BIOMATERIALS - Universitas Hasanuddin · 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

BIOMATERIALS

P • A • R • T • 3

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Source: STANDARD HANDBOOK OF BIOMEDICAL ENGINEERING AND DESIGN



BIOMATERIALS

11.3

CHAPTER 11

BIOPOLYMERS

Christopher Batich and Patrick LeamyUniversity of Florida, Gainesville, Florida

11.1INTRODUCTION 11.311.2POLYMER SCIENCE 11.411.3SPECIFIC POLYMERS 11.12REFERENCES 11.30

Polymers are large molecules synthesized from smaller molecules called monomers. Most polymersare organic compounds with carbon as the base element. Plastics are polymers that are rigid solids atroom temperature and generally contain additional additives. Some common plastics used in bio-medical applications are polymethyl methacrylate for intraocular lenses, braided polyethylene tereph-thalate for vascular grafts, and ultrahigh-molecular-weight polyethylene for the articulating surfacesof orthopedic implants. Polymers and biopolymers in particular encompass a much broader spectrumthan plastics alone. Biopolymers include synthetic polymers and natural polymers such as proteins,polysaccharides, and polynucleotides. This chapter will only cover the most commonly used ex-amples 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 naturallyoccurring high-molecular-weight polymer found in connective tissues and is used to protect the irisand cornea during ophthalmic surgery. Polyvinyl pyrrolidinone is a synthetic polymer used as abinder or additive in 25 percent of all Pharmaceuticals.1 Hydrogels are another class of polymers thathas many biomedical applications. Hydrogels are polymers that swell in water but retain their overallshape. They are therefore soft and moist and mimic many natural tissues. The most wellknownhydrogel series is poly(hydroxyethyl methacrylate) (PHEMA) and PHEMA copolymers, which areused in soft contact lenses.

Gelling polymers are hydrogels that can be formed in situ using chemical or physical bonding ofpolymers in solution. Alginates, for instance, are acidic polysaccharides that can be cross-linked usingdivalent cations such as calcium. Other examples of gelling polymers are the poloxamers that can gelwith an increase in temperature. Alginates are widely used in cell immobilization, and poloxamers areused as coatings to prevent postsurgical adhesions.

Elastomers are low-modulus polymers that can reversibly deform up to many times (some over500 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 usedfor a variety of catheters, soft contact lenses, and foldable intraocular lenses.

11.1 INTRODUCTION



Source: STANDARD HANDBOOK OF BIOMEDICAL ENGINEERING AND DESIGN

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 individualpolymers, including their applications and properties. The polymers are presented in the followingorder: 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 arepresented first. In fact, most polymers do not have a true elastic modulus since they are viscoelasticand 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 physiologicenvironment. No current synthetic biomaterial or biopolymer can mimic these properties effectively.Consequently, the ideal biomaterial or biopolymer performs the desired function, eventuallydisappears, and is replaced by natural tissue. Therefore, degradable polymers are of great interest tothe biomedical engineering community. Polylactides and their copolymers are currently used as bonescrews and sutures since they have good mechanical properties and degrade by hydrolysis so thatthey 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 ofthis chapter, bioerodable polymers such as polylactide are those that degrade by simple chemicalmeans, and biodegradable polymers are those that degrade with the help of enzymes. Most naturalpolymers (proteins, polysaccharides, and polynucleotides) are biodegradable, whereas most syntheticdegradable polymers are bioerodable. The most common degradation reactions for bioerodablepolymers are hydrolysis and oxidation.

Polymers are frequently classified by their synthesis mechanism as either step or chain polymers. Steppolymers are formed by step wise reactions between functional groups. Linear polymers are formedwhen each monomer has two functional groups (functionality = 2). The second type of polymeriza-tion 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 propertiesof 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 unreactedmonomers, whereas step-growth polymers have low-molecular-weight oligomers (short chains) present.

11.2 POLYMER SCIENCE

11.2.1 Polymer Synthesis and Structure



BIOPOLYMERS

BIOPOLYMERS 11.5

These low-molecular-weight species are more mobile or soluble than polymers and hence more likelyto have physiologic effects. For instance, the monomer of PMMA causes a lowering of bloodpressure and has been associated with life-threatening consequences when present (e.g., in some bonecements). Furthermore, the same polymer can be prepared by both mechanisms, leading to differentimpurities. For instance, polylactide is usually prepared by a chain-growth mechanism involving ringopening 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 thepolymer’s structure on the atomic, microscopic, and macroscopic scales. Polymers can be roughlyclassified into two different classes, thermoplastic and thermoset. Thermoplastic polymers are made ofindividual polymer chains that are held together by relatively weak van der Waals and dipole-dipoleforces. 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 andother devices. Although they often degrade or denature before melting, most proteins andpolysaccharides can be considered thermoplastics since they are made of individual chains and can bedissolved in solvents. Finally, thermoplastics can be linear or branched.

