biodegradable polymers, medical applications

Vol. 5 BIODEGRADABLE POLYMERS, MEDICAL APPLICATIONS 263

BIODEGRADABLE POLYMERS,MEDICAL APPLICATIONSIntroduction

Traditional applications of synthetic polymers are mostly based on theirrelative inertness to biodegradation compared with natural macromolecules,such as cellulose, and proteins. Biodegradation of the polymers can occurin several ways including photodegradation, oxidation, and hydrolysis. Prac-tically, biodegradation involves enzymatically promoted breakdown caused byliving organisms, usually microorganisms, but it is now well accepted thatthe biodegradation can occur by hydrolysis, oxidation, or photooxidation ina biological environment. These polymers have been used in many aspectsof life, eg, in environmentally friendly packaging materials (1,2), agricul-ture (3,4), drug delivery (5,6), gene delivery (7,8), and tissue engineering(9,10). (See CONTROLLED RELEASE TECHNOLOGY; ENVIRONMENTALLY DEGRADABLEPOLYMERS; GENE-DELIVERY POLYMERS; TISSUE ENGINEERING). This article empha-sizes the various biodegradable polymers obtained either synthetically or fromnatural resources and their uses for biomedical applications.

Factors Affecting Biodegradation

Effect of Polymer Structures. Synthetic biodegradable polymers containhydrolyzable linkages along the polymer chain; for example, amide enamine, ester,phosphate, phosphazene, carbonate, anhydride, urea, and urethane linkages aresusceptible to biodegradation by microorganisms and hydrolytic enzymes. In ad-dition, polymers containing substituents such as benzyl, hydroxy, carboxy, methyl,and phenyl groups have been prepared in the hope that an introduction of these

Encyclopedia of Polymer Science and Technology. Copyright John Wiley & Sons, Inc. All rights reserved.

264 BIODEGRADABLE POLYMERS, MEDICAL APPLICATIONS Vol. 5

substituents might increase biodegradability (11). Among benzylated polymers,mixed results have been obtained for polyamides. Since most enzyme-catalyzedreactions occur in aqueous media, the hydrophilichydrophobic character of syn-thetic polymers greatly affects their biodegradability. A polymer containing bothhydrophobic and hydrophilic segments seems to have a higher biodegradabilitythan those polymers containing either hydrophobic or hydrophilic structures only.A series of poly(alkylene tartrate)s was found to be readily assimilated by As-pergillus niger. However, the polymers derived from C6 and C8 alkane diols weremore degradable than the more hydrophilic polymers derived from C2 and C4alkane diols or the more hydrophobic polymers derived from the C10 and C12alkane diols. Among the degradable poly(-aminoacid-co--caproic acid)s, the hy-drophilic copolyamide derived from serine was more susceptible than those con-taining only hydrophobic segments. For a synthetic polymer to be degradable byenzyme catalysis, the polymer chain must be exible enough to t into the activesite of the enzyme. This aspect most likely accounts for the fact that while the ex-ible aliphatic polyesters are readily degraded by biological systems, the more rigidaromatic poly(ethylene terephthalate) is generally considered to be inert (12).

Effect of Polymer Morphology. Selective chemical degradation ofsemicrystalline polymer samples shows certain characteristic changes (1316).During degradation, the crystallinity of the sample increases rapidly at rst andthen levels off to a much slower rate as the crystallinity approaches 100%. Thiseffect is attributed to the eventual disappearance of the amorphous portions ofthe sample. The effect of morphology on the microbial and enzymatic degradationof poly(-caprolactone) (PCL), a known biodegradable polymer with a number ofpotential applications, has been studied (17,18). Scanning electronmicroscopy hasshown that the degradation of a partially crystalline polycaprolactone lm by la-mentous fungi proceeds in a selective manner, with the amorphous regions beingdegraded prior to the degradation of the crystalline region. The microorganismsproduce extracellular enzymes responsible for the selective degradation. This se-lectivity can be attributed to the less-ordered packing of amorphous regions, whichpermits easier access for the enzyme to the polymer chains. The size, shape, andnumber of crystallites all have a pronounced effect on the chain mobility of theamorphous regions and thus affect the rate of degradation. This effect has beendemonstrated by studying the effects of changing orientation via stretching on thedegradation (17,18).

Degradation in biological medium, cells, tissues, and body uids proceedsdifferently from chemical degradation as enzymes, biological reagents in the cellorganelles, and uids are involved in the degradation process. Enzyme is able todegrade the crystalline regions faster than hydrolysis. The enzyme system showsno intermediate molecular weight material but shows a much smaller weight shiftwith degradation as compared to chemical degradation. This shift indicates thatalthough degradation is selective, the crystalline portions are degraded shortlyafter the chain ends are made available to the exoenzyme. The lateral size of thecrystallites has a strong effect on the rate of degradation because the edge of thecrystal is where degradation of the crystalline material takes place, because ofthe crystal packing. A smaller lateral crystallite size yields a higher crystalliteedge surface in the bulk polymer. Prior to the saturation of the enzyme active


sites, the rate is dependent on available substrate; therefore, a smaller lateralcrystallite size results in a higher rate of degradation. The degradation rate of aPCL lm is zero order with respect to the total polymer, but is not zero order withrespect to the concentrations of the crystallite edge material. The drawing of PCLlms causes an increase in the rate of degradation, whereas annealing of the PCLcauses a decrease in the rate of degradation (19). This phenomenon is probablydue to opposite changes in lateral crystallite sizes. in vitro chemical and enzymaticdegradations of polymers, especially polyesters, were analyzed with respect tochemical composition and physical properties. It was found quite often that thecomposition of a copolymer giving the lowest melting point is most susceptibleto degradation (19). The lowest packing order, as expected, corresponds with thefastest degradation rate.

