Beyond ISO‐10993: Challenges for the Future

James M. Anderson, MD, PhDDepartments of Pathology, Macromolecular

Science and Biomedical EngineeringCase Western Reserve University

Cleveland, Ohio

BiocompaLbility

“The ability of a material to performwith an appropriate host responsein a specific application”

The biocompaLbility of a long term implantablemedical device refers to the ability of thedevice to perform its intended funcLon, withthe desired degree of incorporaLon in the host,without eliciLng any undesirable local orsystemic effects in that host.

D.F. Williams, Biomaterials, 29 (2008) 2941‐2953

The biocompaLbility of a scaffold or matrix fora Lssue engineering product refers to theability to perform as a substrate that willsupport the appropriate cellular acLvity,including the facilitaLon of molecular andmechanical signalling systems, in order toopLmise Lssue regeneraLon, without eliciLngany undesirable local or systemic responses inthe eventual host.

D.F. Williams, Biomaterials, 29 (2008) 2941‐2953

BiocompaLbility refers to the ability of abiomaterial to perform its desired funcLonwith respect to a medical therapy, withouteliciLng any undesirable local or systemiceffects in the recipient or beneficiary of thattherapy, but generaLng the most appropriatebeneficial cellular or Lssue response in thatspecific situaLon, and opLmising the clinicallyrelevant performance of that therapy

D.F. Williams, Biomaterials, 29 (2008) 2941‐2953

What does it take to bring newly developedpolymer technology from bench‐to‐bedside?

Structure/Property RelaLonship

Polymer Structure/Biological Property RelaLonship

Biological Design Criteria

Biological Response EvaluaLon

Toxicology

Preclinical Models

Mechanisms

Biomaterials‐Tissue InteracLons

BioresorbLon‐BiodegradaLon

Poly(1,3‐Trimethylene Carbonate)

  High Molecular Weight         Low Molecular Weight         Hydrophobic       Hydrophilic

 Lipase‐EnzymaLc DegradaLon    Acid Hydrolysis

OXIDATION OF UHMW POLYETHYLENERADIATION STERILIZATION, STORAGE, IN VIVO

Decrease in ElongaLon to Failure

Increase in ElasLc Modulus

Decrease in FaLgue Crack PropagaLon Resistance

Premature Failure In Vivo

HIGHLY CROSSLINKED UHMW POLYETHYLENEIMPROVES WEAR RESISTANCE

HOWEVER, CROSSLINKING ADVERSELY AFFECTS:UNIAXIAL DUCTILITY

FRACTURE TOUGHNESS

FATIGUE CRACK PROPAGATIONRESISTANCE

BIOCOMPATABILITY “HOT BUTTONS”Chronic InflammaLon

Immune Response

Innate ImmunityAcquired Immunity

InternaLonal Standards OrganizaLon

Known as ISO is a world-wide federation ofnational standards bodies (ISO member bodies)

ISO technical committees prepare standards,requires 75% of votes of whole body to pass asa standard

InternaLonal Standards OrganizaLon‐Scope

The general principles governing the biologicalevaluation of medical devices

The categorization of devices based on the natureand duration of their contact with the body

The selection of appropriate tests Note: does not cover testing of materials and

devices that do not come into direct or indirectcontact with the body nor does it cover biologicalhazards arising from mechanical failure

TesLng‐General Principles

Testing shall be performed on the final productor on a representative sample of the finalproduct or materials used in the final product

Terms and DefiniLons

Medical Device Material Final Product

Medical Devices

Any instrument, apparatus, appliance, material or otherarticle, including software, whether used alone or incombination, intended by the manufacturer to be used, forhuman beings solely or principally for the purpose of► diagnosis, prevention, monitoring, treatment or alleviation of disease► diagnosis, monitoring, treatment, alleviation of or compensation for an

injury or handicap► investigation, replacement modification of the anatomy or of a

physiological process► control of conception

Medical Devices

Also, and which does not achieve its principal intendedaction in or on the human body by pharmacological,immunological or metabolic means, but which may beassisted in its function by such means

Devices are different from drugs and their biologicalevaluation requires a different approach.

Use of the term medical device includes dental devices

Material

Any synthetic or natural polymer, metal, alloy,ceramic, or other nonviable substance includingtissue rendered nonviable, used as a medicaldevice or any part thereof

Final Product

A medical device in its “as-used” state

ISO 10993‐1

3.3   The following should be considered for their relevance    to the overall biological evaluaLon of the device:a) The material(s) of manufactureb) Intended addiLves, process contaminants and residuesc) Leachable substancesd) DegradaLon productse) Other components and their interacLons in the final productf) The properLes and characterisLcs of the final product

3.5 All potenLal biological hazards should be consideredfor every material and final product, but this does notimply that tesLng for all potenLal hazards will benecessary or pracLcal

ISO 10993‐1

5.1 b) The choice of test procedures shall take into account:

3)   The toxological acLvity of the chemical elementsor compounds in the formulaLon of the final product

4)  That certain tests (e.g. those designed to assesssystemic effects) may not be applicable where thepresence of leachable materials has been excludedor where leachables have a known and acceptabletoxicity profile

ISO 10993‐17)  That the protecLon of humans is the primary goal of this document, a

secondary goal being to ensure animal welfare and to minimize thenumber and exposure of test animals.

