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Ứng dụng Polyester phân hủy sinh học trong dược phẩm và môi trường
Macromol. Rapid Commun. 21, 117–132 (2000)117Biodegradable polyesters for medical and ecologicalapplicationsYoshito Ikada*1, Hideto Tsuji21Suzuka University of Medical Science, 1001-1 Kishioka-cho, Suzuka, Mie 510-0293, Japan2Department of Ecological Engineering, Faculty of Engineering, Toyohashi University of Technology,Tempaku-cho, Toyohashi, Aichi 441-8580, Japantsuji@eco.tut.ac.jp(Received: June 9, 1999; revised: August 19, 1999)1. IntroductionPolymer degradation takes place mostly through scissionof the main chains or side-chains of polymer molecules,induced by their thermal activation, oxidation, photolysis,radiolysis, or hydrolysis. Some polymers undergo degra-dation in biological environments when living cells ormicroorganisms are present around the polymers. Suchenvironments include soils, seas, rivers, and lakes on theearth as well as the body of human beings and ani-mals1–18). In this article, biodegradable polymers aredefined as those which are degraded in these biologicalenvironments not through thermal oxidation, photolysis,or radiolysis but through enzymatic or non-enzymatichydrolysis.In a strict sense, such polymers that require enzymesof microorganisms for hydrolytic or oxidative degrada-tion are regarded as biodegradable polymers. This defi-nition does not include polylactides in the category ofbiodegradable polymers, because polylactides arehydrolyzed at a relatively high rate even at room tem-perature and neutral pH without any help of hydrolyticenzymes if moisture is present. This often gives rise toconfusion when we say that polylactides are biodegrad-able. As will be shown later, polylactides, especiallypolyglycolide, are readily hydrolyzed in our body to therespective monomers and oligomers that are soluble inaqueous media2). As a result, the whole mass of thepolymers disappears, leaving no trace of remnants.Generally, such a polymer that loses its weight overtime in the living body is called an absorbable, resorb-able, or bioabsorbable polymer as well as a biodegrad-able polymer, regardless of its degradation mode, inother words, for both enzymatic and non-enzymatichydrolysis. To avoid this confusion, some people insistthat the term “biodegradable” should be used only forsuch ecological polymers that have been developedaiming at the protection of earth environments fromplastic wastes, while the polymers applied for medicalpurposes by implanting in the human body should notbe called biodegradable but resorbable or absorbable. Inthis article, however, the term “biodegradable” is usedin spite of this confusion, since the term has beenwidely utilized in the biomaterial world for the biome-dical polymers that are absorbed in the body evenReview: Numerous biodegradable polymers have beendeveloped in the last two decades. In terms of application,biodegradable polymers are classified into three groups:medical, ecological, and dual application, while in termsof origin they are divided into two groups: natural andsynthetic. This review article will outline classification,requirements, applications, physical properties, biode-gradability, and degradation mechanisms of representativebiodegradable polymers that have already been commer-cialized or are under investigation. Among the biodegrad-able polymers, recent developments of aliphatic poly-esters, especially polylactides and poly(lactic acid)s, willbe mainly described in the last part.Macromol. Rapid Commun. 21, No. 3 i WILEY-VCH Verlag GmbH, D-69451 Weinheim 2000 1022-1336/2000/0302–0117$17.50+.50/0Polarizing optical photomicrograph of a PLLA film annealedat 140 8C after melting at 200 8C 118Y. Ikada, H. Tsujithrough non-enzymatic hydrolysis. In other words, theterm “biodegradable” is used here in broad meaningthat the polymer will eventually disappear after intro-duction in the body, without references to the mechan-isms of degradation. Fig. 1 shows a variety of mechan-isms responsible for polymer resorption.These biodegradable polymers have currently twomajor applications; one is as biomedical polymers thatcontribute to the medical care of patients and the other isas ecological polymers that keep the earth environmentsclean. Most of the currently available biodegradable poly-mers are used for either of the two purposes, but some ofthem are applicable for both, as illustrated in Fig. 2. Bio-degradable polymers can be also classified on the basis ofthe origin, that is, naturally occurring or synthetic. Tab. 1lists biodegradable polymers classified according to thepolymer origin.The purpose of this article is to give a brief overviewon representative biodegradable polymers that haveFig. 1. Modes of resorption of polymersTab. 