in connective tissue and the sinovial fluid that cushions the joints. HA is also found in the vitreous and aqueous humors of the eye. Solutions are injected in the eye during intraocular lens surgery to protect the cornea and the iris from damage during surgery. Table 11.1 shows data on HA concentration,

11.14 BIOMATERIALS

TABLE 11.1 Data for Commercial HA Solutions Used in Ophthalmic Surgery

*n.i. = not investigated. Source: Reproduced from H. B. Dick and O. Schwenn, Viscoelastics in Ophthalmic Surgery. Berlin: Springer- Verlag, 2000, p. 34.

molecular weight, and viscosity for some commercially available HA solutions. HA is currently being investigated to prevent postoperative adhesions. Since HA has many functional groups (OH, carboxylate, acetamido), it can be cross-linked by a variety of reagents. Therefore, HA may have applications as a hydrogel drug-delivery matrix.17

Dextran. Degradation: biodegradable.

Dextran is a simple water-soluble polysaccharide manufactured by Leuconostoc mesenteroides and L. dextranicum (Lactobacteriaceae). Its structure is shown as a linear polymer, but some branching

BIOPOLYMERS 11.15

occurs at the three remaining OH groups. The native form of dextran has a high molecular weight near 5 × 108 g/mol. Dextran is depolymerized to yield a variety of molecular weights depending on the application. Similar to polyvinyl pyrrolidinone, dextran solutions can be used as a blood plasma extender for mass-casualty situations. Dextran of between 50,000 and 100,000 g/mol is used for this application. Like many of the water-soluble polymers, cross-linked dextran can be used as a drug-

delivery matrix in whole or microsphere form. Dextran-coated magnetite (Fe3O4) nanoparticles are finding use as a magnetic resonance imaging (MRI) contrast agent. The dextran adsorbs onto the particle surfaces and provides a steric barrier to prevent agglomeration of the nanoparticles.

Starch. Degradation: biodegradable.

Starch is the primary source of carbohydrate in the human diet. Starch is composed of two monosac- charides: amylose and amylopectin. Amylose is a linear polymer that varies in molecular weight between 100,000 and 500,000 g/mol. Amylopectin is similar to amylose, having the same backbone structure but with 4 percent branching. Starch is insoluble in water but can be made soluble by treating with dilute HCl. Soluble starch has similar properties to dextran and therefore has similar applications.

11.3.2 Gelling Polymers

Gelling polymers are polymers in solution that transform into relatively rigid network structures with a change in temperature or by addition of ionic cross-linking agents. This class of polymers is useful because hydrogels can be formed at mild conditions. These polymers can therefore be used for cell immobilization and for injectable materials that gel in vivo. They are also used as coatings for drug tablets to control release in vivo.

Poloxamers. Degradation: bioinert.

Poloxamers consist of two polyethylene oxide (PEO) blocks attached on both sides of a polypropylene oxide (PPO) block. The polymers are water-soluble, but increasing the temperature or concentration can lead to gel formation. The gelling properties are a function of the polypropylene content and the block lengths. Figure 11.12 shows the viscosity as a function of temperature for poloxamer 407. For a given concentration of poloxamer, the viscosity increases by several orders of magnitude at a transition temperature. The transition temperature decreases as polymer concentration increases. The unique gelling properties of poloxamers make them useful as a coating to prevent postsurgical adhesions. They can be applied as a liquid since they gel at body temperature to provide a strong barrier for the prevention of adhesions. Similarly, poloxamers are being investigated for use as an injectable drug depot. Drug can be mixed with an aqueous poloxamer solution that thermally

11.16 BIOMATERIALS

FIGURE 11.12 Viscosity of poloxamer solutions as a function of temperature and polymer concentration. (Reproduced from L. E. Reeve, “Poloxamers: Their chemistry and applications” in Handbook of Biodegradable Polymers, A. J. Domb, J. K. Kost, and D. M. Wiseman (eds.) London: Harwood Academic Publishers, 1997, p. 235.)

gels in the body and provides a matrix for sustained release. Another research area for poloxamers is for coating hydrophobic polymer microspheres. The PPO block adsorbs to the hydrophobic microsphere, whereas the PEO blocks extend into the solution and provide steric repulsion to prevent coagulation. The PEO blocks also prolong circulation after intravenous injection since the hydrophilic PEO retards removal by the reticuloendothelial system.

