Medical Plastics. Degradation Resistance & Failure Analysis

203 Pages·1998·3.227 MB·English

by  Robert C. Portnoy (Auth.)

FOREWORD
Circumstancesaredevelopingnowtodriveforwardthetechnologyofmedicalapplicationsofplastics
atarapidpace.Theexpansionofcomprehensivemedicalcareacrossallsocio-economicboundariesin
developed nations combines with penetration ofmodem medical care into undeveloped regions to
providethelatentmarketpullformedicaldevicesanddeviceanddrugpackaging. Theoverlayofthe
well-knowncostandsafetyconcernsonthisscenarioproducesahugeandrapidlygrowingmarketfor
plasticmedicalproducts.
Thusthe advancementofthisfieldoftechnology isbeingpursuedonallfronts, atthedrugand
device manufacturers, materials suppliers, machine makers, packaging companies, sterilizationpro
viders,anduniversitiesandresearchinstitutes.Andwhilethelearningswhicharegainedintheseinsti
tutionscarriesforwardtothesupportoftheirindividualpursuits,therealvalueofthisnewknowledge
isitspowertoadvancetheentireindustryonceitisfullydisseminatedasthestate-of-the-art.Thegoal
hereistointroducetothereaderthismonographasanewandeffectiveapproachtothedistributionof
thisinformation.
We are fortunate at this time to have in medical plastics active publishers and seminar, short
course,andconferenceprovidersallseedingthefieldwiththiskindofinformation.Alargenumberof
companies,professionalsocieties,tradegroups,individualsanduniversitiesprovidetrainingcourses,
butseveralorganizationsstandoutforthevolumeandqualityoftheirofferings.Amongpublishersof
periodicalsCanonCommunicationsleadstheindustrywithitswidevarietyofproductsincludingtrade
magazineslikeMedicalDeviceandDiagnosticIndustry,tradejournalslikeMedicalPlasticsandBio
materials, and trade shows and conferences like the several Medical Design and Manufacturing
(MD&M) conferences heldaround the U.S.A. and in Europe eachyear. William Andrew, Incorpo
rated,throughitsPlasticsDesignLibrary(PDL), specializesinthedevelopmentanddisseminationof
organizeddataonmaterialbehaviorincludingplasticssubjectedtoprocessesandstressescharacteris
ticofmedicalapplicationslikesterilizingdosesofhighenergyradiation.TechnomicPublishingCom
panyisalso prominentinthe offeringofshortcourses, seminars,periodicals, andbooks specifically
whichfocus onmedicaldevicesandpackaging.
Astheworld'sleadingnot-for-profitprofessionalsocietyprovidingscientificandtechnicalinfor
mationaboutplastics,theSocietyofPlasticsEngineers(SPE),Internationalofferstothosewhowork
inmedicalplasticsanextensiverangeofeducationalproductsandactivitiesincludingseminars,con
ferences, andabroadcatalogueofbooks. Throughitsdedicatedtechnicaldivision, theMedicalPlas
tics Division, SPEofferstopical conferences andAnnualTechnical Conference sessions. And, most
recently,SPEhasembarkedonthepublicationofatruearchival,peerreviewed,medicalplasticsjour
nal, TheJournalofAppliedMedicalPolymers.
Themagnitudeoftheavailableinformationiscertainlyimpressiveandmustbeusefultothesci
entistsandtechnologistspursuingadvancementsinmedicalplastic.Itisnotsurprising,however,that
thediversityoftheorganizationsofferingthematerialandtheirdifferingmissionsnaturallyresultsin
significantfragmentationoftheinformation.Thatiswhyitissoencouragingtoseetherecenttrendto
wardcooperativeconferencing,publishing,andmarketingofpublicationsamongtheseproviders.Ex
amples ofthis cooperation abound. The SPE Medical Plastics Division has for the last few years
combinedits regionallyofferedtopical conferences with the MD&Mprograms andtherebyreached
iv MedicalPlastics
bothalargerandmorevariedaudiencethanpreviously.Likewise,thepaperswhicharebeingcompiled
for the newJournalofAppliedMedicalPolymers appearfirst inMedicalPlastics andBiomaterials
wheretheyareseenbyamuchlargerandmorediversereadershipthanwouldbeinterestedinsubscrip
tiontothearchivaltechnicaljournal.