1. Classification of biodegradable polymersNatural Polymers Synthetic PolymersSub-classification Examples Sub-classification Examples1. Plant origin 1. Aliphatic polyesters1.1 Polysaccharides Cellulose, Starch, Alginate 1.1 Glycol and dicarbonic acidpolycondensatesPoly(ethylene succinate),Poly(butylene terephthalate)2. Animal origin 1.2 Polylactides Polyglycolide, Polylactides2.1 Polysaccharides Chitin (Chitosan), Hyaluronate 1.3 Polylactones Poly(e-carpolactone)1.4 Miscellaneous Poly(butylene terephthalate)2.2 Proteins Collagen (Gelatin), Albumin 2. Polyols Poly(vinyl alcohol)3. Microbe origin 3. Polycarbonates Poly(ester carbonate)3.1 Polyesters Poly(3-hydroxyalkanoate)3.2 Polysaccharides Hyaluronate 4. Miscellaneous Polyanhydrides,Poly(a-cyanoacrylate)s,Polyphosphazenes,Poly(orthoesters)Fig. 2. Application of biodegradable polymers. PAA: Poly-(acid anhydride); PBS: Poly(butylene succinate); PCA: Poly(a-cyanoacrylate); PCL: Poly(e-caprolactone); PDLLA: Poly(DL-lactide), Poly(DL-lactic acid); PEA: Poly(ester amide); PEC:Poly(ester carbonate); PES: Poly(ethylene succinate); PGA:Poly(glycolide), Poly(glycolic acid); PGALA: Poly(glycolide-co-lactide), Poly(glycolic acid-co-lactic acid); PHA: Poly(hy-droxyalkanoate); PHB: Poly(3-hydroxybutyrate); PLLA:Poly(L-lactide), Poly(L-lactic acid); POE: Poly(orthoester) Biodegradable polyesters for medical and ecological applications119already been commercialized or are under investigationfor biomedical and ecological applications.2. Biomedical applications2.1 BiomaterialsA variety of polymers have been used for medical careincluding preventive medicine, clinical inspections, andsurgical treatments of diseases19–23). Among the polymersemployed for such medical purposes, a specified group ofpolymers are called polymeric biomaterials when theyare used in direct contact with living cells of our body.Typical applications of biomaterials in medicine are fordisposable products (e.g. syringe, blood bag, and cathe-ter), materials supporting surgical operation (e.g. suture,adhesive, and sealant), prostheses for tissue replacements(e.g. intraocular lens, dental implant, and breast implant),and artificial organs for temporary or permanent assist(e.g. artificial kidney, artificial heart, and vascular graft).These biomaterials are quite different from other non-medical, commercial products in many aspects. Forinstance, neither industrial manufacturing of biomaterialsnor sale of medical devices are allowed unless they clearstrict governmental regulatory issues. The minimumrequirements of biomaterials for such governmentalapproval include non-toxicity, sterilizability, and effec-tiveness, as shown in Tab. 2. Biocompatibility is highlydesirable but not indispensable; most of the clinicallyused biomaterials lack excellent biocompatibility,although many efforts have been devoted to the develop-ment of biocompatible materials by biomaterials scien-tists and engineers. A large unsolved problem of bioma-terials is this lack of biocompatibility, especially whenthey are used not temporarily but permanently asimplants in our body. Low effectiveness is another pro-blem of currently used biomaterials.The biological materials composing our living body asskeleton, frame, and tissue matrix are all biodegradable ina strict sense and gradually lose the mass unless addi-tional treatments are given when our heart ceases beating.Recently, biodegradable medical polymers haveattracted much attention7, 10,22). There are at least two rea-sons for this new trend. One is the difficulty in develop-ing such biocompatible materials that do not evoke anysignificant foreign-body reactions from the living bodywhen receiving man-made biomaterials. At present wecan produce biomaterials that are biocompatible if thecontact duration of biomaterials with the living body is asshort as several hours, days, or weeks24). However, thescience and technology of biomaterials have not yetreached such a high level that allows us to fabricate bio-compatible implants for permanent use. On the contrary,biodegradable polymers do not require such excellentbiocompatibility since they do not stay in our body for along term but disappear without leaving any trace of for-eign materials.The other reason for biodegradable polymers attractingmuch attention is that nobody will want to carry foreignmaterials in the body as long-term implants, because onecannot deny a risk of infection eventually caused by theimplants.Although biodegradable polymers seem very promisingin medical applications, these kinds of polymers currentlydo not enjoy large clinical uses, because there is a greatconcern on biodegradable medical polymers. This con-cern is the toxicity of biodegradation by-products, sincethe causes of toxicity of biomaterials are mostly due tolow-molecular-weight compounds that have leached fromthe biomaterials into the body of patients. They includemonomers remaining unpolymerized, ethylene oxideremaining unremoved, additives such as anti-oxidant andpigments, and fragments of polymerization initiator andcatalyst. The content of these compounds in currentlyused biomaterials is below the level prescribed by regula-tions. Water-insoluble polymers generally are not able tophysically and chemically interact with living cells unlessthe material surface has very sharp projections or a highdensity of a cationic moiety24).However, biodegradable polymers always release low-molecular-weight