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BIODEGRADABLE POLYMERS, MEDICAL APPLICATIONS Introduction Traditional applications of synthetic polymers are mostly based on their relative inertness to biodegradation compared with natural macromolecules, such as cellulose, and proteins. Biodegradation of the polymers can occur in several ways including photodegradation, oxidation, and hydrolysis. Practically, biodegradation involves enzymatically promoted breakdown caused by living organisms, usually microorganisms, but it is now well accepted that the biodegradation can occur by hydrolysis, oxidation, or photooxidation in a biological environment. These polymers have been used in many aspects of life, eg, in environmentally friendly packaging materials (1,2), agriculture (3,4), drug delivery (5,6), gene delivery (7,8), and tissue engineering (9,10). (See CONTROLLED RELEASE TECHNOLOGY; ENVIRONMENTALLY DEGRADABLE POLYMERS; GENE-DELIVERY POLYMERS; TISSUE ENGINEERING). This article emphasizes the various biodegradable polymers obtained either synthetically or from natural resources and their uses for biomedical applications.

Factors Affecting Biodegradation Effect of Polymer Structures. Synthetic biodegradable polymers contain hydrolyzable linkages along the polymer chain; for example, amide enamine, ester, phosphate, phosphazene, carbonate, anhydride, urea, and urethane linkages are susceptible to biodegradation by microorganisms and hydrolytic enzymes. In addition, 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.

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substituents might increase biodegradability (11). Among benzylated polymers, mixed results have been obtained for polyamides. Since most enzyme-catalyzed reactions occur in aqueous media, the hydrophilic–hydrophobic character of synthetic polymers greatly affects their biodegradability. A polymer containing both hydrophobic and hydrophilic segments seems to have a higher biodegradability than those polymers containing either hydrophobic or hydrophilic structures only. A series of poly(alkylene tartrate)s was found to be readily assimilated by Aspergillus niger. However, the polymers derived from C6 and C8 alkane diols were more degradable than the more hydrophilic polymers derived from C2 and C4 alkane diols or the more hydrophobic polymers derived from the C10 and C12 alkane diols. Among the degradable poly(α-aminoacid-co-ε-caproic acid)s, the hydrophilic copolyamide derived from serine was more susceptible than those containing only hydrophobic segments. For a synthetic polymer to be degradable by enzyme catalysis, the polymer chain must be flexible enough to fit into the active site of the enzyme. This aspect most likely accounts for the fact that while the flexible aliphatic polyesters are readily degraded by biological systems, the more rigid aromatic poly(ethylene terephthalate) is generally considered to be inert (12). Effect of Polymer Morphology. Selective chemical degradation of semicrystalline polymer samples shows certain characteristic changes (13–16). During degradation, the crystallinity of the sample increases rapidly at first and then levels off to a much slower rate as the crystallinity approaches 100%. This effect is attributed to the eventual disappearance of the amorphous portions of the sample. The effect of morphology on the microbial and enzymatic degradation of poly(ε-caprolactone) (PCL), a known biodegradable polymer with a number of potential applications, has been studied (17,18). Scanning electron microscopy has shown that the degradation of a partially crystalline polycaprolactone film by filamentous fungi proceeds in a selective manner, with the amorphous regions being degraded prior to the degradation of the crystalline region. The microorganisms produce extracellular enzymes responsible for the selective degradation. This selectivity can be attributed to the less-ordered packing of amorphous regions, which permits easier access for the enzyme to the polymer chains. The size, shape, and number of crystallites all have a pronounced effect on the chain mobility of the amorphous regions and thus affect the rate of degradation. This effect has been demonstrated by studying the effects of changing orientation via stretching on the degradation (17,18). Degradation in biological medium, cells, tissues, and body fluids proceeds differently from chemical degradation as enzymes, biological reagents in the cell organelles, and fluids are involved in the degradation process. Enzyme is able to degrade the crystalline regions faster than hydrolysis. The enzyme system shows no intermediate molecular weight material but shows a much smaller weight shift with degradation as compared to chemical degradation. This shift indicates that although degradation is selective, the crystalline portions are degraded shortly after the chain ends are made available to the exoenzyme. The lateral size of the crystallites has a strong effect on the rate of degradation because the edge of the crystal is where degradation of the crystalline material takes place, because of the crystal packing. A smaller lateral crystallite size yields a higher crystallite edge surface in the bulk polymer. Prior to the saturation of the enzyme active

