16 Biodegradable Polymers for Biomedical Applications Samuel J. Huang Institute of Materials Science, University of Connecticut, Storrs, Connecticut I. INTRODUCTION Traditionally synthetic polymers were designed and manufactured with long term stability, as they were mostly used as coatings, packagings and structures. Since 1970s bio- degradable polymers with controllable lifetime have received attentions as biomedical and environmentally compatible consumer products materials [1–7]. Biodegradable polymers are essential in the design, synthesis and applications of biomedical implants and drug delivery system whereas biodegradable polymers prepared from renewable and sustainable resources can be generally disposed through composting. These polymers share many similar structural units but they are different in manner in how they are degraded. Biomedical materials are used and degraded in comparatively narrow range of environments whereas consumer products materials are used and degraded, by contrast, in board environments. This chapter describes synthet ic biodegradable polymers for biomedical applications. II. BIOMEDICAL POLYMERS The first and most successful use of biodegradable polymers is in the area of degradable and absorbable sutures [8,9]. Biodegradable polymers base sutures, drug release delivery systems [10], scaffolds [11,12], and tissue engineering devices [13–15] are current areas of interests. Hydrophobic polyesters derived from glycolic acid (GA) and lactic acid (LA) represent the most commonly used materials with copolyesters of GA, LA and other cyclic esters and carbonate monomers becoming available recently. Among these poly(lactic acid) (PLA) has become the main polymer as the monomer lactic acid is obtained from fermentation of agricultural and food byproducts [16]. PLA and its copolymers have wide ranges of chemical and physical properties and they represent the most important biodegradable biomedical polymers. Copyright 2005 by Marcel Dekker. All Rights Reserved. III. POLYESTERS Aliphatic polymers undergo hydrolysis, both acid or base catalyzed and enzyme catalyzed faster than aromatic polyesters and are generally preferred as biomaterials than aromatic polyesters. A. Polyesters from Hydroxyacids These aliphatic polyesters can be obtained by catalyzed dehydration of hydroxyacids and, more efficiently, by ring opening polymerization of the cyclic esters of hydroxyacids (equations (1) and (2)). Catalysts are generally used to facilitate the polymerization. Among the effective catalysts are Lewis acids in the form of metal salts of Sn, Zn, Ti, Al, and rare earth metals [17–23]; alkali metal alkoxides and super-molecular complexes [20,24,25]; and acids [26]. Polymerization of glycolide. ð1Þ Copolymerization of glycolide and lactide. ð2Þ Copyright 2005 by Marcel Dekker. All Rights Reserved. Thermal dehydration polymerization of hydroxyacids, as shown in (1) for poly(lactic acid) (PLA) is a high energy required process and PLA of low molecular weight (up to thousands) is obtained together with the cyclic dimmer (lactide) [27]. Higher molecular weight PLLA and its copolymers with glycolic acid and e-hydroxycaproic acid can be obtained in direct thermal polymerization in organic solvents [28]. Ring opening polymerizations of cyclic esters with transition metal catalysts are the most effective methods for obtaining polymers of high molecular weight in good yield in bulk. It is generally accepted that these polymerizations proceed via acyl cleavage with insertion of monomers between the metal–carbon bonds of the active sites [20,29]. Sn (II) esters are commonly used since these are easily obtainable and are approved in food products by USDA. Copolymers of glycolic acid and lactic acid by direct thermal polymerizations have T m s 135  C, which is lower than that of copolymers with similar compositions obtained by ring opening polymerization of glycolide and lactide, T m 145  C [28]. Copolyesters from direct polymerization of L-lactic acid and e-hydroxycaproic acid, ring opening polymerization of L-lactide and e-caprolactone, and