1. Standards for Tissue Engineered Medical Products (TEMPs) January 22, 2014

2. Professor Alan J. Russell
TISSUE ENGINEERING
Volume 11, Number 9/10, 2005
© Mary Ann Liebert, Inc.
Editorial
Standardized Experimental Procedures in Tissue Engineering: Cure or Curse?
Professor Alan J. Russell

3. What Is a Standard?
“A standard is a common language that promotes the flow of goods between buyer and seller and protects the general welfare.”
ASTM Examples:
Medical & Surgical Materials & Devices
Anesthetic & Respiratory Equipment
Environment Site Assessment
Jet Fuel

4. Why Are Standards Important?
AID in design, manufacturing, performance, operation and maintenance
ADVANCE safety, health, quality
INCREASE public interest, product certainty, and information availability
TRANSFER technology to the marketplace via standards, handbooks, manuals, and training
PASSPORTS to the global market

5. How Are Standards Used? Developed voluntarily and used voluntarily
Means of communication and quality assurance
Government agencies reference them in codes, certification, regulations, and laws
Over 3,400 ASTM International standards are used as the basis for national standards by reference in regulation in over 75 countries
Used by thousands of individuals/companies/agencies globally to declare conformance/compliance (design and marketing), coordinate research, coordinate product

6. TEMPs Challenges TEMPs = tissue engineered medical products
Complex emerging field
Priority for standards within the field of tissue engineering and regenerative medicine is not established
Global coordination remains uncertain

7. Standards Organizations
ASTM International
ISO (International Organization for Standardization)
IEC (International Electrotechnical Commission)
ITU (International Telecommunication Union)
ANSI (American National Standards Institute)
IEEE (Institution of Electrical Engineers)

8. ASTM International
ASTM provides the structure, resources, forum and technical expertise required to develop standards
ASTM provides the organization required to publish and disseminate standards
ASTM – Previously American Standards for Testing and Materials
Organized as a set of ‘Technical Committees’ covering all broad topics of interest (140)
A Technical Committee may have ‘Divisions’ containing a cluster of sub-committees covering a topic area
A Technical Committee may have several – many ‘Sub-committees’ – focused on a particular broad topic
Each Sub-committee has task groups, each being responsible for developing a particular standard

9. ASTM F04 Division IV – Tissue Engineered Medical Products
Objective
Establish standards and guides for use in tissue engineered medical products.
Consensus based approach, involving Industry, Academia, Federal groups
Involvement of international regulatory interests
Meetings two times per year (May and November)

10. TEMPs Standards Characteristics
Assured patient safety
Function related
Provide reproducible results
Realistic assessment(s)
Requirements should be consistent between different products with similar objectives
Develop through consensus

11. TEMPs Opportunities for Standards
Increased efficiency for Research and Product Development
Reduced costs of product development and manufacture
Increased manufacturing efficiency
Improved clinical effectiveness
Reduced regulatory hurdles and timelines

12. 6 Types of ASTM Standards Documents
Type of Standard
Definition
Active
Guide
An organized collection of information or series of options that does not recommend a specific course of action 23
Test Method
A definitive procedure that produces a test result 7
Practice
A set of instructions for performing one or more specific operations that does not produce a test result
Specification
An explicit set of requirements to be satisfied by a material, product, system or service
Terminology
A document composed of terms, definitions of terms, descriptions of terms, nomenclature, and explanations of abbreviations, acronyms & symbols
Classification
Systematic arrangement or division of materials, products, systems, or services into groups based on similar characteristics such as origin, composition, properties, or use
Total 30

13. Tissue Engineered Medical Products
ASTM F4.04
Tissue Engineered Medical Products
6 Subcommittees with 30 published standards
F4.41 Classification & Terminology for TEMPs (2)
F4.42 Biomaterials & Biomolecules for TEMPs (16)
F4.43 Cells & Tissue Engineered Constructs (6)
F4.44 Assessment of TEMPs (5)
F4.45 Adventitious Agents Safety (1)
F4.46 Cell Signaling (0)

14. Approved TEMPs Standards: F04
Approved TEMPs Standards: F04.41 Classification & Terminology for TEMPs
F Standard Guide for Classification of Therapeutic Skin Substitutes
F Standard Terminology Relating to Tissue Engineered Medical Products