Effect of Molecular Weight. Microorganisms produce both exoenzymes,which degrade polymers from terminal groups, and endoenzymes, which degradepolymers randomly along the chain. One might expect a large molecular effect onthe rate of degradation in the ease of exoenzymes and a relatively small molecu-lar weight effect in the case of endoenzymes. Low molecular weight hydrocarbons,however, can be degraded by microbes. They are taken in by microbial cells, acti-vated by attachment to coenzyme A, and converted to cellular metabolites withinthe microbial cell. However, these processes do not function well (if at all) in anextracellular environment, and the plastic molecules are too large to enter thecell. This problem does not arise with natural molecules, such as starch and cel-lulose, because conversions to low molecular weight components by enzyme reac-tions occur outside the microbial cell. Photodegradation or chemical degradationmay decrease molecular weight to the point that microbial attack can proceed. Hy-drolytic degradation of polyesters and polyanhydrides is affected by the molecularweight as a result of differences in water accessibility to large molecular weightpolymeric materials.

Effect of Radiation and Chemical Treatment. Photodegradation withUV light and the -irradiation of polymers generate radicals and/or ions that oftenlead to cleavage and cross-linking. Oxidation also occurs, complicating the situ-ation, since exposure to light is seldom in the absence of oxygen. Generally thischanges the materials susceptibility to biodegradation. Initially, one expects theobserved rate of degradation to increase until most of the fragmented polymer isconsumed and a slower rate of degradation should follow for the cross-linked por-tion of the polymer. Similarly, photooxidation of polyalkenes promotes (slightly inmost cases) the biodegradation (20). The formation of carbonyl and ester groupsis responsible for this change. Processes have been developed to prepare copoly-mers of alkenes containing carbonyl groups so that they will be more susceptibleto photolytic cleavage prior to degradation. As expected, -ray irradiation greatlyaffects the rate of in vitro degradation of polyesters (21,22). For polyglycolide andpoly(glycolide-co-lactide), the pH of the degradation solution decreased as the pro-cess proceeded. The changetime curves exhibit sigmoidal shapes and consist ofthree stages: early, accelerated, and later; the lengths of these three regions werea function of -irradiation. Increasing radiation dosage shortens the time of theearly stage. The appearance of the drastic pH changes coincides with loss of tensilebreaking strength.


Classication

On the basis of the formation, biodegradable polymers can be classied into twogroups including synthetic biodegradable polymers and natural biodegradablepolymers.

Synthetic Biodegradable Polymers. A representive list of syntheticbiodegradable polymers is given in Table 1, which includes chemical backbonestructures of these polymers. These polymers can be catagorized into two typeson the basis of their backbone structures, namely (1) polymers with hydrolyzablebackbone and (2) polymers with carbon backbone.

Polyester. Polyesters having hydrolyzable ester bond in their backbone areconsidered the best biomaterial with regard to design and performance. Amongpolyesters, poly(lactic acid) (PLA) can be made of the lactic acid monomers whichcontain an asymmetric -carbon atom with three different isomers as D-, L-, andDL-lactic acid (see POLYLACTIDE). The physiochemical properties of optically ac-tive homopolymers poly(D-lactic acid) (PDLA) or poly(L-lactic acid) (PLLA) are thesame, whereas the racemic PLA has very different characteristics (25). RacemicPLA and PLLA have glass-transition temperatures (Tgs) of 57 and 56C respec-tively, but PLLA is highly crystalline with a melting temperature (Tm) of 170C;racemic PLA is purely amorphous. The polymer characteristics are affected bythe comonomer composition, the polymer architecture, and molecular weight (26).The crystallinity of the polymer, an important factor in polymer biodegradation,varies with the stereoregularity of the polymer. Sterilization using -irradiationdecreases the polymer molecular weight by 3040% (26). The irradiated polymerscontinue to decrease in molecular weight during storage at room temperature.This decline in molecular weight affects the mechanical properties and the re-lease rate from the polymers. PLA and its copolymers with less than 50% gly-colic acid content soluble in common solvents such as chlorinated hydrocarbons,tetrahydrofuran, and ethyl acetate. Poly(glycolic acid) (PGA) is insoluble in com-mon solvents but in hexauoroisopropanol and hexauoroacetone sesquihydrate(HFASH). In its highly crystalline form, PGA has a very high tensile strengthof 69138 MPa (10,00020,000 psi) and modulus of elasticity of about 6900 MPa(1,000,000 psi). The solubility parameters were in the range of 16.2 and 16.8,which are comparable to those of polystyrene and polyisoprene (27).

A comparison study on the physicomechanical properties of severalbiodegradable polyesters was reported (28). The thermal properties, tensile prop-erties, and the exural storage modulus as a function of temperature were deter-mined. The following polymers were compared: poly(L-lactic acid), poly(DL-lacticacid), poly(glycolic acid), poly(-caprolactone), poly(hydroxybutyrate) and copoly-mers with hydroxyvaleric acid, and poly(trimethylene carbonate). The thermaland mechanical properties of several of the polymers tested are summarized inTable 2 (28). A comprehensive review on the mechanical properties of severalbiodegradable materials used in orthopedic devices has been published (29). Thetensile and exural strength and modulus, as well as the biodegradation of vari-ous lactide/glycolide polymers, poly(orthoester), and polycaprolactone have beensummarized in a tabular or diagram format.