Thermosetting polymers contain cross-links between polymer chains. Cross-links are covalentbonds between chains and can be formed using monomers with functionalities of greater than 2during synthesis. Some polyurethanes and many silicones are formed using monomers withfunctionalities greater than 2. Cross-links also can be created after the polymer is formed. An exampleof this is vulcanization, which was discovered by Charles Goodyear in 1839 to toughen naturalrubber. Vulcanization uses sulfur as a cross-linking agent.

Thermosets are, in essence, one giant molecule since all the polymer chains are connected throughthe cross-links. Thermosets cannot be melted after they are formed and cannot be dissolved insolvents. 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, whichsometimes 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 percentcrystalline, but some are purely amorphous. Figure 11.3 is a simple model depicting a crystallinepolymer. Polymer chains folding over themselves form crystalline regions. Amorphous regions ofdisordered 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

FIGURE 11.1 Typical polymer molecular weight distribution.



BIOPOLYMERS

11.6 BIOMATERIALS

strength increase with crystallinity. Ductility decreases with crystallinity since polymer chains haveless room to slide past each other.

The primary requirement for crystallinity is an ordered repeating chain structure. This is whystereoregular polymers are often crystalline and their irregular counterparts are amorphous.Stereoregular polymers have an ordered stereostructure, either isotactic or syndiotactic. Isotacticpolymers have the same configuration at each stereo center, whereas configuration alternates forsyndiotactic 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 changedrastically depending on stereostructure. Syndiotactic and isotactic PP have a high degree ofcrystallinity, whereas atactic polypropylene is completely amorphous. Isotactic PP has excellent strengthand flexibility due to this regular structure and makes excellent sutures. Atactic PP is a weak, gumlikematerial. Recent advances in polymer synthesis have made available new polymers with well-controlledtacticity based on olefins. It is likely that they will find use as biomaterials in the future.

FIGURE 11.2 Schematic diagram showing different polymer structures.



BIOPOLYMERS

BIOPOLYMERS 11.7

Crystallinity plays a large role in the physical behavior of polymers. The amorphous regions playperhaps 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 andflexible at room temperature. If PMMA is heated to 105°C, it will soften, and its modulus will bereduced 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 transitiontemperature 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 transitiontemperature and melting temperature Tm occur. DTA involves heating a polymer sample along with a

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



BIOPOLYMERS

11.8 BIOMATERIALS

standard that has no phase transitions in the temperature range of interest. The ambient temperatureis increased at a regular rate, and the difference in temperature between the polymer and the standardis measured. The glass transition is endothermic; therefore, the polymer sample will be coolercompared with the standard at Tg. Similarly, melting is endothermic and will be detected as a negativetemperature compared with the standard. If the polymer were quenched from melt prior to DTAanalysis, 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 showsa schematic DTA curve for a crystalline polymer quenched for melt. A polymer that does notcrystallize would show a glass transition only, and the crystallization and melting peaks would beabsent. These measurements can be made to identify an unknown plastic or to aid in the synthesis ofnew polymers with desired changes in mechanical properties at certain temperatures.

Random copolymers have no pattern to the sequence of monomers. A random copolymer usingrepeat units A and B would be called poly(A-co-B). The term alternating copolymer is fairlyselfexplanatory with an alternating pattern of repeat units. Block copolymers consist of long-chainsegments (blocks) of single-repeat units attached to each other. Block polymers most commonlyemploy two different repeat units and contain two or three blocks. Block copolymers are namedpoly(A-b-B) or simply AB for polymers with two blocks (diblock polymer). A triblock copolymerwould be named poly(A-b-B-b-A) or simply ABA. Graft copolymers consist of a backbone with sidechains 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 randomcopolymer is poly(lactide-co-glycolide), also known as poly(lactic-co-glycolic acid) depending onthe 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 specifycopolymer type.

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

FIGURE 11.4 Stereoisomerism in polypropylene



BIOPOLYMERS

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.



BIOPOLYMERS

11.10 BIOMATERIALS

advantage of thermoplastic elastomers, unlike chemically cross-linked elastomers, is that they can bemelt or solution processed. Many polyurethanes are thermoplastic elastomers. They consist of softsegments, either a polyester or a poly ether, bonded to hard segments. The hard segments areordinarily synthesized by polymerizing diisocyanates with glycols.

Similarly, thermoplastic hydrogels can be synthesized by using a hydrophilic A block and ahydrophobic B block. Poly(ethylene oxide-b-lactides) (PEO-b-PLA) are biodegradable hydrogelpolymers that are being developed for drug-delivery applications. 2–6 PEO is a water-soluble polymerthat promotes swelling in water, and PLA is a hard, degradable polymer that acts as a physical cross-linker.

