ASTM Approach on Standards for ASTM Approach on Standards for Tissue Engineered Medical Tissue Engineered Medical

Products (TEMPS)Products (TEMPS)Anthony Ratcliffe, PhDAnthony Ratcliffe, PhD

President and CEO, Synthasome, Inc., President and CEO, Synthasome, Inc., San Diego, CASan Diego, CA

CoCo--chairman, ASTM Committee 4, chairman, ASTM Committee 4, Division IV, Tissue Division IV, Tissue EngineergedEngineerged Medical Medical

ProductsProducts

Tissue EngineeringTissue Engineering

•• Cells and/or biological agentsCells and/or biological agents

•• Extracellular components, natural and/or Extracellular components, natural and/or syntheticsynthetic

•• Formation of a biologically active unitFormation of a biologically active unit

•• Function to aid, repair or replace Function to aid, repair or replace damaged or diseased tissues and/or damaged or diseased tissues and/or organsorgans

Modifed from Nerem, R.M. Ann Nerem, R.M. Ann BiomedBiomed Eng 19:529, 1991Eng 19:529, 1991

Tissue engineering seeks to evolve from this…..

Into this

TE Products on the MarketTE Products on the Market

CarticelGenzyme1997

ApligrafOrganogenesis1999

DermagraftS&N 2001

TranscyteS&N1997

OrcelOrtec2001

Tissue Engineering:Tissue Engineering:CellCell--Scaffold ApproachScaffold Approach

Growing living human organs and tissuesGrowing living human organs and tissues

Polymer SciencePolymer Science TransplantationTransplantation

BiochemistryBiochemistryCell BiologyCell Biology

BioengineeringBioengineering

Human cells

Biocompatiblescaffold

Cells multiply on scaffold

Matrix proteins

Growth factors

Cells secrete growth factors and human

matrix proteins

Completely human tissue forms

Cell-Scaffold Technology

Components of CellComponents of Cell--Scaffold Scaffold Tissue EngineeringTissue Engineering

Scaffolds

Cells

Bioreactor

Innovative ManufacturingInnovative Manufacturing

•• Automated manufacturing Automated manufacturing capabilitiescapabilities, efficient, efficient

•• Supports highSupports high--volume volume production (bioreactor production (bioreactor design), scaleabledesign), scaleable

•• Provides product Provides product consistency, consistency, reproducible reproducible

•• EconomicEconomic

•• SafeSafe

Potential Solutions using Tissue Engineering

GASTROINTESTINAL TRACT

BONE MARROW

LIVER

COLLAGEN

BONE

HEART VALVES

ECM

Dermal replacementsCARTILAGE

MENISCUS

BONE / CARTILAGE

CRANIOFACIAL RECONSTRUCTION

TENDON / LIGAMENT

VASCULAR GRAFTS

ANGIOGENESIS

EAR

Recommendations for future Recommendations for future tissue engineeringtissue engineering

•• Maximize knowledge base and research Maximize knowledge base and research infrastructure (good science and engineering)infrastructure (good science and engineering)

•• Partnership with regulatory authoritiesPartnership with regulatory authorities•• Develop international standardsDevelop international standards

•• Use robust and realistic business plansUse robust and realistic business plans

ASTM F04 Division IV ASTM F04 Division IV ––Tissue Engineered Medical ProductsTissue Engineered Medical Products

•• ObjectiveObjective––Establish standards and guides for use in tissue Establish standards and guides for use in tissue

engineered medical products. engineered medical products. ––Consensus based approach, involving Industry, Consensus based approach, involving Industry,

Academia, Federal groupsAcademia, Federal groups––Involvement of international regulatory interestsInvolvement of international regulatory interests

•• Meetings two times per year (May and November)Meetings two times per year (May and November)

ASTM F4.04 ASTM F4.04 Tissue Engineered Medical ProductsTissue Engineered Medical Products

•• F04.41 Classification and Terminology for F04.41 Classification and Terminology for TEMPsTEMPs

•• FO4.42 Biomaterials and FO4.42 Biomaterials and BiomoleculesBiomolecules

•• FO4.43 Cells and Tissue Engineered Constructs FO4.43 Cells and Tissue Engineered Constructs