Justthiskindofcooperationhasbeenemployedinthepreparationofthismonograph. William
Andrewdevelopedaconceptfortherapidpublicationinmonographformofcurrentdevelopmentsin
medical plastics science and technology centered on a theme ofparticular interest in the field. The
naturalsourcesforpapersonthetopicweretheSocietyofPlasticsEngineersandCanonCommunica
tions,whichprocessalargevolumeofthismaterialthroughtheirconferenceandperiodicalstructures.
Andbythejointeditorialeffortsofthethreeorganizationsthisbookwascreated.
The success ofthis book will depend upon the reader's appreciation ofits combination ofan
eclecticrangeofpaperswhich,nevertheless,areunifiedbytheunderlyingtheme:improvementofthe
performanceofmedicaldevicesandpackagesthroughtheunderstandingoftheirmanymodesoffail
ure. Includedarebothtutorialpapersreviewingwellestablishedareasoftechnologyandresearchac
counts covering the latest developments in technical areas. There are several papers on analytical
methods.Someoftheseareusedtodetermineorpredicttheperformanceorassurethequalityofmedi
calgoods.Othersareusedtostudyfailedmedicalpartstoelucidatethecauseoffailure.Becausesterili
zationmethodsaresostressfultomanymaterialscommonlyusedinmedicalpartsandpackages,there
isextensivecoverageofthistopic,includingpapersonhighenergy,ethyleneoxide,andautoclavester
ilization ofpolypropylene, polyethylene, polycarbonate, andpolyvinyl chloride. The closelyrelated
areaoftheresistanceofdeviceconstructionmaterialstochemicals andotherenvironmentalstresses
likelowtemperatureisalsocoveredinseveralpapers.Sinceerrorfreeassemblyofdevicesisrequired
forthemtoresistfailure, this istreatedas well. Andfinally, severalnovelmaterialsare discussedin
lightoftheirenhancedpropertieswhichmayreducetheincidenceoffailure.
It is hoped that this material will be useful. Itrepresents both the long developed state ofthe
medicalplasticsartandthelatestinformationwhichcanbeoffered.
RobertC.Portnoy,Ph.D.
ExxonChemicalCompany
5200BaywayDrive
Baytown,TX77520
USA
An Overview of the Use of Polymers in Medical Applications as
Illustrated by the Design, Characterization, and Application of
Tyrosine-Derived Polymers
JoachimKohn
DepartmentofChemistry, Rutgers University, NewBrunswick, NJ08904, USA and
DepartmentofOrthopaedics, NewJerseyMedicalSchool, Newark, NJ07103, USA
Biomaterialsscienceandmedical dtWicedevelopmentpresentuniquelygratifyingareas ofresearch.
Theideathatworkdoneinthelaboratorytodaycanalleviatehumansufferingandevensavelivesto
morrowisapowerfuldrivingforceformanyofthebasicscientistsworkinginthefieldofbiomaterials
andmedicaldevices. Onthe otherhand, the commercializationofbasicbiomaterialsresearchrepre
sentsaparticularlydifficultchallenge.Heresomeofthe"opportunities"and"pitfalls"oftechnology
developmentinthefieldofbiomaterialsandmedicaldevicesarehighlighted,followedbyadiscussion
ofafundamentallynewgroupofmedicalimplantmaterials.
BACKGROUND
Biomaterialsareindispensablecomponentsofallmedicalimplantsanddevices andwhenpatientsus
I
ingcontactlenses, transdermal drug delivery systems, dental implants, and otherextracorporeal de
vices are included in the total count, over 30 million Americans benefit from biomaterials-based
medicaldevices. Sincemanyoftheseimplantsanddevicesarelifesaving,adisruptionintheirsupply
couldhavecatastrophicconsequencesformillionsofpeople.Consequently,themedicaldeviceindus
tryhasgrownintoasignificantsectorofthenation'seconomy,producingabout$50billioninannual
salesandbeingoneoftheveryfewmanufacturingsectorsmaintainingapositivetradebalanceinspite
2
ofincreasingcompetitionfrom EuropeanandAsianmanufacturers.
