生物材料人工心脏

7.4IMPLANTABLECARDIACASSISTDEVICES1.CLINICALNEEDANDAPPLICATIONS2.VENTRICULARASSISTDEVICEDESIGNANDBLOODCONTACTINGMATERIALS3.COMPLICATIONSANDVADBIOCOMPATIBILITYISSUES4.ROTARYBLOODPUMPSFORCHRONICCIRCULATORYSUPPORT5.CONCLUSION1生物材料人工心脏5/9/20241.CLINICALNEEDANDAPPLICATIONSHeartfailureresultsinmorethan43,000deathsperyearintheUnitedStatesandcontributestothedeathofanother220,000individuals.Thereareapproximately400,000newcasesdiagnosedannuallyandthosediagnosedwiththisconditionhaveamortalityrateofabout50%at5years(AmericanHeartAssociation,1999).Forend-stagepatientshearttransplantationhasbecomeaneffectivetreatmentoverthepast20years,largelyasaresultoftheintroductionofsuccessfulimmunesuppressiondrugssuchascyclosporine.Actuarialsurvivalratesforhearttransplantpatientsarecurrently75%at3years(UnitedNetworkforOrganSharing,1999).Thesuccessofhearttransplantationislimited,however,byaninadequateandstagnantdonorsupply.Although35,000–64,000patientscouldpotentiallybenefitfromhearttransplantationannually(Funk,1991),in2003,only2055cardiactransplantswereperformedintheUnitedStates.Whilewaitingforscarcedonororganstobecomeavailable,approximately20%ofindividualslistedforhearttransplantationdieannually(UnitedNetworkforOrganSharing,1999).Toaddresstheneedtosupportthecirculationinpatientswithend-stageheartfailureawidevarietyofmechanicaldeviceshavebeendevelopedoverthepastseveraldecades.Currentdevicesthatarewidelyusedforthepurposeofbridge-to-cardiactransplantationwillbediscussedinthischapter,aswillcirculatorysupportdevicesthatmayenterthemarketinthenearfuture.2生物材料人工心脏5/9/2024Thesedevicesdonotreplacethepatient’sheart(aswouldatotalartificialheart),butratherworkasventricularassistdevices(VADs).ThegeneralconceptbehindaVADcanbeseeninFig.1.2.VENTRICULARASSISTDEVICEDESIGNANDBLOODCONTACTINGMATERIALS3生物材料人工心脏5/9/2024VADshaveprovidedcirculatorysupporttoend-stageheartfailurepatientswhootherwisewouldhavealowlikelihoodofsurvivinguntiladonororganbecameavailable.Nearly70%ofpatientsundergoingVADsupporthavesurviveduntilhearttransplantation(Mehtaetal.,1995).PatientsundergoingVAD“bridging”generallydonotundergofurtherdeteriorationintheirconditionand,evenmarkedlyimprovedend-organfunctionandanimprovementintheirhealthstatusduetoimprovedperfusion(Frazieretal.,1994).Ironically,thesuccessofVADbridginghasbeenimplicatedinintensifyingthedonorshortagebyincludingrecipientswhowouldotherwisehavenotsurviveduntiltransplantation(Massadetal.,1996).AsecondresultofthistrendistheneedforincreasinglyextendedperiodsofVADsupportpriortoorganavailability.Evaluatewhethertheheartmuscleitselfmayundergorecoveryfromthediseaseprocessofheartfailureduringthesupportperiod.Theattractivenessinbridgingtorecoveryliesinfreedomfromtransplantationandimmunosuppressivetherapyforthepatientandanincreaseddonororgansupplyforthecommunity.Earlyclinicalexperiencewiththisprocedureindicatesthat,althoughsuccesscanbeachieved,patientsmustbecarefullyscreenedforthisprocedureandthemajorityofVADpatientsareunlikelytomeetselectioncriteria(Loebeetal.,1999).4生物材料人工心脏5/9/2024AnotherresultoftheincreasinglypositiveexperienceofsupportingpatientsuntiltransplantationwithVADsistheconceptofusingVADsasapermanentsourceofcirculatorysupportorasa“destinationtherapy.”AnumberofpermanentVADimplantshaveoccurredinEuropeinthepastseveralyearsandarandomizedtrialcomparingVADimplantationwithmedicaltherapyinpatientswhorequire,butareineligibleforhearttransplantation,hasbeeninitiatedintheUnitedStateswithsupportfromtheNationalHeart,Lung,andBloodInstitute(Roseetal.,1999).Anumberoffactorshaveledtotheconsiderationandinvestigationofpermanentsupport:thelimiteddonororgansupply,asignificantpatientpopulationthatfailstomeetageandmedicaleligibilityrequirementsfortransplantlisting,andimprovedqualityoflifewithrecentportableVADdesigns.MajorconcernsregardingthisoptionfocusprimarilyonthecomplicationsthatremainassociatedwithVADsupport.Asonemightexpect,biomaterialperformanceanddevicebiocompatibilityarecentraltotheperceivedlimitsofutilizingVADsasalternativestotransplantinend-stageheartfailurepatients.5生物材料人工心脏5/9/2024TAHTAHisadevicethatreplacebothofthetwoventricles.Inthemid-1980s,thefirstimplantsoftheJarvik-7totalartificialheart(TAH)intendedforpermanentsupport(DeVriesetal.,1984).However,medicalcomplicationssuchasinfectionandthromboembolism,aswellasmanufacturingconcerns,ledtothediscontinuationofTAHuseaspermanentsupport.AbiocorCardioWest6生物材料人工心脏5/9/2024Thesuccessofimmunosuppressivetherapieswasbeingreported,raisinghearttransplantationtotheroleofpreferredtherapyforendstageheartfailure.TheTAHwassubsequentlytransferredtoadifferentcorporatesponsor(CardioWest,Tucson,AZ)andutilizedinthebridgetotransplantrole(Guy,1998).Hearttransplantation7生物材料人工心脏5/9/2024InthemeantimeVADswerebeingusedasinvestigationaldevicesforbridgingpatientstotransplantationwithdemonstratedsuccess.Inthe1990sseveralVADsreceivedFDAapprovalforuseasabridgetocardiactransplantation.SupportedprimarilybytheNationalInstitutesofHealth,researchanddevelopmentofTAHsisongoing;however,clinicalcirculatorysupportisaccomplishedalmostexclusivelybyVADs.Thisisnottosay,however,thattheTAHisnotcurrentlyusedinthebridge-tocardiac-transplantationrole.TheCardioWestTAHhasbeenimplantedin150patientssince1993andhasasuccessrateofbridgingpatientstotransplantationcomparabletothatofthemorewidelyutilizedVADs(Arabiaetal.,1999;Copelandetal.,1997).VADs8生物材料人工心脏5/9/2024ThoratecTheThoratecVAD(ThoratecLaboratories,Pleasanton,CA)isbaseduponthePierceDonachyVADoriginallydevelopedinthemid-1970satPennsylvaniaStateUniversityandcurrentlyhasbeenimplantedinover1000patients.Ofparticularnoteistheparacorporealnatureofthisdevice.restsonthelowerabdomenParacorporealdrivelines9生物材料人工心脏5/9/20241.Oneadvantageofthistypeofdesignisthepotentialtoimplantsmallerpatients.2.Havethepotentialtobeusedinabiventricularsupportmodewithtwodevicesimplantedintandem3.Althoughaportablepneumaticsystemisinclinicaltrials,manycurrentThoratecpatientsaretetheredtoaratherlargedriveconsolethatlimitsmobilityandthepotentialfordischargetohome.Performanceinflowcannulaandthepumpingsac——Thoralon,aproprietarypolyurethaneelastomerblendedwithasurface-modifyingagent.outflowcannula——proximallyofThoralonpolyurethanethatfusesdistallywithaDacrongraft,toallowsuturingtotheascendingaorta.Materials10生物材料人工心脏5/9/2024NovacorTheNovacorLeftVentricularAssistSystemisaVADdesignedexclusivelyforleft-sidedsupportoftheheart.DevelopedbyPeerPortnerandcolleaguesinthe1970s(Portneretal.,1978)theNovacorsystemhasundergonedesignrefinementoverthepasttwodecadesandhasnowbeenimplantedinalmost1000patientsworldwide.restspredominantlywithinthebodycavityonlyasinglepercutaneouslinecontrollerandpowerpackonabelt11生物材料人工心脏5/9/20241.Thereducedsizeofthecompletesystemallowsgreatpatientmobilityand,inmanyinstances,dischargetohomewhilethepatientawaitswordofdonororganavailability.2.Theimpactofsuchdischargeontheeconomicsofsupportingpatientswithend-stageheartfailureisgreat.3.SuchportablesystemsalsoofferqualityoflifeimprovementsthathaveleadtotheimplantationoftheNovacorsystemasanalternativetotransplantioninEurope.Theinflowandoutflowconduits——22-mm-diameterlowporosity,gelatin-sealedwovenpolyestergrafts(SulzerVascutek).SmoothBiomerpolyurethanepumpingsacthathasamaximumstrokevolumeof70ml.MaterialsPerformance12生物材料人工心脏5/9/2024HeartMateTheHeartMateVADisthemostwidelyutilizedVADdesigntodatewithmorethan2000patientshavingbeenimplantedworldwide.HeartmateIIHeartmate13生物材料人工心脏5/9/2024BatteryHeartmateController14生物材料人工心脏5/9/2024Fromamaterialsperspective,theHeartMatedesigndepartssubstantiallyfromtheThoratecandNovacorVADs.Thebloodandtissuecontactingsurfacesofthetitaniumcannulaaresurfacecoatedwithsinteredtitaniummicrospheres50–75μmindiameter,asseeninFig.4A.Thepumpingsaciscomposedononesideofatitaniumalloysurfacewithsinteredtitaniummicrospheres.OntheopposingsidetheflexiblepusherplatediaphragmismadeofBiomerpolyurethanethathasbeentexturedonitsblood-contactingsurfacewithsurfaceintegralfibrilsapproximately18μmindiameterand300μminlength,asseeninFig.4B(Menconietal.,1995).