Solid polymer mechanical properties can be classified into three categories: brittle, ductile, andelastomeric (Fig. 11.7). Brittle polymers are polymers with a Tg that is much higher than roomtemperature, such as PMMA. These polymers have a high modulus and high ultimate tensile strengthbut low ductility and toughness. Ductile polymers are semicrystalline polymers such as polyethyleneand PTFE that have a Tg below room temperature for the amorphous polymer content. The crystalslend strength, but the rubbery amorphous regions offer toughness. These polymers have lowerstrength and modulus but greater toughness than brittle polymers. Elastomers have low moduli sincethey have a Tg well below room temperature, but they can return to their original shape followinghigh extensions since cross-links prevent significant polymer chain translations.

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

11.2.2 Polymer Mechanical Properties

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.)



BIOPOLYMERS

BIOPOLYMERS 11.11

For an elastic solid, stress σ is a linear function of the applied strain , and there is no strain-ratedependence. Elastic modulus E is the slope of the stress versus strain curve. An elastic material can bemodeled as a spring, whereas viscous materials can be modeled as a dashpot. For a fluid (viscousmaterial), stress is proportional to strain rate and unrelated to strain. Viscosity η is the slope ofthe stress versus strain rate curve. Figure 11.9 shows the stress/strain relationship for elastic solids andthe stress/strain-rate relationships for viscous liquids.

Polymers can exhibit both viscous and solid mechanical behavior; this phenomenon is calledviscoelasticity. For a given polymer, the degree of viscous behavior depends on temperature. BelowTg, 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.

FIGURE 11.8 Schematic diagram showing strain rate and temperaturedependence 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.)



BIOPOLYMERS

11.12 BIOMATERIALS

polymers exhibit viscoelastic behavior until theyreach their melting temperature, where they behave asliquids.

(11.3)

When designing with polymers, it is important tokeep in mind that many polymers deform over timewhen they are under a continuous load. This deforma-tion with time of loading is called creep. Ideal elasticsolids do not creep since strain (deformation) is propor-tional to stress, and there is no time dependence. Viscousmaterials (liquids) deform at a constant rate with a con-stant applied stress. Equation (11.6) describes the strainin a viscous material under constant load or stress σ.

(11.4)

(11.5)

(11.6)

Figure 11.10 shows the strain with time of con-stant stress for a viscous and elastic material. Thestress is applied at t and removed at tf. The elasticmodel shows an instantaneous deformation whenstress is applied at ti, a constant deformation with time,and then a return to its original length when the loadis removed. Therefore, the elastic solid does notcreep. The viscous (dashpot) model deforms continu-ously (creeps) from ti to tf and remains permanentlydeformed after removal of the load.

Adding spring and dashpot models in series andparallel creates viscoelastic models. Several modelshave been proposed. Figure 11.11 shows the creepbehavior for four viscoelastic models. Stress relaxationis a similar phenomenon and is defined as a reductionin stress during a constant deformation. One exampleof stress relaxation is the use of plastic washers betweena nut and bolt. After the screw is secured, the washerdeformation is constant, but the stress in the washerdiminishes with time (stress relaxation), and the screwis therefore more likely to loosen with time.

Therefore, creep and stress relaxation should beaccounted for when designing with polymers. Thestrain rate for a given application must also be knownsince modulus, ductility, and strength are strain ratedependent.

FIGURE 11.11 Creep response for (a) Maxwell model,(b) Voight-Kelvin model, and (c) four-parameter modelfor constant stress applied at t

i and removed at t

f.

FIGURE 11.10 Response of elastic model (a) and vis-cous model (b) to a constant stress applied from t

i to t

f.

(Reproduced from Encyclopedia of Materials Scienceand Engineering, ed. by M. B. Bever. Cambridge, MA: MITPress, 1986, p. 2919.)



BIOPOLYMERS

BIOPOLYMERS 11.13

Water-soluble polymers are used for a variety of applications. They can be adsorbed or covalentlybound to surfaces to make them more hydrophilic, less thrombogenic, and more lubricious. They canbe used as protective coatings to prevent damage during surgery. Hyaluronic acid solutions are usedin ophthalmic surgery to prevent damage to the cornea and iris. They can be cross-linked to formhydrogels 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 usefulexamples.

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

Poly(N-vinyl-pyrrolidinone) (or PVP) is a widely used water-soluble polymer. Similar to dextran, it hasbeen used as a plasma volume expander to replace lost blood in mass-casualty situations. PVP can alsobe used as a detoxifying agent many toxic compounds form nontoxic complexes with PVP, which thekidneys 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 makehydrophobic surfaces more hydrophilic. These hydrophilic coatings are known to drastically reducebacterial adhesion to substrates, making the surfaces antimicrobial.7–9 PEO also can be coated orgrafted 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 reticuloendothe-lial system (RES). PEO coatings help particles elude the RES, thereby increasing their residence timein the circulation.13–16

Hyaluronic Acid. Degradation: biodegradable.