compounds into the outer environmentas a result of degradation. If they can interact with thecell surface or enter into the cell interior, it is possiblethat the normal condition of the cell is disturbed by suchforeign compounds. One can say that an implanted bio-material induces cyto-toxicity if this disturbance is largeenough to bring about an irreversible damage to the cell.Purified polyethylene and silicone are not toxic but alsonot biocompatible, because thrombus formation andencapsulation by collagenous fibrous tissues take placearound their surface when implanted24). The largest differ-ence in terms of toxicity between biodegradable and non-biodegradable polymers is that biodegradable polymersinevitably yield low-molecular-weight compounds thatmight adversely interact with living cells while any leach-Tab. 2. Minimal requirements of biomaterials1. Non-toxic (biosafe)Non-pyrogenic, Non-hemolytic, Chronicallynon-inflammative, Non-allergenic, Non-carcinogenic,Non-teratogenic, etc.2. EffectiveFunctionality, Performance, Durability, etc.3. SterilizableEthylene oxide, c-Irradiation, Electron beams, Autoclave,Dry heating, etc.4. BiocompatibleInterfacially, Mechanically, and Biologically 120Y. Ikada, H. Tsujiables or extractables eventually contaminating non-biode-gradable polymers can be reduced to such a low level asrequired by governmental regultaions, if the polymers areextensively and carefully manufactured and purified.2.2 Surgical useApplication of biodegradable polymers to medicine didnot start recently and has already a long history. Actualand possible applications of biodegradable polymers inmedicine are shown in Tab. 3. Tab. 4 lists representativesynthetic biodegradable polymers currently used or underinvestigation for medical application. As is seen, most ofthe applications are for surgery. The largest and longestuse of biodegradable polymers is for suturing. Collagenfibers obtained from animal intestines have been longused as absorbable suture after chromium treatment6).The use of synthetic biodegradable polymers for suturestarted in USA in the 1970’s2, 7). Commercial polymersused for this purpose include polyglycolide, which is stillthe largest in volume production, together with a glyco-lide-L-lactide (90:10) copolymer2, 7). The sutures madefrom these glycolide polymers are of braid type processedfrom multi-filaments, but synthetic absorbable sutures ofmono-filament type also at present are commerciallyavailable.The biodegradable polymers of the next largest con-sumption in surgery are for hemostasis, sealing, and adhe-sion to tissues25). Liquid-type products are mostly usedfor these purposes. Immediately after application of aliquid to a defective tissue where hemostasis, sealing, oradhesion is needed, the liquid sets to a gel and covers thedefect to stop bleeding, seal a hole, or adhere two sepa-rated tissues. As the gelled material is no longer neces-sary after healing of the treated tissue, it should be biode-gradable and finally absorbed into the body. The bioma-terials used to prepare such liquid products include fibri-nogen (a serum protein), 2-cyanoacrylates, and a gelatin/resorcinol/formaldehyde mixture.2-Cyanoacrylates solidify upon contact with tissues asa result of polymerization to polymers that are hydrolyz-able at room temperature and neutral pH, but yield for-maldehyde as a hydrolysis by-product2). Regeneratedcollagen is also used as a hemostatic agent in forms offiber, powder, and assemblies.Another possible application of biodegradable poly-mers is the fixation of fractured bones. Currently, metalsare widely used for this purpose in orthopaedic and oralsurgeries in the form of plates, pins, screws, and wires,but they need removal after re-union of fractured bonesby further surgery. It would be very beneficial to patientsif these fixation devices can be fabricated using biode-gradable polymers because there would be no need for are-operation. Attempts to replace the metals with biode-gradable devices have already started, as will bedescribed later.2.3 Pharmaceutical useIn order to deliver drugs to diseased sites in the body in amore effective and less invasive way, a new dosage formtechnology, called drug delivery systems (DDS), startedin the late 1960’s in the USA using polymers. The objec-tives of DDS include sustained release of drugs for aTab. 3. Medical applications of bioabsorbable polymersFunction Purpose ExamplesBonding Suturing Vascular and intestinalanastomosisFixation Fractured bone fixationAdhesion Surgical adhesionClosure Covering Wound cover,Local hemostasisOcclusion Vascular embolizationSeparation Isolation Organ protectionContact inhibition Adhesion preventionScaffold Cellular proliferation Skin reconstruction,Blood vessel reconstructionTissue guide Nurve reunionCapsulation Controlled drugdeliverySustained drug releaseTab. 