Surface microstructuring for controlled drug release in coronary stents [Elektronische Ressource] / Michael Stöver

Description

Technische Universität MünchenLehrstuhl für MedizintechnikSurface Microstructuring for controlled Drug Release incoronary StentsMichael StöverVollständiger Abdruck der von der Fakultät für Maschinenwesen der TechnischenUniversität München zur Erlangung des akademischen Grades einesDoktor-Ingenieur (Dr.-Ing.)genehmigten DissertationVorsitzender: Univ.-Prof. Dr.-Ing. Horst BaierPrüfer der Dissertation:1. Univ.-Prof. Dr. med., Dr.-Ing. habil Erich Wintermantel2. Dr. Sannakaisa Virtanen,Friedrich-Alexander-Universität Erlangen-NürnbergDie Dissertation wurde am 13.09.2006 bei der Technischen Universität MüncheneingereichtunddurchdieFakultätfürMaschinenwesenam21.11.2006angenommen.AbstractThis thesis introduces a novel type of electrochemical microstructuring for 316Lstainless steel. The microstructuring methods were developed as a basis for a drugeluting coronary stent system. Coronary stents are used in order to dilate narrowedarteries. In order to prevent inflammation reactions, which lead to an excessiveproliferation of cells and thus to a renarrowing of the artery, the new generation ofstents are coated with drugs. The aim of this thesis was to create three dimensionalmicrostructures on the surface as a basis for drug coatings. The microstructures aresupposed to provide a protection for the drug during the implantation process and,moreover,controlthereleaseofthedrugbyprovidingmicrodepotsretainingacertainamount of the drug.

Sujets

• Gesundheit

Informations

• Publié par: technische_universitat_munchen
• Publié le: 01 janvier 2006
• Nombre de lectures: 20
• Langue: English
• Poids de l'ouvrage: 10 Mo

Extrait

TechnischeUniversitätMünchen
LehrstuhlfürMedizintechnik

SurfaceMicrostructcouringronaforyrStecontntsrolledDrugReleasein

vStöhaelMicer

VollständigerAbdruckdervonderFakultätfürMaschinenwesenderTechnischen
UniversitätMünchenzurErlangungdesakademischenGradeseines

genehmigtenDissertation

Dr.-Ing.)(enieuroktor-IngD

Vorsitzender:Univ.-Prof.Dr.-Ing.HorstBaier

PrüferderDissertation:

1.Univ.-Prof.Dr.med.,Dr.-Ing.habilErichWintermantel
2.Univ.-Prof.Dr.SannakaisaVirtanen,
Friedrich-Alexander-UniversitätErlangen-Nürnberg

DieDissertationwurdeam13.09.2006beiderTechnischenUniversitätMünchen
eingereichtunddurchdieFakultätfürMaschinenwesenam21.11.2006angenommen.

Abstract

Thisthesisintroducesanoveltypeofelectrochemicalmicrostructuringfor316L
stainlesssteel.Themicrostructuringmethodsweredevelopedasabasisforadrug
elutingcoronarystentsystem.Coronarystentsareusedinordertodilatenarrowed
arteries.Inordertopreventinflammationreactions,whichleadtoanexcessive
proliferationofcellsandthustoarenarrowingoftheartery,thenewgenerationof
stentsarecoatedwithdrugs.Theaimofthisthesiswastocreatethreedimensional
microstructuresonthesurfaceasabasisfordrugcoatings.Themicrostructuresare
supposedtoprovideaprotectionforthedrugduringtheimplantationprocessand,
moreover,controlthereleaseofthedrugbyprovidingmicrodepotsretainingacertain
amountofthedrug.Itwasfoundthatsuitablemicrostructurescanbegenerated
byacombinedetchingmethodcomprisingafirstelectrochemicalgrainboundary
etchingstepfollowedbyanisotropicetchingstep.Thefirststepisperformedwith
nitricacidandcreatesamicrogridofnarrowgrainboundaryfurrows.Thesefurrows
arehollowedoutbyasecondetchingstep,carriedouteitherwithphosphoricacid,
hydrochloricacidoroxalicacid.Thegeneratedstructureswerefoundtobesuperior
orequalintermsofcorrosionpropertiesandcellproliferationbehaviorcompared
toconventionalgritblastedstents.Itwasshownthattheinvitroreleasebehavior
couldbesubstantiallydecelerated,withuptothreetimesmoredrugretentionafter
thefirstweekofreleaseincomparisontogritblastedstents.

