Standards for Tissue
Engineered Medical
Products (TEMPs)
January 22, 2014
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
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
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
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
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
Standards Organizations
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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)
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 ‘Subcommittees’ – focused on a particular broad topic
• Each Sub-committee has task groups, each being responsible
for developing a particular standard
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)
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
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
6 Types of ASTM Standards Documents
Type of
Standard
Definition
Active
An organized collection of information or series of options that does not
recommend a specific course of action
23
A definitive procedure that produces a test result
7
A set of instructions for performing one or more specific operations that does
not produce a test result
0
Specification
An explicit set of requirements to be satisfied by a material, product, system or
service
0
Terminology
A document composed of terms, definitions of terms, descriptions of terms,
nomenclature, and explanations of abbreviations, acronyms & symbols
0
Systematic arrangement or division of materials, products, systems, or
services into groups based on similar characteristics such as origin,
composition, properties, or use
0
Guide
Test Method
Practice
Classification
Total
30
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)
Approved TEMPs Standards:
F04.41 Classification & Terminology for TEMPs
1. F2311-08 Standard Guide for Classification of Therapeutic Skin Substitutes
2. F2312-11 Standard Terminology Relating to Tissue Engineered Medical Products
Approved TEMPs Standards:
F04.42 Biomaterials and Biomolecules for TEMPs
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16.
F2027-08 Standard Guide for Characterization and Testing of Raw or Starting Biomaterials for Tissue-Engineered Medical
Products
F2064-00(2006)e1 Standard Guide for Characterization and Testing of Alginates as Starting Materials Intended for Use in
Biomedical and Tissue-Engineered Medical Product Applications
F2103-11 Standard Guide for Characterization and Testing of Chitosan Salts as Starting Materials Intended for Use in
Biomedical and Tissue-Engineered Medical Product Applications
F2131-02(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
F2150-13 Standard Guide for Characterization and Testing of Biomaterial Scaffolds Used in Tissue-Engineered Medical
Products
F2212-11 Standard Guide for Characterization of Type I Collagen as Starting Material for Surgical Implants and Substrates
for Tissue Engineered Medical Products (TEMPs)
F2259-10(2012)e1 Standard Test Method for Determining the Chemical Composition and Sequence in Alginate by Proton
Nuclear Magnetic Resonance (1H NMR) Spectroscopy
F2260-03(2012)e1 Standard Test Method for Determining Degree of Deacetylation in Chitosan Salts by Proton Nuclear
Magnetic Resonance (1H NMR) Spectroscopy
F2347-11 Standard Guide for Characterization and Testing of Hyaluronan as Starting Materials Intended for Use in
Biomedical and Tissue Engineered Medical Product Applications
F2450-10 Standard Guide for Assessing Microstructure of Polymeric Scaffolds for Use in Tissue Engineered Medical
Products
F2602-13 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)
F2603-06(2012) Standard Guide for Interpreting Images of Polymeric Tissue Scaffolds
F2605-08e1 Standard Test Method for Determining the Molar Mass of Sodium Alginate by Size Exclusion Chromatography
with Multi-angle Light Scattering Detection (SEC-MALS)
F2791-09 Standard Guide for Assessment of Surface Texture of Non-Porous Biomaterials in Two Dimensions
F2883-11 Standard Guide for Characterization of Ceramic and Mineral Based Scaffolds Used for Tissue-Engineered
Medical Products (TEMPs) and as Devices for Surgical Implant Applications
F2900-11 Standard Guide for Characterization of Hydrogels used in Regenerative Medicine
Approved TEMPs Standards:
F04.43 Cells and TE Constructs
1. F2149-01(2007) Standard Test Method for Automated Analyses of Cells-the Electrical
Sensing Zone Method of Enumerating and Sizing Single Cell Suspensions
2. F2210-02(2010) Standard Guide for Processing Cells, Tissues, and Organs for Use in
Tissue Engineered Medical Products
3. F2315-11 Standard Guide for Immobilization or Encapsulation of Living Cells or Tissue
in Alginate Gels
4. F2664-11 Standard Guide for Assessing the Attachment of Cells to Biomaterial
Surfaces by Physical Methods
5. F2739-08 Standard Guide for Quantitating Cell Viability Within Biomaterial Scaffolds
6. F2944-12 Standard Test Method for Automated Colony Forming Unit (CFU) Assays—
Image Acquisition and Analysis Method for Enumerating and Characterizing Cells and
Colonies in Culture
Approved TEMPs Standards:
F04.44 Assessment for TEMPs
1.
2.
3.
4.
5.
F2451-05(2010) Standard Guide for In Vivo Assessment of Implantable
Devices Intended to Repair or Regenerate Articular Cartilage
F2529-13 Standard Guide for In Vivo Evaluation of Osteoinductive
Potential for Materials Containing Demineralized Bone (DBM)
F2721-09 Standard Guide for Pre-clinical In Vivo Evaluation in Critical
Size Segmental Bone Defects
F2884-12 Standard Guide for Pre-clinical In Vivo Evaluation of Spinal
Fusion
F2903-11 Standard Guide for Tissue Engineered Medical Products
(TEMPs) for Reinforcement of Tendon and Ligament Surgical Repair
Approved TEMPs Standards:
F04.45 Adventitious Agents Safety
1. F2383-11 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.
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 F1635-11 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 10993 Biological Evaluation of Medical Devices
• ISO 11135 Sterilization of Health Care Products
F2451 - 05 (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”
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
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
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)
Standards Opportunities for Biomaterials
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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)
Standards Opportunities for
Adventitious Agents & Safety
• Exuberant inflammatory responses
• Tumorgenicity
• Toxicity for cell based constructs
– Assessing cell viability
– Biodistribution of cells after implantation
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
Future Plans for TEMPs
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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
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
Additional Resources
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www.astm.org
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www.iso.org
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www.nist.gov/srm
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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, 2003. Tissue
Engineering, 2005, 11, 985-90.
•
Russell AJ. Standardized experimental procedures in tissue engineering: cure or curse. Tissue
Engineering, 2005, 11, vii-vix.
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Messenger MP, Tomlins PE. Regenerative medicine: a snapshot of the current regulatory
environment and standards. Advanced Healthcare Materials, 2011, 23, H10-H17.
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Leitner E, Bischoff P. Setting standards for technologies in regenerative medicine. Biomedical
Technology (Berlin), 2012, 57, 1051-1054.
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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, 550-8.
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American Academy of Orthopaedic Surgeons. Position Statement: Consensus Standards for Medical
Devices. Rosemont, IL, 2013.
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U.S. Food & Drug Administration. Guidance for Industry and FDA Staff: Frequently Asked Questions
on Recognition of Consensus Standards. White Oak, MD: 2007.