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

11.3 SPECIFIC POLYMERS

11.3.1 Water-Soluble Polymers



BIOPOLYMERS

11.14 BIOMATERIALS

molecular weight, and viscosity for some commercially available HA solutions. HA is currently beinginvestigated to prevent postoperative adhesions. Since HA has many functional groups (OH, carboxy-late, acetamido), it can be cross-linked by a variety of reagents. Therefore, HA may have applicationsas 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

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.



BIOPOLYMERS

BIOPOLYMERS 11.15

occurs at the three remaining OH groups. The native form of dextran has a high molecular weightnear 5 × 108 g/mol. Dextran is depolymerized to yield a variety of molecular weights depending onthe application. Similar to polyvinyl pyrrolidinone, dextran solutions can be used as a blood plasmaextender for mass-casualty situations. Dextran of between 50,000 and 100,000 g/mol is used for thisapplication. 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 arefinding use as a magnetic resonance imaging (MRI) contrast agent. The dextran adsorbs onto theparticle 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 weightbetween 100,000 and 500,000 g/mol. Amylopectin is similar to amylose, having the same backbonestructure but with 4 percent branching. Starch is insoluble in water but can be made soluble bytreating with dilute HCl. Soluble starch has similar properties to dextran and therefore has similarapplications.

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

Poloxamers. Degradation: bioinert.

Poloxamers consist of two polyethylene oxide (PEO) blocks attached on both sides of a polypro-pylene oxide (PPO) block. The polymers are water-soluble, but increasing the temperature orconcentration can lead to gel formation. The gelling properties are a function of the polypropylenecontent and the block lengths. Figure 11.12 shows the viscosity as a function of temperature forpoloxamer 407. For a given concentration of poloxamer, the viscosity increases by several ordersof magnitude at a transition temperature. The transition temperature decreases as polymer concen-tration increases.

The unique gelling properties of poloxamers make them useful as a coating to preventpostsurgical adhesions. They can be applied as a liquid since they gel at body temperature to providea strong barrier for the prevention of adhesions. Similarly, poloxamers are being investigated for useas an injectable drug depot. Drug can be mixed with an aqueous poloxamer solution that thermally

11.3.2 Gelling Polymers



BIOPOLYMERS

11.16 BIOMATERIALS

gels in the body and provides a matrix for sustained release. Another research area for poloxamers isfor coating hydrophobic polymer microspheres. The PPO block adsorbs to the hydrophobicmicrosphere, whereas the PEO blocks extend into the solution and provide steric repulsion to preventcoagulation. The PEO blocks also prolong circulation after intravenous injection since thehydrophilic 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 anatural polysaccharide that is readily cross-linked using divalent or trivalent cations. Cross-linkingoccurs between acid groups of adjacent mannuronic acid units. Ca2+ is commonly used as acrosslinking agent. The sodium salt of alginate (sodium alginate) is used rather than the plain alginatesince the acidic alginate can be harmful to cells and tissues.

FIGURE 11.12 Viscosity of poloxamer solutions as a function of temperature and polymer concentration. (Reproducedfrom 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.)



BIOPOLYMERS

BIOPOLYMERS 11.17

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

Gelatin. Degradation: biodegradable. Gelatin is a protein prepared by hydrolyzing type I collagenusing aqueous acids or bases. Collagen is discussed further in the section on hydrogels. Hydrolysisinvolves disruption of the collagen tertiary triple helix structure and reduction of molecular weight toyield gelatin that is soluble in warm water. Following hydrolysis, gelatin is purified and dried to yielda powder. Contrary to the poloxamers, gelatin solutions (>0.5 wt %) gel with a reduction in tempera-ture. Gelatin gels melt between 23 and 30°C, and gelatin solutions set at around 2 to 5°C lower thanthe melting point. Gelatin is used as a tablet coating or capsule materials to control the release rate ofdrugs. 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 bloodwhen a clot is formed. It is a protein that first polymerizes and then cross-links during clot formationand has been isolated and used as a biological adhesive and matrix for tissue engineering. The gelformation involves mixing fibrinogen with the gelling enzyme (thrombin) and a secondcalciumcontaining solution. Speed of gellation is controlled by concentrations. Biodegradation occursfairly rapidly due to natural enzymatic activity (fibrinolysis) resulting from plasmin in tissue. Fibrinis used as a soft-tissue adhesive and is used in tissue scaffolds.

Hydrogels are materials that swell when placed in aqueous environments but maintain their overallshape. Hydrogels can be formed by cross-linking nearly any water-soluble polymer. Many naturalmaterials such as collagen and chitosan (derived from chitin) absorb significant amounts of water andcan be considered to be hydrogels. Hydrogels are compliant since the polymer chains have highmobilities due to the presence of water. Hydrogel mechanical properties are dependent on watercontent. Modulus and yield strength decrease with water content, whereas elongation tends to in-crease. Hydrogels are lubricious due to their hydrophilic nature. Hydrogels resist protein absorptionand 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 glycoldimethacrylate (which is normally present as a contaminant in the monomer). PHEMA’s hydrogelproperties such as resistance to protein adsorption and lubricity make it an ideal material for contactlenses. Hydrated PHEMA gels have good oxygen permeability, which is necessary for the health ofthe cornea. PHEMA is copolymerized with polyacrylic acid (PAA) or poly(N-vinyl pyrrolidinone) toincrease its water-absorbing capability.

