1、Designation: F2211 13Standard Classification forTissue Engineered Medical Products (TEMPs)1This standard is issued under the fixed designation F2211; the number immediately following the designation indicates the year oforiginal adoption or, in the case of revision, the year of last revision. A numb
2、er in parentheses indicates the year of last reapproval. Asuperscript epsilon () indicates an editorial change since the last revision or reapproval.1. Scope1.1 This classification outlines the aspects of tissue engi-neered medical products that will be developed as standards.This classification exc
3、ludes traditional transplantation of or-gans and tissues as well as transplantation of living cells aloneas cellular therapies.1.2 This classification does not apply to any medical prod-ucts of human origin regulated by the U.S. Food and DrugAdministration under 21 CFR Parts 16 and 1270 and 21 CFRPa
4、rts 207, 807, and 1271.1.3 This standard does not purport to address specificcomponents coverd in other standards. Any safety areas asso-ciated with the medical products use will not be addressed inthis standard. This standard does not purport to address all ofthe safety concerns, if any, associated
5、 with its use. It is theresponsibility of the user of this standard to establish appro-priate safety and health practices and determine the applica-bility of regulatory requirements prior to use.2. Referenced Documents2.1 ASTM Standards:2F2027 Guide for Characterization and Testing of Raw orStarting
6、 Biomaterials for Tissue-Engineered MedicalProductsF2064 Guide for Characterization and Testing of Alginatesas Starting Materials Intended for Use in Biomedical andTissue-Engineered Medical Products ApplicationF2103 Guide for Characterization and Testing of ChitosanSalts as Starting Materials Intend
7、ed for Use in Biomedicaland Tissue-Engineered Medical Product ApplicationsF2131 Test Method forIn Vitro Biological Activity of Re-combinant Human Bone Morphogenetic Protein-2(rhBMP-2) Using the W-20 Mouse Stromal Cell LineF2150 Guide for Characterization and Testing of Biomate-rial Scaffolds Used in
8、 Tissue-Engineered Medical Prod-ucts2.2 Federal Documents:3US FDA CFR 21, Part 3 3.2(e) Product Jurisdiction21 CFR Parts 16 and 1270 Human Tissues, Intended forTransplantation21 CFR Parts 207, 807, and 1271 Human Cells, Tissues, andCellular and Tissue-Based Products: Establishment Reg-istration and
9、Listing2.3 ISO Standard:ISO 10993 Biological Evaluation of Medical Devices43. Terminology3.1 tissue engineering, nthe application, in vivo and invitro, of scientific principles and technologies to form tissueengineered medical products (TEMPs) used for medical treat-ments and as diagnostics. The var
10、ious technologies and prin-ciples are common practices and methods in engineering andbiomedical sciences such as cell, gene, or drug therapy,embryology or other forms of developmental biology, surgicalmethods and technologies used to create traditional devices andbiologics. Tissue engineering could
11、be applied to create prod-ucts for non-human use as well.3.2 tissue engineered medical products (TEMPs),nmedical products that repair, modify, or regenerate therecipients cells, tissues, and organs, or their structure andfunction, or combination thereof. TEMPs may achieve atherapeutic potential from
12、 cells, biomolecules, scaffolds, andother materials, and processed tissues and derivatives used invarious combinations or alone. TEMPs are unique from con-ventional organ transplants. TEMPs may be used in vivo or invitro for disease, injury, elective surgery, and as a diagnostic.3.3 For other defini
13、tions used in this classification, refer tothe terms developed by the subcommittee on tissue engineeredmedical products terminology.3.3.1 DiscussionASTM Committee F04 is continuing torefine definitions for tissue engineered medical products1This classification is under the jurisdiction of ASTM Commi
14、ttee F04 onMedical and Surgical Materials and Devicesand is the direct responsibility ofSubcommittee F04.41 on Classification and Terminology for TEMPs.Current edition approved Oct. 1, 2013. Published December 2013. Originallyapproved in 2002. Last previous edition approved in 2004 as F221104, which
15、 waswithdrawn in January 2013 and reinstated in October 2013. DOI: 10.1520/F2211-13.2For referenced ASTM standards, visit the ASTM website, www.astm.org, orcontact ASTM Customer Service at serviceastm.org. For Annual Book of ASTMStandards volume information, refer to the standards Document Summary p
16、age onthe ASTM website.3Available from U.S. Government Printing Office Superintendent of Documents,732 N. Capitol St., NW, Mail Stop: SDE, Washington, DC 20401.4Available from International Organization for Standardization (ISO), 1 rue deVaremb, Case postale 56, CH-1211, Geneva 20, Switzerland.Copyr
17、ight ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States1(TEMPs) and related areas. A terminology standard forTEMPS will be published.3.4 For specific definitions related to specific standards,refer to the general index and the individual standards