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sites, the rate is dependent on available substrate; therefore, a smaller lateral crystallite size results in a higher rate of degradation. The degradation rate of a PCL film is zero order with respect to the total polymer, but is not zero order with respect to the concentrations of the crystallite edge material. The drawing of PCL films causes an increase in the rate of degradation, whereas annealing of the PCL causes a decrease in the rate of degradation (19). This phenomenon is probably due to opposite changes in lateral crystallite sizes. in vitro chemical and enzymatic degradations of polymers, especially polyesters, were analyzed with respect to chemical composition and physical properties. It was found quite often that the composition of a copolymer giving the lowest melting point is most susceptible to degradation (19). The lowest packing order, as expected, corresponds with the fastest degradation rate. Effect of Molecular Weight. Microorganisms produce both exoenzymes, which degrade polymers from terminal groups, and endoenzymes, which degrade polymers randomly along the chain. One might expect a large molecular effect on the rate of degradation in the ease of exoenzymes and a relatively small molecular weight effect in the case of endoenzymes. Low molecular weight hydrocarbons, however, can be degraded by microbes. They are taken in by microbial cells, “activated” by attachment to coenzyme A, and converted to cellular metabolites within the microbial cell. However, these processes do not function well (if at all) in an extracellular environment, and the plastic molecules are too large to enter the cell. This problem does not arise with natural molecules, such as starch and cellulose, because conversions to low molecular weight components by enzyme reactions occur outside the microbial cell. Photodegradation or chemical degradation may decrease molecular weight to the point that microbial attack can proceed. Hydrolytic degradation of polyesters and polyanhydrides is affected by the molecular weight as a result of differences in water accessibility to large molecular weight polymeric materials. Effect of Radiation and Chemical Treatment. Photodegradation with UV light and the γ -irradiation of polymers generate radicals and/or ions that often lead to cleavage and cross-linking. Oxidation also occurs, complicating the situation, since exposure to light is seldom in the absence of oxygen. Generally this changes the material’s susceptibility to biodegradation. Initially, one expects the observed rate of degradation to increase until most of the fragmented polymer is consumed and a slower rate of degradation should follow for the cross-linked portion of the polymer. Similarly, photooxidation of polyalkenes promotes (slightly in most cases) the biodegradation (20). The formation of carbonyl and ester groups is responsible for this change. Processes have been developed to prepare copolymers of alkenes containing carbonyl groups so that they will be more susceptible to photolytic cleavage prior to degradation. As expected, γ -ray irradiation greatly affects the rate of in vitro degradation of polyesters (21,22). For polyglycolide and poly(glycolide-co-lactide), the pH of the degradation solution decreased as the process proceeded. The change–time curves exhibit sigmoidal shapes and consist of three stages: early, accelerated, and later; the lengths of these three regions were a function of γ -irradiation. Increasing radiation dosage shortens the time of the early stage. The appearance of the drastic pH changes coincides with loss of tensile breaking strength.

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Classification On the basis of the formation, biodegradable polymers can be classified into two groups including synthetic biodegradable polymers and natural biodegradable polymers. Synthetic Biodegradable Polymers. A representive list of synthetic biodegradable polymers is given in Table 1, which includes chemical backbone structures of these polymers. These polymers can be catagorized into two types on the basis of their backbone structures, namely (1) polymers with hydrolyzable backbone and (2) polymers with carbon backbone. Polyester. Polyesters having hydrolyzable ester bond in their backbone are considered the best biomaterial with regard to design and performance. Among polyesters, poly(lactic acid) (PLA) can be made of the lactic acid monomers which contain an asymmetric α-carbon atom with three different isomers as D-, L-, and DL-lactic acid (see POLYLACTIDE). The physiochemical properties of optically active homopolymers poly(D-lactic acid) (PDLA) or poly(L-lactic acid) (PLLA) are the same, whereas the racemic PLA has very different characteristics (25). Racemic PLA and PLLA have glass-transition temperatures (T g ’s) of 57 and 56◦ C respectively, but PLLA is highly crystalline with a melting temperature (T m ) of 170◦ C; racemic PLA is purely amorphous. The polymer characteristics are affected by the 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 γ -irradiation decreases the polymer molecular weight by 30–40% (26). The irradiated polymers continue to decrease in molecular weight during storage at room temperature. This decline in molecular weight affects the mechanical properties and the release rate from the polymers. PLA and its copolymers with less than 50% glycolic acid content soluble in common solvents such as chlorinated hydrocarbons, tetrahydrofuran, and ethyl acetate. Poly(glycolic acid) (PGA) is insoluble in common solvents but in hexafluoroisopropanol and hexafluoroacetone sesquihydrate (HFASH). In its highly crystalline form, PGA has a very high tensile strength of 69–138 MPa (10,000–20,000 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 several biodegradable polyesters was reported (28). The thermal properties, tensile properties, and the flexural storage modulus as a function of temperature were determined. The following polymers were compared: poly(L-lactic acid), poly(DL-lactic acid), poly(glycolic acid), poly(ε-caprolactone), poly(hydroxybutyrate) and copolymers with hydroxyvaleric acid, and poly(trimethylene carbonate). The thermal and mechanical properties of several of the polymers tested are summarized in Table 2 (28). A comprehensive review on the mechanical properties of several biodegradable materials used in orthopedic devices has been published (29). The tensile and flexural strength and modulus, as well as the biodegradation of various lactide/glycolide polymers, poly(orthoester), and polycaprolactone have been summarized in a tabular or diagram format. Polycaprolactone. Poly(ε-caprolactones) (PCL) are synthesized by ringopening polymerization of ε-caprolactones and are soluble in chlorinated and

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Table 1. Examples of Synthetic Biodegradable Polymersa Structure

Name

Polyesters Poly(glycolic acid) (PGA)

O O n

Poly(lactic acid) (PLA)