sequential polymeriza- tion, PLLA with e-caprolactone (CL) have different properties (Table 1). Different sequencing of the repeating monomeric structural units in these copolymers was suggested as the reason for the difference in property. PLLA–PCL–PLA block copolymers obtained from copolymerization of PCL of various molecular weights (530, 2000, 43,000, and 80,000) and L-lactide have higher T g s (30–62  C), T m (54–58  C) for PCL blocks, and T m (153–172  C) for the PLLA blocks [29], Tab suggesting longer block lengths than those obtained from polymerization of PLLA and CL. When high MW PCLs were copolymerized with lactide the block copolyesters thus obtained had lower MW than expected, indicated substantial ester exchange during the thermal polymerization process. The physical properties of the copolyest ers vary greatly wi th the composition and sequence. Materials with properties as weak elastomers to hard thermoplastics can be obtained [30]. The tensile modulus and tensile strength were much higher for PLLA, PDLA, and PCL homopolymers than those of the copolymers. Crosslinking with peroxides increases the impact and tensile strength of PCL and PLA copolymers [31–33]. Micromonomers were prepared from ring opening polymerization of cyclic ester with functionalized initiator (3). Synthesis of polycaprolactone micromonomer. ð3Þ Table 1 Copolyesters of L-lactic acid (LLA) and e-hydroxycaproic acid (HCA). Method of polymerization M w T g ,  C T m ,  C Direct LLA þ HCA 120,000 24 Amorphous Ring opening L-Lactide þ CL 120,000 34 Amorphous Sequential PLLA þCL 130,000 36 127 Data from [28]. Copyright 2005 by Marcel Dekker. All Rights Reserved. B. Poly(ester-co-ether)s Poly(ester-co-ether)s have be en prepared by using polyether with hydroxy-terminal as co-initiator in the ring opening polymerizations of cyclic esters. Among these lactide received the most attention [34–41]. Typically lactide, poly(ethylene glycol) and stannous 2-ethyl hexanoate were heated under nitrogen at 120–150  C for up to 24 hr. The poly(ester-ether)s thus obtained typically show only one, indicating only one amorphous phase. Only crystalline phase for PLLA is observed with low Mw PEG and both crystalline phases for PEG and PLLA are observed when PEG block size approaches 4000 [41]. C. Hydroxylated Polyesters Condensation polymerization of glycols with tartaric acid results in poly(alkylene tartrate)s [42–44]. The hydroxylated polyest ers from C2 and C4 are hydrophilic and water soluble and those from C6 and higher glycol are water insoluble with increase in hydrophobicity with increasing size of glycols. Crosslinkable unsaturated poly(alkylene tartrate)s are obtained by adding maleic anhydride to the polymerization of glycols with tartaric acid (4) [45]. Poly(tartrate) was obtained from the condensation of tartaric acid ketal with tartaric acid diacetate [46]. Synthesis of unsaturated copolymers based on poly(dodecamthetylene) tartarate. ð4Þ Table 2 Typical PLLA–PEG–PLLA triblock copolyesters with PEG M w 1000. M n (NMR) M n (GPC) M w MWD T g ,  C T m ,  C ÁH m , J/g T c ,  C 10,657 12,293 20,590 1.67 34.5 156 47.1 76.2 18,440 15,636 27,296 1.75 42.9 161 44.5 91 26,511 23,318 40,344 1.73 50.6 167 48.4 107 Data from [41]. Copyright 2005 by Marcel Dekker. All Rights Reserved. D. Carboxylated Polyesters Poly(b-malic acid) is the most simple carboxylated polyester [47–49]. It is prepared by ring opening polymerization of the mono-benzyl ester b-lactone of malic acid and subsequent debenzylation. It has been explored as drug carrier. Reaction of itaconic anhydride with PCL with hydroxy terminals results in polyesters with carboxylic and C¼C double bond functional terminals, suitable for further reactions to form networks and gels, (5) a nd (6) [50,51]. Synthesis of PCL diol end-capped with itaconic anhydride, PCLDI. ð5Þ Synthesis of poly(ethylene glycol) end-capped with itac onic a nhydride. ð6Þ Synthesis of PEG-PEG crosslinked gels. ð7Þ Copyright 2005 by Marcel Dekker. All Rights Reserved. E. Polyorthoesters Transesterification reaction between cyclic orthoesters