Biomaterialsresearchasascientificdisciplineisasound,vibrant,andhighlyinteractivefieldthat
has, over the last decade, lead to important scientific breakthroughs in our understanding ofcell
materials interactions. These breakthroughshave the potential to provide us with biologically func
tionalreplacementsforawiderangeoforgansandbodyparts,leadingtofundamentalimprovementsin
thewaywetreatandrepairtraumaoragingrelateddiseases. Unfortunately,biomaterialsscienceand
themedicaldevice industryareheldhostage topowerfullegal, regulatory, andeconomic forces that
have thepotentialto chokeoffscientific innovationandpreventouradvancingscientificknowledge
frombeingdevelopedintoclinicallyusefulproducts.Whileoptimistspointtothehugepotentialofthe
underlying science,pessimists argue that the business and legal climate in the United Stateshas be
comesounfavorablethatthedemiseoftheU.S.-basedmedicaldeviceindustryisarealpossibility.2
2 MedicalPlastics
OPPORTUNITIESAND SCIENTIFIC CHALLENGES
Currently,medicaldevicedesignersarelimitedtoarelativelysmallnumberofoff-the-shelfmaterials
thatwerenotoriginallydesignedtobeusedinmedicalimplants.InarecentlyconvenedNIHworkshop
on"BiomaterialsandMedicalDeviceScience",about 100ofthenation'sleadingexpertsreachedthe
conclusionthatthematerialsbaseofthemedicaldeviceindustryisoutdatedandthat"materialsandde
vicesendowedwithbiologicalstructureandfunctionmustbedesignedanddeveloped".3Thedevelop
ment ofsuch new biomaterials requires a betterunderstanding ofthe mechanisms that control cell
materialsinteractions. Thenewmaterialswillprovidebothcarefullytailoredphysicomechanicaland
chemicalproperties as wellasbiologicallyfunctional interfaceswithlivingcells. As suchimproved
materialsbecomeavailable, thereplacementofwholeorgansbysyntheticsubstitutesbecomesareal
possibility. However, the real impactofthe "biomaterials revolution" is in the envisioned improve
mentsinsafetyandefficacyofhundredsofmedicaldevices,makingitnecessaryoverthenext20years
toredesignalargefraction ofthecurrentlyavailablemedicalimplantsanddevices. Thiswillprovide
significantcommercialopportunitiesforcutting-edgecompanies.
PRODUCT LIABILITYAND INNOVATION
Whileeveryoneinthefieldseemstoagreethatfundamental scientificbreakthroughswilloccurover
thenextfewyears,leadingtodramaticallyimprovedtherapeuticapproaches,itisnotcleartowhichex
tent these scientific breakthroughs canbe translated into clinically used devices and implants. The
medical device industry faces a numberofchallenges in bringing innovative science into the clinic
(Table1).Someofthesechallengesareunavoidable,suchasthecost-intensiveandlong-termnatureof
medicalresearch.However,therearealsoobstaclesthatareartificiallyimposedupontheindustry.The
mostcontroversialissuehereintheUnitedStateshasbeentheeffectofproductliabilitylitigationon
themedicaldeviceindustry.Thelackofreasonableprotectionstorawmaterialsuppliersandmanufac
turersundercurrentproductliabilitylawsandthehugecostofmedicaltortcasessettheUnitedStates
asidefrom allothernations.
Productliability,ascurrentlypracticedintheUnitedStates,hasbeenidentifiedasaseriousthreat
tothesurvivalofthemedicaldeviceindustry.Thepointhasbeenmadethatlitigationhasdrainedbil
lions ofdollars from the medical device industry. These resources, ifused in research and develop
ment, wouldhavebeenmore than enoughto improvethe safetyandefficacyofthe medical devices
thatwerethesubjectoflitigation.Instead,productsthatbecomeengulfedinlawsuitsareusuallywith
drawn from the market, the manufacturers are forced into bankruptcy, and allresearchanddevelop
menteffortsaimedattheimprovementoftheproductscometoanend.Theneteffectofmasstortcases
isalossofavailabletreatmentoptionsforthepatient,achillingeffectoninnovationandthedevelop
mentofbetterimplants,marginalcompensationforasmallnumberofpatients,whilethelawyerswho
arguethecasesareassuredofextremelylucrativeprofits.