15. Approved TEMPs Standards: F04
Approved TEMPs Standards: F04.42 Biomaterials and Biomolecules for TEMPs
F Standard Guide for Characterization and Testing of Raw or Starting Biomaterials for Tissue-Engineered Medical Products
F (2006)e1 Standard Guide for Characterization and Testing of Alginates as Starting Materials Intended for Use in Biomedical and Tissue-Engineered Medical Product Applications
F Standard Guide for Characterization and Testing of Chitosan Salts as Starting Materials Intended for Use in Biomedical and Tissue-Engineered Medical Product Applications
F (2012) Standard Test Method for In Vitro Biological Activity of Recombinant Human Bone Morphogenetic Protein-2 (rhBMP-2) Using the W-20 Mouse Stromal Cell Line
F Standard Guide for Characterization and Testing of Biomaterial Scaffolds Used in Tissue-Engineered Medical Products
F Standard Guide for Characterization of Type I Collagen as Starting Material for Surgical Implants and Substrates for Tissue Engineered Medical Products (TEMPs)
F (2012)e1 Standard Test Method for Determining the Chemical Composition and Sequence in Alginate by Proton Nuclear Magnetic Resonance (1H NMR) Spectroscopy
F (2012)e1 Standard Test Method for Determining Degree of Deacetylation in Chitosan Salts by Proton Nuclear Magnetic Resonance (1H NMR) Spectroscopy
F Standard Guide for Characterization and Testing of Hyaluronan as Starting Materials Intended for Use in Biomedical and Tissue Engineered Medical Product Applications
F Standard Guide for Assessing Microstructure of Polymeric Scaffolds for Use in Tissue Engineered Medical Products
F Standard Test Method for Determining the Molar Mass of Chitosan and Chitosan Salts by Size Exclusion Chromatography with Multi-angle Light Scattering Detection (SEC-MALS)
F (2012) Standard Guide for Interpreting Images of Polymeric Tissue Scaffolds
F e1 Standard Test Method for Determining the Molar Mass of Sodium Alginate by Size Exclusion Chromatography with Multi-angle Light Scattering Detection (SEC-MALS)
F Standard Guide for Assessment of Surface Texture of Non-Porous Biomaterials in Two Dimensions
F Standard Guide for Characterization of Ceramic and Mineral Based Scaffolds Used for Tissue-Engineered Medical Products (TEMPs) and as Devices for Surgical Implant Applications
F Standard Guide for Characterization of Hydrogels used in Regenerative Medicine

16. Approved TEMPs Standards: F04.43 Cells and TE Constructs
F (2007) Standard Test Method for Automated Analyses of Cells-the Electrical Sensing Zone Method of Enumerating and Sizing Single Cell Suspensions
F (2010) Standard Guide for Processing Cells, Tissues, and Organs for Use in Tissue Engineered Medical Products
F Standard Guide for Immobilization or Encapsulation of Living Cells or Tissue in Alginate Gels
F Standard Guide for Assessing the Attachment of Cells to Biomaterial Surfaces by Physical Methods
F Standard Guide for Quantitating Cell Viability Within Biomaterial Scaffolds
F Standard Test Method for Automated Colony Forming Unit (CFU) Assays— Image Acquisition and Analysis Method for Enumerating and Characterizing Cells and Colonies in Culture

17. Approved TEMPs Standards:
F04.44 Assessment for TEMPs
F (2010) Standard Guide for In Vivo Assessment of Implantable Devices Intended to Repair or Regenerate Articular Cartilage
F Standard Guide for In Vivo Evaluation of Osteoinductive Potential for Materials Containing Demineralized Bone (DBM)
F Standard Guide for Pre-clinical In Vivo Evaluation in Critical Size Segmental Bone Defects
F Standard Guide for Pre-clinical In Vivo Evaluation of Spinal Fusion
F Standard Guide for Tissue Engineered Medical Products (TEMPs) for Reinforcement of Tendon and Ligament Surgical Repair

18. Approved TEMPs Standards: F04.45 Adventitious Agents Safety
F Standard Guide for Assessment of Adventitious Agents in Tissue Engineered Medical Products (TEMPs)
Approved TEMPs Standards:
F04.46 Cell Signaling
This is a new subcommittee and does not have any published standards yet.

19. TEMPS Standards Used in a 510K Submission to FDA - A Living Example
X-Repair (Synthasome):
Woven, degradable mesh (poly-L-lactic acid)
Augments surgical repair of tendons & soft tissues
Received 510k clearance in 2009
Standards Used in 510k Application:
ASTM D3786 Standard Test Method for Bursting Strength of Textile Fabrics - Diaphragm Bursting Strength Tester Method
ASTM D5035 Standard Test Method for Breaking Force & Elongation of Textile Fabrics (Strip Method)
ASTM D5587 Standard Test Method for Tearing Strength of Fabrics by Trapezoid Procedure
ASTM F Standard Test Method for in vitro Degradation Testing of Hydrolytically Degradable Polymer Resins and Fabricated Forms for Surgical Implants 
ASTM F2211 Standard Classification for Tissue Engineered Medical Products (TEMPs)
ASTM F2312 Standard Terminology Relating to TEMPs
ASTM F2027 Standard Guide for Characterization and Testing of Raw or Starting Biomaterials for Tissue-Engineered Medical Products
ASTM F2150 Standard Guide for Characterization of Biomaterial Scaffolds Used in TEMPs
ISO Biological Evaluation of Medical Devices
ISO Sterilization of Health Care Products