4. Representative synthetic biodegradable polymers currently used or under investigation for medical applicationPolymers StructureMwkDDegradation rate Medical applicationPoly(glycolide) Crystalline – 100% in 2–3 months Suture, Soft issue anaplerosisPoly(glycolic acid-co-L-lactic acid) Amorphous 40–100 100% in 50–100 days Suture, Fracture fixation, Oral implant,Drug delivery microspherePoly(L-lactide) Semicrystalline 100–300 50% in 1–2 years Fracture fixation,Ligament augmentationPoly(L-lactic acid-co-e-caprolactone) Amorphous 100–500 100% in 3–12 months Suture, Dural substitutePoly(e-caprolactone) Semicrystalline 40–80 50% in 4 years Contraceptive delivery implant,Poly(p-dioxanone) Semicrystalline – 100% in 30 weeks Suture, Fracture fixationPoly(orthoester) Amorphous 100–150 60% in 50 weeks(saline, 37 8C)Contraceptive delivery implant Biodegradable polyesters for medical and ecological applications121desired duration at an optimal dose, targeting of drugs todiseased sites without affecting healthy sites, controlledrelease of drugs by external stimuli, and simple deliveryof drugs mostly through skin and mucous membranes.Polymers are very powerful for this new pharmaceuticaltechnology. If a drug is administered through a parenteralroute like injection, the polymer used as a drug carriershould be preferably absorbable, because the polymer isno longer required when the drug delivery has beenaccomplished. Therefore, biodegradable polymers arewidely used, especially for the sustained release of drugsthrough administration by injection or implantation intothe body. For this purpose, absorbable nanospheres,microspheres, beads, cylinders, and discs are preparedusing biodegradable polymers26–28). The shape of the mostwidely used drug carriers is a microsphere, which incor-porates drugs and releases them through physical diffu-sion, followed by resorption of the microsphere material.Such microspheres can be prepared with a solvent-eva-poration method using glycolide-lactide copolymers.Naturally occurring biodegradable polymers are alsoused as drug carriers for a sustained release of drugs. Ifthe drug carrier is soluble in water, the polymer need notto be biodegradable, because this polymer will beexcreted from the body, associated with urine or fecesalthough excretion will take a long time if the molecularweight of the polymer is extremely high.2.4 Use for tissue engineeringTissue engineering is an emerging technology to createbiological tissues for replacements of defective or lost tis-sues using cells and cell growth factors23). Also, scaffoldsare required for tissue construction if of the lost part of thetissue is so large that it cannot be cured by conventionaldrug administration. At present, such largely diseased tis-sues and organs are replaced either with artificial organs ortransplanted organs, but both of the therapeutic methodsinvolve some problems. As mentioned earlier, the biocom-patibility of clinically used artificial organs is mostly notsafisticatory enough to prevent severe foreign-body reac-tions and to fully perform the objective of the artificialorgans aimed for patients. The biofunctionality of currentartificial organs is still poor. On the contrary, the biofunc-tionality of transplanted organs is as excellent as healthyhuman organs, but the patients with transplanted organsare suffering from side-effects induced by immuno-sup-presive drugs administered. Another major problem oforgan transplantation is shortage of organ donors.The final objective of tissue engineering is to solvethese problems by providing biological tissues and organsthat are more excellent in both biofunctionality and bio-compatibility than the conventional artificial organs.Biodegradable polymers are required to fabricate scaf-folds for cell proliferation and differentiation which resultin tissue regeneration or construction23). Biodegradablepolymers are necessary also for a sustained release ofgrowth factors at the location of tissue regeneration. Gen-erally, scaffolds used in tissue engineering are porous andthree-dimentional to encourage infiltration of a largenumber of cells into the scaffolds14). Currently, the poly-mers used for scaffolding include collagen, glycolide-lac-tide copolymers, other copolymers of lactide, and cross-linked polysaccharides.3. Ecological applications3.1 Processing of plastic wastesThe other major application of biodegradable polymers isin plastic industries to replace biostable plastics for main-taining our earth environments clean.The first choice for processing of plastic wastes isreuse, but only some plastic products can be re-used afteradequate processing, and many of them are very difficultto recycle. In these cases, wastes are processed by landfillor incineration, but these processes often pollute theenvironments. If biodegradation by-products do not exertadverse effects on animals and plants on the earth, biode-gradable plastics can be regarded as environment-friendlyor ecological materials. Therefore, much attention hasbeen focused on manufacturing biodegradable plasticswhich, however, should address several requirements.They are to be low in product cost, satisfactory inmechanical properties, and not harmful to animals andplants when biodegraded. The biodegradation kinetics arealso an important issue of biodegradable plastics.Expected applications of