and glycols gives polyorthoesters. They can also be obtained through the reactions of diketene acetals with glycols [52–56]. These esters are relatively stable in bases and are hydrolyzed slowly in physiological pH and fast in low pH condition. They have been explored as drug delivery systems. F. Polycarbonates Trimethylene carbonate, TMC, is a commonly used co-monomer for poly(glycolide-co- lactide) base sutures [57,58]. Incorpo ration of the carbonate structure provides flexibility and toughness to the otherwise rigid and brittle copolyesters. IV. POLY(AMIDE-ESTER)S Polydepsipeptides, poly(a-aminoacid-alt-a-hydroxyacid )s can be obtained by ring opening polymerization of morpholine-2,5-dione derivatives which are prepared from a-amono- acids and a-hydroxyacids, (8) and (9) [59]. Those prepared from optically active monomers are partially crystalline whereas those prepared from racemic monomers are amorphous. T g s of the poly(amide-ester) from valine and lactic acid are between 90–92  C, 30 degrees higher than that of PLA. Depsipeptides have been explored as sutures [60]. Alternating poly(amide-ester)s have also been prepared from a-aminoacids, e-aminocaproic acid with b-hydroxyacid [61] and glycolic acid [62]. Alternating amide and ester structure containing poly(amide-ester)s have been prepared from a-amino acids, glycols, and dicarboxylic acids, (10) [63–65]. These poly(amide-ester)s are biodegraded according to known enzyme specificity. Synthesis of polydepsipeptides. ð8Þ Synthesis of poly(depsipeptide- co-lactide). ð9Þ Copyright 2005 by Marcel Dekker. All Rights Reserved. ð10Þ Synthesis of poly(Z-Tyr-Tyr-Y-imnocarbonate). ð11Þ Alternating poly(amide-ester)s have been prepared from aminoalcohols and alkanedicarboxylic acids [67]. These are partially cryst alline polymers with various rates of hydrolysis and subtilisin catalyzed degradations. a,o-Diaminoalkanes were converted into a,o-di(hydroxy acetamido)alkanes, which were then polymerized with succinyl chloride into poly(amide-ester)s [67,68]. These polymers are hydrolyzed faster than polyesters but slower than polyamides. V. POLYAMIDES AND POLYAMINOACIDS Polyamides are generally degraded slower than polyesters with similar structures [1–4]. As a result their uses as biodegradable materials have not been explored as often as that of polyesters. Interests in degradable polyamides have been mainly directed toward those derived from a-aminoacids [70]. Since polypeptides are out of the scope of this chapter and will be described here, poly(glutamic acid) and its esters have been studied as drug release syst ems [71]. However their syntheses, generally by ring opening poly- merization of N-carboxyanhydrides are tedious, and slower hydrolysis rates limited their potential use. Poly(aspartic acid), PASP, on the other hand, can be easily obtained on large scales by thermal polymerization aspartic acid to give polysuccinimide, PSI, followed by hydrolysis to give PASP [72]. There are only few biomedical applications Copyright 2005 by Marcel Dekker. All Rights Reserved. reported [73]. Synthesis of poly(aspartic acid), PASP. ð12Þ VI. POLYENAMINES Condensation of diamines with diacetoacetyl compounds give poly(enamine-carbonyl)s [74–77]. The enamine-carbonyl system form hydrogen-bonded rings and are stabilized. They are slightly acidic and form metal chelates. They are hydrolyzed faster in acidic than in neutral and basic conditions. The hydrolysis produces diamines (basic) and diacetoacetyl compounds (acidic) providing self-buffering of the pH of the system. This is similar to the hydrolysis of polypeptides. VII. POLYETHERS Polyoxyethylenes, poly(ethylene glycol) with M w less than 20,000 PEG, are obtained from the polymerization of oxirane and are described in another chapter. They received increasing interest as biomedical polymers due to their bio-/blood compatibility in linear, grafted, and crosslinked gel forms [78–88]. PEGs have been functionalized with various terminals for chemical modifications, (7) [51,89]. VIII. POLYPHOSP HAZENES Polyphosphazenes with hydrolytically sensitizing