biocompatibility, fda and iso 10993

8/9/2019 Biocompatibility, FDA and ISO 10993

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B iocompatib i l i ty, FDA and ISO 10993

Steven S. Saliterman, MD, FACPDepartment of Biomedical Engineering, University of Minnesotawww.tc.umn.edu/~drsteve


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Steven S. Saliterman, MD, FACP

Medical Microdevices

Microni t, Galambos, Affymetrix,, Lifescan, Medtronic


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Biocompatibility

Biocompatibility testing answers two

fundamental questions: Is the material safe?

Does it have the necessary physical andmechanical properties for its proposed function?

The extent to which a material needs to becharacterized depends on: Type of material,

End use of the device (is it a medical device?), Function of the material within the device.

Availability of existing data on the material.


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Biofouling Biofouling is the process whereby functioning of a

BioMEMS device is interfered with by the biologicalresponse of the host. This commonly occurs when macrophages and

foreign body giant cells (FBGCs) attach to theimplanted device, accumulate, grow and interfere

with normal operation. Surface coating of biomaterials seems one good

approach to lessen the inflammatory response,lessen macrophage adhesion and FBGCs growth,

and improve wound healing. The foreign body response by the host is largely

independent of the material’s being polymeric,ceramic or metallic; being hydrophobic orhydrophilic; or being hard or soft.


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Steven S. Saliterman, MD, FACP Voskerician, G., et al., Biomaterials 24(11), 2003

SEM photomicrographs showing fusion of macrophagesinto foreign body giant cells: Individual macrophage aggregation on silicon dioxide (day 7) (left).

Enlarging giant cell with fusion of cytoplasm and consolidation ofnuclei (day 14) (right).

Foreign Body Giant Cells


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Biocompatibility needs to be considered at the onset of

design: Use known biocompatible materials.

Individual components as well as overall packaging areimportant.

Material testing is performed to determine toxicity ofthe material, leachable substances and degradationproducts.

The FDA relies on ISO 10993 Standard and has

additional recommended steps. Outsourcing testing may be required for most

institutions and companies.


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ISO Definition of a Medical Device

Any instrument, apparatus, appliance, material

or other article, including software, whetherused alone or in combination, intended by themanufacturer to be used for human beingssolely or principally for the following purposes:

Diagnosis, prevention, monitoring, treatment oralleviation of disease;

Diagnosis, monitoring, treatment, alleviation of orcompensation for an injury or handicap;

Investigation, replacement or modification of theanatomy or of a physiological process;

Control of conception.


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The ISO 10993 Standard

The ISO 10993 International Standard pertains

to: Surface devices on the skin, mucosal membranes,

breached or compromised surfaces.

External communicating devices with blood, tissue,bone, dentin.

Implantable devices.

Its purpose is to protect humans and to serveas a framework for selecting tests to evaluate

biological responses. In so doing consideration has been given to

minimize the number and exposure of testanimals.


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Flowchart for Biocompatibility

Subparts ISO 10993 & FDA Evaluation Tests

Not all medical devices require ISO 10993

testing, including the following: Lab-on-a-chip (LOC) devices,

Micro total chemical analysis systems (µTAS) usedin laboratory instrumentation,

Point-of-care systems or hand-held devices that donot contact or penetrate the skin,

MEMS devices used in medical imaging machines.


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Characterization Methods Identification of a materials constituents and:

Changes of the material over time, Changes with exposure to different environments,

Lot-to-lot consistency for manufacturing purposes.

Methodologies: Infrared spectral analysis (IR), Thermal analysis,

Density analysis,

Molecular weight distribution,

Mechanical properties,

Surface properties,

Extract Characterization.


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Infrared Spectral Analysis (IR)

Albert, DE, Medical Device Technology,

Octo Media Ltd, June 2004


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Purified Water Extracts




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Isopropyl Alcohol Extracts




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Cytotoxicity

Cytotoxicity refers to cell damage caused by

materials, either by direct contact or byleachable substances (extracts).

Cell damage may occur by a variety of means

including activation of the complement system. The complement system involves a number of

serum factors that are activated in the presence of

antigen-antibody binding, bacteria and viruses, or

foreign materials.