biodegradable polymers inplastic industries are listed in Tab. 5. As can be seen, theapplications cover a wide range of industries includingagriculture, fishery, civil engineering, construction, out-Tab. 5. Ecological applications of biodegradable polymersApplication Fields ExamplesIndustrialapplicationsAgriculture, Forestry Mulch films, Temporaryreplanting pots, Deliverysystem for fertilizersand pesticidesFisheries Fishing lines and nets,Fishhooks, Fishing gearsCivil engineering andconstruction industryForms, Vegetation nets andsheets, Water retention sheetsOutdoor sports Golf tees, Disposable plates,cups, bags, and cutleryComposting Food package Package, Containers,Wrappings, Bottles, Bags,and Films, Retail bags,Six-pack ringsToiletry Diapers, Feminine hygieneproductsDaily necessities Refuge bags, Cups 122Y. Ikada, H. Tsujidoor leisure, food, toiletry, cosmetics, and other consumerproducts. It is possible that the waste left as a result ofoutdoor activity and sports will stay for a long time innatural environments, possibly damaging them. On theother hand, when plastics are used indoors as food con-tainers that are difficult to separate from the food remain-ing after use, the waste can be utilized as compostable ifit is biodegradable.3.2 Classification of ecological plasticsBiodegradable ecological plastics are defined as polymersthat maintain mechanical strength and other material per-formances similar to conventional non-biodegradableplastics during their practical use but are finally degradedto low-molecular-weight compounds such as H2O andCO2and non-toxic byproducts by microorganisms livingin the earth environments after their use29). Therefore, themost remarkable feature of ecological plastics is theirbiodegradability.In the infancy stage of ecological plastics, natural poly-mers, especially polysaccharides, were promising candi-dates for biodegradable polymers. They included starch,chitin, cellulose, and mucopolysaccharides, but not muchattention is now paid to these polysaccharides except forcellulose and its derivatives because of their low proces-sability in molding. However, chemically substituted,grafted, and blended starch and cellulose have been inten-sively studied to improve processability and physicalproperties30, 31). For example, cellulose acetate has beenproven to be a thermoplastic and exhibit good barrierproperties to grease and oil though chemical substitutionof cellulose is well known to slow down its biodegrada-tion, while starch-poly(vinyl alcohol) (PVA) blend hasbeen investigated for relacement of low density poly-ethylene (LDPE) and polystyrene (PS).Among the biodegradable polymers that have beenmost intensively investigated are aliphatic polyesters ofboth natural and synthetic origins. Their chemical struc-tures are given in Tab. 6. They are except for poly(a-hydroxyacid)s32, 33)degraded by enzymes excreted frommicroorganisms.The synthesis of poly(a-hydroxyacid)s such as polygly-colide or poly(glycolic acid) is carried out by direct con-densation polymerization of HO1R1COOH or ring-opening polymerization of01R1CO1O1R1CO1O104).————————————The former polymerization generally yields oligomerswhile the latter results in high-molecular-weight poly-mers. Poly(hydroxyalkanoate)s (PHA) are biosynthesizedby microorganisms such as Bacillus megaterium usingstarch from corn and potato as raw materials, whilepoly(x-hydroxyalkanoate)s are synthesized by ring-open-ing polymerization of lactones9, 16). Poly(alkylene dicar-boxylate)s are generally produced by condensation ofprepolymers having hydroxyl or carboxyl terminal groupsusing chain extenders such as diisocyanate34). Direct con-densation polymerization between low-molecular-weightHO1R11OH and HOOC1R21COOH generally pro-duces only low-molecular-weight polymers.3.3 Physical properties of ecological plasticsFig. 3 shows the melting and glass-transition tempera-tures as well as the tensile moduli of representative biode-gradable polymers without any special treatments, alongwith those of typical conventional polymers. As is appar-ent, biodegradable polymers can be divided into twogroups, that is, polyethylene(PE)-like and poly(ethyleneterephthalate) (PET)-like polymers. The biodegradablepolymers with a relatively large number of methylenegroups and planar zigzag structure in a molecule are PE-like, including poly(e-caprolactone) and poly(butylenesuccinate) (PBS), while PET-like polymers such aspoly(3-hydroxybutyrate) (PHB) and poly(L-lactide)(PLLA) have helix structures and bulky side-chains.However, the elongation-at-break of PHB and PLLAobserved at tensile testing is much lower than that ofPET, resulting in low toughness and poor impactstrength9, 16). This means that some modifications, forTab. 