Alginate. Degradation: slow or nondegradable.

As this structure shows, alginate is a copolymer of guluronic and mannuronic acids. Alginate is a natural polysaccharide that is readily cross-linked using divalent or trivalent cations. Cross-linking occurs between acid groups of adjacent mannuronic acid units. Ca2+ is commonly used as a crosslinking agent. The sodium salt of alginate (sodium alginate) is used rather than the plain alginate since the acidic alginate can be harmful to cells and tissues.

BIOPOLYMERS 11.17

Since cross-linking is chemically mild and easily accomplished, calcium cross-linked alginate is commonly used for cell immobilization. Cells are immobilized to prevent immune response in vivo and to prevent them from traveling from the desired location in vivo. Immobilization is most often accomplished by adding cells to a sodium alginate solution, followed by dripping the solution into a calcium chloride solution to cross-link the alginate and entrap cells.

Gelatin. Degradation: biodegradable. Gelatin is a protein prepared by hydrolyzing type I collagen using aqueous acids or bases. Collagen is discussed further in the section on hydrogels. Hydrolysis involves disruption of the collagen tertiary triple helix structure and reduction of molecular weight to yield gelatin that is soluble in warm water. Following hydrolysis, gelatin is purified and dried to yield a powder. Contrary to the poloxamers, gelatin solutions (>0.5 wt %) gel with a reduction in temperature. Gelatin gels melt between 23 and 30°C, and gelatin solutions set at around 2 to 5°C lower than the melting point. Gelatin is used as a tablet coating or capsule materials to control the release rate of drugs. Gelatin sponges are similar to collagen sponges and are used as hemostatic agents.

Fibrin. Degradation: biodegradable. Fibrin is the monomer formed from fibrinogen in the blood when a clot is formed. It is a protein that first polymerizes and then cross-links during clot formation and has been isolated and used as a biological adhesive and matrix for tissue engineering. The gel formation involves mixing fibrinogen with the gelling enzyme (thrombin) and a second calciumcontaining solution. Speed of gellation is controlled by concentrations. Biodegradation occurs fairly rapidly due to natural enzymatic activity (fibrinolysis) resulting from plasmin in tissue. Fibrin is used as a soft-tissue adhesive and is used in tissue scaffolds.

11.3.3 Hydrogels

Hydrogels are materials that swell when placed in aqueous environments but maintain their overall shape. Hydrogels can be formed by cross-linking nearly any water-soluble polymer. Many natural materials such as collagen and chitosan (derived from chitin) absorb significant amounts of water and can be considered to be hydrogels. Hydrogels are compliant since the polymer chains have high mobilities due to the presence of water. Hydrogel mechanical properties are dependent on water content. Modulus and yield strength decrease with water content, whereas elongation tends to increase. Hydrogels are lubricious due to their hydrophilic nature. Hydrogels resist protein absorption and microbial attack due to their hydrophilicity and dynamic structure.

Poly(hydroxyethyl methacrylate). Degradation: bioinert.

Poly(hydroxyethyl methacrylate) (PHEMA) is a hydrogel generally cross-linked with ethylene glycol dimethacrylate (which is normally present as a contaminant in the monomer). PHEMA’s hydrogel properties such as resistance to protein adsorption and lubricity make it an ideal material for contact lenses. Hydrated PHEMA gels have good oxygen permeability, which is necessary for the health of the cornea. PHEMA is copolymerized with polyacrylic acid (PAA) or poly(N-vinyl pyrrolidinone) to increase its water-absorbing capability.

11.18 BIOMATERIALS

Chitosan. Degradation: biodegradable.