18、.4. Significance and Use4.1 This classification outlines aspects of TEMPs whichincludes their individual components.4.2 The categories outlined in this classification are in-tended to list, identify, and group the areas pertinent to TissueEngineered Medical Products. This classification will be used
19、by the Tissue Engineered Medical Products subcommittees forthe organization of the development of standards for the fieldof tissue engineering, TEMPs, and protocols for their use. Thedevelopment of products from the new tissue engineeringtechnologies necessitates creation and implementation of newst
20、andards (1).54.3 Since interactions may occur among the componentsused in TEMPs, new standard descriptions, test methods, andpractices are needed to aid the evaluation of these interactions.The degree of overall risk for any given TEMP is reflected bythe number and types of tests required to demonst
21、rate productsafety and efficacy.5. Classification of Tissue Engineered Medical Products5.1 Aspects of TEMPs are classified according to theproduct components, site of action, therapeutic target, thera-peutic effect, mode of action, duration of therapy, and lifetime(see Fig. X2.1). TEMPs are composed
22、 of cells, biomolecules,tissues, and biomaterials, alone or in combination, which aredesigned, fabricated, and specified through the principles oftissue engineering. The human body is composed of severalorgan systems that are coordinated to achieve the functionsnecessary for life. For the purposes o
23、f the ASTM CommitteeF04 TEMPs standard effort, 10 organ and tissue systems havebeen classified. They are: Integument, Hematopoietic,Cardiovascular, Musculoskeletal, Respiratory, Digestive,Nervous, Urinary, Endocrine, and Reproductive. (See X2.2 forexamples of each of the human systems). Examples of
24、productapplications under development are given in X2.4.6. Components6.1 TEMPs are often combination products, as defined bythe U.S. FDA 21 CFR Part 3 3.2(e), Product Jurisdiction, thatincorporate attributes of at least two of the medical productclassifications, that is, a traditional biologic, devi
25、ce, or drug.However, in other countries, the definition may be different.For example, the European Union (EU) defines a combinationproduct as having two active components. Also, what isreferred to in the U.S. as a carrier often is an excipient in theEU. In many cases, interactions occur among these
26、combinedmaterials to stimulate repair and regeneration of tissues andorgan function. The biological materials, cells, and cellularproducts (therapeutic biomolecules) are often used to providethe biological message to initiate the repair function.Additionally, the three-dimensional material (natural
27、or syn-thetic biomaterials) may provide the architecture for thestructural support of the cells and repository for bioactivesubstances. The interaction results in the integration of theproduct with the patient, maintenance of the biological integ-rity of the product, and controlled signaling between
28、 theproduct and the patients cells. Synthetic biomaterials used inthe product can also have interactions and effects on theproduct performance.6.2 Cells, that is, of autologous, allogeneic, xenogeneicorigin or genetically modified cells of any species, may becomponents of the TEMP. The cells may be
29、viable, inactivated,or nonviable. They may be embryonic, neonatal, adult, stem, orprogenitor cells. As such, it is important to verify aspects ofTEMP production, that is, cell or tissue sourcing, procurement,good tissue practices, facilities, storage, transportation, anddistribution. Other features
30、of cells used for TEMPs mayinclude genotype and phenotype characterization and safety,that is, absence of adventitious agents. When feasible, stan-dardized methods should be provided.6.2.1 Other aspects of TEMPs with cells may be productspecific. Here, the TEMP developers may need to rely uponstanda
31、rds and methodologies appropriate for the cell type andspecies. For instance, if the TEMP is comprised of non-humancells, the xenogeneic cell identity and safety and immunologi-cal responses must be considered. The use of cells from otheranimal species presents additional issues and increased regu-l
32、atory surveillance including those of ethics and public percep-tion.6.2.2 Other aspects of TEMPs may require unique measuresused by the TEMP developers and accepted by the regulatoryagencies for cell type specific characterizations, process andtest methods, and end-product use and performance. Since
33、 livecells may be used, the maintenance of their viability, andgenetic/phenotypic functional integrity should be addressed.Microbiological safety is critical, thus the verified absence ofadventitious agents must be addressed and methodologiesprovided.6.2.3 Standards will be developed to identify gen