6. Classification of aliphatic polyestersPolymers Chemical structure ExamplesPoly(a-hydroxylacid)s 1(O1CHR1CO)n1 R:H Poly(glycolide) (PGA)R:CH3Poly(L-lactide) (PLLA)Poly(3-hydroxyalkanoate)s 1(O1CHR1CH21CO)n1 R: CH3Poly(3-hydroxybutyrate) (PHB)R:CH3, C2H5Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV)Miscellaneous 1[O1(CH2)m1CO]x1 m = 3 Poly(c-butyrolactone)Poly(x-hydroxyalkanoate)s m = 3–5 m = 4 Poly(d-valerolactone)m = 5 Poly(e-caprolactone)Poly(alkylene dicarboxylate) 1[O1(CH2)m1O1CO1(CH2)n1CO]x1 m = 2, n = 2 Poly(ethylene succinate) (PES)m = 4, n = 2 Poly(butylene succinate) (PBS)m = 4, n = 2,4Poly(butylene succinate-co-butylene adipate) (PBSA) Biodegradable polyesters for medical and ecological applications123instance, copolymerization, blending, or addition, will berequired for a large industrial production of these biode-gradable polymers as real ecological plastics.Another disadvantage of biodegradable polymers istheir low crystallization temperature, which lowers thecrystallization rate. This property brings about low pro-cessability when fibers are manufactured from these poly-mers.Tab. 7 shows the moisture barrier, oxygen barrier, andmechanical properties of representative biodegradablepolymers, together with their cost31). Evidently, physicalproperties as well as the cost of these polymers dependon their chemical and physical structures. This table willgive important information to determine which polymerhas a low cost/performance for respective end uses.3.4 BiodegradabilitySimilar to biodegradation of cellulose and chitin by cellu-lase and chitinase, aliphatic polyesters undergo enzymaticdegradation. Esterases are the enzymes responsible forhydrolytic degradation of aliphatic polyesters35). As thisenzymatic reaction is of heterogeneous type, hydrolyticenzyme molecules first adsorb on the surface of substratepolymers through the binding site of enzyme mole-cules35–38). Then, the active site of the enzyme comes intodirect contact with the ester bond of the substrate mole-cule. Different activities of different hydrolytic enzymesfor the same substrate polymer may be due to differentbinding capacities of the enzymes to the substrate, asthere is no large difference in the hydrolytic activityamong enzymes. The enzymes excreted from microor-ganisms may hydrolyze polymers to low-molecular-weight compounds which will serve as a source of nutri-ents to the mother microorganisms.An important group of esterases for biodegradation ofaliphatic polyesters are lipases32, 33). These enzymes areknown to hydrolyze triacylglycerols (fat) to fatty acid andgycerol. It seems probable that lipase can hydrolyze ali-phatic polyesters in contrast with aromatic polyesters,Fig. 3. Melting and glass-transition temperatures and tensilemodulus of representative biodegradable and typical conven-tional polymers. HDPE: High-density polyethylene; LDPE:Low-density polyethylene; PA6: Nylon-6; PA66: Nylon-66;PBS: Poly(butylene succinate); PCL: Poly(e-caprolactone);PET: Poly(ethylene terephthalate); PHB: Poly(3-hydroxybuty-rate); PLLA: Poly(L-lactide); PP: Poly(propylene)Tab. 7. Moisture barrier, oxygen barrier, mechanical properties, and cost of representative biodegradable polymers31)Materials Moisture barriera)Oxygen barrierb)Mechanical Propertiesc)Cost ($/lb)Collagen Poor Good Moderate 49.00–54.00d)Gelatin Poor Good NA 2.40–2.60e)High Amylose Starch Poor Moderate Moderate 0.60–0.70e)Methyl Cellulose Moderate Moderate Moderate 4.50–7.00e)Cellulose Acetate Moderate Poor Moderate 1.60–2.10f, g)Starch/PVA Poor Good Good 1.50–3.00f)P(3HB-4HV) Good Good Moderate 3.00–6.00f)PLA Moderate Poor Good 1.00–5.00f)a)Test conditions: L38 8C, 0–90% RH (RH = relative humidity). Poor: 10–100 g N mm/mm2N d N kPa; Moderate: 0.1–10 g N mm/mm2N d N kPa; Good: 0.01–0.1 g N mm/mm2N d N kPa (LDPE: 0.08 g N mm/mm2N d N kPa).b)Test conditions: L25 8C, 0–50% RH. Poor: 100–1000 cm3lm/m2N d N kPa; Moderate: 10–100 cm3lm/m2N d N kPa; Good: 1–10cm3lm/m2N d N kPa. (Ethylene vinyl alcohol copolymer: 0.1 cm3lm/m2N d N kPa)c)Test conditions: L25 8C, 50% RH. Moderate tensile strength (rB): 10–100 MPa, Moderate elongation-at-break (eB): 10–50%(LDPE: rB= 13 MPa, eB= 500%; Oriented PP: rB= 165 MPa, eB= 60%).d)Finished film cost from supplier.e)Material cost range from suppliers.f)Compares to $/lb resin (and finished film) costs for LDPE: $0.50 ($1.00); PS: $0.55 ($2.00); PET: $0.75 ($3.00).g)Finished film cost from supplier is $4.00/lb. 124Y. Ikada, H. Tsujibecause the flexibility of the main-chain and the hydro-philicity of aliphatic polyesters is so high to allow inti-mate contact between the polyester chain and the activesite of lipases in marked contrast with the rigid main-chain and hydrophobicity of aromatic polyesters.The biodegradability of polyesters is investigated interms of the hydrophilic/hydrophobic balance of poly-ester molecules, since their balance seems to be crucialfor the enzyme binding to the substrate and the subse-quent hydrolytic action of the enzyme. Interestingly,lipases are not able to hydrolyze polyesters having anoptically active carbon such as PHB and PLLA32, 33, 39).The hydrolysis of PHA is catalyzed by PHA depoly-merase which has a sequence of -Asn-Ala-Trp-Ala-Gly-Ser-Asn-Ala-Gly-Lys- as the active center40). It is reportedthat PHB is hydrolyzed by PHA depolymerase morequickly than a copolymer of 3-hydrolxybutyrate (3HB)and 3-hydroxyvalerate (3HV) [P(3HB-3HV)] but moreslowly than the copolymer of 3HB and 