O O n

Poly(ε-caprolactone) (PCL)

O O n

Poly(β-hydroxybutyrate)

O O

n

Poly(propylene-fumarate)

O O

HO

OH

O

n

O

Poly(lactide-glycolide)

O O

xO

y

O O

Poly(p-dioxane-co-glycolide)

O

O x

O

O

y

Poly(p-dioxane-cocaprolactone)

O O

O

O

y

x

O

Poly(orthoesters) O OR O

O

Poly(orthoester) I m

OCH2

CH2O

OCH2

CH2O

Poly(orthoester) II O m

R O

C

Poly(orthoester) III

O O

R m

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Table 1. (continued) Structure

Name

Other polyesters O

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

O n

O O

O O

N H

x

O

Poly(ester amide)

H N

O

y

O

n

Polyphosphate ester

O O P O R

m

Polyphosphazenes Poly(aryloxyphosphazene)

O N P O

m

O

O N P

m

O

O

O

Poly(PEG-phosphazene)

O

Amino acid derived polymers Poly(amino acid)

O

H N

m

R O

Polyleucine

H N m

H N

Polylysine

O

NH2

m

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Table 1. (continued) Structure

Name

O

Poly(glutamic acid)

H N m

HO

O

Polyanhydrides Poly(fumaric acid)

O O O

m

O

O

O

Poly(terephthalic-coisophthalic acid)

O O

Ox

y m

O

Block-poly(sebacic anhydride)-co-poly(lactic acid)

CH3

O x

O

y

O

O

m

Polysaccharides OH

CH2 O

O

O OH

OH OH

OH

O

O

O

OH

OH

OH

OH

OH

OH

O

O OH

O OH

OH

OH

O

O O

OH

m

Chitosan

OH

OH

Elsinan

O

O

OH

m

O

OH OH

Pullulan

OH

O

NH2

NH2

m

Levan CH2

O

O

O

OH OH

O OH

OH OH

OH

m

269

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Table 1. (continued) Structure

Name

Polyurethanes Poly(urethanes)

O R

N H

O n

Poly(amide-amines) O R

Poly(amide-enamines)

H N

N H

n

Natural polypeptides O

H N

m

R

A plasma glycoprotein belonging structurally to the keratin–myosin group. Synthesized and secreted by hepatic parenchymal cells. Essential to the clotting of blood. The molecular weight is 340,000. Soluble, but forms an insoluble gel on conversion to fibrin. Fibrin monomer is fibrinogen from which one or two peptides have been removed by means of thrombin. Polypeptide substance comprising one third of the total protein in mammalian organisms; main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different types of collagens exist. A heterogeneous mixture of water-soluble proteins of high average molecular weight. Derived from collagen. Swells up in water to form a gel/insoluble in organic solvents.

Fibrinogen

Collagen (qv)

Gelatin (qv)

a The structures of polymers and description of their properties and applications can be found in either

Ref. 23 or Ref. 24.

aromatic hydrocarbons, cyclohexanone, and 2-nitropropane but insoluble in aliphatic hydrocarbons, diethyl ether, and alcohols (30). The homopolymer of PCL melts at 59–64◦ C with a T g of −60◦ C. Copolymerization with lactide increases the T g with the increase in the lactide content in the polymer (31). The crystallinity of the polymer decreases with the increase in polymer molecular weight; polymer of 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 of PCL by fungi, and have shown that PCL can be degraded enzymatically. Blends of PCL and polyesters prepared from alkanediols and alkane dicarboxylic acids with natural substances such as tree bark have been molded into shaped containers for horticultural seeding plantouts (34). After 3 months of soil burial, the PCL

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Table 2. Thermal and Mechanical Properties of Biodegradable Polyestersa

Polymer

Mw

Poly(lactic acid) L-PLA L-PLA L-PLA DL-PLA Poly(glycolic acid) (PGA) Poly(β-hydroxybutyrate) PHB P(HB-11%HV) Poly(ε-caprolactone) (PCL) Poly(trimethylene carbonate) PTC Poly(orthoesters) t-CDM:1,6-HDc (35:65) t-CDM:1,6-HDc (70:30)

50,000 100,000 300,000 107,000 50,000

Tg , C

◦

Elongation Tensile Tensile T m , strength, modulus, Yield, Break, ◦ C MPab MPab % %

54 58 59 51 35

170 159 178 — 210

28 50 48 29 NA

1200 2700 3000 1900 NA

3.7 2.6 1.8 4.0 NA

6.0 3.3 2.0 5.0 NA

370,000 1 529,000 2 44,000 −62 48,000 −15

171 145 57 —

36 20 16 0.5

2500 1100 400 3

2.2 5.5 7.0 20

2.5 17 80 160

— —

20 19

820 800

4.1 4.1

220 180

99,000 101,000

55 84

a Taken

from Ref. 28. convert MPa to psi, multiply by 145. c t-CDM: 1,6-HD=trans-cyclohexane dimethanol: 1,6-hexanediol. b To

