Biocompatibility, FDA and ISO 10993

Biocompatibility, FDA and ISO 10993
Steven S. Saliterman, MD, FACP

Department of Biomedical Engineering, University of Minnesota
www.tc.umn.edu/~drsteve
Medical Microdevices
Micronit, Galambos, Affymetrix,, Lifescan, Medtronic
Biocompatibility
z
Biocompatibility testing answers two

fundamental questions:
z
z
Is the material safe?

Does it have the necessary physical and
mechanical properties for its proposed function?
The extent to which a material needs to be

characterized depends on:
z
z
z
z
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.
Biofouling
z
Biofouling is the process whereby functioning of a

BioMEMS device is interfered with by the biological
response of the host.
z This commonly occurs when macrophages and
foreign body giant cells (FBGCs) attach to the
implanted device, accumulate, grow and interfere
with normal operation.
z Surface coating of biomaterials seems one good
approach to lessen the inflammatory response,
lessen macrophage adhesion and FBGCs growth,
and improve wound healing.
z The foreign body response by the host is largely
independent of the materials being polymeric,
ceramic or metallic; being hydrophobic or
hydrophilic; or being hard or soft.
Foreign Body Giant Cells

z
SEM photomicrographs showing fusion of macrophages

into foreign body giant cells:
z
z
Individual macrophage aggregation on silicon dioxide (day 7) (left).

Enlarging giant cell with fusion of cytoplasm and consolidation of
nuclei (day 14) (right).
Voskerician, G., et al., Biomaterials 24(11), 2003
Biocompatibility needs to be considered at the onset of

design:
z
z
z
z
Use known biocompatible materials.

Individual components as well as overall packaging are
important.
Material testing is performed to determine toxicity of

the material, leachable substances and degradation
products.
The FDA relies on ISO 10993 Standard and has
additional recommended steps.
Outsourcing testing may be required for most
institutions and companies.
ISO Definition of a Medical Device

z
Any instrument, apparatus, appliance, material

or other article, including software, whether
used alone or in combination, intended by the
manufacturer to be used for human beings
solely or principally for the following purposes:
z
z
z
z
Diagnosis, prevention, monitoring, treatment or

alleviation of disease;
Diagnosis, monitoring, treatment, alleviation of or
compensation for an injury or handicap;
Investigation, replacement or modification of the
anatomy or of a physiological process;
Control of conception.
The ISO 10993 Standard

z
The ISO 10993 International Standard pertains

to:
z
z
z
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 serve

as a framework for selecting tests to evaluate
biological responses.
In so doing consideration has been given to
minimize the number and exposure of test
animals.
z
z
z
z
Flowchart for Biocompatibility

Subparts
ISO 10993 & FDA Evaluation Tests
Not all medical devices require ISO 10993
testing, including the following:
z
z
z
z
Lab-on-a-chip (LOC) devices,

Micro total chemical analysis systems (TAS) used
in laboratory instrumentation,
Point-of-care systems or hand-held devices that do
not contact or penetrate the skin,
MEMS devices used in medical imaging machines.
Characterization Methods
z
Identification of a materials constituents and:

z
z
z
Changes of the material over time,

Changes with exposure to different environments,
Lot-to-lot consistency for manufacturing purposes.
Methodologies:
z
z
z
z
z
z
z
Infrared spectral analysis (IR),

Thermal analysis,
Density analysis,
Molecular weight distribution,
Mechanical properties,
Surface properties,
Extract Characterization.
Infrared Spectral Analysis (IR)
Albert, DE, Medical Device Technology,

Octo Media Ltd, June 2004
Purified Water Extracts

Isopropyl Alcohol Extracts

Cytotoxicity
z
Cytotoxicity refers to cell damage caused by

materials, either by direct contact or by
leachable substances (extracts).
Cell damage may occur by a variety of means
including activation of the complement system.
z
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.
Mouse Fibroblast Cells
Normal
Cytotoxicity
Image Courtesy of NAMSA
Sensitization
z
Sensitization refers to a materials ability to

induce specific delayed-type hypersensitivity in
the body upon initial exposure:
z
z
z
Haptens,
Langerhans cells and T-cell lymphocytes,
Lymphokines.
Testing:
z
z
z
Guinea pig maximization test (GPMT),

Closed-patch test (Buehler test),
Murine Local Lymph Node Assay.
Guinea Pig Maximization Test
Irritation
z
Irritation refers to a non-specific inflammatory

response to a single, repeated or continuous
application of a material.
Areas tested:
z
z
z
z
z
Skin,
Eyes,
Oral mucosa,
Genitalia,
Rectum.
Rabbits and human subjects are often used.
Dermal Irritation
Systemic Toxicity
z
Systemic toxicity (body at large):

z
z
z
z
Acute toxicity - within 24 hours,

Subacute toxicity - single dose or multiple
doses of a test sample during a period from 14
to 28 days,
Subchronic toxicity - at 90 days, but not
exceeding 10% of the life cycle of the device,
Chronic toxicity - single or multiple exposures
to medical devices, materials and extracts
during at least 10% of their lifespan of the test
animal.
Genotoxicity, Carcinogenicity and