4-hydroxyvalerate(4HV) [P(3HB-4HV)]41). This difference in hydrolysisrate may be explained in terms of bulkiness of the side-chain of PHA which hinders the enzymatic attack on theester bond of PHA through a steric hindrance effect.Both lipases and PHA depolymerase are enzymes ofthe endo-type which breaks bonds randomly along themain-chain of the substrate polymer, in contrast toenzymes of the exo-type which attack zipper-like thebonds at the end of the main-chain42).Finally, effects of the physical structure of the substratepolymers on their hydrolysis should be mentioned. Fig. 4gives the hydrolysis rate of films prepared from copoly-mers of butylene succinate (BS) and ethylene succinate(ES) by lipase from Phycomyces nitensas a function ofthe BS content in the copolymers43). It seems that theenzymatic hydrolysis of the copolymers greatly dependson the chemical composition. However, the more directfactor influencing the hydrolysis is not the chemical com-position but the crystallinity of the copolymer films, sincethere is a linear correlation between the hydrolysis rateand the crystallinity of the films, as is obvious from com-parison of Fig. 4 and Fig. 543), where the film crystallinityis plotted against the chemical composition of the films.Such a clear dependence of polymer hydrolysis on thesubstrate crystallinity can be also recognized in Fig. 6,Fig. 4. Increase in total organic carbon (TOC) after hydroysisof films prepared from copolymers of butylene succinate (BS)and ethylene succinate (ES) by lipase from Phycomyces nitensat 30 8C for 16 h as a function of the BS content in the copoly-mers43)Fig. 5. Crystallinity of films prepared from copolymers ofbutylene succinate (BS) and ethylene succinate (ES) as a func-tion of the BS content in the copolymers43)Fig. 6. Increase in total organic carbon (9) and weight loss (0)of PCL filaments after hydrolysis by lipase from Phizopus arrhi-zus at 30 8C for 16 h as a function of the draw ratio of the fila-ments43) Biodegradable polyesters for medical and ecological applications125where the hydrolysis rate of PCL filaments is given as afunction of the draw ratio of the filaments44). Obviously,an increase in draw ratio promotes the crystallization ofthe filaments.4. Dual applications4.1 Polylactides and PCLThere is a group of polymers that is used for both medicaland ecological applications. Among them are PLLA andPCL. Both aliphatic polyesters are synthesized by ring-opening polymerization. PLLA is degraded non-enzyma-tically in both earth environments and the human body,while PCL is enzymatically degraded in earth environ-ments, but non-enzymatically in the body45–48). Here,focus is given on polylactide, i.e., poly(lactic acid) (PLA)alone, because PLA has much more applications thanPCL and, hence, has attracted much more attention. Thegeneral term “polylactides” include not only PLLA,poly(DL-lactide), and poly(DL-lactic acid) (PDLLA), butalso PGA.4.2 Synthesis of PLAThe monomers used for ring-opening polymerization oflactides are synthesized from glycolic acid,DL-lacticacid,L-lactic acid, orD-lactic acid. Among them, onlyL-lactic acid is optically active and produced by fermenta-tion using Lactobacilli49).The raw materials for this fer-mentation are corn, potato, sugar cane, sugar beat, etc.49)All of them are natural products, similar to those of PHA.This is a great advantage over conventional polymers,which consume oil as their starting material. Natural pro-ducts can be supplied without limit, whereas oil isthought to be exhausted sooner or later in the future,though some processing energy for fermentation isneeded for the production of lactic acids. The effects ofproducing biodegradable polymers on natural environ-ments should be discussed not only by consumption ofnatural resources but also by energy consumption andeffects of by-products. However, no sufficient informa-tion concerning this issue has been obtained so far.There is a debate on the future potential of PLLA andPHA. Some researchers think that PHA will dominatePLLA in the future when plants modified with gene tech-nology will become capable of producing PHA on a largescale, while others say that ring-opening polymerizationin chemical industries is more controllable and producesa larger amount of polymer than biosynthesis in the out-door field. It seems too early to give a conclusion on thisissue, although it is clear that the most important influen-tial factor is the production cost of these polymers, andthis is a complex issue depending on many factors.The widely used catalyst for ring-opening polymeriza-tion of PLA is stannous octoate and the regulator of chainlength is lauryl alcohol50–52). By changing the concentra-tion of these additives, bulk polymerization of lactidesaround 120–140 8C yields PLA with molecular weightsranging from several thousands to several millions53).Ajioka et al. succeeded in the synthesis of PLLA by aone-step condensation polymerization ofL-lactic acidusing azeotropic solvents such as diphenyl ether54).4.3 Physical properties of PLAPhysical properties of polymeric materials depend ontheir molecular characteristics as well as ordered struc-Tab. 8. Physical properties of PGA, PLLA, PDLLA, and PCLPGA PLLA PDLLA PCLTm/ 8C 225–230 170–190 – 60Tm0 a)/ 8C – 200–215 – 71, 79Tg/ 8C 40 50–60 50–60 –60DHm(xc= 100%)/(J/g) 180–207 93 – 142Density/(g/cm3) 1.50–1.69 1.25–1.29 1.27 1.06–1.13Solubility parameter (25 8C)/(J/cm3)0.5– 22.7 21.1 20.8[a]D25in chloroform – –155 l 1 0 0WVTRb)/(g/m2/day) – 82–172 – 177rBc)/(kg/mm2) 8–100d)12–230d)4–5e)10–80d)Ef)/(kg/mm2) 400–1400d)700–1000d)150–190e)–eBg)/% 30–40d)12–26d)5–10e)20–120d)a)Equilibrium melting temperature.b)Water vapor transmission rate at 25 8C.c)Tensile strength.d)Oriented fiber.e)Non-oriented film.f)Young’s modulus.g)Elongation-at-break. 