AstudycommissionedbytheHealthIndustryManufacturersAssociation,HIMA,andconducted
byAronoffAssociates2 investigatedtheeffectofproductliabilityonthemedicaldeviceindustryand
predictedthatamajorpartoftheUnitedStatesbasedmedicaldeviceindustrywillbelostoverthenext
fewyears. Inparticular,themarketstudypredictedthatabiomaterialscrisiswilloccurunlesssubsti
tute materials are found and approvedfor marketing, thatpatientswill nothave access to lifesaving
AnOverviewoftheUseofPolymers 3
Table1. ChallengesandObstaclestotheProcessofInnovationintheMedicalDeviceIndustrya
IntrinsicChallenges
Implantanddevice developmentrequires significantstartupcapitaland is bynature
Highcost
veryexpensivetoperform
Medicaldevicesrequirehighprofitmarginstocompensateforunsuccessfulresearch
Highrisk
effortsandforthehighdevelopmentcosts
KeyObstaclestotheDevelopmentofImprovedImplantsandDevicesinthe
UnitedStates
Excessiveand costlylitigation(oftenwithoutscientificbaseormerit)havediverted
Productliability researchand developmentfunds, slowedinnovation, andreducedthe willingness of
majorcorporationstoparticipateinthemarket
Medical device development, manufacture and marketing is highly regulated. The
Comprehensive
regulatory process discourages fundamental innovation. Compared to many other
regulation
nations,theregulatoryprocessintheUnitedStatesappearstobeslower
Governmentcontrol
Governmentcontroloverreimbursementsleads to delays and additionalrisks inthe
of the health care
marketingofmedicaldevicesandinthetestingofexperimentaldevices
market
Lack of long-term Whilefundamentalinnovationinbiomaterialssciencerequiresalong-terminvestment
financingforstartup view,venturecapitalfunds intheUnitedStatestendtofocusonshort-termgains
companies
'adaptedfromdatacontainedin1994ReferenceGuidefor theHealth Care TechnologyIndustry, HealthCareTechnology
Institute, 1994;PolicyBriefTheDialogofDeviceInnovation:AnOverviewoftheMedicalTechnologyInnovationProcess,
HealthCareTechnologyInstitute,1993.
medicalimplants,thataprimarysourceofmedicalimplantinnovationwillvanishwiththedemiseof
small manufacturers, and that major segments ofthe medical implant industry will move overseas.
Someofthepredictionscanalreadybeconfirmedbystatisticalevidence.Until 1992,themedicalde
viceindustrywasthesecondfastestgrowingAmericanindustry,providing64%oftheglobalsalesof
medicaldevices.After1992,growthslowedandtheUnitedStatesworldleadershippositionhasbegun
to erode. By 1995,theU.S. shareofglobalsaleshaddroppedto46%.4
Insummary,thescientificfoundationisnowinplacetodevelopsignificantlyimprovedmedical
implants. Tissueengineeringwillleadtoreplacementsforbodypartsandorgansthatfeelandbehave
muchmorelikenaturaltissuethanthe currentlyusedimplantsmanufacturedfrommetalsandsimple
engineeringplastics. Promisingadvancesindrugtargeting, theuseofproteinsandpeptidesas drugs,
andgene therapyalsobenefitfrom novelbiomaterials-baseddelivery systems. Whilecountrieswith
responsive regulatory, legal, and business infrastructures will be able to translate these scientific
4 MedicalPlastics
breakthroughs effectivelyintoclinicallyusefulproducts,thedevelopmenteffortintheUnitedStates
hasbegunto lagbehinditsEuropeanandAsiancompetitors.
IntheUnitedStates,productliabilityhasemergedasasignificantobstacletothedevelopmentof
improvedproductsbasedonfundamentalbreakthroughsinbasicscience.Thereismountingevidence
thatalegalsystemthataffordssubstantialfinancialgaintolawyerswhoinitiatelawsuitsirrespectiveof
scientificandrationalbasisisnotpromotingbettertreatmentoptionsfortheindividualpatientandis
notinthebestnationalinterest.
Inthefinal analysis,everyonestandstogainbytheadoptionofrational,fair, andjuststandards
governingtheconductofthemedicaldeviceindustry.Ifoneconsidersthatlawyers'feesandprofitsare
expectedtoexceed$2billioninthebreastimplantlitigationalone,onemayconcludethatakeyissueis
to redirect valuable resources from unproductive legal costs back to R&D efforts leading to better
products.
