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 biodegradable polymers with controllable lifetime have received attentions as biomedical and environmentally compatible consumer products materials [17]. 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 dierent 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 synthetic biodegradable polymers for biomedical applications.

II.

BIOMEDICAL POLYMERS

The rst 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], scaolds [11,12], and tissue engineering devices [1315] 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.

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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 eciently, by ring opening polymerization of the cyclic esters of hydroxyacids (equations (1) and (2)). Catalysts are generally used to facilitate the polymerization. Among the eective catalysts are Lewis acids in the form of metal salts of Sn, Zn, Ti, Al, and rare earth metals [1723]; alkali metal alkoxides and super-molecular complexes [20,24,25]; and acids [26].

Polymerization of glycolide.

Copolymerization of glycolide and lactide. 2

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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 eective 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 metalcarbon 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 Tms 135  C, which is lower than that of copolymers with similar compositions obtained by ring opening polymerization of glycolide and lactide, Tm 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 polymerization, PLLA with e-caprolactone (CL) have dierent properties (Table 1). Dierent sequencing of the repeating monomeric structural units in these copolymers was suggested as the reason for the dierence in property. PLLAPCLPLA block copolymers obtained from copolymerization of PCL of various molecular weights (530, 2000, 43,000, and 80,000) and L-lactide have higher Tgs (3062  C), Tm (5458  C) for PCL blocks, and Tm (153172  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 copolyesters vary greatly with 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 [3133]. Micromonomers were prepared from ring opening polymerization of cyclic ester with functionalized initiator (3).

Synthesis of polycaprolactone micromonomer. 3

Table 1 Copolyesters of L-lactic acid (LLA) and e-hydroxycaproic acid (HCA). Mw 120,000 120,000 130,000 Tg,  C 24 34 36 Tm,  C Amorphous Amorphous 127

Method of polymerization Direct Ring opening Sequential

Data from [28].

LLA HCA L-Lactide CL PLLA CL

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B.

Poly(ester-co-ether)s

Poly(ester-co-ether)s have been 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 [3441]. Typically lactide, poly(ethylene glycol) and stannous 2-ethyl hexanoate were heated under nitrogen at 120150  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 [4244]. The hydroxylated polyesters 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. 4

Table 2 Typical PLLAPEGPLLA triblock copolyesters with PEG Mw 1000. Mn (NMR) 10,657 18,440 26,511
Data from [41].

Mn (GPC) 12,293 15,636 23,318

Mw 20,590 27,296 40,344

MWD 1.67 1.75 1.73

Tg,  C 34.5 42.9 50.6

Tm,  C 156 161 167

Hm, J/g 47.1 44.5 48.4

Tc,  C 76.2 91 107

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D.

Carboxylated Polyesters

Poly(b-malic acid) is the most simple carboxylated polyester [4749]. 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 CC double bond functional terminals, suitable for further reactions to form networks and gels, (5) and (6) [50,51].

Synthesis of PCL diol end-capped with itaconic anhydride, PCLDI. 5

Synthesis of poly(ethylene glycol) end-capped with itaconic anhydride. 6

Synthesis of PEG-PEG crosslinked gels. 7

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E.

Polyorthoesters

Transesterication reaction between cyclic orthoesters and glycols gives polyorthoesters. They can also be obtained through the reactions of diketene acetals with glycols [5256]. 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-colactide) base sutures [57,58]. Incorporation of the carbonate structure provides exibility 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-amonoacids and a-hydroxyacids, (8) and (9) [59]. Those prepared from optically active monomers are partially crystalline whereas those prepared from racemic monomers are amorphous. Tgs of the poly(amide-ester) from valine and lactic acid are between 9092  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) [6365]. These poly(amide-ester)s are biodegraded according to known enzyme specicity.

Synthesis of polydepsipeptides. 8

Synthesis of poly(depsipeptide-co-lactide). 9

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10

Synthesis of poly(Z-Tyr-Tyr-Y-imnocarbonate). 11

Alternating poly(amide-ester)s have been prepared from aminoalcohols and alkanedicarboxylic acids [67]. These are partially crystalline 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 [14]. 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 systems [71]. However their syntheses, generally by ring opening polymerization 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

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reported [73].

Synthesis of poly(aspartic acid), PASP. 12 VI. POLYENAMINES

Condensation of diamines with diacetoacetyl compounds give poly(enamine-carbonyl)s [7477]. 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-buering of the pH of the system. This is similar to the hydrolysis of polypeptides.

VII.

POLYETHERS

Polyoxyethylenes, poly(ethylene glycol) with Mw 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 [7888]. PEGs have been functionalized with various terminals for chemical modications, (7) [51,89].

VIII.

POLYPHOSPHAZENES

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 polyenamines polyphosphazenes hydrolysis produces self-buering 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 rst biodegradable synthetic suture [9294]. Copoly(glycolide-co-lactide), PGLA, usually 90/10 came later. All these partially crystalline polymers are rigid and brittle. Braided bers 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 exibility and toughness. Block copolymers with blocks containing dierent composition and sequence are

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the bases for sutures of various properties. PLA and PCL copolymers lms 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 [9698]. 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 diuse 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 diusion 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 [100103]. A composite articial tendon scaold implant constructed with PHEMA/PCL matrix reinforced with PGA bers 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 scaold materials [105]. Increasing the surface areas of implants is essential for the uses of hydrophobic biodegradable polyesters as scaolds 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 eorts 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 proles, production of acids, and poor proteins deposition characteristics contribute to the observed results. The use of microspheres improves the reformance [110]. Hydrophilichydrophobic materials are more suitable due to their better biocompatibility and diusion characteristics. Swellable poly(alkylene tartrate)s, polyenamine, and oxidized poly(vinyl alcohol) were found to be eective matrix materials for controlled and sustained releases [77,111113]. Hydrogels have become the most studied release systems [114,115]. PLA/PEG block copolymers are degraded slowly in blood and are thus potentially useful [116]. Poly(g-glutamic acid) crosslinked with dihaloalkane gels were found to be eective in the release of hormones for 2030 days [117]. It has been shown that the attachment of PEG to polylysines reduces the toxicity of polylysines in gene delivery applications [118]. XII. SUMMARY

Even with the rapidly increased interest in biodegradable polymers for biomedical applications the advance has been material limited due to the diculty in balancing the controlled lifetime, property, and biocompatibility.

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