11.3.3 Hydrogels



BIOPOLYMERS

11.18 BIOMATERIALS

Chitosan. Degradation: biodegradable.

Chitin is a polysaccharide that is the major component of the shells of insects and shellfish. Chitosanis 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 ofacetylation has a large influence on properties, in particular solubility. Chitin is difficult to use as abiomaterial since it is difficult to process. It cannot be melt processed and is insoluble in most aqueousand organic solutions. It is soluble only in strong acid solutions. Chitosan, on the other hand, issoluble in dilute organic acids; acetic acid is most commonly used. Chitosan has a positive charge dueto the primary amines in its structure. The positive charge is significant because most tissues arenegatively charged. Chitosan has been used for artificial skin and sutures and as a drugdeliverymatrix.18

Chitosan absorbs a significant amount of water when placed in aqueous solution. Equilibriumwater content of 48 percent was determined by immersing chitosan films in deionized water. Tensiletesting on these wet films resulted in an ultimate tensile stress of approximately 1600 psi with 70percent elongation at break.19

Collagen. Degradation: biodegradable. Collagen is the major structural protein in animals and exists insheet and fibrillar forms. Collagen fibrils consist of a triple helix of three protein chains. Type I collagenis a fibrillar form of collagen that makes up 25 percent of the protein mass of the human body. Due toits prevalence and ability to be separated from tissues, type 1 collagen is most often used in medicaldevices. Collagen fibrils are strong and biodegradable, and collagen is hemostatic, making it useful ina variety of applications. Table 11.2 shows many of the applications for collagen. Collagen is usuallyobtained from bovine corium, the lower layer of bovine hide. Bovine collagen is nonimmunogenic formost 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 acombination 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 littleuse in the preparation of materials and devices since it quickly resorbs in the moist environment ofthe 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 intomaterials and devices. Collagen cannot be melt processed and is therefore processed by evaporating



BIOPOLYMERS

BIOPOLYMERS 11.19

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 isremoved during lyophilizing. Freezing temperature controls ice crystal size, and 14-µm pores resultfrom freezing at -80°C and 100-µm pores at -30°C. Fibers and tubes are formed by extrudingcollagen 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 andto reduce degradation. Viswwanadham and Kramer21 showed that water content of untreated collagenhollow fibers (15 to 20 µm thick, 400 µm outer diameter) is a function of humidity. The absorbedwater plasticizes collagen, lowering both the modulus and yield strength. Table 11.3 summarizesthese results. Cross-linking the fibers using ultraviolet (UV) radiation increased the modulus of thefibers.21

TABLE 11.2 Medical Applications of Collagen

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



BIOPOLYMERS

11.20 BIOMATERIALS

Albumin. Degradation: biodegradable. Albumin is a globular, or soluble, protein making up 50percent of the protein content of plasma in humans. It has a molecular weight of 66,200 and contains17 disulfide bridges.22 Numerous carboxylate and amino (lysyl) groups are available for cross-linkingreactions, providing for a very broad range of mechanical behavior. Heating is also an effectivecross-linking method, as seen in ovalbumin (egg white cooking). This affords another gelling mecha-nism and is finding increasing use in laser welding of tissue, where bond strengths of 0.1 MPa havebeen achieved.23

As with collagen, the most common cross-linking agent used is glutaraldehyde, and toxicbyproducts are of concern. Careful cleaning and neutralization with glycine wash have providedbiocompatible albumin and collagen structures in a wide variety of strengths up to tough, very slowlydegradable solids. It should be noted that albumin and collagen solidification generally is differentfrom that of fibrin, which gels by a normal biological mechanism. The glutaraldehyde methods yielda variety of nonbiologic solids with highly variable mechanical properties. This has led to anextensive literature and a very wide range of properties for collagen and albumin structures, whichare used for tissue substitutes and drug-delivery vehicles.

Oxidized Cellulose. Degradation: bioerosion. Oxidized cellulose is one of the fastest-degrading poly-mers 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 disappearscompletely in 21 days when placed in phosphate-buffered saline (PBS). Similarly, it dissolves 80percent after 2 weeks in vivo. Cellulose is oxidized using nitrogen tetroxide (N2O4). Commerciallyavailable 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

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

*1 ksi = 1000 psi.