Polycaprolactone. Poly(-caprolactones) (PCL) are synthesized by ring-opening polymerization of -caprolactones and are soluble in chlorinated and


Table 1. Examples of Synthetic Biodegradable Polymersa

Structure Name

Polyesters

O

O

n

Poly(glycolic acid) (PGA)

O

O

n

Poly(lactic acid) (PLA)

O

n

O

Poly(-caprolactone) (PCL)

O

O

n

Poly(-hydroxybutyrate)

nHO

OO

OH

O

O Poly(propylene-fumarate)

OO

O

O

x y

Poly(lactide-glycolide)

OO

O

O

x

O

y

Poly(p-dioxane-co-glycolide)

OO

Ox y

O

O Poly(p-dioxane-co-caprolactone)

Poly(orthoesters)

OO OR

m

Poly(orthoester) I

O

OCH2

OCH2

CH2O

CH2O O

m

Poly(orthoester) II

OC

O

O

R

Rm

Poly(orthoester) III


Table 1. (continued)Structure Name

Other polyesters

O O

On

Poly(1,5-dioxipan-2-one)

ONH

O

O

OHN

O

Ox y

n

Poly(ester amide)

O P

R

O

O

m

Polyphosphate ester

Polyphosphazenes

O

P

O

Nm

Poly(aryloxyphosphazene)

N PO

O

OO

OO

m

Poly(PEG-phosphazene)

Amino acid derived polymers

HN

O

Rm

Poly(amino acid)

HN

O

m

Polyleucine

HN

NH2

O

m

Polylysine



HN

O

HO O

m

Poly(glutamic acid)

Polyanhydrides

O

O

O

m

Poly(fumaric acid)

O

O

O

OO O

x

m

y

Poly(terephthalic-co-isophthalic acid)

OO

O

O CH3

Ox

m

y

Block-poly(sebacicanhydride)-co-poly(lacticacid)

Polysaccharides

O

CH2

OOH

O

O

OH

OH

OHOH

OHO

O

OH

OH

OH

m

Pullulan

O

OOH

O

O

OH

OHOH

OHO

O

OH

OH

OH

m

OH Elsinan

O O

OH

NH2NH2

OH

m

OH

OH O O

Chitosan

OCH2

OH

OO

OH OH

O

OH

OHOH

m

Levan



Polyurethanes

RNH

O

O

n

Poly(urethanes)

Poly(amide-amines)

RNH

O H

N

n

Poly(amide-enamines)

Natural polypeptides

HN

R

O

m

A plasma glycoprotein belonging structurally to thekeratinmyosin group. Synthesized and secreted byhepatic parenchymal cells. Essential to the clottingof blood. The molecular weight is 340,000. Soluble,but forms an insoluble gel on conversion to brin.Fibrin monomer is brinogen from which one or twopeptides have been removed by means of thrombin.

Fibrinogen

Polypeptide substance comprising one third of the totalprotein in mammalian organisms; main constituentof skin, connective tissue, and the organic substanceof bones and teeth. Different types of collagens exist.

Collagen (qv)

A heterogeneous mixture of water-soluble proteins ofhigh average molecular weight. Derived fromcollagen. Swells up in water to form a gel/insolublein organic solvents.

Gelatin (qv)

aThe structures of polymers and description of their properties and applications can be found in eitherRef. 23 or Ref. 24.

aromatic hydrocarbons, cyclohexanone, and 2-nitropropane but insoluble inaliphatic hydrocarbons, diethyl ether, and alcohols (30). The homopolymer of PCLmelts at 5964C with a Tg of 60C. Copolymerization with lactide increases theTg with the increase in the lactide content in the polymer (31). The crystallinityof the polymer decreases with the increase in polymer molecular weight; polymerof weight 5000 is 80% crystalline whereas the polymer of weight 60,000 is 45%crystalline (32).

Tokiwa and Suzuki (33) have discussed the hydrolysis and biodegradation ofPCL by fungi, and have shown that PCL can be degraded enzymatically. Blends ofPCL and polyesters prepared from alkanediols and alkane dicarboxylic acids withnatural substances such as tree bark have been molded into shaped containersfor horticultural seeding plantouts (34). After 3 months of soil burial, the PCL


Table 2. Thermal and Mechanical Properties of Biodegradable Polyestersa

ElongationTensile TensileTg, Tm, strength, modulus, Yield, Break,

Polymer Mw C C MPab MPab % %

Poly(lactic acid)L-PLA 50,000 54 170 28 1200 3.7 6.0L-PLA 100,000 58 159 50 2700 2.6 3.3L-PLA 300,000 59 178 48 3000 1.8 2.0DL-PLA 107,000 51 29 1900 4.0 5.0Poly(glycolic acid) (PGA) 50,000 35 210 NA NA NA NAPoly(-hydroxybutyrate)PHB 370,000 1 171 36 2500 2.2 2.5P(HB-11%HV) 529,000 2 145 20 1100 5.5 17Poly(-caprolactone) (PCL) 44,000 62 57 16 400 7.0 80Poly(trimethylenecarbonate) PTC

48,000 15 0.5 3 20 160

Poly(orthoesters)t-CDM:1,6-HDc (35:65) 99,000 55 20 820 4.1 220t-CDM:1,6-HDc (70:30) 101,000 84 19 800 4.1 180aTaken from Ref. 28.bTo convert MPa to psi, multiply by 145.ct-CDM: 1,6-HD=trans-cyclohexane dimethanol: 1,6-hexanediol.

containers were found to be embrittled, disintegrated, and biodegraded, whichsuggests that the extracellular enzymes in the soil may cleave the polymer chainprior to the assimilation of the polymer by microorganisms.