Table2. MaterialsCommonlyUsed inthe ManufactureofMedicalImplantsand Devices
TypeofMaterial SpecificExamples
Biostable polymers and Polyurethanes,siliconerubber,Teflon®,Dacron®,nylon,polymethylmethacrylate,
resins PMMA
Biodegradablepolymers Poly(lacticacid),poly(glycolicacid),polydioxanone
Natural and semi- Treated porcine grafts, bovine pericardium, processed cellulose, processed
syntheticproducts collagen
316and316Lstainlesssteel,Vitallium®,titaniumalloys,Co-Cralloy,Co-Cr-Mo
Metals
alloy
Aluminum oxides, calcium aluminates, titanium oxides, pyrolytic carbon,
Ceramics
Bioglass®,hydroxyapatite
Composites Apatitecomposites,carboncoatedmetals,carbonreinforcedpolymers
NEWPOLYMERS DERIVED FROM THE NATURALAMINOACID L·TYROSINE
As mentionedabove, one ofthe limitingfactors inthe designofimprovedmedicalimplantsandde
vices is the lackoffundamentallynewmaterials. As showninTable2,mostofthematerialsusedin
implantand device manufacturearesimpleengineeringplasticsandmetals whichwerenotintended
initiallyformedicalapplications.
Toaddress thisproblem,thenaturalaminoacidL-tyrosinewasusedas thebuildingblockfora
widerange ofnewpolymers. Firstdescribedin 1987,5degradablepolymersderivedfrom L-tyrosine
areoneofthenewestclassesofpolymersbeinginvestigatedasimplantable,degradablematerialsfor
medicalapplications. Inherentto alltyrosine-derivedpolymersisthatnon-amidebondsare incorpo
rated into thebackbone ofthepolymersby linkingindividual aminoacid-derivedmonomers viathe
AnOverviewoftheUseofPolymers 5
functional groups on the amino acid side chains. The resulting materials have been found to be
uniquelydifferentfromconventionalpoly(aminoacid)sinthattheyexhibitedsolubilityinorganicsol
ventsandprocessibilitybyconventionalmeltprocessingtechniques. Consequently,thefeasibilityof
fabricating tyrosine-derived polymers into fibers, films, rods, microspheres, porous foams, or other
configurationsappropriateformedicaldeviceshasbeenestablished.Theunderlyinghypothesisofthe
design oftyrosine-derived polymers was that a material consisting ofand degrading into nontoxic,
naturallyoccurringmetabolites(aminoacids)willelicitafavorable biologicalresponse. Recentbio
compatibility studies have exploredthis hypothesis. The following isa shortsummaryofproperties
andpossibleapplicationsofthesepolymers.
TYROSINE-DERIVED POLYCARBONATES
Thefamilyoftyrosine-derived
A polycarbonatesbasedonalkyl
o0~ #-CH2-CH2oII-C-NH'1H-~CH~2~O"-C0 esters of desaminotyrosyl
tyrosine has been studied in
c=o
oI great detail.6•9 This polymer
family consists of four
tyrosine-basedpolycarbonates
designated poly(DTE carbon
dlphenol component ate), poly(DTB carbonate),
n
poly(DTH carbonate), and
-a---------------------- poly(DTO carbonate) that re-
spectively carry either ethyl,
dlacnld component butyl, hexyl, or octyl ester
pendent chains (Figure 1).
Synthesizingthisfamilyofre
lateddegradablepolymershas
2Q~tOo-CH2-CH.J-NH'9H-CH2D-O provedfruitfulforithasfacili
c=o
I tated the study of structure
o
property correlation and pro
vided a series of polymers
with a gradient in material
dlphenol component n properties.
Tyrosine-derived poly
carbonateswerefoundtohave
Figure1.(A):Thechemicalstructureoftyrosine-derivedpolycarbonatesconsistsof relatively high strengths (50
desaminotyrosyl-tyrosinealkylesterswithdifferentestergroups:ethyl(x=2),butyl
70 MPa) and stiffness (I - 2
(x=4),hexyl(x=6),octyl(x=8).Inthetext,thecorrespondingdiphenolcompo
nentsareabbreviatedasDTE,DTB,DTH,andDTO,respectively.(B):Thechemical GPa).6The strongestandstiff
structureofpolyarylatesconsistsofadiacidcomponentandadiphenolcomponent. est polymer was poly(DTE
Thediacidsselectedforthepreparationofbiocompatiblepolyarylatesincludesuc carbonate). Increasing the
cinicacid(y=2),adipicacid(y=4),subericacid(y=6),andsebacicacid(y=8).
pendent chain length was
Thediphenolcomponentsarethesamedesaminotyrosyltyrosinealkylestersusedin
found to decrease the strength
polycarbonatesynthesis.