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BIOPOLYMERS 11.21

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

Silicones and polyurethanes are the two classes of elastomers used for in vivo applications. Both areversatile polymers with a wide range of mechanical properties. Polyurethanes tend to be stiffer andstronger than silicones, whereas silicones are more inert and have the advantage of beingoxygenpermeable. Polyurethanes are more versatile from a processing standpoint since many polyure-thanes 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-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. R� is a low-Tg (Tg << room temperature) polyester or polyether. Polyurethanes with polyester soft blocks aredegradable, whereas those with polyether blocks degrade very slowly. Polyurethanes are usuallyelastomers since hard and soft blocks are present. Rubbers of different hardness or durometer can beprepared by varying the ratio of R� to R�. Covalently cross-linked polymers can be prepared by usingmonomers with functionalities greater than 2. However, the most useful polyurethanes for medicalapplications 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 leadinsulation, vascular grafts, and ventricular assist device/artificial heart membranes.25 Table 11.4 showsproperties for thermoplastic polyurethane elastomers available from Cardio Tech International, Inc.These values are for the Chronoflex C series of polymers.

11.3.4 Elastomers



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11.22 BIOMATERIALS

Silicone Elastomers (Polysiloxanes). Degradation: bioinert.

Silicone elastomers are cross-linked derivatives of poly(dimethyl siloxane) (PDMS). Polysiloxaneliquids with functional endgroups such as OH or sidegroups such as can be molded at room tempera-ture and cross-linked to form elastomers using various cross-linking agents. Silicone elastomer kitsconsisting of the polysiloxane precursor liquids and cross-linking agents are commercially availablefrom corporations such as GE Bayer Silicones (Table 11.5). Silicones crosslinked at room temperatureare called room-temperature vulcanized (RTV) elastomers, and those requiring elevated temperaturesare called heat-cured silicone elastomers.

Silicones are more flexible and of lower strength than polyurethanes. However, they are morechemically 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 formembrane oxygenators and soft contact lenses.26

Most bioinert rigid polymers are commodity plastics developed for nonmedical applications. Due totheir 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 elasticmodulus. Polymers such as the nylons and polyethylene terephthalate) slowly degrade by hydrolysisof the polymer backbone. However, they are considered bioinert since a significant decrease inproperties 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.

11.3.5 Rigid Polymers

TABLE 11.4 Properties of Chronoflex Thermoplastic Polyurethanes Available from CardioTech



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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

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

*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.



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11.24 BIOMATERIALS

Cellulose. Degradation: bioinert.

Cellulose is a partially crystalline polysaccharide and is the chief constituent of plant fiber. Cotton isthe purest natural form of cellulose, containing 90 percent cellulose. Cellulose decomposes beforemelting and therefore cannot be melt processed. It is insoluble in organics and water and can only bedissolved in strong basic solutions. Regenerated cellulose, also known as rayon, is cellulose that hasbeen precipitated form a basic solution. Cellulose is used in bandages and sutures. Cuprophan iscellulose 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 areused 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-carbonsequences. Nylon is tough, abrasion resistant, and has a low coefficient of friction, making it a popularsuture material.27 Nylon 6,6 is hydrophilic and absorbs water when placed in tissues or in humid environ-ments (9 to 11 percent water when fully saturated28). Absorbed water acts as a plasticiser, increasing theductility and reducing the modulus of Nylon 6,6. Nylon bioerodes at a very slow rate. Nylon 6,6implanted 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 lowermelting temperature and its properties are more moisture-sensitive.



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BIOPOLYMERS 11.25

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

Poly(ethylene terephthalate) (PET), also known simply as polyester or Dacron, is a rigid semicrystal-line polymer. It is widely used as a material for woven large-diameter vascular grafts. PET is usuallyconsidered 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, transparentmaterial with a refractive index of 1.5 and is therefore used for intraocular lenses and hard contactlenses. 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 monomeror monomer-polymer syrup and polymerizing can also form PMMA. PMMA plates, commonlyknown 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 largeinflammatory 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 athermoplastic and can be melt processed.

Polypropylene (PP). Degradation: bioinert.

Commercial polypropylene is isotactic since atactic polypropylene has poor mechanical propertiesand 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 iscommonly 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 aretypically not used in vivo since they cannot be autoclaved. HDPE can be autoclaved and is used in



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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 hipprosthesis. 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 pointand, 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 andlow coefficient of friction. Expanded PTFE (ePTFE) contains micropores created by stretching PTFEfilm 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 meltprocessed, PTFE is formed by pressing PTFE powder, followed by heating to sinter the powder, or itis 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) andhexafluoropropylene (HFP). FEP has similar properties to PTFE, but its lower melting temperature of275°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 arepopular since they have good mechanical properties and degrade to nontoxic metabolites (glycolic orlactic acid). Polylactide, polyglycolide, and copolymers of the two find clinical use in degradablesutures and orthopedic pins and screws. Recent research has focused on their use as a drug-deliverymatrix since sustained release of drugs can be achieved as the materials degrade. Drug-deliverymatrices include monoliths and microspheres. Microspheres are routinely prepared by dissolution ofpolymer and drug in chloroform (or dichloromethane), suspension in aqueous poly vinyl alcohol (toform an oil-in-water emulsion), and evaporation to form drug-entrapped microspheres ornanospheres. Primarily stirring speed and polymer-drug concentration in the oil phase (chloroform ordichloromethane solution) control sphere size.