Chitin is a polysaccharide that is the major component of the shells of insects and shellfish. Chitosan is deacetylated chitin. Deacetylation is accomplished using basic solutions at elevated temperatures. Chitin is not 100 percent acetylated, and chitosan is not 100 percent deacetylated. The degree of acetylation has a large influence on properties, in particular solubility. Chitin is difficult to use as a biomaterial since it is difficult to process. It cannot be melt processed and is insoluble in most aqueous and organic solutions. It is soluble only in strong acid solutions. Chitosan, on the other hand, is soluble in dilute organic acids; acetic acid is most commonly used. Chitosan has a positive charge due to the primary amines in its structure. The positive charge is significant because most tissues are negatively charged. Chitosan has been used for artificial skin and sutures and as a drugdelivery matrix.18 Chitosan absorbs a significant amount of water when placed in aqueous solution. Equilibrium water content of 48 percent was determined by immersing chitosan films in deionized water. Tensile testing on these wet films resulted in an ultimate tensile stress of approximately 1600 psi with 70 percent elongation at break.19

Collagen. Degradation: biodegradable. Collagen is the major structural protein in animals and exists in sheet and fibrillar forms. Collagen fibrils consist of a triple helix of three protein chains. Type I collagen is a fibrillar form of collagen that makes up 25 percent of the protein mass of the human body. Due to its prevalence and ability to be separated from tissues, type 1 collagen is most often used in medical devices. Collagen fibrils are strong and biodegradable, and collagen is hemostatic, making it useful in a variety of applications. Table 11.2 shows many of the applications for collagen. Collagen is usually obtained from bovine corium, the lower layer of bovine hide. Bovine collagen is nonimmunogenic for most people, but immune response may be triggered in those with allergies to beef.20 Both water-soluble and water-insoluble collagen can be extracted from animal tissues. Watersoluble collagen can be extracted from collagen using salt solutions, organic acids, or a combination of organic acids and proteases. Proteases break down cross-links and nonhelical ends, yielding more soluble collagen than acid alone or the salt solutions. Water-soluble collagen finds little use in the preparation of materials and devices since it quickly resorbs in the moist environment of the body. Water-insoluble collagen, however, is routinely used in the manufacture of medical devices. Waterinsoluble collagen is ground and purified to yield a powder that can be later processed into materials and devices. Collagen cannot be melt processed and is therefore processed by evaporating

BIOPOLYMERS 11.19

TABLE 11.2 Medical Applications of Collagen

Source: Reproduced from F. H. Silver and A. K. Garg, “Collagen characterization, processing, and medical applications,” in Handbook of Biodegradable Polymers, A. J. Domb, J. Krost, and D. M. Wiseman (eds.). London: Harwood Academic Publishers, 1997, Chap. 17, p. 336.

water from collagen suspensions. Insoluble collagen disperses well at pH between 2 and 4. Evaporating 1% suspensions forms collagen films. Freezing suspensions followed by lyophilizing (freeze drying) forms sponges. Ice crystals form during freezing and result in porosity after water is removed during lyophilizing. Freezing temperature controls ice crystal size, and 14-µm pores result from freezing at -80°C and 100-µm pores at -30°C. Fibers and tubes are formed by extruding collagen suspensions into aqueous solutions buffered at pH 7.5.20 Collagen absorbs water readily in the moist environment of the body and degrades rapidly; therefore, devices are often cross-linked or chemically modified to make them less hydrophilic and to reduce degradation. Viswwanadham and Kramer21 showed that water content of untreated collagen hollow fibers (15 to 20 µm thick, 400 µm outer diameter) is a function of humidity. The absorbed water plasticizes collagen, lowering both the modulus and yield strength. Table 11.3 summarizes these results. Cross-linking the fibers using ultraviolet (UV) radiation increased the modulus of the fibers.21

11.20 BIOMATERIALS

TABLE 11.3 Water Absorption and Its Effect on Modulus E and Yield Strength of Collagen Hollow Fibers21

*1 ksi = 1000 psi.

Albumin. Degradation: biodegradable. Albumin is a globular, or soluble, protein making up 50 percent of the protein content of plasma in humans. It has a molecular weight of 66,200 and contains 17 disulfide bridges.22 Numerous carboxylate and amino (lysyl) groups are available for cross-linking reactions, providing for a very broad range of mechanical behavior. Heating is also an effective cross-linking method, as seen in ovalbumin (egg white cooking). This affords another gelling mechanism and is finding increasing use in laser welding of tissue, where bond strengths of 0.1 MPa have been achieved.23 As with collagen, the most common cross-linking agent used is glutaraldehyde, and toxic byproducts are of concern. Careful cleaning and neutralization with glycine wash have provided biocompatible albumin and collagen structures in a wide variety of strengths up to tough, very slowly degradable solids. It should be noted that albumin and collagen solidification generally is different from that of fibrin, which gels by a normal biological mechanism. The glutaraldehyde methods yield a variety of nonbiologic solids with highly variable mechanical properties. This has led to an extensive literature and a very wide range of properties for collagen and albumin structures, which are used for tissue substitutes and drug-delivery vehicles.