I

sungZusammenfas

EswurdeeinneuesVerfahrenzurOberflächenmodifikationvonbiokompatiblem
MikrEdelstahlometerbentwicereickhelt,ausmitdendemintrdurcinsischhenelektroMatchemiscerialstrukheÄturentzungerzeugtMikrwoerstrdenukturkenönnen.im
DasVerfahrendientalsBasisfüreineMedikamentenbeschichtungvonStützenfür
verengteHerzkranzgefässe(Stents).EingroßesProblembeidieserBehandlungist
eineDiesehkoheanndurcWiedervheineerscBeschlussrate,hichtungdiedesdurchStenEntsmitzüntendungsrtzünduneaktgionenshemmendverursacenhtMedikwird.a-
mentenverhindertwerden.MitHilfedesVerfahrenswerdenineinemzweistufigen
ÄtMedikzprozamessentaMikroufzunehkavitätenmenundverzeugt,erzögdieertindfreizuseterzLagene.Essind,wurdeeinenagechwigsseewiesen,Mengedaassn
dieerzeugtenOberflächeninHinblickaufinvitroKorrosions-undZellbesiedelungs-
eigenschaftenbesserodergleichwertigzukonventionellensandgestrahltenOber-
flächensind.DerinvitroMedikamentenReleasekonnteerheblichverzögertwerden,
dieerzeugtenOberflächenwiesennacheinerWocheReleasenocheineimVergleich
zusandgestrahltenStentsbiszudreimalhöhereMengeangespeichertemMedika-
auf.tmen

II

Acknowledgements

IliketothankProf.Dr.Dr.ErichWintermantelforprovidingmetheopportunity
todevelopthisthesis,forhiscordialityandtheproductiveatmosphereinhisinsti-
e.tutMyrefereeProf.Dr.SannakaisaVirtanenalsodeservesmygratidueforherinterest
inthetopic,hersupportandherproductiveinputs.
SpecialthankstoDr.JuliaWillwhoguidedmethroughthefirstandmostdemand-
ingpartofthisthesisandcontributedsubstantiallytothesuccessofthiswork.
IalsowouldliketothankDr.JuliaKunzeforsupervisingtheelectrochemicalanal-
ysis.IamcommittedtogreatthanktoGernotKrobathforthetirelessthoroughand
criticalproofreading.InthiscontextIalsoliketothankDr.MarkusEblenkamp
andMichaelBrosch.
MycolleguesMagdaRenke-GluszkoandDr.TomSchratzenstallerdeservethanks
forthegoodcooperationandsupport.ThanksalsotoDr.BorisBehnischfrom
TransluminaLabsforprovidingthecountlessamountsofstentsandfortheproduc-
ions.discussetivMoreoverIliketothankallotherpersonswhocontributedtothesuccessofthiswork:
SusanneSchnell-Witteczek,RalfRettig,SteffiBlechinger,BarbaraRöhrnbauer,Do-
minikRietzel,FlorianBrunschön,ShadiSabeti,NilsKlink,HannaDressel,Adrian
Frenzel,UliEbnerandJosephHintermair.
NotatleastIwouldliketothankmyparentsandmysisterfortheirconsistent
supportatallmydecisions.