containers were found to be embrittled, disintegrated, and biodegraded, which suggests that the extracellular enzymes in the soil may cleave the polymer chain prior to the assimilation of the polymer by microorganisms. Poly(β-hydroxybutyrate). Poly(β-hydroxybutyrate) (PHB) is made by a controlled bacterial fermentation (see POLY(3-HYDROXYALKANOATES). The producing organism occurs naturally. An optically active copolymer of 3-hydroxybutyrate (3HB) and 3-hydroxyvalerate (3HV) has been produced from propionic acid or pentanoic acid by Alcaligenes eutrophus. PHB is characterized as having a high molecular weight (>100,000, [η] > 3 dL/g) with a narrow polydispersity and a crystallinity of around 50%. The melting point depends on the polymer composition; P(3HB) homopolymer melts at 177◦ C with a T g at 9◦ C, the 91:9 copolymer with 4HB melts at 159◦ C, and the 1:1 copolymer with 3HV melts at 91◦ C. The PHB properties in the living cells of A. eutrophus were determined using X-ray and variable-temperature 13 C NMR relaxation studies (35). PHB is an amorphous elastomer with a T g around −40◦ C in its “native” state within the granules. The biodegradation of these polymers in soil and activated sludge show the rate of degradation to be in the following order (36): P(3HB−co−9%4HB) > P(3HB) = P(3HB−co−50%3HV) Microspheres degraded slowly in phosphate buffer at 85◦ C and after 5 months, 20–40% of the polymer eroded under these conditions. Copolymers having a higher fraction of 3HV and low molecular weight polymers were more susceptible to hydrolysis (36).

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Poly(phosphoesters). Poly(phosphoesters) are synthesized from the reaction of ethyl or phenyl phosphorodichloridates and various dialcohols including bisphenol A and poly(ethylene glycol) of various molecular weights (37). Leong and co-workers (38) have incorporated phosphoester groups into poly(urethanes). Poly(urethanes) have been used as blood-contacting biomaterials because of their having 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 release application by introducing phosphoester linkage in poly(urethane) (38). Introduction of phosphoester linkage does not change the mechanical properties inherent in the poly(urethanes) and provides excellent biodegradable materials. Polycarbonates. Polycarbonates are synthesized from the reaction of dihydroxy compounds with phosgene or with bischloroformates of aliphatic dihydroxy compounds by transesterification, and by polymerization of cyclic carbonates (39). These polymers have been synthesized from carbon dioxide and the corresponding epoxides in the presence of organometallic compounds as initiators. Poly(ethylene carbonate) and poly(propylene carbonate) are linear thermoplastic polyesters of carbonic acid with aliphatic dihydroxy compounds (39). Poly(dihydropyrans) were developed for contraceptive delivery. The in vivo and in vitro release of contraceptive steroids and antimalarial agents from polymer matrices has been studied. Poly(p-dioxanone) is clinically used as an alternative to poly(lactide) in absorbable sutures with similar properties to poly(lactide) with the advantage of better irradiation stability during sterilization (40). This polymer has not yet been developed as a carrier for controlled drug delivery. Biodegradable polymers derived from naturally occurring, multifunctional hydroxy acids and amino acid have been investigated by Lenz and Guerin (41). Poly(amides). The utilization of amide-based polymers, especially natural proteins, in the preparation of biodegradable matrices have been extensively investigated in recent years (42). Microcapsules and microspheres of cross-linked collagen, gelatin, and albumin have been used for dug delivery (43). The synthetic ability to manipulate amino acid sequences has seen its maturity over the last two decades with new techniques and strategies continually being introduced. Poly(amides) such as poly(glutamic acid) and poly(lysine) and their copolymers 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 material have been reported (46–48). 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 a substitution reaction of the reactive poly(dichlorophosphazene) with a wide range of reactive nucleophiles such as amines, alkoxides, and organometallic molecules. The reaction is carried out in general at room temperature in tetrahydrofuran or aromatic hydrocarbon solutions (49). Two different types of polyphosphazenes are of interest as bioinert materials: those with strongly hydrophobic surface characteristics and those with hydrophilic surfaces. Polycarbonates (qv) bearing fluoroalkoxy side groups are some of the most hydrophobic synthetic polymers known (50,51). Such polymers are as hydrophobic as poly(tetrafluoroethylene) (Teflon), but unlike Teflon, polyphosphazenes of this type are flexible or elastomeric, easy to prepare, and they can be used as coatings for other materials.