Oxidized Cellulose. Degradation: bioerosion. Oxidized cellulose is one of the fastest-degrading polymers at physiologic pH. It is classified as bioerodable since it degrades without the help of enzymes. It is relatively stable at neutral pH, but above pH 7, it degrades. Oxidized cellulose disappears completely in 21 days when placed in phosphate-buffered saline (PBS). Similarly, it dissolves 80

percent after 2 weeks in vivo. Cellulose is oxidized using nitrogen tetroxide (N2O4). Commercially available oxidized cellulose contains between 0.6 and 0.93 carboxylic acid groups per glucose unit, which corresponds to between 16 and 24 wt/% carboxylic acid.24

BIOPOLYMERS 11.21

Oxidized cellulose is used as a degradable hemostatic agent. The acid groups promote clotting when placed in wounds. Furthermore, oxidized cellulose swells with fluid to mechanically close damaged vessels. Oxidized cellulose sheets are placed between damaged tissues following surgery to prevent postsurgical adhesions. The sheets separate tissue during healing and dissolve in a few weeks after healing occurs.24

11.3.4 Elastomers

Silicones and polyurethanes are the two classes of elastomers used for in vivo applications. Both are versatile polymers with a wide range of mechanical properties. Polyurethanes tend to be stiffer and stronger than silicones, whereas silicones are more inert and have the advantage of being oxygenpermeable. Polyurethanes are more versatile from a processing standpoint since many polyurethanes are thermoplastics, whereas silicones rely on covalent cross-linking and are therefore thermosets.

Polyurethane elastomers. Degradation: bioinert or slow bioerosion.

This repeat unit can describe most polyurethanes. Polyurethanes are a versatile class of block copoly- Ј Љ mers consisting of a hard block (R ) and a soft block (R ). The hard block is a glassy polymer (Tg above room temperature) often synthesized by polymerizing diisocyanates with glycols. RЉ is a low-

Tg (Tg << room temperature) polyester or polyether. Polyurethanes with polyester soft blocks are degradable, whereas those with polyether blocks degrade very slowly. Polyurethanes are usually elastomers since hard and soft blocks are present. Rubbers of different hardness or durometer can be prepared by varying the ratio of RЈ to RЉ. Covalently cross-linked polymers can be prepared by using monomers with functionalities greater than 2. However, the most useful polyurethanes for medical applications are the thermoplastic elastomers since these can be melt processed or solution cast. Polyurethanes have good fatigue strength and blood compatibility and are used for pacemaker lead insulation, vascular grafts, and ventricular assist device/artificial heart membranes.25 Table 11.4 shows properties for thermoplastic polyurethane elastomers available from Cardio Tech International, Inc. These values are for the Chronoflex C series of polymers.

11.22 BIOMATERIALS

TABLE 11.4 Properties of Chronoflex Thermoplastic Polyurethanes Available from CardioTech

Silicone Elastomers (Polysiloxanes). Degradation: bioinert.

Silicone elastomers are cross-linked derivatives of poly(dimethyl siloxane) (PDMS). Polysiloxane liquids with functional endgroups such as OH or sidegroups such as can be molded at room temperature and cross-linked to form elastomers using various cross-linking agents. Silicone elastomer kits consisting of the polysiloxane precursor liquids and cross-linking agents are commercially available from corporations such as GE Bayer Silicones (Table 11.5). Silicones crosslinked at room temperature are called room-temperature vulcanized (RTV) elastomers, and those requiring elevated temperatures are called heat-cured silicone elastomers. Silicones are more flexible and of lower strength than polyurethanes. However, they are more chemically stable and are used for artificial finger joints, blood vessels, heart valves, breast implants, outer ears, and chin and nose implants. Silicones have high oxygen permeability and are used for membrane oxygenators and soft contact lenses.26

11.3.5 Rigid Polymers

Most bioinert rigid polymers are commodity plastics developed for nonmedical applications. Due to their chemical stability and nontoxic nature, many commodity plastics have been used for implant- able materials. This subsection on rigid polymers is separated into bioinert and bioerodable materials. Table 11.6 contains mechanical property data for bioinert polymers and is roughly ordered by elastic modulus. Polymers such as the nylons and polyethylene terephthalate) slowly degrade by hydrolysis of the polymer backbone. However, they are considered bioinert since a significant decrease in properties takes years. Most rigid degradable polymers degrade without the aid of enzymes and are therefore bioerodable. Table 11.7 shows mechanical property data for bioerodable polymers.