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



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BIOPOLYMERS 11.27

amorphous poly (DL-lactide). Similarly, the crystalline poly(L-lactide) degrades completely in vivoin 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 similarmechanical properties and degradation rates as poly (DL-lactide). Pure poly glycolide is very strongand 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 and11.14 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 directcondensation of lactic and glycolic acid. Although it is rare, synthesis of polylactic and glycolic acidscan be achieved by direct condensation, but this results in a low-molecular-weight polymer (on theorder 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 fromcaprolactone using stannous octoate in a similar manner to polylactide or polyglycolide. PCL has avery low modulus of around 50 ksi since it has a low Tg of -60°C. PCL degrades very slowly, andtherefore, it is usually not used as a homopolymer. Caprolactone, however, is copolymerized withglycolide 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 onlyanions 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 wateris believed to initiate polymerization in many applications. R in the preceding figure represents an alkylchain. 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 aninjectable glue for repair of arteriovenous malformations. Microspheres and nanospheres can also beprepared by dispersion and emulsion polymerization and loaded with drugs for drug-delivery applica-tions.

Degradation is slow at neutral or acidic conditions, but above pH 7, polycyanoacrylates degradefaster. 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 increasewith increasing alkyl chain length (R) since hydrophobicity increases with alkyl chain length.Degradation occurs at the polymer surface; therefore, surface degradation rates are highly surfacearea 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 (methylcyanoacrylate) nanospheres degrade completely in 20 minutes in PBS at pH 7.4 and 1 hour in fetalcalf serum.38 The longer alkyl chain poly (isobutyl cyanoacrylate) and poly (isohexyl cyanoacrylate)



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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 Handbookof Biodegradable Polymers, A. J. Domb, J. K. Kost, and D. M. Wiseman (eds.). London: HarwoodAcademic 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 Handbookof Biodegradable Polymers, A. J. Domb, J. K. Kost, and D. M. Wiseman (eds.). London: HarwoodAcademic Publishers, 1997, p. 12.)



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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 areacompared with microspheres and nanospheres.35

1. Encyclopedia of Polymer Science and Engineering, vol. 17. New York: Wiley, 1985, pp. 198–257.

2. Chen, X. H., S. P. McCarthy, and R. A. Gross, “Synthesis and characterization of [L]-lactide-ethylene oxide multiblockcopolymers,” Macromolecules, 30(15):4295–4301 (1997).

3. Cohn, D., and H. Younes, “Biodegradable Peo/Pla block copolymers,” Journal of Biomedical Materials Research,22(11):993–1009 (1988).

4. Hu, D. S. G., and H. J. Liu, “Structural analysis and degradation behavior in polyethylene-glycol poly (L-lactide) copoly-mers,” Journal of Applied Polymer Science, 51(3):473–482 (1994).

5. Li, Y. X., and T. Kissel, “Synthesis and properties of biodegradable aba triblock copolymers consisting of poly(L-lactic acid)or poly(L-lactic-co-glycolic acid) a-blocks attached to central poly(oxyethylene) b-blocks,” Journal of Controlled Re-lease, 27(3):247–257 (1993).

6. Yamaoka, T., et al., “Synthesis and properties of multiblock copolymers consisting of poly(L-lactic acid) andpoly(oxypropylene-co-oxyethylene) prepared by direct poly condensation,” Journal of Polymer Science [A], 37(10):1513–1521 (1999).

7. Razatos, A., et al., “Force measurements between bacteria and poly(ethylene glycol)-coated surfaces,” Langmuir,16(24):9155–9158 (2000).

8. Vigo, T. L., and K. K. Leonas, “Antimicrobial activity of fabrics containing cross-linked polyethylene glycols,” TextileChemist and Colorist & American Dyestuff Reporter, 1(1):42–46 (1999).

9. Park, K. D., et al., “Bacterial adhesion on PEG modified polyurethane surfaces,” Biomaterials, 19(7–9): 851–859 (1998).

10. Guo, Y. Q., and S. W. Hui, “Poly(ethylene glycol)-conjugated surfactants promote or inhibit aggregation of phospholipids,”Biochimica et Biophysica Acta, 1323(2):185–194 (1997).

11. Slepushkin, V. A., et al., “Sterically stabilized pH-sensitive liposomes: Intracellular delivery of aqueous contents andprolonged circulation in vivo,” Journal of Biological Chemistry, 272(4):2382–2388 (1997).

12. Woodle, M. C., M. S. Newman, and J. A. Cohen, “Sterically stabilized liposomes: Physical and biological properties,”Journal of Drug Targeting, 2(5):397–403 (1994).

13. Dunn, S. E., et al., “Polystyrene-poly(ethylene glycol) (PS-PEG 2000) particles as model systems for sitespecific drug-delivery: 2. The effect of PEG surface-density on the in vitro cell-interaction and in vivo biodistribution,” PharmaceuticalResearch, 11(7):1016–1022 (1994).