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The uniqueness of the polyphosphazenes stems from its inorganic backbone (N P) which with certain organic side groups can be hydrolyzed to phosphate and ammonia. Several polymer structures have been used as matrix carriers for drugs (51) or as a hydrolyzable polymeric drug, where the drug is covalently bound to the polymer backbone and released from the polymer by hydrolysis (52). A comprehensive review on the synthesis, characterization, and medical applications of polyphosphazenes was published (53). Poly(orthoesters). Poly(orthoesters) were first designated as Chronomer and later as Alzamer (54). They were prepared by a transesterification reaction. The molecular weight of poly(orthoesters) were significantly dependent on the type of diol and catalyst used for synthesis. A linear, flexible diol like 1,6-hexanediol gave molecular weights greater than 200 kDa, whereas bisphenol A in the presence of catalyst gave molecular weights around only 10,000 kDa (55). Mechanical properties of the linear poly(orthesters) can be varied over a large range by selecting various compositions of diols. It was shown that the T g of the polymer prepared from 3,9-diethylidene-2,4,8,10-tetraoxaspiro[5,5]undecane can be varied from 25 to 110◦ C by simply changing the amount of 1,6-hexanediol in trans-1,4 cyclohexane dimethanol from 100% to 0% (29). A linearly decreasing relationship between the T g and percentage of 1,6 hexanediol is observed. One could take advantage of the above relationship in selecting the polymer for in vivo applications because in vivo the T g of the polymer would drop because of the inhibition of water, resulting in the loss of stiffness and rigidity of the polymer. Polyanhydrides. The majority of the polyanhydrides (qv) are prepared by melt polycondensation. The sequence of reaction involves first the conversion of a dicarboxylic acid monomer into a prepolymer consisting of a mixed anhydride of the diacid with acetic anhydride. This is achieved by simply refluxing the diacid monomer with acetic anhydride for a specified length of time. The polymer is obtained subsequently by heating the prepolymer in vacuo to eliminate the acetic anhydride (56). Almost all polyanhydrides show some degree of crystallinity as manifested by their crystalline melting points. An in-depth X-ray diffraction analysis was conducted with the homopolymers of sebacic acid (SA), bis(carboxyphenoxy)propane (CPP), bis(carboxyphenoxy)hexane (CPH), and fumaric acid, and the copolymers of SA with CPP, CPH, and fumaric acid (57). The results indicated that the homopolymers were highly crystalline and the crystallinity of the copolymers was determined, in most cases, by the monomer of highest concentration. Copolymers with a composition close to 1:1 were essentially amorphous (57). The melting point of the aliphatic–aromatic copolyanhydrides is proportional to the aromatic content. For this type of copolymers there is characteristically a minimum T m between 5 and 20 mol% of the lower melting component (57). The majority of polyanhydrides dissolve in solvents such as dichloromethane and chloroform. However, the aromatic polyanhydrides display much lower solubility than the aliphatic polyanhydrides. In an attempt to improve the solubility and decrease the T m , copolymers of two different aromatic monomers were prepared. These copolymers displayed a substantial decrease in T m and an increase in solubility than did the corresponding homopolymers of aromatic diacids (57). Natural Biodegradable Polymers. Biopolymers formed in nature during the growth cycles of all organisms are referred to as natural polymers. Their

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synthesis generally involves enzyme-catalyzed, chain-growth polymerization reactions of activated monomers, which are typically formed within cells by complex metabolic processes. Polysaccharides. For materials applications, the principal polysaccharides of interest are cellulose and starch because of their easy and cheap resources, but increasing attention is being given to the more complex carbohydrate polymers produced 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. In all of these plants, starch is produced in the form of granules, which vary in size and 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, amylopectin, the remainder. Research on starch includes investigation of its wateradsorptive capacity, the chemical modification of the molecule, its behavior under agitation and high temperature, and its resistance to thermomechanical shear. The starch molecule has two important functional groups, the OH group that is susceptible to substitution reactions and the C O C bond that is susceptible to chain breakage. By reaction of its OH group, modification of various properties can be obtained. One example is the reaction with silane to improve its dispersion in polyethylene (58). Cross-linking or bridging of the OH groups changes the structure into a network while increasing the viscosity, reducing water retention and increasing its resistance to thermomechanical shear. Acetylated starch does have several advantages as a structural fiber or film-forming polymer as compared to native starch. Starch acetate has an improved solubility compared to starch and is easily cast into films from simple solvents. The degree of acetylation is easily controlled by transesterification, allowing polymers to be produced with a range of hydrophobicities. Since isocyanates are highly reactive with hydroxyl groups, they can be used to prepare a number of reactive resins that cross-link with starch. The addition of starch to isocyanate resins considerably reduced costs and improved solvent resistance and strength properties (59). Starch can be modified with nonpolar groups, such as fatty esters, before the isocyanate reaction to improve the degree of reactivity (60). Cellulose. Cellulose (qv) is a very highly crystalline, high molecular weight polymer, which is insoluble in water and organic solvents. It is soluble in aggressive, hydrogen bond-breaking solvents such as N-methylmorpholine-N-oxide. Because of its insolubility, cellulose is usually converted into derivatives to make it more processable. The important derivatives of cellulose are reaction products of one or more of the three hydroxyl groups, which are present in each glucopyranoside repeating unit, including (1) ethers (61,62), eg, methyl cellulose and hydroxylethyl cellulose; (2) esters (63), eg, cellulose acetate and cellulose xanthate, which are used as soluble intermediates for processing cellulose into either fibre or film forms, during which the cellulose is regenerated by controlled hydrolysis; and (3) acetals (64), especially the cyclic acetal formed between the C2 and C3 hydroxyl groups and butyraldehyde. Chitin and Chitosan. Chitin is a macromolecule found in the shells of crabs, lobsters, shrimps, and insects (see CHITIN AND CHITOSAN). It consists of

