Biocompatability,FDA,

ISO10993,andIVDregulation
ENAS411/711
04242014

Biocompatibility
Twofundamentalquestions:
Isthematerialsafe?
Doesithavethenecessaryphysicalandmechanicalpropertiesforits
proposedfunction?

Extentoftestingdependson:
Typeofmaterial
Enduseofdevice
Functionofmaterialwithindevice

FDAGuidance
GoodGuidancePractices implementedbytheFDACenterforDevices
andRadiologicalHealth
Processing
Content
Evaluation

Design
Production
Manufacturing
Testingofregulatedproducts
Inspectionandenforcementofprocedures

ReferstotheuseofInternationalStandardISO10993
Outsourcingofbiocompatibilitytestingispossible(Ie.NAMSA)

InternationalOrganizationforStandardization
Federationofnationalstandardbodies
IntheUnitedStates:ANSI
AmericanNationalStandardsInstitute

CollaborateswiththeIEC
InternationalElectrotechnical Commission

Adraftinternationalstandardneeds75%approvaltobecome
publishedasaninternationalstandard.

ISO10993Standard
Pertainstothebiologicalevaluationofmedicaldevices
ApplicabletomanybioMEMS devices:
Surfacedevicesforskin,mucosalmembranes,breachedsurfaces
Externalcommunicatingdeviceswithblood,tissue,bone,anddentin
Implantabledevices

DoesNOTpertaintolaboratoryinstrumentation,pointofcare
systems,handhelddevicesthatdonotcontactorpenetrateskin,
medicalimagingdevices

MedicalDevices
Anyinstrument,apparatus,appliance,material,orotherarticle,
includingsoftware,whetherusedaloneorincombination,intendedby
themanufacturertobeusedforhumanbeingssolelyorprincipallyfor
thepurposeofdiagnosis,prevention,monitoring,treatment,or
alleviationofdisease;diagnosis,monitoring,treatment,alleviationof
orcompensationforaninjury,orhandicap;investigation,replacement
ormodificationoftheanatomyorofaphysiologicalprocess;orfor
controlofconception[ISO109931]

MedicalDevices
Longtermimplantation:ie.Implantedendoprosthetic devicesto
substituteforbone,joint,orrelatedstructures
Intermediatetermimplantation:ie.Insulinpumpandpacemaker
Shorttermimplantation:ie.Drugdeliverysystemssuchas
microsphereencapsulation

Biologicalevaluation
Biologicaltestingisonlyrequiredifthedevicewillbedirectlyor
indirectlycontactingthebody.
Surfacecontactingdevices(skin/mucosalmembranes)
Externalcommunicatingdevices(blood,tissue,bone,dentin)
Implanteddevices(tissue,bone,blood)

Frequencyofexposure:
Limitedexposure(upto24hours)
Prolongedexposure(24hoursto30days)
Permanentcontact(over30days)

ISO10933standardsubparts
1.
2.
3.

Overviewofevaluationandtesting
12.
Animalwelfarerequirements
13.
Testsforgenotoxicity,carcinogenicity,and
reproductivetoxicity
14.
4. Selectionoftestsforinteractionwithblood
15.
5. Testforinvitrocytotoxicity
6. Testforlocaleffectsafterimplanation
16.
7. Ethyleneoxidesterilizationresiduals
17.
8. Selectionandquantificationofreference
materialsforbiologicaltests
9. Frameworkforidentificationandquantificationof18.
potentialdegredation products
19.
10. Testsforirritationanddelayedtypesensitivity
11. Testforsystemictoxicity

Samplepreparationandreferencematerials
Identificationandquantificationofdegredation
productsfrompolymericmedicaldevices
Identificationandquantificationofdegredation
productsfromceramics
Identificationandquantificationofdegredation
productsfrommetalsandalloys
Toxicokinetics studydesignfordegredation
productsandleechables
Establishmentofallowablelimitsforleechable
substances
Chemicalcharacterizationofmaterials
Physiochemical,mechanical,morphologicaland
topographicalcharacterizationofmaterials

Characterizationmethods
Infraredspectralanalysis
Thermalanalysis
Densityanalysis
Gelpermeationchromatography
Electronmicroscopy
Atomicforcemicroscopy
Extractcharacterization
Ie:leeching

Cytotoxicity
Celldamagecausedbymaterialseitherbydirectcontactorleechable
substances

Albert(2004)

Testing
Qualitativemicroscopicevaluation:

Morphology
Detachment
Celllysis
Membraneintegrity

Quantitativeevaluation:

Celldeath
Inhibitionofgrowth
Proliferation
Secretions

SystemicToxicity
Effectswithinthebodyatlarge
Notjustatsiteofexposure
Toevaluatethepotentialeffectsofchemicalextractables from
medicaldevicesonorgansystems

AcuteToxicity
Adverseeffectsthatoccurwithin24hours
Estimatepotentialharmfuleffectsofsingleormultipleexposureina
periodoflessthan24hours
Canleadtosystemictoxicity