Poly(-hydroxybutyrate). Poly(-hydroxybutyrate) (PHB) is made by a con-trolled bacterial fermentation (see POLY(3-HYDROXYALKANOATES). The producingorganism occurs naturally. An optically active copolymer of 3-hydroxybutyrate(3HB) and 3-hydroxyvalerate (3HV) has been produced from propionic acid orpentanoic acid by Alcaligenes eutrophus. PHB is characterized as having a highmolecular weight (>100,000, [] > 3 dL/g) with a narrow polydispersity and acrystallinity of around 50%. The melting point depends on the polymer composi-tion; P(3HB) homopolymer melts at 177C with a Tg at 9C, the 91:9 copolymerwith 4HB melts at 159C, and the 1:1 copolymer with 3HV melts at 91C. ThePHB properties in the living cells of A. eutrophus were determined using X-rayand variable-temperature 13C NMR relaxation studies (35). PHB is an amorphouselastomer with a Tg around 40C in its native state within the granules. Thebiodegradation of these polymers in soil and activated sludge show the rate ofdegradation to be in the following order (36):

P(3HBco9%4HB)>P(3HB) = P(3HBco50%3HV)

Microspheres degraded slowly in phosphate buffer at 85C and after5 months, 2040% of the polymer eroded under these conditions. Copolymershaving a higher fraction of 3HV and low molecular weight polymers were moresusceptible to hydrolysis (36).


Poly(phosphoesters). Poly(phosphoesters) are synthesized from the reac-tion of ethyl or phenyl phosphorodichloridates and various dialcohols includingbisphenol A and poly(ethylene glycol) of various molecular weights (37). Leongand co-workers (38) have incorporated phosphoester groups into poly(urethanes).Poly(urethanes) have been used as blood-contacting biomaterials because of theirhaving a broad range of physical properties: from hard and brittle to soft and tacky(38). Leong and co-workers has designed inert biomaterial for controlled releaseapplication by introducing phosphoester linkage in poly(urethane) (38). Introduc-tion of phosphoester linkage does not change the mechanical properties inherentin the poly(urethanes) and provides excellent biodegradable materials.

Polycarbonates. Polycarbonates are synthesized from the reaction of dihy-droxy compounds with phosgene or with bischloroformates of aliphatic dihydroxycompounds by transesterication, and by polymerization of cyclic carbonates (39).These polymers have been synthesized from carbon dioxide and the correspondingepoxides in the presence of organometallic compounds as initiators. Poly(ethylenecarbonate) and poly(propylene carbonate) are linear thermoplastic polyesters ofcarbonic acid with aliphatic dihydroxy compounds (39). Poly(dihydropyrans) weredeveloped for contraceptive delivery. The in vivo and in vitro release of contra-ceptive steroids and antimalarial agents from polymer matrices has been studied.Poly(p-dioxanone) is clinically used as an alternative to poly(lactide) in absorbablesutureswith similar properties to poly(lactide) with the advantage of better irradi-ation stability during sterilization (40). This polymer has not yet been developedas a carrier for controlled drug delivery. Biodegradable polymers derived fromnaturally occurring, multifunctional hydroxy acids and amino acid have been in-vestigated by Lenz and Guerin (41).

Poly(amides). The utilization of amide-based polymers, especially naturalproteins, in the preparation of biodegradable matrices have been extensively in-vestigated in recent years (42). Microcapsules and microspheres of cross-linkedcollagen, gelatin, and albumin have been used for dug delivery (43). The syntheticability to manipulate amino acid sequences has seen its maturity over the lasttwo decades with new techniques and strategies continually being introduced.

Poly(amides) such as poly(glutamic acid) and poly(lysine) and their copoly-mers with various amino acids have also been studied as drug carriers (41,44,45).Pseudopoly(amino acids), prepared from N-protected trans-4-hydroxy-L-proline,and poly(iminocarbonate) from tyrosine dipeptide as monomeric starting mate-rial have been reported (4648). The properties, biodegradability, drug release,and biocompatibility of this class of polymers have been reviewed (42,46).

Polyphosphazenes. The polymers are most commonly synthesized by asubstitution reaction of the reactive poly(dichlorophosphazene) with a wide rangeof reactive nucleophiles such as amines, alkoxides, and organometallic molecules.The reaction is carried out in general at room temperature in tetrahydrofuran oraromatic hydrocarbon solutions (49). Two different types of polyphosphazenes areof interest as bioinert materials: those with strongly hydrophobic surface charac-teristics and those with hydrophilic surfaces. Polycarbonates (qv) bearing uo-roalkoxy side groups are some of the most hydrophobic synthetic polymers known(50,51). Such polymers are as hydrophobic as poly(tetrauoroethylene) (Teon),but unlike Teon, polyphosphazenes of this type are exible or elastomeric, easyto prepare, and they can be used as coatings for other materials.


The uniqueness of the polyphosphazenes stems from its inorganic backbone(N P) which with certain organic side groups can be hydrolyzed to phosphate andammonia. Several polymer structures have been used as matrix carriers for drugs(51) or as a hydrolyzable polymeric drug, where the drug is covalently bound tothe polymer backbone and released from the polymer by hydrolysis (52). A com-prehensive review on the synthesis, characterization, and medical applications ofpolyphosphazenes was published (53).

Poly(orthoesters). Poly(orthoesters) were rst designated as Chronomerand later as Alzamer (54). They were prepared by a transesterication reaction.Themolecularweight of poly(orthoesters)were signicantly dependent on the typeof diol and catalyst used for synthesis. A linear, exible diol like 1,6-hexanediolgave molecular weights greater than 200 kDa, whereas bisphenol A in the pres-ence of catalyst gave molecular weights around only 10,000 kDa (55). Mechanicalproperties of the linear poly(orthesters) can be varied over a large range by select-ing various compositions of diols. It was shown that theTg of the polymer preparedfrom 3,9-diethylidene-2,4,8,10-tetraoxaspiro[5,5]undecane can be varied from 25to 110C by simply changing the amount of 1,6-hexanediol in trans-1,4 cyclohex-ane dimethanol from 100% to 0% (29). A linearly decreasing relationship betweenthe Tg and percentage of 1,6 hexanediol is observed. One could take advantage ofthe above relationship in selecting the polymer for in vivo applications because invivo the Tg of the polymer would drop because of the inhibition of water, resultingin the loss of stiffness and rigidity of the polymer.