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2-acetamide-2-deoxy-b-d-glucose through the b-(1-4)-glycoside linkage. Chitin can be degraded by chitinase. Chitin fibers have been utilized for making artificial skin and absorbable sutures (65). Chitin is insoluble in its native form but chitosan, the partly deacetylated form, is water-soluble. The materials are biocompatible and have antimicrobial activities as well as the ability to chelate heavy metal ions. They also find applications in the cosmetic industry because of their water-retaining and moisturizing properties. Using chitin and chitosan as carriers, a water-soluble prodrug has been synthesized (66). Modified chitosans have been prepared with various chemical and biological properties (67). N-Carboxymethylchitosan and N-carboxybutylchitosan have been prepared for use in cosmetics and in wound treatment (68). Chitin derivatives can also be used as drug carriers (69), and a report of the use of chitin in absorbable sutures shows that chitins have the lowest elongation among suture materials including chitin (70), PGA, plain catgut, and chromic catgut. The tissue reaction of chitin is similar to that of PGA (71). Alginic Acid. Alginate is a binary linear heteropolymer containing 1,4linked α-l-guluronic acid and β-d-mannuronic acid. Alginates have been studied 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 molecular weight amines, and quaternary ammonium compounds. It becomes waterinsoluble in the presence of polyvalent cations such as Ca2+ ·, Be2+ ·, Cu2+ ·, Al3+ ·, and Fe3+ ·. Alginate gels have been used widely in controlled release drug delivery systems (73). Alginates have also been used to encapsulate various herbicides, microorganisms, and cells. Naturally Occurring Polypeptides. The proteins that have found applications as materials are, for the most part, neither soluble nor fusible without degradation and so they are used in the form in which they are found in nature. This description is especially true for the fibrous proteins wool (qv), silk (qv), and collagen (qv). All proteins are specific polymers with regular arrangements of different types of a-amino acids; so the biosynthesis of proteins is an extremely complex process involving many different types of enzymes. In contrast, the enzymatic degradation of proteins, with general-purpose proteases, is a relatively straightforward, amide hydrolysis reaction. Gelatin. Gelatin (qv), an animal protein, consists of 19 amino acids joined by peptide linkages and can be hydrolyzed by a variety of proteolytic enzymes to yield its constituent amino acids or peptide components (74). This nonspecificity is a desirable factor in intentional biodegradation. Gelatin is a water-soluble, biodegradable polymer with extensive industrial, pharmaceutical, and biomedical uses, which has been employed for coatings and microencapsulating various drugs (75,76) and for preparing biodegradable hydrogels (77). A method was developed to prepare a simple, flexible gelatin film-based artificial skin that could adhere to an open wound and protect it against fluid loss and infection. The approach was to mix polyglycerols, either as is or after reaction with epichlorohydrin, with commercially available gelatin and then cast films on Teflon-covered trays (78). The films were tough and adhered to open wounds spontaneously. They could be loaded with bioactive molecules, such as growth factors and antibiotics that would be released over several days. The films could be sterilized with γ -rays or prepared under sterile conditions.

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Toxicity and Biocompatibility In all the potential uses of polymeric materials, a direct contact between the polymer and biological tissues is evident; therefore, for the eventual human application of these biomedical implants and devices, an adequate testing for safety and biocompatibility of the specific polymer matrix is essential. Biocompatibility deals with how the tissue reacts to foreign materials and the ability of a material to perform with an appropriate host response in a specific application. Poly(lactic-co-glycolide). Whenever a synthetic polymer material is to be utilized in vivo, the possible tissue–implant interactions must be taken into consideration. In the case of biodegradable matrices, not only the possible toxicity of the polymer has to be evaluated, but also the potential toxicity of its degradation products. Moreover, biocompatibility is considered as the foundation for biocompatibility of degradable polymer systems. Thus, PLLA is defined as a safe biomaterial for in vivo use because its degradation product L-lactic acid is a natural metabolite of the body. Even though PLGA is extensively used and represents the gold standard of degradable polymers, increased local acidity due to its degradation 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 pH in local environment of PLGA implant. The feasibility of lactide/glycolide polymers for the controlled release of bioactive agents is well proven, and they are the most widely investigated biodegradable polymers for drug delivery. The lactide/glycolide copolymers have been subjected to extensive animal and human trials without any significant harmful side effects (80). However, some limited incompatibility of certain macromolecules with lactide/glycolide polymers was observed. Bezwada and co-workers (81) studied in vitro and in vivo biocompatibility and efficacy 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 of Capronor (Schering), which is an implantable 1-year contraceptive delivery system composed of a levonorgestrel-ethyl oleate slurry within a poly(caprolactone) capsule. In a preliminary 90-day toxicology study of Capronor in female rats and guinea pigs, except a bland response at the implant site and a minimal tissue encapsulating reaction, no toxic effects were observed (82). The Capronorpolycaprolactone contraceptive delivery system was also tested implanted in rats and monkeys (83). Based on animal clinical and physical data such as blood and urine analysis, ophthalmoscopic tests, and histopathology after necropsy, no significant differences between the test and control groups was observed. Phase I and II clinical trials with Capronor were recently carried out in different medical centers (83). Polyphosphazenes. Biocompatibility and safety testing of polyphosphazenes by subcutaneous implantation in animals have shown minimal tissue response (84). The connection between hydrophobicity and tissue compatibility has been noted for classical organic polymers (85). Thus, these hydrophobic polyphosphazenes have been mentioned as good candidates for use in heart valves, heart pumps, blood vessel prostheses, or as coating materials for