Subacute,subchronic,andchronictoxicity
Subactute toxicity:Adverseeffects1428days.
Subchronic toxicity:Adverseeffectsat90daysbutnotexceeding10%
ofthedevicelifecycle.
Chronictoxicity:Adverseeffectsduringatleast10%ofthetestanimal
lifespan

Genotoxicity,carcinogenicity,reproduction
Genotoxicity tests:experimentstodetermineiftestmaterialscause
dna orchromosomalchange
Genemutationtests:ie.ames bacterialreversemutationassayand
mouselymphomaassay
Chromosomalaberrationtests:ie.Presense/absenceofexogenous
metabolicactivationinChinesehamsterovarycellsandmousebone
marrowmicronucleustest
Carcinogenicitytests:testforthedevelopmentofcancereither
duringorafterexposuretotestsubstances
Reproductivetoxicity:reproduction,fertility,orbirthdefects

Hemocompatability
Evaluatestheeffectsofbloodcontactingmedicaldevices
Evaluatesmaterialsonbloodcomponents

Hemocompatability Testing
Thrombosis:detectedwithlightorscanningEM.invivoorexvivo
testscanalsobeperformed.Deviceisplacedinclinicalsettingand
removedtoevaluatethedegreeofthrombosis.
Coagulation:measurethepartialthromboplastin time
Plateletcounts
Absolutecellcounts(RBC,WBC)
Immunologicalstudies:Complementfactors

Biofouling
Biofouling:processwherethefunctionofabioMEMS deviceis
interferedwithbythebiologicalresponseofhost.
Ie.Accumulationofforeignbodygiantcells

Mediatedby:
Surfacecoating
Surfacechemistryandtopology
Surfacemicroarchitecture

Biocompatibilityofothermaterials

Singlecrystalsilicon
Silicondioxide
Siliconnitride
Polysilicon
Titanium
SU8photoresist
AllexceptsiliconnitrideandSU8fellbelowdetectablelimitsinwater
Cytotoxicitywasbelowgrade2forallmaterials.
Allmaterialsclassifiedasnoniritants in112weekrabbitmuscleimplant
Kotzar etal.2002

Biocompatibilityofothermaterials
Metallicgold
Siliconnitride
Silicondioxide
Silicon
SU8
Performedsubcutaneouscageimplant
Allmaterialsexceptsiliconhadsimilarresponsestoemptycontrol.

Kotzar etal.2002

Spinefusionandpressuresensors

Ferraraetal.2003

BrainTissueMicroelectrode

Kristensen etal.2001

IVDregulatoryprocessforFDAapproval
Invitrodiagnosticproductsarethosereagents,instruments,and
systemsintendedforuseindiagnosisofdiseaseorotherconditions,
includingadeterminationofthestateofhealth,inordertocure,
mitigate,treat,orpreventdiseaseoritssequelae.Suchproductsare
intendedforuseinthecollection,preparation,andexaminationof
specimenstakenfromthehumanbody.[21CFR809.3]

Pathwaysforregulatoryapproval
1)510(k)premarketsubmission
2)PMAsubmission
3)Denovo reclassification
4)Marketingunderinhousedevelopedassay

Espina andLiotta.Springer.2012

Pathwaysforregulatoryapproval
Generalrequirements:
a) Availabilityofadequatespecimenswithassociatedclinicaldata
b) Samplesrelevanttointendedmarket/question
c) Compliantwithinformedconsentand/orregulatoryissues
d) Lackoflegalorethicalissues

Espina andLiotta.Springer.2012

510(k)
Generallyusedforteststhatmonitordiseaseprogression
Rapidregulatorypathforthemarketingofdiagnostictestordevice.
Qualifiesforapprovalifthenewtestisshowntobesubstantially
equivalenttoanexistingtestonthemarket

Espina andLiotta.Springer.2012

PMA
Requiredforscreeningtests
Ifthenewdiagnostictechnologycannotbeconsideredsubstantially
equivalenttoexistingtechnology
and
Willbeusedtomakeacriticalmedicaldecisionconcerningthe
diagnosis,treatment,ormedicalmanagementofapatient

Espina andLiotta.Springer.2012

Denovoreclassification
Lowtomoderateriskdeviceortestthatdoesnothaveapredicate
device
First,a510(k)issubmittedforFDAruling
Ifnotsubstantiallyequivalentthenpetitionfordenovo
reclassification.

Espina andLiotta.Springer.2012

HomeBrew
FDAdoesnotspecificallyregulatethesetypesofassays,butisin
chargeofitsclassificationintheUSA.
Inhousedevelopedtestsbroughttomarketbyaspecificmedical
centerorreferencelab.
Testisperformedinhouseonlyinthedesignatedlaboratory.
Testisperformedonpatientsamplessentdirectlytothelabfroma
outsidephysiciansofficeormedicalfacility.

Espina andLiotta.Springer.2012