PolymersasBiomaterials

SourceInformationforthefollowingslides: 1)Okada,M.Prog.Polym.Sci.2002,27,87133. 2)Nair,L.etal.Prog.Polym.Sci.2007,32,762798. 3)B.Ratner,A.Hoffman,F.Schoen,andJ.Lemons:BiomaterialsScience, 2nd edition(SanDiego:ElsevierAcademicPress.2004).

PolymericBiomaterialsApplications
Therangeofapplicationsforpolymericbiomaterialsisbroad andcomplex Therearenouniversalpolymersforbiomaterials Needfordevelopingawiderangeofnon degradable\biodegradablematerialsforimplantfabrication thatappropriatelymatchthespecificandunique requirementsofeachindividualmedicalapplication. Forexample:Applicationsjustforbiodegradablepolymeric materialsaloneinclude:
largeimplants,suchasbonescrews,boneplatesandcontraceptive reservoirs smallimplants,suchasstaples,suturesandnano ormicrosizeddrug deliveryvehicles plainmembranesforguidedtissueregeneration multifilamentmeshesorporousstructuresfortissueengineering

ImportantPropertiesofPolymericBiomaterials
Thematerialshouldnotevokeasustainedinflammatoryortoxicresponse uponimplantationinthebody. Thematerialshouldhaveacceptableshelflife. Thedegradationtimeofthematerialshouldmatchthehealingor regenerationprocess(appliestobiodegradablepolymers) Thematerialshouldhaveappropriatemechanicalpropertiesforthe indicatedapplicationandthevariationinmechanicalpropertieswith degradationshouldbecompatiblewiththehealingorregeneration process((appliestobiodegradablepolymers)) Thedegradationproductsshouldbenontoxic,andabletoget metabolizedandclearedfromthebody((appliestobiodegradable polymers) Thematerialshouldhaveappropriatepermeabilityandprocessibility for theintendedapplication.

PolymerProperties
Inherentpropertiesofpolymericbiomaterialscan haveanaffectontheirbiocompatibility: materialchemistry molecularweight solubility shapeandstructureoftheimplant hydrophilicity/hydrophobicity lubricity surfaceenergy waterabsorption degradationanderosionmechanism.

PropertiesofCommonPolymersUsedin Biomaterials

B.Ratner,A.Hoffman,F.Schoen,andJ.Lemons:BiomaterialsScience, 2nd edition(SanDiego:ElsevierAcademicPress.2004).69.

B.Ratner,A.Hoffman,F.Schoen,andJ.Lemons:BiomaterialsScience, 2nd edition(SanDiego:ElsevierAcademicPress.2004).68.

B.Ratner,A.Hoffman,F.Schoen,andJ.Lemons:BiomaterialsScience, 2nd edition(SanDiego:ElsevierAcademicPress.2004).70.

B.Ratner,A.Hoffman,F.Schoen,andJ.Lemons:BiomaterialsScience, 2nd edition(SanDiego:ElsevierAcademicPress.2004).70.

B.Ratner,A.Hoffman,F.Schoen,andJ.Lemons:BiomaterialsScience, 2nd edition(SanDiego:ElsevierAcademicPress.2004).73.

B.Ratner,A.Hoffman,F.Schoen,andJ.Lemons:BiomaterialsScience, 2nd edition(SanDiego:ElsevierAcademicPress.2004).73.

Poly(esters)

Poly(esters)arethermoplasticpolymerswithhydrolyticallylabile aliphaticesterlinkagesinthebackbone Poly(esters)comprisetheearliestandmostextensivelyinvestigated classofbiodegradablepolymers

Someofthecommerciallydevelopedpolyesterbasedmeniscusrepairdevices.(Lefttoright)Mitek MeniscalRepairsystem,Clearfix Screw,Arthrex Dart,Bionx MeniscusArrow,Linvatec Biostinger,Smith& NephewTfix,20Ethibond suture.

E.Farng andO.Sherman,Meniscalrepairdevices:aclinicalandbiomechanical literaturereview,JArthrosc Relat Surg 20(2004),pp.273286.