BIOPOLYMERS 11.23

TABLE 11.5 Mechanical Properties of Cured Silicone Available from GE Bayer Silicones

TABLE 11.6 Literature Values for Physical Properties of Bioinert Plastics

*Tested at 0.2 percent moisture content. †Tested after conditioning at 50 percent relative humidity. Sources: aData from Modern Plastics Encyclopedia, New York: McGraw-Hill, 1999. bData from Encyclopedia of Polymer Science and Engineering, 2d ed. New York: Wiley, 1985. cData from Polymer Handbook, 3d ed. New York: Wiley, 1989. dData from Encyclopedia of Materials Engineering. Cambridge, MA: MIT Press, 1986.

TABLE 11.7 Physical Properties of Degradable Polyesters Available from Birmingham Polymers, Inc.

11.24 BIOMATERIALS

Cellulose. Degradation: bioinert.

Cellulose is a partially crystalline polysaccharide and is the chief constituent of plant fiber. Cotton is the purest natural form of cellulose, containing 90 percent cellulose. Cellulose decomposes before melting and therefore cannot be melt processed. It is insoluble in organics and water and can only be dissolved in strong basic solutions. Regenerated cellulose, also known as rayon, is cellulose that has been precipitated form a basic solution. Cellulose is used in bandages and sutures. Cuprophan is cellulose precipitated from copper hydroxide solutions to form hemodialysis membranes.

Cellulose acetate. Degradation: bioinert.

Cellulose acetate is a modified cellulose that can be melt processed. Cellulose acetate membranes are used for hemodialysis.

Nylon 6,6. Degradation: slow bioerosion.

Poly (hexamethylene adipimide) is also known as Nylon 6,6 since its repeat unit has two six-carbon sequences. Nylon is tough, abrasion resistant, and has a low coefficient of friction, making it a popular suture material.27 Nylon 6,6 is hydrophilic and absorbs water when placed in tissues or in humid environments (9 to 11 percent water when fully saturated28). Absorbed water acts as a plasticiser, increasing the ductility and reducing the modulus of Nylon 6,6. Nylon bioerodes at a very slow rate. Nylon 6,6 implanted in dogs lost 25 percent of its tensile strength after 89 days and 83 percent after 725 days.29

Nylon 6: Poly(caprolactam). Degradation: slow bioerosion.

Nylon 6 has similar properties to Nylon 6,6, the primary difference being that Nylon 6 has a lower melting temperature and its properties are more moisture-sensitive.

BIOPOLYMERS 11.25

Poly(ethylene terephthalate). Degradation: very slow bioerosion.

Poly(ethylene terephthalate) (PET), also known simply as polyester or Dacron, is a rigid semicrystalline polymer. It is widely used as a material for woven large-diameter vascular grafts. PET is usually considered to be stable, but it undergoes very slow bioerosion in vivo.

Poly(methyl methacrylate) (PMMA). Degradation: bioinert.

PMMA is an amorphous polymer with a high Tg around 100°C. PMMA is a stiff, hard, transparent material with a refractive index of 1.5 and is therefore used for intraocular lenses and hard contact lenses. PMMA is very bioinert but less so than PTFE due to possible hydrolysis of ester sidegroups. PMMA is a thermoplastic that can be formed by injection molding or extrusion. Casting monomer or monomer-polymer syrup and polymerizing can also form PMMA. PMMA plates, commonly known as Plexiglass or Lucite, are formed this way.

Polyvinyl chloride. Degradation: nondegradable.

Polyvinyl chloride (PVC) a rigid glassy polymer that is not used in vivo because it causes a large inflammatory response probably due to metal stabilizers and residual catalysts. However, PVC soft- ened with plasticizers such as dioctyl phthalate is used for medical tubing and blood bags. PVC is a thermoplastic and can be melt processed.