126Y. Ikada, H. Tsujitures such as crystalline thickness, crystallinity, spheruli-tic size, morphology, and degree of chain orientation.These physical properties are very important, becausethey reflect the highly ordered structure of the materialsand influence their mechanical properties and theirchange during hydrolysis. Tab. 8 summarizes the physicalproperties of PGA PLLA, PDLLA, and PCL.4.3.1 Molecular weight effectTmincreases with a rise in M—wand approaches a constantvalue around 180 8C, while xcdecreases gradually withthe increasing M—w. A physical property (P) of a poly-meric material in general can be expressed using M—nbyEq. (1):P = P0– K/M—n(1)where K is a constant and P0is the physical property ofthe polymer with infinite M—n. Fig. 7 shows the physicalproperties of solution cast PLLA and PDLA films includ-ing tensile strength (rB), Young’s modulus (E), and elon-gation-at-break (eB) as a function of 1/M—n55). Evidently,PLLA films have non-zero tensile strength when their1/M—nis lower than 2.2 610–5, in other words, M—nis higherthan 4.5 6104. The tensile properties almost linearlyincrease with a decrease in 1/M—nbelow 2.2 610–5.4.3.2 Copolymerization effectTmand xcof PLA are generally reduced by a decrease intacticity. DSC thermograms of poly(L-lactide-co-glyco-lide) [P(LLA-GA)] and poly(D-lactide-co-glycolide)[P(DLA-GA)] having differentL-lactide(LLA) andD-lac-tide(DLA) contents (XLland XDl, respectively) are shownin Fig. 856). It is obvious that Tmand xcdecrease withincreasing fraction of the GA unit, finally losing the crys-tallizability of P(LLA-GA) and P(DLA-GA) for XLlandXDlbelow 0.75. Similarly, PLA stereocopolymers losetheir crystallizability for DLA contents (XD) below 0.83and above 0.1557, 58). This result and Eq. (1) suggest thatthe crystalline thickness (Lc) of copolymers decreaseswith increasing comonomer content. The result of crystal-lizability tests of PLA stereocopolymers having differentXDfrom the melt implies that the critical isotacticsequence length of PLA for crystallization is approxi-mately 15 isotactic lactate units.The weight of poly(DL-lactide-co-glycolide) [P(DLLA-GA)] remaining after their in vitro hydrolysis is shown inFig. 959). A rapid decrease of the remaining weight isobserved for P(DLLA-GA) having high GA contents.This is probably due to the high hydrophilicity of the GAunit compared to theDL-lactide (DLLA) unit, which willaccelerate the hydrolysis rate of the copolymers havinghigh GA contents.Fig. 7. Tensile strength (rB), Young’s modulus (E), and elonga-tion-at-break (eB) of solution cast PLLA (9) and PDLA (0) filmsas a function of 1/M—n55) [...]...127 Biodegradable polyesters for medical and ecological applications Fig 9 Weight remaining for P(DLLA-GA) with DLLA contents of 100 (9), 66 (F), 42 (H), and 27% (0) as a function of hydrolysis time59) Fig 8 DSC thermograms... Fig 11 suggests that the decrease in rB of PLLA films prepared at high Ta may be ascribed to the formation of large size spherulites and crystallites in the film at high Ta PLLA is known to exhibit strong piezoelectricity when polymer chains are highly oriented Fig 12 shows piezoelectric constants of PLLA films as a function of the draw ratio at room temperature65) It is seen that both piezoelectric... miscible with PHB when the Mn of PLLA was as low Fig 11 Polarizing optical photomicrographs of PLLA films annealed at 100 (A), 120 (B), 140 (C), and 160 8C(D) after melting at 200 8C62) 129 Biodegradable polyesters for medical and ecological applications Fig 12 Piezoelectric constants of PLLA films at room temperature as a function of the film drawing ratio (9) d14 , (0) e1465) Fig 14 DSC thermograms of... temperature 0 Tm : Equilibrium melting temperature TOC: Tortal organic carbon WVTR: Water vapor transmission rate xc : Crystallinity XDl : Mol fraction of DLA in P(DLA-GA) [DLA/(GA+DLA)] 131 Biodegradable polyesters for medical and ecological applications XD : DLA content in PLA stereocopolymer [DLA/(LLA+DLA)] or PDLA content in enantiomeric polymer blends from PLLA and PDLA [PDLA/(PLLA+PDLA)] XLl : Mol . chitinase, aliphatic polyesters undergo enzymaticdegradation. Esterases are the enzymes responsible forhydrolytic degradation of aliphatic polyesters35). As. andgycerol. It seems probable that lipase can hydrolyze ali-phatic polyesters in contrast with aromatic polyesters,Fig. 3. Melting and glass-transition temperatures