III

tentsCon

1Introduction1
1.1SurfaceModificationofImplants....................1
1.2StentsasaTreatmentofCoronaryHeartDisease...........3
1.2.1PathologyofAtherosclerosis...................3
1.2.2CoronaryStenting........................5
1.2.3PathologyofRestenosisandStrategiesforitsPrevention...6
1.2.4DrugDeliveryStentSystems...................8

2WorkingHypothesisandProceeding

10

3ElectrochemicalTheory16
3.1Basics...................................16
3.2SelectiveEtching.............................18
3.3TheAlloyingElementsof316L.....................19
3.4ElectrochemicalBehaviorofCr-Ni-Steels................21
3.4.1EffectofHydrochloricAcidonStainlessSteel.........22
3.4.2EffectofNitricAcidonStainlessSteel.............25
3.4.3EffectofOxalicAcidonStainlessSteel.............26
3.4.4EffectofPhosphoricAcidonStainlessSteel..........27

4MaterialandMethods29
4.1Material..................................29
4.2TheEtchingAssembly..........................30
4.2.1CalculationofCurrentDensities.................33
4.3TopographicSurfaceAnalysis......................34
4.4CrossSectionalMicrographs.......................36
4.5SoftwareAnalysisoftheDepotStructures...............37
4.6CalculationofDepotProperties.....................37
4.7CoatingProcessandAnalysisofCoatings...............39

IV

5

6

7

8

4.8ChemicalSurfaceAnalysis........................
4.8.1SEM-EDS.............................
4.8.2AugerElectronSpectroscopy...................
4.9ElectrochemicalAnalysis.........................
4.9.1CyclicVoltammetry.......................
4.9.2PotentiostaticTestsforDeterminationofIonRelease.....
4.10CellSeedings...............................
4.10.1SeedingProcess..........................
4.10.2PreparationforSEM-Imaging..................
4.11MechanicalTests.............................

MicrostructuringwithHydrochloricAcid
5.1Results...................................
5.2AnalysisoftheFormationProcess....................

MicrostructuringwithNitricAcid
6.1Results...................................
6.2AnalysisoftheFormationProcess....................
6.3ChemicalAnalysis............................
6.4MathematicalDescriptionoftheEtchingProcess...........

CombinationEtchingsonNitricAcidBasis
7.1PhosphoricAcid..............................
7.1.1ParameterAnalysisonStents..................
7.1.2SoftwareAnalysis.........................
7.2HydrochloricAcid.............................
7.2.1ParameterAnalysisonStents..................
7.2.2SoftwareAnalysis.........................
7.3OxalicAcid................................
7.3.1ParameterAnalysisonStents..................
7.3.2SoftwareAnalysis.........................
7.4EtchingswithoutpreviousElectropolishing...............

PerformanceofthemodifiedStents
8.1ChemicalPerformance..........................
8.1.1CyclicVoltammetry.......................
8.1.2ReleaseTestsofNickel......................
8.1.3AnalysisofthePassivityLayer.................
8.2BiologicalPerformance..........................

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901991949559

V

8.2.1CellSeeding............................95
8.3MechanicalPerformance.........................100
8.3.1RadialStrengthTests.......................100
8.3.2FatigueTests...........................101
8.4CoatingBehavior.............................102
8.5ReleaseKinetics..............................104

9SummaryandOutlook108
9.1Summary.................................108
9.1.1MicrostructuringwithHydrochloricAcid............108
9.1.2MicrostructuringwithNitricAcid................109
9.1.3CombinationEtchings......................110
9.1.4Performance............................111
9.1.5Conclusion.............................112
9.2Outlook..................................112

114dixenApp1010.1DeterminationofGrainSize.......................114
10.2CalculationofPolygonLine.......................114
10.3CellCultures...............................115
10.4CompositionofRingersSolution.....................117
10.5ApproximationofStrain.........................117

VI

onductintroI1

1.1SurfaceModificationofImplants

Apluralityofsubstanceshasbeenestablishedforthepurposeofsubstitutingor
supportingorganicfunctionsofthehumanbody,rangingfrommetalstoceramics
topolymers.Almostallmaterialscurrentlyusedarestillbeingoptimizedinterms
ofcompositionandprocessing.Inrecenttimes,paralleltothedevelopmentinother
fields,thefocushasbeenaimingmoreandmoreatthesurfacepropertiesofthema-
terial.Sincebodytissuenormallyinteractsonlywiththeupmostfewmicrometers
ofanimplantedmaterial,thechemicalandtopographicpropertiesoftendecideover
thesuccessorfailureofanimplantationprocess.Depe