6 MedicalPlastics
andstiffnessofthepolymer.Noteworthyisthatthestiffuessofpoly(DTEcarbonate)exceedsthatof
otherdegradablepolymersproposedformedicalusesuchaspoly(e-caprolactone),polydioxanone,and
poly(orthoester)s. However,poly(DTEcarbonate)is moreflexible thanpoly(L-lacticacid) (2.4 - 10
GPa)andpoly(glycolicacid)(6.5GPa),twodegradablepolymerswhicharealreadyinclinicaluseas
pinsfor smallbonefixation.
The glass transition temperatures ofthis family ofamorphous polymers decreased from 93 to
52°Cwhenthelengthofthependentchainwasincreasedfromtwotoeightcarbonatoms.6Asexpected,
successive additionofmethylene groups to thependentchainmade a fairly constantcontributionto
loweringtheglasstransitiontemperature.Thedecompositiontemperaturesoftheentireserieswerein
dependentofthependentchainlengthandexceeded290°C.6Thewidegapbetweentheglasstransition
and thermal decomposition temperatures makes these polymers readilyprocessiblebyconventional
polymer processing techniques including extrusion, compression molding, and injection molding.
This highdegree ofprocessing stability is unusual among amino acidderivedpolymers whichtypi
callydecomposeinthemoltenstate.
Beingabletosystematicallyvarytheglasstransitiontemperaturesovera40°Crangetoalowof
52°Ccanbeasignificantadvantageinfacilitatingthethermalfabrication ofcontrolleddrugdelivery
devicescontainingheatsensitivedrugs. Forexample, Integrilin™ (acyclicheptapeptidethatinhibits
plateletaggregationlO) anddopamine (usedto treatParkinson'sdiseasell) were successfullyincorpo
ratedintopolymermatricesatprocessingtemperaturesaslowas80°e.Thisisinmarkedcontrasttothe
widelyinvestigatedpoly(L-lacticacid) whichrequiresprocessingtemperaturesupwards ofl70°e.
Inin vitro andin vivo studieshave found tyrosine-derivedpolycarbonatesto degraderelatively
slowly,retaining50-70%oftheirinitialmolecularweightsaftersixmonthsofincubation. Theinher
6-8
enthydrophobicityofthese materials prevents significantwatermigration requiredto hydrolyze the
polymer. Themosthydrophilicofthepolycarbonateseries,poly(DTEcarbonate),hasanequilibrium
watercontentofonly3-5%.Thedegradationratesoftyrosine-derivedpolycarbonatesarecomparable
tothedegradationrate ofpoly(L-lacticacid).
MEDICALAPPLICATIONS FORTYROSINE-DERIVED POLYCARBONATES
Controlledintracranialreleaseofdopamine from apoly(DTH carbonate)matrixwas oneofthe first
medicalapplicationsinvestigatedfortyrosine-derivedpolycarbonates.12 Poly(DTHcarbonate)hasa
,13
relatively low processing temperature and its backbone is structurally related to dopamine which
seemedto improvedopamine incorporationintothepolymer. Inin vitroexperiments, dopaminewas
releasedfromthematricesatafairly consistentrateof1-2llg/dayoveraprolonged 180dayperiod.
Thisreleaserateiswithinthetherapeuticallyusefulrangeandsetsthestagefordetailedinvivostudies.
Tyrosine-derivedpolycarbonatesappearparticularlysuitedfororthopedicdevicessuchassmall
bonefixation pinsforthe handandwrist. Consequently,biocompatibilitytestingoftyrosine-derived
polycarbonates has focused on the response ofbone to these materials. In a canine bone chamber
mode1,7theboneresponsetotyrosine-derivedpolycarbonateswassignificantlydifferentfromthere
sponseelicitedbymedicalgradepoly(L-lacticacid):Thetyrosine-derivedpolycarbonatesmaintained
closeappositiontobone,appearedtobestronglyosteoconductive,andthebone-materialinterfacewas
free ofan intervening fibrous tissue layer. In contrast, bone ingrowth into poly(L-lactic acid) test
chamberspeakedat24weeksandfelloffdramaticallyby48weeks.Histologicalanalysisofthebone-
AnOverviewoftheUseofPolymers 7
poly(L-lacticacid) interfacerevealedaninterveningfibrous tissue layerandsignificantboneresorp
tionwithaninflammatoryresponse atthe latertimepoints. Theseresults confirmedobservationsre
ported earlier when the bone response to poly(DTH carbonate) pins was compared to the response
elicitedbyOrthosorb™ pinsimplantedtranscorticallyinrabbitfemurs andtibiae.8
Thebiologicalresponse totyrosine-derivedpolycarbonatesappears tobefundamentally differ
entfromotherwidelyinvestigateddegradablepolymersfororthopedicapplications.Thefactthatthese
polymers do not degrade to crystalline particulate nor release acidic degradation products may be
partlyresponsible. Likewise, the use ofthe naturally occurring amino acid tyrosine as the building
blockforthesepolymersmaycontribute, inwaysnotfullyunderstood,tothefavorablebiologicalre
sponse elicited. Currently, long-termstudiesusing arabbitmodelare underway to documentfull re
sorption and to assure long-term biocompatibility ofthe series oftyrosine-derived polycarbonates.