14. Verrecchia, T., et al., “Non-stealth (poly(lactic acid albumin)) and stealth (poly(lactic acid-polyethylene glycol))nanoparticles as injectable drug carriers,” Journal of Controlled Release, 36(1–2):49–61 (1995).

15. Maruyama, K., et al., “Immunoliposomes bearing polyethyleneglycol-coupled Fab� fragment show prolonged circulationtime and high extravasation into targeted solid tumors in vivo,” FEBS Letters, 413(1): 177–180 (1997).

16. Vittaz, M., et al., “Effect of PEO surface density on long-circulating PLA-PEO nanoparticles which are very low complementactivators,” Biomaterials, 17(16):1575–1581 (1996).

17. Kost, J., and R. Goldbart, “Natural and modified polysaccharides,” in Handbook of Biodegradable Polymers, A. J. Domb, J.Kost, and M. W. Wiseman (eds.) London: Harwood Academic Publishers, 1997, pp. 285–286.

18. Kost, J., and R. Goldbart, “Natural and modified polysaccharides,” in Handbook of Biodegradable Polymers, A. J. Domb, J.Kost, and M. W. Wiseman (eds.). London: Harwood Academic Publishers, 1997, pp. 282–284.

19. Qurashi, M. T., H. S. Blair, and S. J. Allen, “Studies on modified chitosan membranes; 1. Preparation and characterization,”Journal of Applied Polymer Science, 46(2):255–261 (1992).

20. Silver, F. H., and A. K. Garg, “Collagen: Characterization, processing, and medical applications,” in Handbook of Biodegrad-able Polymers, A. J. Domb, J. Kost, and M. W. Wiseman (eds.) London: Harwood Academic Publishers, 1997, pp. 319–346.

21. Viswanadham, R. K., and E. J. Kramer, “Elastic properties of reconstituted collagen hollow fiber membranes,” Journal ofMaterials Science, 11(7):1254–1262 (1976).

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22. Mathews, C., and K. Holde, Biochemistry. San Francisco: Benjamin Cummings, 1990, p. 578.

23. Chivers, R., “In vitro tissue welding using albumin solder: Bond strengths and bonding temperatures,” InternationalJournal of Adhesion and Adhesives, 20:179–187 (2000).

24. Stillwell, R. L., et al., “Oxidized cellulose: Chemistry, processing and medical applications,” in Handbook of BiodegradablePolymers, A. J. Domb, J. Kost, and M. W. Wiseman (eds.). London: Harwood Academic Publishers, 1997, pp. 291–306.

25. Ratner, B. D., et al. (eds.), Biomaterials Science: An Introduction to Materials in Medicine. New York: Academic Press, 1996,p. 60.


27. Encyclopedia of Polymer Science and Engineering, Vol. 11. New York: Wiley, 1985, pp. 315–381.


29. Zaikov, G. E. “ Quantitative aspects of polymer degradation in the living body,” Journal of Macromolecular Science-Reviewsin Macromolecular Chemistry and Physics, C25(4):551–597 (1985).

30. Ratner, B. D. et al. (eds.), Biomaterials Science: An Introduction to Materials in Medicine. New York: Academic Press, 1996,p. 58.

31. Encyclopedia of Polymer Science and Engineering, Vol. 17. New York: Wiley, 1985, pp. 577–647.

32. Perrin, D. E., and J. P. English, “Polyglycolide and polylactide,” in Handbook of Biodegradable Polymers, A. J. Domb, J. Kost,and M. W. Wiseman (eds.). London: Harwood Academic Publishers, 1997, pp. 2–27.

33. Perrin, D. E., and J. P. English, “Polycaprolactone,” in Handbook of Biodegradable Polymers, A. J. Domb, J. Kost, and M. W.Wiseman (eds.). London: Harwood Academic Publishers, 1997, pp. 63–77.

34. Wade, C., and F. Leonard, “Degradation of poly(methyl 2-cyanoacrylates),” Journal of Biomedical Materials Research,6:215–220 (1992).

35. Vezin, W. R., and T. Florence, “In vitro heterogenious degradation of poly(n-alkyl α-cyanoacrylates),” Journal of BiomedicalMaterials Research, 14:93–106 (1980).

36. Leonard, F., et al., “Synthesis and degradation of poly(alkyl α-cyanoacrylates),” Journal of Applied Polymer Science,10:259–272 (1966).

37. Tuncel, A., et al., “Monosize poly(ethylcyanoacrylate) microspheres: Preparation and degradation properties,” Journal ofBiomedical Materials Research, 29:721–728 (1995).

38. Muller, R. H., et al., “In vitro model for the degradation of alkylcyanoacrylate nanoparticles,” Biomaterials, 11:590–595(1990).



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BIOMATERIALS - Universitas Hasanuddin · 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