Standards for biomaterials in tissue
engineering
Paul Tomlins
Stem Cell Translation: Strategies, Best Practices
and Regulatory Considerations San Francisco 28/9/10
Thursday, September 30, 2010
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Overview
• Why are standards useful?
• Standards bodies
• The process of standardisation
• Relevant activity within the standards area
• Examples of the contents of an ASTM guide
• Where are we now with standards in tissue
engineering?
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What use are standards?
A measure of product/data quality and
consistency, valuable for:
• Customer confidence?
• Regulator confidence?
• Vendors liability?
Standards facilitate trade
Help establish emerging technologies
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Standards and biomaterials
• Characterisation of raw materials
• Structure/performance assessment
• Assessment of ‘product’ performance
• Detection of contaminants
• Sterilisation (ISO 10993/7)
• (Packaging)
• Degradation
• Quality management system (ISO 134885)
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International standards bodies
International standards developed by:
•IEC (Int. electrotechnical committee)
•ITU (Int. telecommunications union)
•ISO (International Organization for Standardization)
•ASTM International
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‘Regional’ standards bodies e.g.
• CEN, CENELEC, ETSI, and IRMM in Europe.
• Pacific Area Standards Congress
• African Organization for Standardization
(ARSO)
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ISO and national standards bodies
•163 national members
•One nation one vote system
•17000+ standards
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ASTM International
• Global membership ~30,000 (>120 countries)
• One member one vote system
• 12000+ standards listed in 80 volumes
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ISO/TC 194: Medical devices
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The role of ISO/TC 194 (Biological
evaluation of medical devices)
• Ensuring compliance with regulatory bodies (Japan, EU, USA etc)
• Reducing developmental cost – through harmonization
• Eliminating unnecessary animal testing
• Device quality – increasingly important in litigation
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Tissue engineered
Medical products
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ISO TC150 SC7: Tissue engineered medical
products (current portfolio)
• Quantification of sulphated
glycosaminoglycans (sGAG) in regenerated
articular cartilage
• In vivo bone formation in porous materials
using rat mesenchymal cells –
standardisation to evaluate bone forming
ability of biomaterials
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ASTM International
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ASTM F04 Division
F04.41 - Classification and Terminology for TEMPs
F04.42 - Biomaterials and Biomolecules
F04.43 - Cells and Tissue Engineered Constructs
F04.44 - Assessment
F04.45 - Adventitious Agents Safety
F04.46 - Cell Signaling
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Current standards/standard guides
Area Guide Protocol Work items
Terminology/
classification 1 2 1G
Assessment (pre-
clinical evaluation) 2 5G 3P
Biomaterials and
biomolecules 8 6 3G
Adventitious agents
safety 1 1G
Cells and TEMPS 5 4 2G 3P
Cell signalling 9P 3G
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Biomaterials and Biomolecules: ASTM activity
• - Characterization and testing of raw or starting biomaterials for tissue engineered medical products.
• - Characterization and testing of alginates as starting materials • -Characterization and testing of chitosan salts as starting materials • - Method for in vitro biological activity of recombinant human bone
morphogenetic protein-2 (RHBMP-2) using the W-20 mouse stromal cell line
• - Characterization and testing of biomaterial scaffolds • - Characterization of type I collagen as a starting material for surgical
implants and substrates • - Method fordetermining the chemical composition and sequence in
alginate by proton nuclear magnetic resonance (1H NMR) • - Method for the • determination of the degree of deacetylation of chitosan salts by proton
nuclear magnetic resonance (1H NMR) • Assessing microstructure of polymeric scaffolds • - Determination of the molar mass of chitosan and chitosan salts by
size exclusion chromatography with multi-angle light scattering detection (SEC-MALS).
• - Interpreting images of polymeric tissue scaffolds
• •
•
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BSI
• Responsible for UK input into ISO/TC 194
and CEN/TC 206
• Preparation of PAS (Publicly Available
Specification) documents
• Coordinating UK participation in
ISO/TC150/SC7 work items
BSI CH/194 Biological evaluation of
medical devices
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Relevant BSI PAS documents (1)
www.bsigroup.com
• PAS 84 Regenerative medicine glossary
• PAS 83:2006 Guidance on codes of practice,
standardised method and regulations for cell-based
therapeutics – From basic research to clinical
applications
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Relevant BSI PAS documents (2)
•PAS 131 Terminology for medical, health and personal
care applications of nanotechnologies
•PAS 132 Terminology for the bio-nano interface
•PAS 133 Terminology for nanoscale measurement and
instrumentation
•PAS 134 Terminology for carbon nanostructures
•PAS 135 Terminology for nanofabrication
•PAS 136 Terminology for nanomaterials
www.bsigroup.com
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The process of standardisation
Pre-standardisation
activity – round-robin
New work item
Draft standard
Balloting
VAMAS
(ISO)
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VAMAS
• Versailles project on advanced materials
and standards
• Established 1982
• Facilitates international trade of high tech
products through consensus documents
• Biomaterials technical working area
http://www.vamas.org
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When are standards needed?
New market
Mature market
Single manufacturer/end user
Many manufacturers/end users
Private agreement
Consensus agreement
Monaco-Extra Summer School, Antalya
2009
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ASTM Standard Guide
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What characteristics do tissue scaffolds
have? • Biocompatible
• ‘Spacious’ for cell mobility and proliferation
Plentiful supply of nutrients
Plentiful supply of oxygen
Efficient removal of waste products
• Appropriate mechanical properties
• Reliable In vivo performance – accommodating
degradation
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Pore types
Blind-end
Open
Closed
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Interconnectivity
Blind-end
Open
Closed
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Pore size distribution and functionality
0.010m 100m 1m
‘Service’ conduits?
‘Cell’ conduits?
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Fenestrated pores?
~30m
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Morphology of Fibrin gel and with cells
Cell Cell
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Length scales accessible by
different techniques
0.1 1 10 100 1000 10 10^5 10^6
Pore Width (nm)
Adsorption Condensation Hg Intrusion
Thermoporometry
X-ray scattering (diffraction) Electron Microscopy
Fluid Flow Light Microscopic Image Analysis
Holography
Mechanical Tracing Scanning tunnel microscopy
micropores esopores macropores microcapillaries
capillaries macrocapillaries
^4
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Summary: Where are we on standards?
• Main focus on terminology
• Informative guides
• Still much work to be done!
www.astm.org
www.iso.org
www.bsi-global.com
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Acknowledgements
• Nilofar Faruqui (NPL)
• Elzbieta Gurdak (NPL)
• Richard Leach (NPL)
• Melissa Mather (NPL)