Also, studies are ongoing using radioactively labeled polymers to track the fate ofthe degradation
productsinlivinganimals.Thesestudiesmayleadtotheinitiationofclinicaltrialsinhumansinthefu
ture.
TYROSINE-DERIVED POLYARYLATES
Thecharacterizationoftheseriesoftyrosine-derivedpolycarbonateshintedatthepromiseoftailoring
polymerpropertiesforspecificapplicationsbysynthesizingfamilies ofrelatedpolymersthatencom
pass a range ofproperties. To extend this concept, a series oftyrosine-derived polyarylates was re
centlysynthesizedwhichexhibitedcontinuousgradientsofchemicalmaterialandpossiblybiological
properties.14·17
Tyrosine-derivedpolyarylatesarestrictlyalternatingcopolymersofadiacidcomponentandadi
phenol component (Figure 1). By selecting a series ofdiacids with variable numbers ofmethylene
groupsandaseriesofdiphenolswithvariablependentchains,thestructureofthepolymerbackbone
and the structure of the pendent chain could be changed independently. Therefore, the series of
tyrosine-derivedpolyarylates encompasses abroadrange ofphysicalproperties. Theglass transition
temperatures,Tg'withinthisseriesofpolyarylatesrangedfrom7SoCtowellbelowbodytemperatureat
12°C.14Theadditionofmethylenegroupstoeitherthebackboneorpendentchainwasequallyeffective
inreducingtheT Likewise,concomitantwithanincreaseinpendentchainlengthfromtwoto eight
g'
carbons,asignificantdecreaseinstrengthandstiffnesswasobserved.Poly(DTEadipate),thestiffest
andstrongestpolymerofthefamily,approachesthepropertiesofthetyrosine-derivedpolycarbonates.
However, the tensilemodulusofpoly(DTOadipate)wasreducedbytwo ordersofmagnitudebythe
additionofsixcarbonstothependentchain.Themoreflexiblematerials,suchaspoly(DTOsebacate),
resemblesoftsiliconrubberintheirgeneralpropertiesandmayindeedbyasuitablereplacementfor
siliconesinanumberofmedicalapplications.
Tyrosine-derivedpolyarylatesillustratethatstructure-propertycorrelationestablishedattheout
setmaybeeffectivelyusedtohelptailormaterialpropertiestospecificapplications.Forexample,one
canselectmaterialsfrom amongthepolyarylatesthatrangefrom softandrubberytostrongandstiff,
i.e.,polymerssuitedforapplicationsasdiverseasvasculargraftsorbonefixation.Itisalsoreasonable
to assume that alterations in polymerchemistry can impactthe degradation rates and biological re
sponsetothesematerials. Oncethisfamilyofpolymersisfullycharacterized,itshouldbepossibleto
select candidate polymers that address specific application requirements. To date, tyrosine-derived
8 MedicalPlastics
polyarylateshavebeeninvestigatedasdrugdeliverysystemsfortheantithrombotic,cyclicheptapep
tideIntegrilinTM.18Promisinginvitrodatahaveledtotheinitiationofinvivoexperimentstodetermine
whetherpolyarylatefilmscanlocallyreleasethedrugatvascularstentimplantsitesandhinderthrom
busformation. Biocompatibilitystudiesofthispolymerseriesarealsounderway.
ACKNOWLEDGMENTS
TheworkreviewedinthispublicationwassupportedbyNIHGrantsGM39455andGM49894,byan
"AdvancedTechnologyProgram"grantoftheNationalInstituteofStandardsandTechnology,andby
several seed grants provided bythe New Jersey Center for Biomaterials and Medical Devices. The
authoralsoacknowledgesthesupportofaNIHResearchCareerDevelopmentAward(GM00550).
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