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pacemakers or other implantable devices; however, more in vivo testing and clinical trials are needed (53). In their bioerosion reactions polyphosphazenes display a uniqueness that stems from the inorganic backbone, and the appropriate side groups can undergo facile hydrolysis to phosphate and ammonia. The phosphate can be metabolized and the ammonia excreted. Theoretically, if side groups attached to the polymer are released by the same process being excretable or metabolizable, then the polymer can be eroded under hydrolytic conditions without the danger of a toxic response. Polyphosphazenes of this type are potential candidates as erodible biostructural materials for sutures, or as matrices for controlled delivery of drugs (53). Poly(orthoesters). As mentioned previously, the Chronomer poly(orthoester) material from Alza Corp. or Alzamer has been investigated as bioerodible inserts for the delivery of the narcotic antagonist naltrexone, and for the delivery of the contraceptive steroid norethisterone (86,87). In vitro studies have shown that good control over release of tetracycline could be achieved, and very good in vitro adhesion to bovine teeth demonstrated (88). However, studies in beagle dogs with naturally occurring periodontitis were not successful because ointment-like polymers with a relatively low viscosity are squeezed out of the pocket within about 1 day, despite good adhesiveness (54). Naturally Occurring Polymers. The use of natural biodegradable polymers to deliver drugs continues to be an area of active research despite the advent of synthetic biodegradable polymers (43). Natural polymers remain attractive primarily because they are natural products of living organisms, readily available, relatively inexpensive, and capable of a multitude of chemical modifications (89). Most investigations of natural polymers as matrices in drug delivery systems have focused on the use of proteins (polypeptides or polyamides) such as gelatin, collagen, and albumin. Collagen is a major structural protein found in animal tissues where it is normally present in the form of aligned fibers. Because of its unique structural properties, collagen has been used in many biomedical applications as absorbable sutures, sponge wound dressings, composite tissue tendon allografts, injectables for facial reconstructive surgery, and as drug delivery systems especially 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 patient tolerance of ocular inserts have adversely influenced its use as a drug delivery vehicle (90). For example, 5-fluorouracil and bleomycin cross-linked sponges made from purified bovine skin collagen were implanted in rabbit eyes to test their posssible use in preventing fibroblast proliferation following ophthalmic surgery, resulting in a chronic inflammatory reaction elicited by the sponges even in 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 albumin include its reported biodegradation into natural products, its lack of toxicity, and noninmunogenicity (93).

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Medical Applications Over the past decade the use of polymeric materials for the administration of pharmaceuticals and as biomedical devices has increased dramatically. Important biomedical application of biodegradable polymers is in the areas of controlled drug delivery systems (92–96) and in the form of implants and devices for fracture repairs (97–100), ligament reconstruction (101), surgical dressings (102), dental repairs, artificial 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-joint replacements, artificial heart valves and arteries, tooth reconstruction, and intraocular lenses; (2) to assist in the repair of tissue, including the obvious sutures, but also bone fracture plates and ligament and tendon repair devices; (3) to replace all or part of the functions of the major organs, such as in haemodialysis, oxygenation (lungs), left ventricular or whole heart assistance (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 vascular and orthopedic surgery, as implantable matrices for the controlled long-term release of drugs inside the body, as absorbable surgical sutures, and for use in the eye (106,107). Surgical Sutures. Tissue damage that results in a loss of structural integrity, for example, a deep cut in soft tissue or a fracture of a bone, may not be capable of unassisted self-healing. The insertion of a device to hold the tissue together may facilitate the healing process. The classic examples are the use of sutures to hold both deep and superficial wounds together. Once the healing is complete, the suture becomes redundant and can impose undesirable constraints on the healing tissues. It is preferable to remove the material from the site, either physically or by self-elimination. Synthetic absorbable sutures were developed in the 1960s, and because of their good biocompatibility in tissues they are now widely used in tracheobronchial surgery, as well as general surgery. They are multifilament-type sutures, which have good handle ability (106). However, for continuous suturing, braided sutures with nonsmooth surfaces are not useful. Monofilament sutures have smooth surfaces and are adequate for continuous suturing. For a monofilament suture, PGA or PLA are too stiff and inflexible. The more flexible polydioxanones and polyglyconates can be used as sutures because of their lower bending moduli (108). Furthermore, copolymers of l-lactide and ε-caprolactone-poly(caprolactone-lactic acid) are bioabsorbable elastic materials and their clinical applications have been studied (109). Bone Fixation Devices. Although metal fixation in fracture treatment for undisturbed bone healing is a successful procedure, cortical bone and steel have