groups are easily hydrolyzed to give ammonium and phosphate compounds and have been explored as biodegradable biomedical polymers [90,91]. These groups include aminoacid esters, glucosyl, glyceryl, glycolate, lactate, and imidazoyl. Similar to the polyenam ines polyphosphazenes hydrolysis produces self-buffering ammonium phosphate systems. IX. SUTURES AND WOUND REPAIRS Synthetic sutures are the most successful commercial products of biodegradable polymers [57,58]. Poly(glycolide), PGA, was the first biodegradable synthetic suture [92–94]. Copoly(glycolide-co-lactide), PGLA, usually 90/10 came later. All these partially crystalline polymers are rigid and brittle. Braided fibers are used as sutures. The hydrophobic polyesters cause blood proteins deposition and scar tissues formations which is one draw back of the materials. Dioxanone, trimethylene carbonate, and e-caprolactone are added to the PGLA polymerization to provide flexibility and toughness. Block copolymers with blocks contai ning different composi tion and sequence are Copyright 2005 by Marcel Dekker. All Rights Reserved. the bases for sutures of various properties. PLA and PCL copolymers films have been used for wound dressing [95]. X. IMPLANTS AND SCAFFOLD FOR TISSUE ENGINEERING The results on initial approaches using biodegradable polyesters as implant materials were mixed. The hydrolysis and enzymatic (and microbial) degradations of hydrophobic aliphatic polyester proceed in selective manners. The amorphous regions of the polymers are degraded prior to the crystalline region forming small crystalline particles in the case of linear polymers [96–98]. In cases of small surface to volume implants the inside part of the implants was found to be degraded faster than the outside due to the self-catalysis of the not yet diffuse oligomeric acid formed during the hydrolysis resulting in harrowing of the implants. All these might lead to complications. Hydrophilic/hydrophobic systems are closer to bio-systems and provide better diffusion of the degraded products out of the implants in addition to the observed better blood compatibility [99]. Binary systems containing crosslinked poly(2-hydroxyethyl methacrylate), PHEMA, and PCL were found to have higher strength and better biocompatibility than PHEMA, a commonly used biomedical hydrogel [100–103]. A composite artificial tendon scaffold implant constructed with PHEMA/PCL matrix reinforced with PGA fibers was successfully tested in rabbit [104]. Polyether base polymers that can be injected and then transformed into gels chemically or thermally are of great potential as tissue engineering scaffold materials [105]. Increasing the surface areas of implants is essential for the uses of hydrophobic biodegradable polyesters as scaffolds for tissue engineering [14,15,106,107]. These might include, nets, porous foams, membranes, non-wovens, harrow tubes, etc. XI. RELEASE AND DELIVERY SYSTEMS Although intense efforts have been directed toward the use of biodegradable polyesters and polyanhydrides for drug release and delivery the results were mixed at best [108,109]. The complicated degradation profiles, production of acids, and poor proteins deposition characteristics contribute to the observed results. The use of microspheres improves the reformance [110]. Hydrophilic–hydrophobic materials are more suitable due to their better biocompatibility and diffusion characteristics. 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Copolymers of glycolic acid and lactic acid by direct thermal polymerizations have T m s 135  C, which is lower than that of copolymers with similar compositions obtained by ring opening polymerization. homopolymers than those of the copolymers. Crosslinking with peroxides increases the impact and tensile strength of PCL and PLA copolymers [31–33]. Micromonomers were prepared from ring opening polymerization. polymerization of cyclic ester with functionalized initiator (3). Synthesis of polycaprolactone micromonomer. ð3Þ Table 1 Copolyesters of L-lactic acid (LLA) and e-hydroxycaproic acid (HCA). Method of polymerization