•• FO4.44 Assessment FO4.44 Assessment

•• FO4.45 Adventitious Agents Safety of FO4.45 Adventitious Agents Safety of TEMPsTEMPs

TEMPs Standards CharacteristicsTEMPs Standards Characteristics

•• Assured patient safetyAssured patient safety

•• Function related Function related

•• Provide reproducible resultsProvide reproducible results

•• Realistic assessment(s)Realistic assessment(s)

•• Requirements should be consistent between Requirements should be consistent between different products with similar objectivesdifferent products with similar objectives

•• Develop through consensusDevelop through consensus

TEMPsTEMPs Opportunities for StandardsOpportunities for Standards

•• Increased manufacturing efficiencyIncreased manufacturing efficiency

•• Reduced costs of development and Reduced costs of development and manufacturemanufacture

•• Improved clinical effectivenessImproved clinical effectiveness

•• Reduced regulatory hurdles and timelines Reduced regulatory hurdles and timelines

TEMPs ChallengesTEMPs Challenges

•• Complex emerging fieldComplex emerging field

•• No established strategic plan agreed by No established strategic plan agreed by industry, academia, and federal groupsindustry, academia, and federal groups

•• Priority for standards within the field of Priority for standards within the field of tissue engineering is not establishedtissue engineering is not established

•• Coordination between US and International Coordination between US and International organizationsorganizations

TEMPsTEMPs Approved StandardsApproved Standards

F4.41 Classification and TerminologyF4.41 Classification and Terminology•• F2211F2211--02 02 –– Standard Specification for General Standard Specification for General

Classification for Tissue Engineered Medical Classification for Tissue Engineered Medical ProductsProducts Contact: Grace Contact: Grace PiccioloPicciolo

•• F2311F2311——Standard Guide for Classification of Standard Guide for Classification of Therapeutic Skin SubstitutesTherapeutic Skin Substitutes. Contact Fred Kahn . Contact Fred Kahn

•• F2312F2312---- Standard terminology relating to Standard terminology relating to TEMPsTEMPs. . Contact Joan Contact Joan ZeltingerZeltinger

TEMPsTEMPs Approved StandardsApproved Standards

F4.42 Biomaterials and F4.42 Biomaterials and BiomoleculesBiomolecules•• F2027 F2027 -- Standard Guide for Characterization and Testing of Standard Guide for Characterization and Testing of

Substrate Materials for TissueSubstrate Materials for Tissue--Engineered Medical ProductsEngineered Medical Products Contact: Contact: LiisaLiisa KuhnKuhn

•• F2064 F2064 -- Standard Guide for Characterization and Testing of Alginates Standard Guide for Characterization and Testing of Alginates as Starting Materials Intended for Use in Biomedical and Tissueas Starting Materials Intended for Use in Biomedical and Tissue--Engineered Medical Products ApplicationEngineered Medical Products Application Contact: David Kaplan Contact: David Kaplan

•• F2103 F2103 -- Standard Guide for Characterization and Testing of Standard Guide for Characterization and Testing of ChitosanChitosanSalts as Starting Materials Intended for Use in Biomedical and Salts as Starting Materials Intended for Use in Biomedical and TissueTissue--Engineered Medical Product ApplicationsEngineered Medical Product Applications Contact: David Contact: David KaplanKaplan

•• F2150 F2150 -- Standard Guide for Characterization and Testing of Standard Guide for Characterization and Testing of Biomaterial Scaffolds Used in TissueBiomaterial Scaffolds Used in Tissue--Engineered Medical ProductsEngineered Medical ProductsContact: Contact: DebiDebi MukherjeeMukherjee

TEMPsTEMPs Approved StandardsApproved Standards

•• F2131 F2131 –– Test Method for In Vitro Biological Activity of Test Method for In Vitro Biological Activity of Recombinant Human Bone Morphogenetic ProteinRecombinant Human Bone Morphogenetic Protein--2 (RHBMP2 (RHBMP--2) 2) Using the WUsing the W--20 Mouse 20 Mouse StromalStromal Cell LineCell Line Contact: Thomas Porter Contact: Thomas Porter

•• F2259F2259--03 03 –– Test Method for Determination of Monomer Test Method for Determination of Monomer Sequence and Composition of Alginate by NMR Sequence and Composition of Alginate by NMR Contact: Michael Contact: Michael DornishDornish