Polyanhydrides. The majority of the polyanhydrides (qv) are prepared bymelt polycondensation. The sequence of reaction involves rst the conversionof a dicarboxylic acid monomer into a prepolymer consisting of a mixed anhy-dride of the diacid with acetic anhydride. This is achieved by simply reuxingthe diacid monomer with acetic anhydride for a specied length of time. Thepolymer is obtained subsequently by heating the prepolymer in vacuo to elimi-nate the acetic anhydride (56). Almost all polyanhydrides show some degree ofcrystallinity as manifested by their crystalline melting points. An in-depth X-raydiffraction analysis was conducted with the homopolymers of sebacic acid (SA),bis(carboxyphenoxy)propane (CPP), bis(carboxyphenoxy)hexane (CPH), and fu-maric acid, and the copolymers of SA with CPP, CPH, and fumaric acid (57). Theresults indicated that the homopolymers were highly crystalline and the crys-tallinity of the copolymers was determined, in most cases, by the monomer ofhighest concentration. Copolymers with a composition close to 1:1 were essen-tially amorphous (57). The melting point of the aliphaticaromatic copolyanhy-drides is proportional to the aromatic content. For this type of copolymers thereis characteristically a minimum Tm between 5 and 20 mol% of the lower meltingcomponent (57).

The majority of polyanhydrides dissolve in solvents such as dichloromethaneand chloroform. However, the aromatic polyanhydrides display much lower solu-bility than the aliphatic polyanhydrides. In an attempt to improve the solubilityand decrease the Tm, copolymers of two different aromatic monomers were pre-pared. These copolymers displayed a substantial decrease in Tm and an increasein solubility than did the corresponding homopolymers of aromatic diacids (57).

Natural Biodegradable Polymers. Biopolymers formed in nature dur-ing the growth cycles of all organisms are referred to as natural polymers. Their


synthesis generally involves enzyme-catalyzed, chain-growth polymerization re-actions of activated monomers, which are typically formed within cells by complexmetabolic processes.

Polysaccharides. Formaterials applications, the principal polysaccharidesof interest are cellulose and starch because of their easy and cheap resources, butincreasing attention is being given to the more complex carbohydrate polymersproduced by bacteria and fungi, especially to polysaccharides such as xanthan,curdlan, pullulan, and hyaluronic acid (see CARBOHYDRATE POLYMERS).

Starch. Starch thermoplastic (qv) is a polymer that occurs widely in plants.The principal crops used for its production include potatoes, corn, and rice. Inall of these plants, starch is produced in the form of granules, which vary in sizeand somewhat in composition from plant to plant. In general, the linear polymer,amylose, makes up about 20 wt% of the granule, and the branched polymer, amy-lopectin, the remainder. Research on starch includes investigation of its water-adsorptive capacity, the chemical modication of the molecule, its behavior underagitation and high temperature, and its resistance to thermomechanical shear.The starch molecule has two important functional groups, the OH group that issusceptible to substitution reactions and the C O C bond that is susceptible tochain breakage. By reaction of its OH group, modication of various propertiescan be obtained. One example is the reaction with silane to improve its dispersionin polyethylene (58). Cross-linking or bridging of the OH groups changes thestructure into a network while increasing the viscosity, reducing water retentionand increasing its resistance to thermomechanical shear. Acetylated starch doeshave several advantages as a structural ber or lm-forming polymer as comparedto native starch. Starch acetate has an improved solubility compared to starch andis easily cast into lms from simple solvents. The degree of acetylation is easilycontrolled by transesterication, allowing polymers to be produced with a rangeof hydrophobicities.

Since isocyanates are highly reactive with hydroxyl groups, they can be usedto prepare a number of reactive resins that cross-link with starch. The additionof starch to isocyanate resins considerably reduced costs and improved solventresistance and strength properties (59). Starch can be modied with nonpolargroups, such as fatty esters, before the isocyanate reaction to improve the degreeof reactivity (60).

Cellulose. Cellulose (qv) is a very highly crystalline, high molecular weightpolymer, which is insoluble in water and organic solvents. It is soluble in ag-gressive, hydrogen bond-breaking solvents such as N-methylmorpholine-N-oxide.Because of its insolubility, cellulose is usually converted into derivatives to makeit more processable. The important derivatives of cellulose are reaction productsof one or more of the three hydroxyl groups, which are present in each glucopy-ranoside repeating unit, including (1) ethers (61,62), eg, methyl cellulose and hy-droxylethyl cellulose; (2) esters (63), eg, cellulose acetate and cellulose xanthate,which are used as soluble intermediates for processing cellulose into either breor lm forms, during which the cellulose is regenerated by controlled hydrolysis;and (3) acetals (64), especially the cyclic acetal formed between the C2 and C3hydroxyl groups and butyraldehyde.