Poly(esters)

Allpolyestersaretheoreticallydegradable:esterificationisachemically reversibleprocess
Onlyaliphaticpolyesterswithreasonablyshortaliphaticchainsbetweenester bondsdegradeoverthetimescalerequiredformostbiomedicalapplications

SynthesisofPoly(esters)
CondensationPolymerization Synthesizedfromavarietyofmonomersviacondensation polymerization
Condensationofhydroxy acids,diacids withdiols,diacid chlorideswith diols Esterinterchage reactionofdiesters anddiols
O HO R O OH + HO R' OH O R O O R' O
n

+ H2O

Difficultyinachievinghighmolecularweightpolymersby polycondensation haslimiteditsusefordevelopmentof biomaterials

SynthesisofPoly(esters)
Example:Enzymecatalyzedpolycondensation Sugarcontainingpolyestersynthesizedfromsorbitolanddivinyl sebacate usingCandidaantarctica lipaseascatalystinacetonitrile Regioselectively acylated atthe1 and6positions

H.Uyama,E.Klegraf,S.WadaandS.Kobayashi.Chem Lett (2000),p.800.

SynthesisofPoly(esters)
Ringopeningpolymerization Synthesizedfromavarietyofmonomersviaringopening polymerization

Lactides,lactonestypicalmonomers Catalysts:tin(II)2ethylhexanoate(Sn(Oct)2)(mostcommonly usedsinceitisapprovedbytheFDAasafoodstabilizer) AdvantagesofROP

Mildreactionconditions(insomecases) Reasonablereactiontimes Absenceofreactionbyproducts Canproceedinalivingfashion,controlledMW

SynthesisofPoly(esters)
Example:CatalyticCationicLivingROPofLactones CoordinationofCLtoSc(OTf)3 affordsthecationiccomplex1,followedby theattackofROHtoproducehydroxy ester2 Equilibria among2,3,4,and1 mustberapid AdvantageouscomparedwithmostanionicROPoflactoneswhichare moisture,airsensitive

N.Nomura,A.Taira,K.TomiokaandM.Okada.Macromolecules 33 (2000),

Poly(esters)Examples:Poly(glycolide)
Poly(glycolide)
Consideredtobeoneofthefirstsyntheticbiodegradablepolymers investigatedforbiomedicalapplications Highlycrystalline(45 55%crystallinity)
Hightensilemodulus Lowsolubilityinorganicsolvents

Tg rangingfrom35 40Candmeltingpointgreaterthan200C Processablebyextrusion,injectionmolding ApprovedbyFDAin1969asDEXONforbiodegradablesynthetic sutures,Biofixasbonefixationdevices Degradesbybulkerosion,randomscissionofesterlinkages

Poly(esters)Examples:Poly(Lactides)

Unlikeglycolide,lactide ischiralandexistsintwoopticallyactiveforms:L lactide andDlactide (Llactide isnaturallyoccurring) Polymerizationleadstosemicrystallinepolymers Racemicpolymerizationleadstoamorphouspolymers Poly(Llactide)(PLLA)isapprox.37%crystallinity,degreeofcrystallinity dependsonMWandpolymerprocessingparameters
Goodtensilestrength,lowextension,highmodulus(4.8GPa) Tg 6065C,Meltingtemp175C

Consideredasanidealmaterialforloadbearingapplications,i.e. orthopaedic fixationdevices PhantomSoftThreadSoftTissueFixationScrew,PhantomSutureAnchor (DePuy),FullThreadBioInterferenceScrew (Arthrex),BioScrew,Bio Anchor,MeniscalStinger (Linvatec)

Poly(esters)Examples:Poly(Lactides)
PLLAismorehydrophobicthanpolyglycolide andisslowdegradingin comparison Completeinvivoresorption:2 5.6years Hydrolyticdegradationviabulkerosionmechanismbyrandomscissionof theesterbackbone
Degradesintolacticacid(anormalhumanmetabolicbyproduct)whichisbrokendown intowaterandCO2 viathecitricacidcycle

Losesstrengthinapprox.6monthswhenhydrolysed,butnolongterm massloss Poly(DLlactide)(PDLLA)isamorphous,randomdistributionofL andD lactide unitsandhasaTgof5560C. Lowerstrength(1.9GPa) Losesstrengthin12monthswhenhydrolysed andundergoesmassloss within1216months Preferredfordrugdeliveryvehicles,lowstrengthscaffoldingfortissue regeneration