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very different mechanical properties. The elasticity constant of bone is only 1/10 of implanted steel while tensile strength is 10 times lower (110). Thus, the removal of metal implants can result in weakened bone with a danger of refracture. Biodegradable implants can meet the dynamic processes of bone healing, decreasing the mechanical strength of the material. After months, the entire material will disappear and no secondary surgery will be required. PGA, PLA, polydioxanone, and PHB have potential roles in this area. For clinical applications, polydioxanone was recommended for ligament augmentation, for securing a ligament suture, as a kind of internal splinting suture, and as a kind of internal splinting to allow for early motion of the extremities after an operation (108,109). Biodegradable polymers are useful for many other applications. A marrow spacer can help to save autologous bone material. A plug for closing the bone marrow is employed for endoprosthetic joint replacement. Fibers are used for filling large bone defects without mechanical loads (110). Vascular Grafts. Many studies have been undertaken to develop acceptable small diameter vascular prostheses. Niu and co-workers (111) designed small diameter vascular prostheses with incorporated matrices that can be absorbed into a growing anastomotic neointima. It was pointed out that a gelatin–heparin complex when adequately cross-linked, could simultaneously function as a temporary antithrombogenic surface and as an excellent substructure for an anastomotic neointima. Adhesion Prevention. Tissue adhesion after surgery occasionally causes serious complications. Materials that prevent tissue adhesion should be flexible and tough enough to provide a tight cover over the traumatized soft tissues, and should be biodegradable and reabsorbable after the injured tissue is completely regenerated. Matsuda and co-workers (112,113) developed photocurable mucopolysaccharides for a newly designed tissue adhesion prevention material that meets numerous requirements such as nonadherent surface characteristics, biocompatibility, biodegradability in accordance with the wound healing rate, and nontoxicity. Mucopolysaccharides (hyaluronic acid and chondroitin sulphate) partially functionalized with photoreactive groups, such as cinnamate or thyamine, were subjected to UV irradiation to produce water-insoluble gels via intermolecular photodimerization of the photoreactive groups (113). Photocured films with lower degrees of substitution, which had high water swellability and flexibility, prevented tissue adhesion and exhibited enhanced biodegradability. It was suggested that these newly designed mucopolysaccharide gels may aid injured tissue repair in a bioactive manner. Artificial Skin. For healing burns, skin substitutes or wound dressings made of biodegradable polymeric materials have recently been developed. Until now, most of the commercially developed artificial skins have utilized biodegradable polymers such as collagen (114), chitin, and poly-l-leucine (115,116) which are enzymatically degradable polymers. Recently, Koide and co-workers (117) developed a new type of biomaterial for artificial skin, in the form of a sponge, by combining fibrillar collagen (F-collagen) with gelatin. The sponge was physically and metabolically stabilized by introducing cross-links. Although several types of collagen-based artificial skins have been developed (118–120), some undesirable characteristics of native collagen were noticed (121), such as inducing rod-like shapes in fibroblasts and enhancing the expression of collagenase genes

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in fibroblasts. F-collagen with gelatin was found to overcome the above problems. Yasutomi and co-workers (122) developed a biosynthetic wound dressing with a drug delivery capability. This medicated wound dressing is composed of a spongy mixture sheet of chitosan-derivatized collagen, which is laminated with a gentamycin sulphate impregnated polyurethane membrane. From In vitro evaluation, it was shown that this wound dressing is capable of suppressing bacterial growth and minimizing cellular damage. Evaluation of this wound dressing was conducted in 80 clinical cases including superficial second-degree burns, deep second-degree burns, donor sites, and pressure sores, and achieved excellent results. The development of hybrid artificial skins is also another important target in biomedical engineering. Here, synthetic polymers and cell cultures are combined to form a synthetic–biological composite. In this case, a biodegradable polymer may be required as the template for growing cells and tissue cultures in vivo. Drug Delivery Systems. Biodegradable and non-degradable polymers have been used for controlled delivery of drugs (see CONTROLLED RELEASE TECHNOLOGY). The limitations of conventional methods of drug delivery, by tablet or injection for example, are well known. As a dose is applied, the plasma levels will be raised, but these will be rapidly decreased as the drug is metabolized and will soon be below therapeutic levels. The next dose takes the plasma level high again and a cyclic pattern may be established, with most of the drug plasma levels possibly being outside the optimal range. In addition, the drug usually permeates throughout the body and it is not targeted to the location where it is specifically required. Among the many possible solutions to these problems is the use of controlled drug delivery systems (123,124), from which the drug is released at a constant, predetermined rate, and possibly targeted to a particular site. One of the most prominent approaches is that in which the drug is contained within a polymer membrane or is otherwise encapsulated in a polymer matrix, and where the drug diffuses out into the tissues following implantation, and erosion or dissolution of the polymer contributes to the release mechanism. It sounds, therefore, feasible to produce systems that allow easy and safe processing and can be injected into a body cavity without the need for surgical retrieval after completion of the release. Furthermore, the differential rates of drug delivery might be of profound interest for cases where elevated drug doses are necessary in the beginning of treatment.

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NEERAJ KUMAR AVIVA EZRA TIRTSA EHRENFROIND MICHAL Y. KRASKO ABRAHAM J. DOMB The Hebrew University of Jerusalem