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Beyond ISO‐10993: Challenges for the Future
James M. Anderson, MD, PhDDepartments of Pathology, Macromolecular
Science and Biomedical EngineeringCase Western Reserve University
Cleveland, Ohio
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BiocompaLbility
“The ability of a material to performwith an appropriate host responsein a specific application”
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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
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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
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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
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What does it take to bring newly developedpolymer technology from bench‐to‐bedside?
Structure/Property RelaLonship
Polymer Structure/Biological Property RelaLonship
Biological Design Criteria
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Biological Response EvaluaLon
Toxicology
Preclinical Models
Mechanisms
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Biomaterials‐Tissue InteracLons
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BioresorbLon‐BiodegradaLon
Poly(1,3‐Trimethylene Carbonate)
High Molecular Weight Low Molecular Weight Hydrophobic Hydrophilic
Lipase‐EnzymaLc DegradaLon Acid Hydrolysis
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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
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HIGHLY CROSSLINKED UHMW POLYETHYLENEIMPROVES WEAR RESISTANCE
HOWEVER, CROSSLINKING ADVERSELY AFFECTS:UNIAXIAL DUCTILITY
FRACTURE TOUGHNESS
FATIGUE CRACK PROPAGATIONRESISTANCE
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BIOCOMPATABILITY “HOT BUTTONS”Chronic InflammaLon
Immune Response
Innate ImmunityAcquired Immunity
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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
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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
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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
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Terms and DefiniLons
Medical Device Material Final Product
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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
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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
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Material
Any synthetic or natural polymer, metal, alloy,ceramic, or other nonviable substance includingtissue rendered nonviable, used as a medicaldevice or any part thereof
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Final Product
A medical device in its “as-used” state
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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
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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
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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.
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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
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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
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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
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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
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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
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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
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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
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CategorizaLon of Medical Devicesby DuraLon of Body Contact
Limited exposure- < 24 hrs Prolonged exposure- 24hrs-30 days Permanent contact- exceeds 30 days
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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)
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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
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Biological EvaluaLon TestsIniLal
• Cytotoxicity• Sensitization• Irritation• Intracutaneous reactivity• Systemic Toxicity (acute)• Subacute/Subchronic Toxicity• Genotoxicity• Implantation• Hemocompatibility
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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
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Biological EvaluaLon TestsSupplemental
• Chronic Toxicity• Carcinogenicity• Reproductive Toxicity• Biodegradation• Toxicokinetics• Immunotoxicity
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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
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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
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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
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ALTERNATIVE TESTING
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ALTERNATIVE TESTINGSKIN IRRITATION AND SENSITIZATION
•ReducLon in TesLng Time
•Lower Costs
•No Animals
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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
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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
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Toxicity Pathway‐Based Risk Assessment:Preparing for Paradigm Change
NRC/NAS Symposium, May 11‐13, 2009
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Toxicity TesLng in the 21st Century:A Vision and a StrategyNRC/NAS Report 2007
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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
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TISSUE ENGINEERINGIMMUNOTOXICITY
ImmunosuppressionImmunosLmulaLonHypersensiLvityChronic InflammaLonAutoimmunity
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BIOCOMPATABILITY “HOT BUTTONS”Chronic InflammaLon
Immune Response
Innate ImmunityAcquired Immunity
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What does it take to bring newly developedpolymer technology from bench‐to‐bedside?
Structure/Property RelaLonship
Polymer Structure/Biological Property RelaLonship
Biological Design Criteria
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Design of Replacement Tissues
Sequence of Events
Intended Application
Tissue Procurement and Material
In Vitro, In Vivo, Ex Vivo Testing
Regulatory Issues (Safety)
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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