Materials15生物材料人工心脏5/9/2024Thesesurfacesrapidlyclotupondeviceplacement,and,whileclotsrapidlyformonthesesurfaces,thesethrombiaredenselyadherentanddonotappeartoembolizeintothebloodstreaminaclinicallyrelevantmanner.Theblood-contactingbiologicalinterfacethatdevelopsfromtheinitialsurfacecoagulumafterapproximately1weekisreferredtoasthepseudointimallayer(Fig.5)andhasbeenshownnottogrowinthicknessexceeding150μmoverperiodsofimplantationontheorderof1year(Menconietal.,1995).16生物材料人工心脏5/9/20243.COMPLICATIONSANDVADBIOCOMPATIBILITYISSUESComplicationsassociatedwiththeimplantationandoperationofVADsincludethromboembolism,infection,andbleeding.Manyoftheprocessescontributingtothecomplicationmaybeindependentofthebiomaterialimplant.Ofparticularrelevancehereisthehealthstatusofthepatientatthetimeofdeviceimplantation.IndependentofVADimplantationend-stageheartfailurepatientsareatriskforinfectionduetopoorperfusion,compromisedimmunefunction,extendedexposuretonosocomialinfections,andinvasivemonitoringdevices.17生物材料人工心脏5/9/2024ThromboembolismThromboembolicratesforVADsupportvarywidelyamongthespecificdevicesstudiedandthereportingcenters.RatescanvarysimplyduetotheaverageimplantperiodoftheVAD,thehealthofthepatientsselectedforsupport,andthepatientmedicalmanagementroutine.Aswithallcardiovasculardevices,anticoagulationandantiplatelettherapyareoptionstocontrolthereactionsatthedevice–bloodinterface.MostcommonlypatientswithNovacorandThoratecdevicesaremanagedacutelywithheparinandchronicallywithoralanticoagulants(i.e.,warfarin)andantiplateletagents.FortheHeartMateVADpatientsgenerallyarenotgivenchronicanticoagulation,andinonlyafractionofthepatientpopulationareantiplateletagentsadministered.ThelowerrateforthromboemboliccomplicationsinHeartMateVADpatientsisattributedtothetexturedsurfacesdiscussedearlierwhichleadtotheformationofabiologicalpseudointima.18生物材料人工心脏5/9/2024InfectionInfectionisconsideredbymanyphysiciansandinvestigatorstobethemostseriouscomplicationfacingVADpatientsandamajorobstacletotheimplementationofcurrentVADdesignsaspermanentimplantstotreatend-stageheartfailure.Asimplantperiodsforbridge-to-transplantpatientsincrease,theprimarycauseofdeathbecomesinfection(El-Banayosyetal.,1999a).Infectionratesgenerallyfallnear50%forallthreeaforementionedtypesofVADs(Sunetal.,1999;McBrideetal.,1999;El-Banayosyetal.,1999a).Theseinfectionscanbeclassifiedaspositiveculturesfrompercutaneousdrivelinesandcannulas,andfromtheVADpocketormediastinum.19生物材料人工心脏5/9/2024Managementofinfectioninpatientscanbeaccomplishedtoareasonabledegreewithantibioticsandantifungalagents.ForthosepatientswithsuspectedinfectionoftheinteriorVADsurfaces,ithasbeensuggestedthatdevicereplacementmaybeaneffectivemethodoftreatmentiftransplantisnotashort-termoption(Argenzianoetal.,1997).InFig.7abioprostheticinflowvalveremovedfromaNovacorVADpatientsufferingfromaCandidaalbicansinfectionisseen.20生物材料人工心脏5/9/2024Preventionofinfectionisaprimarygoalduringdeviceimplantationandlaterpatientmedicalmanagement.1.Prophylacticantibioticsand,insomeinstances,antifungalagentsareutilizedintheperioperativeperiod.2.Carefulcleaningandattentiontothepercutaneousdrivelineandcannulasitesarealsoofprimaryimportance.3.Fromabiomaterialsperspectivetwoimportantdesignissuesarise.First,itiscriticalfortheexteriorsurfacesofthedrivelinesandcannulastorapidlyencouragetissuehealingandtodiscouragebacterialcolonization.Second,themechanicalpropertiesofthepercutaneouslinesareofrelevanceinthatlargemismatchesinstiffnessbetweentheskinandlinesplacesstressatthebiomaterial–tissueinterface.Theresultingabrasionmaypreventorretardadequatewoundhealing.21生物材料人工心脏5/9/2024TheVADdesignimprovementmostlikelytoaffectinfectionrateswillbetheintroductionoftranscutaneousenergytransmission(TET)andcontrolsystems,andeliminationofthepercutaneousline(Weissetal.,1999).PercutaneouslinesTET22生物材料人工心脏5/9/2024AVADmodelusedtranscutaneousenergytransmission(TET)system.23生物材料人工心脏5/9/2024BleedingBleedingremainsapotentiallylethalcomplicationassociatedwithVADimplantation,butonethatgenerallyoccursintheearlypostoperativeperiod,whennumerouswoundsitesexist.Reportedbleedingratesfallinthe30–35%range(McBrideetal.,1999;El-Banayosyetal.,1999b).Subsequenttripstotheoperatingroomtoaddressbleedingplacepatientsatriskforbacterialandfungalcolonization,linkingthiscomplicationtoinfectionrisk.Afterpostoperativestabilization,ThoratecandNovacorpatientsareplacedonchronicanticoagulationtherapy,whichcarriesanongoingriskforover-anticoagulation(andpossiblebleeding).Ofparticularconcernintheextendedsupportsettingarecerebralbleedsleadingtoneurologiccomplications.AnticoagulationintheseVADpatientsisthuscarefullymonitoredthroughouttheimplantperiod.Toreducetheincidenceofbleedingintheperioperativeperiod,antifibrinolyticdrugs,suchasaprotinin(抑肽酶),arenowroutinelyutilizedandhavehadmarkedeffectsinreducingbloodlossandperioperativemortality(Goldsteinetal.,1995).24生物材料人工心脏5/9/2024MechanicalFailureIntheextensiveclinicalexperiencewithVADsoverthepastdecadetherehavebeenveryfewreportedincidentsofmechanicalfailurerelatedtomaterialissues.Inbridge-to-transplantimplantations,bearingwearhasbeenreportedbuthasnotledtocatastrophicfailure(Sunetal.,1999).OthercomplicationsreportedinvolvetearingofDacroninflowconduitsintheHeartMatedeviceasseeninFig.8(Scheldetal.,1997).Thiscomplicationwaslikelyduetowearfromthemetalsupportcagerubbingonthegraftsurface,andthedesignhassincebeenalteredtoconstraincagemotion.25生物材料人工心脏5/9/20244.ROTARYBLOODPUMPSFORCHRONICCIRCULATORYSUPPORTIn1994theNationalHeart,LungandBloodInstitute(NHLBI)issuedarequestforproposals(RFP)entitled,“InnovativeVentricularAssistSystems—IVAS”(NHLBI-HV-94-25).Someofthefeaturesdesiredintheseinnovativemechanicalcirculatorysupportdeviceswere:●Fiveyearoperationwith90%reliability●Totallyimplantablewithnoexternalventing●Sizeandweightcharacteristicssuitableforimplantationinbothmalesandfemalesbetween18and70yearsofage●Demonstratedbiocompatibilityincludingavoidanceofclinicallysignificantthromboembolism,bleeding,tissueovergrowth,infection,tissueheating,andleakageofdevicefluidsintosurroundingtissuesAcceptablylowlevelsofaudiblenoiseandmechanicalvibration●Flowcapacityof3–7L/minagainstameanarterialpressureof90mmHg(whenoperatingasaVADinsupportoftheleftventricle)●Capabilityfortransmissionofenergyfromoutsidetoinsidethebody,anddiagnosticsintoandoutoftheimplantableVAD26生物材料人工心脏5/9/2024RotarybloodpumpshaveanumberofadvantagesovertheVADscurrentlyusedclinically.Therotarypumpsaresignificantlysmaller,havefewermovingparts,andarefreefromvalvesandcyclicactuatorsthusmorereliableanddurable.LoweroverallvolumesofimplantedmaterialswillmakethesesystemsapplicabletopatientsgenerallyexcludedfromcurrentimplantableVADs,e.g.,smallerwomenandchildren.Also,withthesmallerpumpsize,lessofapocketneedstobecreatedinthebodyforimplantationandthismayreducebleedingandinfectionrates.Withoutvalvesandthecompressionofapumpingsac,therotarypumpsarealsomuchquieterthancurrentpulsatile-flowgeneratingdevices.VAD(Heartmate)Rotatorybloodpump27生物材料人工心脏5/9/202428生物材料人工心脏5/9/2024Anrotator