Reproduction
z
Genotoxicity - DNA damage to somatic cells

and second generation effects through
damage to germ cells.
Carcinogenicity toxicity observation of test
animals for a major portion of their life span for
development of cancer. This observation may
occur during or after exposure to test
substances.
Reproductive toxicity - reproduction, fertility
and teratogenicity (the ability to cause birth
defects).
Genotoxicity
z Gene
or point mutations, small deletions,

mitotic recombination or microscopically
visible chromosome changes.
z Studies available:
Ames bacterial reverse mutation assay,
z Mouse lymphoma assay,
z Chinese hamster ovary cells,
z Mouse bone marrow micronucleus test.
z
Implantation
z Tests
for assessment of the local

effects of implant material on living
tissue.
z Comparison is made with reactions
observed to medical devices whose
clinic acceptability has already been
established.
z Short term vs. long term studies.
z Solid vs. non-solid materials.
Histological Changes
Hemocompatibility
z Hemocompatiblity
tests evaluate the

effects of medical devices or materials
that are in contact (or indirect contact)
with blood, on blood components.
Hemolysis is the abnormal breakdown of
blood cells.
z Thrombosis is the clotting of blood with
obstruction of a blood vessel and potential
for embolization.
z
Toxin Exposure
Normal Red and White Blood Cells
White Blood Cell Karyorrhexis
Degradation
z Degradation
is the unwanted breakdown

of implanted BioMEMS materials.
z Ideally in an implanted device all
materials of degradation are ultimately
removed by the body without toxicity.
z Polymer degradation.
z Ceramic degradation.
z Metal and alloy electrochemical effects,
Polymer Degradation
z
z
z
z
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 thermal
instability.
Metal induced degradation from impurities,
additives or hybrid construction
Biocompatibility of Polymers
z
Properties of polymers that determine their

biocompatibility through protein absorption,
cell adhesion, cytotoxicity, blood compatibility,
and tissue compatibility include:
z
z
z
z
z
z
z
Interfacial free energy,

Balance between hydrophilicity and hydrophobicity
on 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.
Other Characteristics
z
Low molecular weight polymers have less

protein adsorption and platelet adhesion than
higher ones.
Molecules that are rigid and globular are less
able to attach to cell membranes compared to
linear and branched polymers with greater
flexibility.
Surface roughness may be more related to
inducing thrombosis than other surface
properties.
Summary
z
Biocompatibility testing answers two

fundamental questions:
z
z
Is the material safe?

Does it have the necessary physical and
mechanical properties for its proposed function?
Biofouling is the process whereby functioning

of a BioMEMS device is interfered with by the
biological response of the host.
The ISO 10993 Standard is to protect humans
and to serve as a framework for selecting tests
to evaluate biological responses.
ISO 10993 Subparts discussed:

z
z
z
z
z
z
z
z
z
Characterization
Cytotoxicity
Sensitization
Irritation
System Toxicity
Genotoxicity
Implantation
Hemocompatibility
Degradation

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What are the two fundamental questions addressed in biocompatibility testing?

What are the two fundamental questions addressed in biocompatibility testing?

What is biofouling and how can it interfere with implanted devices?

What is biofouling and how can it interfere with implanted devices?

Biocompatibility, FDA and ISO 10993

Steven S. Saliterman, MD, FACP

Steven S. Saliterman, MD, FACP

Micronit, Galambos, Affymetrix,, Lifescan, Medtronic

Biocompatibility testing answers two

Is the material safe?

The extent to which a material needs to be

Steven S. Saliterman, MD, FACP

Biofouling is the process whereby functioning of a

Steven S. Saliterman, MD, FACP

Foreign Body Giant Cells

SEM photomicrographs showing fusion of macrophages

Individual macrophage aggregation on silicon dioxide (day 7) (left).

Steven S. Saliterman, MD, FACP

Voskerician, G., et al., Biomaterials 24(11), 2003

Biocompatibility needs to be considered at the onset of

Use known biocompatible materials.

Material testing is performed to determine toxicity of

Steven S. Saliterman, MD, FACP

ISO Definition of a Medical Device

Any instrument, apparatus, appliance, material

Diagnosis, prevention, monitoring, treatment or

Steven S. Saliterman, MD, FACP

The ISO 10993 Standard

The ISO 10993 International Standard pertains

Surface devices on the skin, mucosal membranes,

Its purpose is to protect humans and to serve

Steven S. Saliterman, MD, FACP

Flowchart for Biocompatibility

Lab-on-a-chip (LOC) devices,

Steven S. Saliterman, MD, FACP

Identification of a materials constituents and:

Changes of the material over time,

Infrared spectral analysis (IR),

Steven S. Saliterman, MD, FACP

Infrared Spectral Analysis (IR)

Steven S. Saliterman, MD, FACP

Albert, DE, Medical Device Technology,

Purified Water Extracts

Steven S. Saliterman, MD, FACP

Albert, DE, Medical Device Technology,

Isopropyl Alcohol Extracts

Steven S. Saliterman, MD, FACP

Albert, DE, Medical Device Technology,

Cytotoxicity refers to cell damage caused by

The complement system involves a number of

Steven S. Saliterman, MD, FACP

Mouse Fibroblast Cells

Sensitization refers to a materials ability to

Guinea pig maximization test (GPMT),

Steven S. Saliterman, MD, FACP

Guinea Pig Maximization Test

Steven S. Saliterman, MD, FACP

Irritation refers to a non-specific inflammatory

Rabbits and human subjects are often used.