Chitin and Chitosan. Chitin is a macromolecule found in the shells ofcrabs, lobsters, shrimps, and insects (see CHITIN AND CHITOSAN). It consists of


2-acetamide-2-deoxy-b-d-glucose through the b-(1-4)-glycoside linkage. Chitin canbe degraded by chitinase. Chitin bers have been utilized for making arti-cial skin and absorbable sutures (65). Chitin is insoluble in its native form butchitosan, the partly deacetylated form, is water-soluble. The materials are bio-compatible and have antimicrobial activities as well as the ability to chelateheavy metal ions. They also nd applications in the cosmetic industry becauseof their water-retaining and moisturizing properties. Using chitin and chitosanas carriers, a water-soluble prodrug has been synthesized (66). Modied chi-tosans have been prepared with various chemical and biological properties (67).N-Carboxymethylchitosan and N-carboxybutylchitosan have been prepared foruse in cosmetics and in wound treatment (68). Chitin derivatives can also be usedas drug carriers (69), and a report of the use of chitin in absorbable sutures showsthat chitins have the lowest elongation among suture materials including chitin(70), PGA, plain catgut, and chromic catgut. The tissue reaction of chitin is similarto that of PGA (71).

Alginic Acid. Alginate is a binary linear heteropolymer containing 1,4-linked -l-guluronic acid and -d-mannuronic acid. Alginates have been stud-ied extensively for their ability to form gels in the presence of divalent cations(72,73). Alginic acid forms water-soluble salts with monovalent cations, low molec-ular weight amines, and quaternary ammonium compounds. It becomes water-insoluble in the presence of polyvalent cations such as Ca2+, Be2+, Cu2+, Al3+,and Fe3+. Alginate gels have been used widely in controlled release drug deliverysystems (73). Alginates have also been used to encapsulate various herbicides,microorganisms, and cells.

Naturally Occurring Polypeptides. The proteins that have found appli-cations as materials are, for the most part, neither soluble nor fusible withoutdegradation and so they are used in the form in which they are found in nature.This description is especially true for the brous proteins wool (qv), silk (qv),and collagen (qv). All proteins are specic polymers with regular arrangementsof different types of a-amino acids; so the biosynthesis of proteins is an extremelycomplex process involving many different types of enzymes. In contrast, the en-zymatic degradation of proteins, with general-purpose proteases, is a relativelystraightforward, amide hydrolysis reaction.

Gelatin. Gelatin (qv), an animal protein, consists of 19 amino acids joinedby peptide linkages and can be hydrolyzed by a variety of proteolytic enzymesto yield its constituent amino acids or peptide components (74). This nonspeci-city is a desirable factor in intentional biodegradation. Gelatin is a water-soluble,biodegradable polymer with extensive industrial, pharmaceutical, and biomedi-cal uses, which has been employed for coatings and microencapsulating variousdrugs (75,76) and for preparing biodegradable hydrogels (77).

A method was developed to prepare a simple, exible gelatin lm-based ar-ticial skin that could adhere to an open wound and protect it against uid lossand infection. The approach was to mix polyglycerols, either as is or after reac-tion with epichlorohydrin, with commercially available gelatin and then cast lmson Teon-covered trays (78). The lms were tough and adhered to open woundsspontaneously. They could be loaded with bioactive molecules, such as growth fac-tors and antibiotics that would be released over several days. The lms could besterilized with -rays or prepared under sterile conditions.


Toxicity and Biocompatibility

In all the potential uses of polymeric materials, a direct contact between the poly-mer and biological tissues is evident; therefore, for the eventual humanapplicationof these biomedical implants and devices, an adequate testing for safety and bio-compatibility of the specic polymer matrix is essential. Biocompatibility dealswith how the tissue reacts to foreign materials and the ability of a material toperform with an appropriate host response in a specic application.

Poly(lactic-co-glycolide). Whenever a synthetic polymer material is tobe utilized in vivo, the possible tissueimplant interactions must be taken intoconsideration. In the case of biodegradable matrices, not only the possible toxicityof the polymer has to be evaluated, but also the potential toxicity of its degra-dation products. Moreover, biocompatibility is considered as the foundation forbiocompatibility of degradable polymer systems. Thus, PLLA is dened as a safebiomaterial for in vivouse because its degradation product L-lactic acid is a naturalmetabolite of the body. Even though PLGA is extensively used and represents thegold standard of degradable polymers, increased local acidity due to its degrada-tion can lead to irritation at the site of polymer implant. Agrawal and Athanasiou(79) have introduced a technique in which basic salts are used to control the pHin local environment of PLGA implant. The feasibility of lactide/glycolide poly-mers for the controlled release of bioactive agents is well proven, and they arethe most widely investigated biodegradable polymers for drug delivery. The lac-tide/glycolide copolymers have been subjected to extensive animal and humantrials without any signicant harmful side effects (80). However, some limitedincompatibility of certain macromolecules with lactide/glycolide polymers was ob-served. Bezwada and co-workers (81) studied in vitro and in vivo biocompatibilityand efcacy of block copolymer of poly(glycolide) and PCL in the form of Monocryl(Ethicon) sutures.

Poly(caprolactone). The biocompatibility and toxicity of poly-(caprolactone) have mostly been tested in conjuction with evaluations ofCapronor (Schering), which is an implantable 1-year contraceptive delivery sys-tem composed of a levonorgestrel-ethyl oleate slurry within a poly(caprolactone)capsule. In a preliminary 90-day toxicology study of Capronor in female ratsand guinea pigs, except a bland response at the implant site and a minimaltissue encapsulating reaction, no toxic effects were observed (82). The Capronor-polycaprolactone contraceptive delivery system was also tested implanted in ratsand monkeys (83). Based on animal clinical and physical data such as bloodand urine analysis, ophthalmoscopic tests, and histopathology after necropsy, nosignicant differences between the test and control groups was observed. Phase Iand II clinical trials with Capronor were recently carried out in different medicalcenters (83).