•• F2260F2260--03 03 –– Test Method for the Determination of the Degree of Test Method for the Determination of the Degree of DeacetylationDeacetylation of of ChitosanChitosan Salts by Proton Nuclear Salts by Proton Nuclear MagneticResonanceMagneticResonance (1H NMR) Spectroscopy(1H NMR) Spectroscopy Contact: Michael Contact: Michael DornishDornish

•• F2212F2212--02 02 –– Guide for Characterization of Type I Collagen as a Guide for Characterization of Type I Collagen as a Starting Material for surgical Implants and Substrates for TissuStarting Material for surgical Implants and Substrates for Tissue e Engineered Medical ProductsEngineered Medical Products

TEMPsTEMPs Approved StandardsApproved Standards

F4.43 Cells and Tissue Engineered ConstructsF4.43 Cells and Tissue Engineered Constructs•• F2149 F2149 -- Standard Test Method for Automated Analyses Standard Test Method for Automated Analyses

of Cellsof Cells——the Electrical Sensing Zone Method of the Electrical Sensing Zone Method of Enumerating and Sizing Single Cell SuspensionsEnumerating and Sizing Single Cell SuspensionsContact: Steve Contact: Steve SzaboSzabo

•• F2210F2210--02 02 –– Guide for the Processing of Cells, Tissues Guide for the Processing of Cells, Tissues and Organs for Use in Tissue Engineered Medical and Organs for Use in Tissue Engineered Medical ProductsProducts Contact: Paul PriceContact: Paul Price

•• F2315F2315——Standard Standard GuildeGuilde for Immobilization or for Immobilization or encapsulation of living cells in alginate gelsencapsulation of living cells in alginate gels. Contact . Contact Michael Michael DornishDornish

TEMPS standards now being used:TEMPS standards now being used:Living exampleLiving example

•• Connective Tissue Repair DeviceConnective Tissue Repair Device––F2211: ClassificationF2211: Classification––F2312: TerminologyF2312: Terminology––F2027: Testing materialsF2027: Testing materials––F2150: Testing scaffoldsF2150: Testing scaffolds––F2212: Characterization of collagenF2212: Characterization of collagen––F2149: Numeration of cellsF2149: Numeration of cells––F2210: Processing of cells and tissuesF2210: Processing of cells and tissues

Future Plans For TEMPsFuture Plans For TEMPs

•• Continue standards developmentContinue standards development•• Develop strategy Develop strategy •• Increase involvement by individuals and groups Increase involvement by individuals and groups

(AAOS, March 2004)(AAOS, March 2004)•• Prioritize standard developments for prePrioritize standard developments for pre--clinical clinical

and clinical Assessment and clinical Assessment •• Spur selective safety document developmentSpur selective safety document development•• Continue and encourage international Continue and encourage international

cooperationcooperation

Questions Questions –– Answers?Answers?

•• Are different Approaches necessary? Are different Approaches necessary? ––Use of established processes successfulUse of established processes successful

•• How to ensure early coordination among How to ensure early coordination among stakeholders and standards groups?stakeholders and standards groups?––Consensus, Consensus,

––Rapid implementation of identified needRapid implementation of identified need

•• Should standards lead technology?Should standards lead technology?––Develop standards in parallel with technology Develop standards in parallel with technology

developmentdevelopment

SummarySummary•• Tissue engineered medical products are already on the Tissue engineered medical products are already on the

market addressing previously unmet clinical needsmarket addressing previously unmet clinical needs

•• Tissue engineering continues to grow and expand as an Tissue engineering continues to grow and expand as an academic, industry, regulatory partnership enterpriseacademic, industry, regulatory partnership enterprise

•• Quality of science and engineering, and understanding of Quality of science and engineering, and understanding of the technologies and clinical markets, is improving rapidlythe technologies and clinical markets, is improving rapidly

•• New New TEMPsTEMPs will continue to be developed for usewill continue to be developed for use

•• Commerce needs to gain approval by multiple regulatory Commerce needs to gain approval by multiple regulatory agencies globallyagencies globally

•• The need for The need for International StandardsInternational Standards will increase, will increase, concensusconcensus standards are being developed, and Standards standards are being developed, and Standards are being used. are being used.