Polypropylene (PP). Degradation: bioinert.

Commercial polypropylene is isotactic since atactic polypropylene has poor mechanical properties and isotactic is difficult to synthesize. Polypropylene has similar structure and properties as HDPE, except that it has superior flex-fatigue properties and a higher melting point. Polypropylene is commonly used for nondegradable sutures. Like PE, polypropylene can be melt processed.26

Polyethylene (PE). Degradation: bioinert.

Polyethylene is a flexible polymer with a Tg of around -125°C. It is available in three different forms: low density (LDPE), linear low density (LLDPE), and high density (HDPE). LDPE and LLDPE are typically not used in vivo since they cannot be autoclaved. HDPE can be autoclaved and is used in

11.26 BIOMATERIALS

tubing for drains and as a catheter material. Ultrahigh-molecular-weight polyethylene (UHMWPE) has a high molecular weight (~2 × 106 g/mol) and is used for the articulating surfaces of knee and hip prosthesis. UHMWPE, like all PE, has a low coefficient of friction but is very hard and abrasion- resistant.30 With the exception of UHMWPE, PE can be melt processed. UHMWPE has a high melting point and, like PTFE, is formed by pressing and sintering of powders.

Polytetrafluoroethylene (PTFE). Degradation: very bioinert.

Polytetrafluoroethylene (PTFE, Teflon, Fluorel) is best known for its excellent chemical stability and low coefficient of friction. Expanded PTFE (ePTFE) contains micropores created by stretching PTFE film and is used in small-diameter vascular grafts and for artificial heart valve sewing rings (e.g., Gore-Tex). PTFE is highly crystalline (92 to 98 percent) and degrades near its melting temperature of 327°C; therefore, it cannot be melt processed even though it is a thermoplastic. Due to its inability to be melt processed, PTFE is formed by pressing PTFE powder, followed by heating to sinter the powder, or it is heated and pressed simultaneously (pressure sintered).31

Perfluorinated Ethylene-Propylene Polymer (FEP). Degradation: bioinert.

Perfluorinated ethylene-propylene polymer (FEP) is a copolymer of tetrafluoroethylene (TFE) and hexafluoropropylene (HFP). FEP has similar properties to PTFE, but its lower melting temperature of 275°C allows it to be melt processed.31

Polylactide, Polyglycolide, and Copolymers. (Also known as polylactic acid and polyglycolic acid.) Degradation: bioerosion; polylactide: ; polyglycolide: .

Polylactide and polyglycolide are the most widely used synthetic degradable biopolymers. They are popular since they have good mechanical properties and degrade to nontoxic metabolites (glycolic or lactic acid). Polylactide, polyglycolide, and copolymers of the two find clinical use in degradable sutures and orthopedic pins and screws. Recent research has focused on their use as a drug-delivery matrix since sustained release of drugs can be achieved as the materials degrade. Drug-delivery matrices include monoliths and microspheres. Microspheres are routinely prepared by dissolution of polymer and drug in chloroform (or dichloromethane), suspension in aqueous poly vinyl alcohol (to form an oil-in-water emulsion), and evaporation to form drug-entrapped microspheres or nanospheres. Primarily stirring speed and polymer-drug concentration in the oil phase (chloroform or dichloromethane solution) control sphere size.

Polylactide differs from polyglycolide in that R is a methyl group (CH3) for polylactide and a hydrogen for polyglycolide. Polylactide and polyglycolide are usually synthesized from lactide and glycolide cyclic monomers using initiators such as stannous 2-ethyl hexanoate (stannous octoate). As with polypropopylene, the stereochemistry of the repeat unit has a large effect on the structure and properties of polylactide. Poly(DL-lactide) is atactic, meaning that it has no regular stereostructure and as a result is purely amorphos. Poly(D-lactide) and poly(L-lactide) are isotactic and consequntly are approximatley 35 percent crystalline. Poly(D-lactide) is seldom used commercially since D-lactic acid (degradation product of D-lactide) does not occur naturally in the human body, whereas L-lactic acid is a common metabolite. Poly(L-lactide) has a higher modulus and tensile strength than the

