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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

2

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?


3

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


5

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)


6

International standards bodies

International standards developed by:

•IEC (Int. electrotechnical committee)

•ITU (Int. telecommunications union)

•ISO (International Organization for Standardization)

•ASTM International


7

‘Regional’ standards bodies e.g.

• CEN, CENELEC, ETSI, and IRMM in Europe.

• Pacific Area Standards Congress

• African Organization for Standardization

(ARSO)


8

ISO and national standards bodies

•163 national members

•One nation one vote system

•17000+ standards


9

ASTM International

• Global membership ~30,000 (>120 countries)

• One member one vote system

• 12000+ standards listed in 80 volumes


10

ISO/TC 194: Medical devices


11

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


12

Tissue engineered

Medical products


13

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


14

ASTM International


15

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


16

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


17

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

• •

•


18

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


20

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

http://www.bsigroup.com/PAS84


20

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

http://www.bsigroup.com/PAS84


21

The process of standardisation

Pre-standardisation

activity – round-robin

New work item

Draft standard

Balloting

VAMAS

(ISO)


22

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


23

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

24

ASTM Standard Guide


2009

25

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


2009

26

Pore types

Blind-end

Open

Closed


2009

27

Interconnectivity

Blind-end

Open

Closed


2009

28

Pore size distribution and functionality

0.010m 100m 1m

‘Service’ conduits?

‘Cell’ conduits?


2009

29

Fenestrated pores?

~30m


30

Morphology of Fibrin gel and with cells

Cell Cell


2009

31

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


32

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

http://www.astm.org/

http://www.iso.org/

http://www.iso.org/

http://www.iso.org/

http://www.iso.org/


34

Acknowledgements

• Nilofar Faruqui (NPL)

• Elzbieta Gurdak (NPL)

• Richard Leach (NPL)

• Melissa Mather (NPL)

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