34、eral meth-ods of processing the cells, matrices, and tissue used for theTEMPs; to preserve cells and tissues used for TEMPs; toenumerate cells of various kinds; to characterize cell and tissueviability; to identify general methods for vitro production andtesting of TEMPs; and, to characterize genera
35、l features of cells.6.3 Synthetic or natural biomaterials may be used as supportstructures or delivery systems for therapeutic cells or biomol-ecules (2). Raw materials, referred to as substrates, may beformed or processed into scaffolds to provide load-bearingcapacity, or a framework for tissue for
36、mation, or as a cellcontact surface coating. Control of substrate and scaffoldsurface and bulk characteristics, toxicity, degradation, andreplacement rates require methods selection and protocoldevelopment. Specific naturally-occurring biomaterials andderivatives, which may be produced through vario
37、us methodsand technologies, should be characterized first following sub-strate recommendations. Once processed into a scaffold, the5The boldface numbers in parentheses refer to the list of references at the end ofthis standard.F2211 132biocompatibility and the interactions with the other productcomp
38、onents and the patient must be evaluated.6.3.1 Several naturally occurring materials are used for avariety of TEMPs. Standards for characterization, sourcing andtest methods for alginate, chitosan, and collagen will beimportant for many TEMPs and are being developed.6.4 A biomolecule may be added to
39、 the product as anindividual component, the cells that are a product componentmay produce them, or they may be elicited from the patientstissue by product components. When biomolecules are addedto or produced by the product to impact therapy, their identity,characterization, and function should be d
40、etermined usingspecific standards and test methods. It is important to describethe biomolecule formulation and the formulations compatibil-ity with the matrix. There may also be a need to control thelevel of non-efficacious biomolecules, which may be antigenicor toxic.6.4.1 A test method for the in
41、vitro bioassay of bonemorphogenetic protein-2 has been established (Test MethodF2131) to determine the component identity, potency, andquantity. There is a need to establish bioactivity standards forother protein biomolecules that are components of TEMPs.6.4.2 Test methods to determine protein conce
42、ntration, in-cluding chromatographic purity methods for naturally occur-ring materials are necessary due particularly to the variabilityof the sources for these materials.6.4.3 Dye-binding test methods for specific protein matriceswill aid in the identity verification.6.4.4 There is need for guidanc
43、e for development of in vitroassays to measure release of therapeutic proteins from matri-ces.6.4.5 Standards are needed for characterization and sourc-ing of growth factors and methods for their assay.6.4.6 Standards are needed to develop conditions to storethese materials for future use without lo
44、ss of potency.7. Characterization of TEMP7.1 Tissue characterization is important for the final productconfiguration as well as component description. This is impor-tant for all phases of product development from in vitro testingto post-market surveillance. Given the variety of tests, it iscritical
45、to choose the appropriate method for the applicationsuch that they give information for safety and efficacy. TEMPscan be characterized with imaging modalities, mechanicaltesting, or biochemical measurements and other measurements,or combination thereof.7.1.1 As the characteristics of TEMPs alter in
46、many cases,the changes occurring in use must be monitored at variouscritical time points during the process of integration with thehost tissue. This is particularly true when the component isdesigned to degrade and be replaced by the host tissue. Thebalance in the biodegradation and replacement rate
47、s will beinfluenced by the characteristics of the materials in the productand host response to the product, which also relates to thebiocompatibility of the product. Therefore, monitoring duringthese critical phases of the product lifetime will be necessary.This in turn will impact the structural, m
48、echanical and func-tional properties and require appropriate testing methods andprotocols.7.2 Imaging ModalitiesImaging modalities will includeall forms of light microscopy (including spectral, fluorescent,and optical coherence tomography), electron microscopy, andimaging using other forms of energy
49、. Standards for analysesthat enable the relevant characterization of TEMPs (includingdigital image analysis) will also be developed.7.3 Mechanical CharacterizationMechanical character-ization will include all forms of bench-top testing for quanti-fying mechanical properties (including compressive, tensile,burst pressure), and testing using novel test methods forspecific applications. Standards for analyses of the data andcalibration will also be referenced or developed de novo whennot otherwise available.7.4 Biochemical CharacterizationBiochemical character-ization wi