20. Used in applications to the FDA
F (2010) Standard Guide for in vivo Assessment of Implantable Devices Intended to Repair or Regenerate Articular Cartilage
Consensus document developed over two years with input from academics, companies, clinicians, and FDA
Approved in 2005
Used in applications to the FDA
Key document referenced in FDA guidance document for articular cartilage repair:
“Guidance for Industry: Preparation of IDEs and INDs for Products Intended to Repair or Replace Knee Cartilage”

21. Standards Opportunities for Animal Models
Standard guides for pre clinical in-vivo evaluation of cranio-facial defects
Cranial
Facial
Neurological
Standardization of surgical procedures
Standard guide for assessing scarring, healing & regeneration of the skin
Surgical incisions
Open wound defects
Burns
Skin regeneration
Wound infection
Rapid screening model for cartilage repair
Tendon (mobility, lack of scarring, scaffold materials)
Ligament (focus on strength)
Muscle (focus on function and mass, fibrosis)
Soft tissue augmentation
Standard practice/guide for nerve repair

22. Standards Opportunities for Clinical Studies
Assessment of clinical outcomes
Measurement of patient-reported outcomes
Measurement of clinically relevant biomechanical functions
Identification and coding of clinical conditions
Current standards of care for managing various conditions

23. Standards Opportunities for Cells & Tissue Engineered Constructs
Standard guide to normal versus dystrophic mineralization
Standard guide for cellular alkaline phosphatase activity
Standard guide for characterization of osteoblasts and other lineages
Standard guide for characterization of progenitor populations (proliferation, differentiation, purity, viability)
Standard for apoptosis
Standardize terminology regarding MSCs/progenitors (what is it now, what can it become, and what does it do)

24. Standards Opportunities for Biomaterials
Standard guide to host response
Cell attachment
Mechanical properties
Porosity
Loading
Cell-mediated degradation
Cell and scaffold tracking in vivo
Vascular supply
Innervation
Assessing sensory and autonomic function
Biointegration
Biomaterial behavior in a contaminated/infected environment (Performance standards for biofilm formation)

25. Standards Opportunities for Adventitious Agents & Safety
Exuberant inflammatory responses
Tumorgenicity
Toxicity for cell based constructs
Assessing cell viability
Biodistribution of cells after implantation

26. Standards Opportunities for Cell Signaling
Apoptosis mechanism
Cell signaling mechanism-based assays for stress/cytotoxicity
Greater predictive capability compared to live/dead
Controlled extracellular matrix preparations for systematic studies
Expected physical and chemical properties of protocols and response from cells
Criteria for evaluating cells after storage
Integrity with genetics, response to environment, ‘health’
Quantitative methods for cell area determination
Robust benchmarking protocol for fixing, staining and analyzing morphologies of cells in a population
Criteria for qualifying a cell-based assay
What criteria are required for assuring a robust, reproducible, and valid biomarker assay(s) relevant to biological interpretation
Fluorescent labels

27. Future Plans for TEMPs Continue standards development
Increase involvement by individuals and groups
Continue and encourage international cooperation
Prioritize standard developments for pre-clinical and clinical assessment
Spur selective safety document development
Refine strategy
Continue coordination with ISO/international partners

28. Summary
TEMPs are already on the market addressing previously unmet clinical needs
New TEMPs will continue to be developed for use
Commerce needs to gain approval by multiple regulatory agencies globally
The need for International Standards will increase
Consensus standards are being developed
TEMPs standards are being used
Standards are an integral component of all industries
Standard development is an active and ongoing process within TERM
Standards are a valuable and necessary component of applications to the FDA
Standards enhance efficiency of research, product development & manufacturing
Risk: If you don’t develop (or participate in) the standard, someone else will

29. Additional Resources www.astm.org www.iso.org www.nist.gov/srm
Plant AL, Horowitz E. Symposium on metrology and standards for cell signaling: impact on tissue engineering, National Institute for Standards and Technology, October 14-15, Tissue Engineering, 2005, 11,
Russell AJ. Standardized experimental procedures in tissue engineering: cure or curse. Tissue Engineering, 2005, 11, vii-vix.
Messenger MP, Tomlins PE. Regenerative medicine: a snapshot of the current regulatory environment and standards. Advanced Healthcare Materials, 2011, 23, H10-H17.
Leitner E, Bischoff P. Setting standards for technologies in regenerative medicine. Biomedical Technology (Berlin), 2012, 57,
Yokoi M, Hattori K, Narikawa K et al. Feasibility and limitations of the round robin test for assessment of in vitro chondrogenesis evaluation protocol in a tissue-engineered medical product. Journal of Tissue Engineering and Regenerative Medicine, 2012, 6,
American Academy of Orthopaedic Surgeons. Position Statement: Consensus Standards for Medical Devices. Rosemont, IL, 2013.
U.S. Food & Drug Administration. Guidance for Industry and FDA Staff: Frequently Asked Questions on Recognition of Consensus Standards. White Oak, MD: 2007.