Polyphosphazenes. Biocompatibility and safety testing of polyphosp-hazenes by subcutaneous implantation in animals have shown minimal tissueresponse (84). The connection between hydrophobicity and tissue compatibilityhas been noted for classical organic polymers (85). Thus, these hydrophobicpolyphosphazenes have been mentioned as good candidates for use in heartvalves, heart pumps, blood vessel prostheses, or as coating materials for


pacemakers or other implantable devices; however, more in vivo testing andclinical trials are needed (53).

In their bioerosion reactions polyphosphazenes display a uniqueness thatstems from the inorganic backbone, and the appropriate side groups can undergofacile hydrolysis to phosphate and ammonia. The phosphate can be metabolizedand the ammonia excreted. Theoretically, if side groups attached to the poly-mer are released by the same process being excretable or metabolizable, thenthe polymer can be eroded under hydrolytic conditions without the danger of atoxic response. Polyphosphazenes of this type are potential candidates as erodiblebiostructural materials for sutures, or as matrices for controlled delivery of drugs(53).

Poly(orthoesters). As mentioned previously, the Chronomerpoly(orthoester) material from Alza Corp. or Alzamer has been investigatedas bioerodible inserts for the delivery of the narcotic antagonist naltrexone,and for the delivery of the contraceptive steroid norethisterone (86,87). Invitro studies have shown that good control over release of tetracycline could beachieved, and very good in vitro adhesion to bovine teeth demonstrated (88).However, studies in beagle dogs with naturally occurring periodontitis werenot successful because ointment-like polymers with a relatively low viscosityare squeezed out of the pocket within about 1 day, despite good adhesiveness(54).

Naturally Occurring Polymers. The use of natural biodegradable poly-mers to deliver drugs continues to be an area of active research despite the adventof synthetic biodegradable polymers (43). Natural polymers remain attractive pri-marily because they are natural products of living organisms, readily available,relatively inexpensive, and capable of a multitude of chemical modications (89).Most investigations of natural polymers asmatrices in drug delivery systems havefocused on the use of proteins (polypeptides or polyamides) such as gelatin, colla-gen, and albumin. Collagen is a major structural protein found in animal tissueswhere it is normally present in the form of aligned bers. Because of its uniquestructural properties, collagen has been used in many biomedical applications asabsorbable sutures, sponge wound dressings, composite tissue tendon allografts,injectables for facial reconstructive surgery, and as drug delivery systems espe-cially in the form of microspheres (90).

Besides the collagen biocompatibility and nontoxicity for most tissues(91), several factors including the possible occurrence of antigenic responses,tissue irritation due to residual aldehyde cross-linking agents, and poor patienttolerance of ocular inserts have adversely inuenced its use as a drug deliveryvehicle (90). For example, 5-uorouracil and bleomycin cross-linked spongesmade from puried bovine skin collagen were implanted in rabbit eyes to testtheir posssible use in preventing broblast proliferation following ophthalmicsurgery, resulting in a chronic inammatory reaction elicited by the sponges evenin the absence of drug (92).

Noncollagenous proteins, particularly albumin and to a lesser extent gelatin,continue to be developed as drug delivery vehicles. The exploitable features of albu-min include its reported biodegradation into natural products, its lack of toxicity,and noninmunogenicity (93).


Medical Applications

Over the past decade the use of polymeric materials for the administration ofpharmaceuticals and as biomedical devices has increased dramatically. Importantbiomedical application of biodegradable polymers is in the areas of controlled drugdelivery systems (9296) and in the form of implants and devices for fracturerepairs (97100), ligament reconstruction (101), surgical dressings (102), dentalrepairs, articial heart valves, contact lenses, cardiac pacemakers, vascular grafts(103), tracheal replacements (104), and organ regeneration (105).

Biomaterials in general are used for the following purposes:

(1) to replace tissues that are diseased or otherwise nonfunctional, as in-jointreplacements, articial heart valves and arteries, tooth reconstruction, andintraocular lenses;

(2) to assist in the repair of tissue, including the obvious sutures, but also bonefracture plates and ligament and tendon repair devices;

(3) to replace all or part of the functions of the major organs, such as inhaemodialysis, oxygenation (lungs), left ventricular or whole heart assis-tance (heart), perfusion (liver), and insulin delivery (pancreas);

(4) to deliver drugs to the body, either to targeted sites (eg, directly to a tumor)or sustained delivery (insulin, pilocarpine, contraceptives).

Biodegradable plastics have been developed as surgical implants in vascu-lar and orthopedic surgery, as implantable matrices for the controlled long-termrelease of drugs inside the body, as absorbable surgical sutures, and for use in theeye (106,107).

Surgical Sutures. Tissue damage that results in a loss of structural in-tegrity, for example, a deep cut in soft tissue or a fracture of a bone, may notbe capable of unassisted self-healing. The insertion of a device to hold the tissuetogether may facilitate the healing process. The classic examples are the use ofsutures to hold both deep and supercial wounds together. Once the healing iscomplete, the suture becomes redundant and can impose undesirable constraintson the healing tissues. It is preferable to remove the material from the site, eitherphysically or by self-elimination.

Synthetic absorbable sutures were developed in the 1960s, and because oftheir good biocompatibility in tissues they are nowwidely used in tracheobronchialsurgery, as well as general surgery. They are multilament-type sutures, whichhave good handle ability (106). However, for continuous suturing, braided sutureswith nonsmooth surfaces are not useful. Monolament sutures have smooth sur-faces and are adequate for continuous suturing. For a monolament suture, PGAor PLA are too stiff and inexible. The more exible polydioxanones and polyg-lyconates can be used as sutures because of their lower bending moduli (108).Furthermore, copolymers of l-lactide and -caprolactone-poly(caprolactone-lacticacid) are bioabsorbable elastic materials and their clinical applications have beenstudied (109).