Expanded test protocols may combine iniLal evaluaLon tests.Examples could be sensiLzaLon, irritaLon and intracutaneousreacLvity tests in a single, expanded protocol; or systemic toxicity,subacute and subchronic toxicity, chronic toxicity and implantaLontests in a single, expanded protocol.

The biological evaluaLon performed in accordance with this part ofISO 10993 should be considered in conjuncLon with the nature andmobility of the ingredients in the materials used to manufacture thedevice and other informaLon, other non‐clinical tests, clinical studiesand post‐market experience for an overall assessment.

General Principles of Biological EvaluaLon ofMedical Devices

Selection and evaluation of a material or medical devicefor use in humans requires a structured program ofassessment

In selection of materials the first consideration is withregard to characteristics and properties of the material,including chemical, toxicological, physical, electrical,morphological and mechanical properties

General Principles of Biological EvaluaLon ofMedical Devices

The following need to be considered for theirrelevance to the overall biological evaluation ofthe device

The material(s) of manufacture Intended additives, contaminants or residues Leachable products Degradation products Other components and their interaction with the final product Properties and characteristics of the final product

If appropriate, identification and quantificationof extractable chemical entities of the finalproduct should preceed biological evaluation

General Principles of Biological EvaluaLon ofMedical Devices

Tests to be used in biological evaluation and the interpretation of theresults of such tests should take into account the chemicalcomposition of the materials, including the conditions of exposure andthe nature, degree, frequency and duration of exposure of the deviceor its constituents to the body and therefore devices can becategorized

The range of biological hazards can be Short term effects-acute toxicity, irritation to tissues, hemolysis,

thrombogenicity Long-term or specific toxic effects-sensitization, genotoxcity,

carcinogenicity, and effects on reproduction

General Principles of Biological EvaluaLon ofMedical Devices

All potential biological hazards should be consideredfor every material and final product, but does notimply that testing for all potential hazards will benecessary or practical

Any in vitro tests shall, be based on end-useapplications and require good laboratory practicefollowed by evaluation by competent people

Whenever possible in vitro screening should proceedin vivo testing

General Principles of Biological EvaluaLon ofMedical Devices

The materials or final product shall be considered forbiological re-evaluation if any of the following occur: Any change in the source or in the specification of the

materials used in the manufacture of the product Any change in the formulation, processing, primary

packaging or sterilization of the product Any change of the final product during storage Any change in the intended use of the product Any evidence that the product may produce adverse

effects in humans

CategorizaLon of Medical Devices

Based on the previous, medical devices can becategorized to facilitate the selection ofappropriate tests. Accordingly they arecategorized:To the nature of body contactDuration of body contact

Note: non contact devices are not included

CategorizaLon of Medical Devisesby Nature of Body Contact

Surface Contacting Devices Skin- electrodes, compression bandages Mucosal membranes- contact lenses, stomach tube Breached or combined surfaces-dressings, healing patches

External Communicating Devices Blood path indirect- solution administration sets Tissue/bone/dentin- dental cement, arthroscopes Circulating blood- catheters, temporary pacemakers,

oxygenators

Implant Devices Tissue/bone or tissue/tissue fluids- pins, plates, breast

implants, replacement joints, pacemakers, drug supplydevices

Blood- pacemaker electrodes, heart valves, vascular grafts,VADs

CategorizaLon of Medical Devicesby DuraLon of Body Contact

Limited exposure- < 24 hrs Prolonged exposure- 24hrs-30 days Permanent contact- exceeds 30 days

TesLng‐General Principles

Choice of tests should take into account the following withregard to the final product:

Nature, degree, duration frequency and conditions of exposure toor contact with the device

Chemical and physical nature Toxicological activity of the chemical elements or compounds in

the formulation Certain tests (systemic effects) may not be applicable (leachability) Relationship of the device to body size Existing information based on literature, experience or non-clinical

studies Protection of humans is the primary goal, animal welfare is also

considered (harm and reduction of numbers)

TesLng‐General Principles

If extracts of the device are prepared, the solventsand conditions of extraction used shall be appropriateto the nature and use of the final product

Positive and negative controls shall be used Test results cannot ensure potential for biological

hazard, therefore, biological evaluations shall befollowed by careful observations for unexpectedadverse reactions or events in humans during clinicaluse

Biological EvaluaLon TestsIniLal

• Cytotoxicity• Sensitization• Irritation• Intracutaneous reactivity• Systemic Toxicity (acute)• Subacute/Subchronic Toxicity• Genotoxicity• Implantation• Hemocompatibility