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Mouse Fibroblast Cells

Normal Cytotoxicity

Image Courtesy of NAMSA


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Sensitization

Sensitization refers to a materials ability to

induce specific delayed-type hypersensitivity inthe body upon initial exposure:

Haptens,

Langerhans cells and T-cell lymphocytes, Lymphokines.

Testing:

Guinea pig maximization test (GPMT), Closed-patch test (Buehler test),

Murine Local Lymph Node Assay.


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Guinea Pig Maximization Test


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Dermal Irritation


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Systemic Toxicity Systemic toxicity (body at large):

Acute toxicity - within 24 hours, Subacute toxicity - single dose or multiple

doses of a test sample during a period from 14to 28 days,

Subchronic toxicity - at 90 days, but notexceeding 10% of the life cycle of the device,

Chronic toxicity - single or multiple exposures

to medical devices, materials and extractsduring at least 10% of their lifespan of the testanimal.


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Genotoxicity, Carcinogenicity and

Reproduction

Genotoxicity - DNA damage to somatic cells

and second generation effects throughdamage to germ cells.

Carcinogenicity toxicity – observation of testanimals for a major portion of their life span for

development of cancer. This observation mayoccur during or after exposure to testsubstances.

Reproductive toxicity - reproduction, fertility

and teratogenicity (the ability to cause birthdefects).


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Genotoxicity

Gene or point mutations, small deletions,

mitotic recombination or microscopicallyvisible chromosome changes.

Studies available:

Ames bacterial reverse mutation assay,

Mouse lymphoma assay,

Chinese hamster ovary cells, Mouse bone marrow micronucleus test.


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Steven S. Saliterman, MD, FACP Image Courtesy of NAMSA


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Implantation

Tests for assessment of the local

effects of implant material on livingtissue.

Comparison is made with reactions

observed to medical devices whoseclinic acceptability has already beenestablished.

Short term vs. long term studies.Solid vs. non-solid materials.


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Histological Changes



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Hemocompatibility

Hemocompatiblity tests evaluate the

effects of medical devices or materialsthat are in contact (or indirect contact)

with blood, on blood components.

Hemolysis is the abnormal breakdown of

blood cells.

Thrombosis is the clotting of blood with

obstruction of a blood vessel and potential

for embolization.


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Toxin Exposure

Normal Red and White Blood Cells White Blood Cell Karyorrhexis



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Degradation

Degradation is the unwanted breakdown

of implanted BioMEMS materials. Ideally in an implanted device all

materials of degradation are ultimately

removed by the body without toxicity.

Polymer degradation.

Ceramic degradation. Metal and alloy electrochemical effects,


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Polymer Degradation

Chemical bond scission due to hydrolytic and

oxidative processes. Enzymes, proteins and other cellular activity

can alter the rate and nature of degradation.

Ultraviolet cleavage of chemical bonds. Gamma and electron radiation that cause

embrittlement, discoloration and thermalinstability.

Metal induced degradation from impurities,additives or hybrid construction


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Biocompatibility of Polymers

Properties of polymers that determine theirbiocompatibility through protein absorption,cell adhesion, cytotoxicity, blood compatibility,and tissue compatibility include: Interfacial free energy,

Balance between hydrophilicity and hydrophobicityon the surface,

Chemical structure and functional groups,

The type and density of surface charge,

Molecular weight of the polymer, Conformational flexibility of the polymer,

Surface topography and roughness.


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Summary

Biocompatibility testing answers two

fundamental questions: Is the material safe?

Does it have the necessary physical andmechanical properties for its proposed function?

Biofouling is the process whereby functioningof a BioMEMS device is interfered with by thebiological response of the host.

The ISO 10993 Standard is to protect humansand to serve as a framework for selecting teststo evaluate biological responses.


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ISO 10993 Subparts discussed:

Characterization Cytotoxicity

Sensitization

Irritation System Toxicity

Genotoxicity

Implantation Hemocompatibility

Degradation

biocompatibility, fda and iso 10993

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