Poly(esters)Examples:Polydioxanone

Polydioxanone firstcommerciallydevelopedmonofilamentsutureunder thetradenameofPDS inthe1980s. Multifilamentsutureshaveahigherriskofinfectionassociatedwiththeir useandcausesagreateramountoffrictionwhenpenetratingtissues. Verylowglasstransi ontemperaturerangingfrom10 Cto0 C Slowtomoderatelydegradingmaterial Brokendownintoglycoxylate andexcretedintheurineorconvertedinto glycineandsubsequentlyintocarbondioxideandwater Modulusisverylow(approximately1.5 GPa)comparedtopolyglycolides. Knowntoloseitsstrengthwithin12monthsanditsmasswithin612 monthsbyhydrolyticdegradation

Poly(esters)Examples:Polycaprolactone

Polycaprolactone (PCL) semicrystalline polyesterandisofgreatinterest asitcanbeobtainedbytheROPofarelativelycheapmonomericunit caprolactone PCLishighlyprocessible,solubleinawiderangeoforganicsolvents, Meltingpoint(5560C)andglasstransi ontemperature(60C) Lowtensilestrength(approximately23 MPa)butextremelyhigh elongationatbreakage(>700%) Abilitytoformmiscibleblendswithwiderangeofpolymers. Slowdegradation,highpermeabilitytomanydrugsandnontoxicity,PCL wasinitiallyinvestigatedasalongtermdrug/vaccinedeliveryvehicle.
LongtermcontraceptivedeviceCapronor,iscomposedofPCL,developedforthelong termzeroorderreleaseoflevonorgestrel CompositesofPCLwithcalciumphosphatebasedceramicsarealsocurrentlybeing investigatedassuitablescaffoldsforbonetissueengineering

Poly(esters)Examples:Poly(trimethyl carbonate)

Highmolecularweightflexiblepoly(trimethylene carbonate)(PTMC)can beobtainedbytheROPoftrimethylene carbonate Elastomericaliphaticpolyesterwithexcellentflexibilityandpoor mechanicalstrength

Investigatedasacandidateimplantmaterialforsofttissueregeneration

Unlikethepreviouslydescribedpolyesters,PTMCundergoessurface degradationwiththerateofinvivo degradationwasfoundtobemuch higherthaninvitro degradation.

Higherinvivo degradationratepresumablyduetothecontributionofinvivo enzymatic degradationprocess

Lowmechanicalperformanceofthehomopolymer significantlylimitsits applications

Developedasblockcopolymersoftrimethylene carbonateandglycolides foruseas flexiblesuturematerials(Maxon)andorthopaedic tacksandscrews(Acufex)

Poly(esters)Examples:BacterialPolyesters
CH3 CH CH2 O O
n

poly(3-hydroxybutyrate)

Bacterialpolyestersarenaturallyoccurringbiodegradablepolyesters producedbymanybacteriaastheirenergysource Mostcommonpolymeramongthisclassispoly(3hydroxybutyrate)(PHB), producedbythebacteriaBacillusmegaterium,discoveredinthe1920s Otherbacterialstrainsproducethesamepolymerasasemicrystalline isotacticpolymer Undergoessurfaceerosionbyhydrolyticcleavageoftheesterbonds Meltingtemperatureintherangeof160180 C Glasstransi ontemperatureintherangeof5to20 C. HydrolyticdegradationofPHBresultsintheformationofd()3hydroxy butyricacidwhichisanormalconstituentofblood

Poly(esters)Examples:BacterialPolyesters BiosynthesisofPHB

Twoenzymesinvolvedinthereactionsforconvertingaceticacidto3 hydroxybutyricacid Ketothiolase (1),whichcatalyzesthedimerizationoftheCoenzymeA derivativeofaceticacid,acetylCoA,toacetoacetylCoA, Reductase (2),whichcatalyzesthehydrogenationofthelatterto[R]3 hydroxybutyryl CoA,themonomerthatispolymerizedtoPHBbya synthase(3)

Oeding,V.;Schlegel,H.G.Biochem.J.1973,134,239. Senior,P.J.;Dawes,E.A.Biochem.J.1973,134,225.

PHBgranulesinthecholoroplast ofArabidopsisthaliana