ANIMAL MODELS FOR THE IN VIVO ASSESMENT OF MEDICAL DEVICESDEVICE CLASSIFICATIONCardiovascular

Heart Valves

Vascular grams

Stents

Ventricular assist devices

ArLficial Hearts

Ex vivo shunts

Orthopedic/bone

Bone regeneraLon/subsLtutes

Total joints – hips, knees

Vertebral implants

Craniofacial implants

CarLlage

Tendon and ligament subsLtutes

Neurological

Peripheral nerve regeneraLon

Electrical sLmulaLon

Ophthalmological

Contact lens

Intraocular lens

ANIMAL

Sheep

Dog, pig

Pig, rabbit, dog

Calf

Calf

Baboon, dog

Rabbit, dog, pig, mouse, rat

Dog, goat, nonhuman primate

Sheep, goat, baboon

Rabbit, pig, dog, nonhuman primate

Rabbit, dog

Dog, sheep

Rat, cat, nonhuman primate

Rat, cat, nonhuman primate

Rabbit

Rabbit, monkey

Biological EvaluaLon TestsSupplemental

• Chronic Toxicity• Carcinogenicity• Reproductive Toxicity• Biodegradation• Toxicokinetics• Immunotoxicity

POTENT IMMUNOLOGICAL EFFECTS AND RESPONSES

EFFECTS

HypersensiLvity

Type I – anaphylacLc

Type II – cytotoxic

Type III – immune complex

Type IV – cell‐mediated (delayed)

Chronic inflammaLon

Immunosuppression

ImmunosLmulaLon

Autoimmunity

RESPONSES

Histopathological changes

Humoral responses

Host resistance

Clinical symptoms

Cellular responses

T cells

Natural killer cells

Macrophages

Granulocytes

REPRESENTATIVE TESTS FOR THE EVALUATION OF IMMUNE RESPONSES

FUNCTIONAL ASSAYS

Skin TesLng

Immunoassays (e.g. ELISA)

Lymphocyte proliferaLon

Plaque‐forming cells

Local lymph node assay

Mixed lymphocyte reacLon

Tumor cytotoxicity

AnLgen presentaLon

Phagocytosis

PHENOTYPING

Cell surface markers

MHC markers

Chemokines

BasoacLve amines

SOLUBLE MEDIATORS

AnLbodies

Complement

Immune complexes

Cytokine paoerns

(T‐cell subsets)

Cytokines (IL‐1,

IL‐1ra, TNFα, IL‐6,

TGF‐β, IL‐4, IL‐13)

SIGNS OF ILLNESS

Allergy

Skin rash

UrLcaria

Edema

Summary

Materials induce cell and tissue responses-“biocompatibility”

Medical device, material(s) and final product

General principles of biological evaluation of medicaldevices

Categorization of medical devices

Testing- general and specific aspects

ALTERNATIVE TESTING

ALTERNATIVE TESTINGSKIN IRRITATION AND SENSITIZATION

•ReducLon in TesLng Time

•Lower Costs

•No Animals

European Union CosmeLcs DirecLve

1976, 1993, 2003, 2009

  ‐  Bans animal use for:   Skin Irritancy     Corrosivity

   SensiLvity to Light     Skin absorpLon

   GeneLc Toxicity          Eye Irritancy

   Acute Toxicity

  ‐  Bans import of cosmeLcs that have beentested by these methods

European Centre for the ValidaLon ofAlternaLve Methods (ECVAM)

hop://ecvam.irc.it/

EPISKINTM and EpidermTM AssaysPrimary Endpoint – MTT Cell Viability

Secondary Endpoint – IL‐1α Cell AcLvaLon

Toxicity Pathway‐Based Risk Assessment:Preparing for Paradigm Change

NRC/NAS Symposium, May 11‐13, 2009

Toxicity TesLng in the 21st Century:A Vision and a StrategyNRC/NAS Report 2007

ISO 10993‐4 HEMOCOMPATABILITY

hemolysis (both direct and indirect contact)

complement activation with direct contact, measuringboth C3a and SC5b9 (concern is for potential foranaphylaxis)

material-mediated thrombogenicity, tested underpreferred in vivo, non-heparinized, venous implantmodel

FDA Requirements for ALL Devices in Contact with BloodRegardless of the DuraLon of Contact

TISSUE ENGINEERINGIMMUNOTOXICITY

ImmunosuppressionImmunosLmulaLonHypersensiLvityChronic InflammaLonAutoimmunity

BIOCOMPATABILITY “HOT BUTTONS”Chronic InflammaLon

Immune Response

Innate ImmunityAcquired Immunity

What does it take to bring newly developedpolymer technology from bench‐to‐bedside?

Structure/Property RelaLonship

Polymer Structure/Biological Property RelaLonship

Biological Design Criteria

Design of Replacement Tissues

Sequence of Events

Intended Application

Tissue Procurement and Material

In Vitro, In Vivo, Ex Vivo Testing

Regulatory Issues (Safety)

USP United States Pharmacopia

ASTM American Society for Testing of Materials

BSI British Standards Institute

Tripartite Agreement Standards-Canada, Great Britain,USA

ISO International Standards Organization

Safety EvaluaLon of Biomaterials