1、Designation: F 2211 04Standard Classification forTissue Engineered Medical Products (TEMPs)1This standard is issued under the fixed designation F 2211; the number immediately following the designation indicates the year oforiginal adoption or, in the case of revision, the year of last revision. A nu
2、mber in parentheses indicates the year of last reapproval. Asuperscript epsilon (e) 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
3、excludes 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 CF
4、RParts 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, associa
5、ted 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:2F 2027 Guide for Characterization and Testing of SubstrateM
6、aterials for Tissue-Engineered Medical ProductsF 2064 Guide for Characterization and Testing of Alginatesas Starting Materials Intended for Use in Biomedical andTissue-Engineered Medical Products ApplicationF 2103 Guide for Characterization and Testing of ChitosanSalts as Starting Materials Intended
7、 for Use in Biomedicaland Tissue-Engineered Medical Product ApplicationsF 2131 Test Method for in vitro Biological Activity ofRecombinant Human Bone Morphogenetic Protein-2(rhBMP-2) Using the W-20 Mouse Stromal Cell LineF 2150 Guide for Characterization and Testing of Biomate-rial Scaffolds Used in
8、Tissue-Engineered Medical Products2.2 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 Li
9、sting2.3 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 vario
10、us 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 be
11、 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 c
12、ells, 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 definiti
13、ons 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 products(TEMPs) and related areas. A terminology standard forTEMPS wil
14、l be published.1This classification is under the jurisdiction of ASTM Committee F04 onMedical and Surgical Materials and Devices and is the direct responsibility ofSubcommittee F04.41 on Classification and Terminology for TEMPs.Current edition approved Oct. 1, 2004. Published October 2004. Originall
15、yapproved in 2002. Last previous edition approved in 2002 as F 2211 02.2For 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 page onthe AST
16、M 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.1Copyright ASTM In
17、ternational, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959, United States.3.4 For specific definitions related to specific standards,refer to the general index and the individual standards.4. Significance and Use4.1 This classification outlines aspects of TEMPs whichincludes t
18、heir 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 usedby the Tissue Engineered Medical Products subcommittees forthe organization of the develo
19、pment 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 newstandards (1).54.3 Since interactions may occur among the componentsused in TEMPs, new stan
20、dard 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 demonstrate productsafety and efficacy.5. Classification of Tissue Engineered Medical Products5.
21、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 of cells, biomolecules,tissues, and biomaterials, alone or in combination, which aredesi
22、gned, 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 of the ASTM CommitteeF04 TEMPs standard effort, 10 organ and tissue systems havebeen class
23、ified. They are: Integument, Hematopoietic, Cardio-vascular, Musculoskeletal, Respiratory, Digestive, Nervous,Urinary, Endocrine, and Reproductive. (See X2.2 for examplesof each of the human systems). Examples of product applica-tions under development are given in X2.4.6. Components6.1 TEMPs are of
24、ten 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, device, or drug.However, in other countries, the definition may be different.For example,
25、 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 combinedmaterials to stimulate repair and regeneration of tissues andorgan function.
26、The biological materials, cells, and cellularproducts (therapeutic biomolecules) are often used to providethe biological message to initiate the repair function. Addition-ally, the three-dimensional material (natural or synthetic bio-materials) may provide the architecture for the structuralsupport
27、of the cells and repository for bioactive substances.The interaction results in the integration of the product with thepatient, maintenance of the biological integrity of the product,and controlled signaling between the product and the patientscells. Synthetic biomaterials used in the product can al
28、so haveinteractions and effects on the product 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 viable, inactivated,or nonviable. They may be embryonic, neonatal, adult, stem, orpr
29、ogenitor 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 of cells used for TEMPs mayinclude genotype and phenotype characterization and safet
30、y,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 uponstandards and methodologies appropriate for the cell type andspecies. For instance, if the
31、 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-latory surveillance including those of ethics and public percep-tion.6.2.2 Other aspe
32、cts 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 livecells may be used, the maintenance of their viability, andgenetic/phenotypic fu
33、nctional 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 general meth-ods of processing the cells, matrices, and tissue used for theTEMPs; to pr
34、eserve 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 general features of cells.6.3 Synthetic or natural biomaterials may be used as supportstru
35、ctures or delivery systems for therapeutic cells or biomol-ecules (3). Raw materials, referred to as substrates, may beformed or processed into scaffolds to provide load-bearingcapacity, or a framework for tissue formation, or as a cellcontact surface coating. Control of substrate and scaffoldsurfac
36、e and bulk characteristics, toxicity, degradation, andreplacement rates require methods selection and protocoldevelopment. Specific naturally-occurring biomaterials andderivatives, which may be produced through various methodsand technologies, should be characterized first following sub-strate recom
37、mendations. Once processed into a scaffold, the5The boldface numbers in parentheses refer to the list of references at the end ofthis standard.F2211042biocompatibility and the interactions with the other productcomponents and the patient must be evaluated.6.3.1 Several naturally occurring materials
38、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 the product as anindividual component, the cells that are a product componentmay pro
39、duce 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 determined usingspecific standards and test methods. It is important to describethe bi
40、omolecule 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 vitro bioassay of bonemorphogenetic protein-2 has been established (Test MethodF 2131
41、) 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 concentration, in-cluding chromatographic purity methods for naturally occur-ring materia
42、ls 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 guidance for development of in vitroassays to measure release of therapeutic proteins from
43、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 loss of potency.7. Characterization of TEMP7.1 Tissue characterization is important fo
44、r 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 to choose the appropriate method for the applicationsuch that they give information
45、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 many cases,the changes occurring in use must be monitored at variouscritical time po
46、ints 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 rates will beinfluenced by the characteristics of the materials in the productand host r
47、esponse 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, mechanical and func-tional properties and require appropriate testing methods andprot
48、ocols.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. Standards for analysesthat enable the relevant characterization of TEMPs (includin
49、gdigital 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 will include all forms of tests that determine theactivity, content, purity, or identit