BIOPOLYMERS 11.27

amorphous poly (DL-lactide). Similarly, the crystalline poly(L-lactide) degrades completely in vivo in 20 months to 5 years, whereas poly(DL-lactide) degrades much faster, in 6 to 17 weeks.32 Copolymers of glycolide and lactide [poly(lactide-co-glycolide)] are amorphous and have similar mechanical properties and degradation rates as poly (DL-lactide). Pure poly glycolide is very strong and stiff yet has similar degradation as the poly(DL-lactides) and the lactide-glycolide copolymers. Polyglycolide is highly crystalline, with crystallinities between 35 and 70 percent.32 Figures 11.13 and 11.14 show degradation rates for polyglycolide and poly(L-lactide). Polylactide, polyglycolide, and poly(lactide-co-glycolide) are often called polylactic acid, polglycolic acid, and poly(lactic-co-glycolic acid) since their structures can be deduced by the direct condensation of lactic and glycolic acid. Although it is rare, synthesis of polylactic and glycolic acids can be achieved by direct condensation, but this results in a low-molecular-weight polymer (on the order of 2000 g/mol) with poor mechanical properties but increased degradation rates.

Polycaprolactone. Degradation: bioerosion.

Polycaprolactone (PCL) is a biodegradable semicrystalline polyester that is synthesized from caprolactone using stannous octoate in a similar manner to polylactide or polyglycolide. PCL has a

very low modulus of around 50 ksi since it has a low Tg of -60°C. PCL degrades very slowly, and therefore, it is usually not used as a homopolymer. Caprolactone, however, is copolymerized with glycolide to make a flexible suture material (trade name Monocryl).33

Poly(Alkylcyanoacrylates). Degradation: bioerosion.

Cyanoacrylates are reactive monomers initiated by nearly any anion to form a rigid polymer. The only anions that cannot initiate polymerization are the conjugate bases of strong acids (e.g., Cl-, , ). The reactive nature of cyanoacrylate monomers makes them useful adhesives. OH- from adsorbed water is believed to initiate polymerization in many applications. R in the preceding figure represents an alkyl chain. Methyl cyanoacrylate ( ) is found in commercial adhesives for nonmedical applications. Butyl cyanoacrylate is approved by the Food and Drug Administration (FDA) and is used as an injectable glue for repair of arteriovenous malformations. Microspheres and nanospheres can also be prepared by dispersion and emulsion polymerization and loaded with drugs for drug-delivery applications. Degradation is slow at neutral or acidic conditions, but above pH 7, polycyanoacrylates degrade faster. Formaldehyde is one of the degradation products (especially for methyl cyanoacrylate); therefore, there is some question as to the safety of polycyanoacrylates.34–36 Degradation rates increase with increasing alkyl chain length (R) since hydrophobicity increases with alkyl chain length. Degradation occurs at the polymer surface; therefore, surface degradation rates are highly surface area dependent. For example, poly (ethyl cyanoacrylate) microspheres37 degrade completely in PBS (pH 7.4) in 4 to 20 hours. Depending on polymerization conditions, smaller-sized poly (methyl cyanoacrylate) nanospheres degrade completely in 20 minutes in PBS at pH 7.4 and 1 hour in fetal calf serum.38 The longer alkyl chain poly (isobutyl cyanoacrylate) and poly (isohexyl cyanoacrylate)

11.28 BIOMATERIALS

FIGURE 11.13 In vitro degradation of polyglycolide. Retained tensile strength versus time. (Reproduced from D. E. Perrin and J. P. English, “Polyglycolide and polylactide,” in Handbook of Biodegradable Polymers, A. J. Domb, J. K. Kost, and D. M. Wiseman (eds.). London: Harwood Academic Publishers, 1997, p. 12.)

FIGURE 11.14 In vitro degradation of poly (L-lactide). Retained tensile strength versus time. (Reproduced from D. E. Perrin and J. P. English, “Polyglycolide and polylactide,” in Handbook of Biodegradable Polymers, A. J. Domb, J. K. Kost, and D. M. Wiseman (eds.). London: Harwood Academic Publishers, 1997, p. 12.)

BIOPOLYMERS 11.29

nanospheres take over 24 hours to degrade completely.38 Larger poly (ethyl cyanoacrylate) particles, near 100 µm in size, take weeks to degrade completely at pH 7.4 due to their small surface area compared with microspheres and nanospheres.35

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