Bone Fixation Devices. Although metal xation in fracture treatment forundisturbed bone healing is a successful procedure, cortical bone and steel have


very different mechanical properties. The elasticity constant of bone is only 1/10of implanted steel while tensile strength is 10 times lower (110). Thus, the re-moval of metal implants can result in weakened bone with a danger of refracture.Biodegradable implants can meet the dynamic processes of bone healing, decreas-ing the mechanical strength of the material. After months, the entire material willdisappear and no secondary surgery will be required. PGA, PLA, polydioxanone,and PHB have potential roles in this area. For clinical applications, polydioxanonewas recommended for ligament augmentation, for securing a ligament suture, asa kind of internal splinting suture, and as a kind of internal splinting to allow forearly motion of the extremities after an operation (108,109).

Biodegradable polymers are useful for many other applications. A marrowspacer can help to save autologous bone material. A plug for closing the bonemarrow is employed for endoprosthetic joint replacement. Fibers are used forlling large bone defects without mechanical loads (110).

Vascular Grafts. Many studies have been undertaken to develop accept-able small diameter vascular prostheses. Niu and co-workers (111) designed smalldiameter vascular prostheseswith incorporatedmatrices that can be absorbed intoa growing anastomotic neointima. It was pointed out that a gelatinheparin com-plex when adequately cross-linked, could simultaneously function as a temporaryantithrombogenic surface and as an excellent substructure for an anastomoticneointima.

Adhesion Prevention. Tissue adhesion after surgery occasionally causesserious complications. Materials that prevent tissue adhesion should be exibleand tough enough to provide a tight cover over the traumatized soft tissues,and should be biodegradable and reabsorbable after the injured tissue is com-pletely regenerated. Matsuda and co-workers (112,113) developed photocurablemucopolysaccharides for a newly designed tissue adhesion prevention materialthat meets numerous requirements such as nonadherent surface characteristics,biocompatibility, biodegradability in accordance with the wound healing rate, andnontoxicity. Mucopolysaccharides (hyaluronic acid and chondroitin sulphate) par-tially functionalized with photoreactive groups, such as cinnamate or thyamine,were subjected to UV irradiation to produce water-insoluble gels via intermolec-ular photodimerization of the photoreactive groups (113). Photocured lms withlower degrees of substitution, which had high water swellability and exibility,prevented tissue adhesion and exhibited enhanced biodegradability. It was sug-gested that these newly designed mucopolysaccharide gels may aid injured tissuerepair in a bioactive manner.

Articial Skin. For healing burns, skin substitutes or wound dressingsmade of biodegradable polymeric materials have recently been developed. Untilnow, most of the commercially developed articial skins have utilized biodegrad-able polymers such as collagen (114), chitin, and poly-l-leucine (115,116) whichare enzymatically degradable polymers. Recently, Koide and co-workers (117) de-veloped a new type of biomaterial for articial skin, in the form of a sponge,by combining brillar collagen (F-collagen) with gelatin. The sponge was phys-ically and metabolically stabilized by introducing cross-links. Although severaltypes of collagen-based articial skins have been developed (118120), some un-desirable characteristics of native collagen were noticed (121), such as inducingrod-like shapes in broblasts and enhancing the expression of collagenase genes


in broblasts. F-collagen with gelatin was found to overcome the above prob-lems. Yasutomi and co-workers (122) developed a biosynthetic wound dressingwith a drug delivery capability. This medicated wound dressing is composed of aspongy mixture sheet of chitosan-derivatized collagen, which is laminated with agentamycin sulphate impregnated polyurethane membrane. From In vitro eval-uation, it was shown that this wound dressing is capable of suppressing bacte-rial growth and minimizing cellular damage. Evaluation of this wound dress-ing was conducted in 80 clinical cases including supercial second-degree burns,deep second-degree burns, donor sites, and pressure sores, and achieved excel-lent results. The development of hybrid articial skins is also another importanttarget in biomedical engineering. Here, synthetic polymers and cell cultures arecombined to form a syntheticbiological composite. In this case, a biodegradablepolymer may be required as the template for growing cells and tissue culturesin vivo.

Drug Delivery Systems. Biodegradable and non-degradable poly-mers have been used for controlled delivery of drugs (see CONTROLLEDRELEASE TECHNOLOGY). The limitations of conventional methods of drug delivery,by tablet or injection for example, are well known. As a dose is applied, the plasmalevels will be raised, but these will be rapidly decreased as the drug is metabo-lized and will soon be below therapeutic levels. The next dose takes the plasmalevel high again and a cyclic pattern may be established, with most of the drugplasma levels possibly being outside the optimal range. In addition, the drug usu-ally permeates throughout the body and it is not targeted to the location whereit is specically required. Among the many possible solutions to these problemsis the use of controlled drug delivery systems (123,124), from which the drug isreleased at a constant, predetermined rate, and possibly targeted to a particularsite. One of the most prominent approaches is that in which the drug is containedwithin a polymer membrane or is otherwise encapsulated in a polymer matrix,and where the drug diffuses out into the tissues following implantation, and ero-sion or dissolution of the polymer contributes to the release mechanism. It sounds,therefore, feasible to produce systems that allow easy and safe processing and canbe injected into a body cavity without the need for surgical retrieval after com-pletion of the release. Furthermore, the differential rates of drug delivery mightbe of profound interest for cases where elevated drug doses are necessary in thebeginning of treatment.

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NEERAJ KUMARAVIVA EZRATIRTSA EHRENFROINDMICHAL Y. KRASKOABRAHAM J. DOMBThe Hebrew University of Jerusalem

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