1、Designation: F 2212 02 (Reapproved 2007)e1Standard Guide forCharacterization of Type I Collagen as Starting Material forSurgical Implants and Substrates for Tissue-EngineeredMedical Products (TEMPs)1This standard is issued under the fixed designation F 2212; the number immediately following the desi
2、gnation indicates the year oforiginal adoption or, in the case of revision, the year of last revision. A number in parentheses indicates the year of last reapproval. Asuperscript epsilon (e) indicates an editorial change since the last revision or reapproval.e1NOTEFormatting and grammar were correct
3、ed editorially throughout in April 2007.INTRODUCTIONCollagen-based medical devices are becoming more prevalent, especially in the area of soft tissueaugmentation. The use of collagen in surgery dates back to the late 1800s, with the use of catgutsutures, human cadaveric skin, and fascia. More recent
4、ly, collagen has been used in hemostaticsponges, dermal equivalents, injectables for soft tissue augmentation, as a matrix for cell-basedproducts and as a vehicle for drug delivery. It is because of the versatility of collagen in medicalapplications that specific characterizations should be performe
5、d as a way to compare materials.1. Scope1.1 This guide for characterizing collagen-containing bio-materials is intended to provide characteristics, properties, andtest methods for use by producers, manufacturers, and re-searchers to more clearly identify the specific collagen mate-rials used. With g
6、reater than 20 types of collagen and thedifferent properties of each, a single document would becumbersome. This guide will focus on the characterization ofType I collagen, which is the most abundant collagen inmammals, especially in skin and bone. Collagen isolated fromthese sources may contain oth
7、er types of collagen, for example,Type III and Type V. This guide does not provide specificparameters for any collagen product or mix of products or theacceptability of those products for the intended use. Thecollagen may be from any source, including, but not limited to,animal or cadaveric sources,
8、 human cell culture, or recombi-nant sources. The biological, immunological, or toxicologicalproperties of the collagen may vary, depending on the sourcematerial. The properties of the collagen prepared from each ofthe above sources must be thoroughly investigated, as thechanges in the collagen prop
9、erties as a function of sourcematerials is not thoroughly understood. This guide is intendedto focus on purified Type I collagen as a starting material forsurgical implants and substrates for Tissue-Engineered MedicalProducts (TEMPs); some methods may not be applicable forgelatin nor for tissue impl
10、ants. This guide may serve as atemplate for characterization of other types of collagen.1.2 The biological response to collagen in soft tissue hasbeen well documented by a history of clinical use (1, 2)2andlaboratory studies (3, 4, 5, 21). Biocompatibility and appropri-ateness of use for a specific
11、application(s) is the responsibilityof the device manufacturer.1.3 The following precautionary caveat pertains only to thetest method portion, Section 5, of this guide. This standarddoes not purport to address all of the safety concerns, if any,associated with its use. It is the responsibility of th
12、e user of thisstandard to establish appropriate safety and health practicesand determine the applicability of regulatory requirementsprior to use.2. Referenced Documents2.1 ASTM Standards:3E 1298 Guide for Determination of Purity, Impurities, andContaminants in Biological Drug ProductsF 619 Practice
13、 for Extraction of Medical PlasticsF 720 Practice for Testing Guinea Pigs for Contact Aller-gens: Guinea Pig Maximization Test1This guide is under the jurisdiction of ASTM Committee F04 on Medical andSurgical Materials and Devices and is the direct responsibility of SubcommitteeF04.42 on Biomaterial
14、s and Biomolecules for TEMPs.Current edition approved Feb. 1, 2007. Published February 2007. Originallyapproved in 2002. Last previous edition approved in 2002 as F 2212 02.2The boldface numbers in parentheses refer to the list of references at the end ofthis standard.3For referenced ASTM standards,
15、 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 ASTM website.1Copyright ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 194
16、28-2959, United States.F 748 Practice for Selecting Generic Biological Test Meth-ods for Materials and DevicesF 749 Practice for Evaluating Material Extracts by Intracu-taneous Injection in the RabbitF 756 Practice for Assessment of Hemolytic Properties ofMaterialsF 763 Practice for Short-Term Scree
17、ning of Implant Mate-rialsF 813 Practice for Direct Contact Cell Culture Evaluation ofMaterials for Medical DevicesF 895 Test Method for Agar Diffusion Cell Culture Screen-ing for CytotoxicityF 981 Practice for Assessment of Compatibility of Bioma-terials for Surgical Implants with Respect to Effect
18、 ofMaterials on Muscle and BoneF 1251 Terminology Relating to Polymeric Biomaterials inMedical and Surgical DevicesF 1439 Guide for Performance of Lifetime Bioassay for theTumorigenic Potential of Implant MaterialsF 1903 Practice for Testing For Biological Responses toParticles in vitroF 1904 Practi
19、ce for Testing the Biological Responses toParticles in vivoF 1905 Practice For Selecting Tests for Determining thePropensity of Materials to Cause ImmunotoxicityF 1906 Practice for Evaluation of Immune Responses InBiocompatibility Testing Using ELISA Tests, LymphocyteProliferation, and Cell Migratio
20、nF 1983 Practice for Assessment of Compatibility ofAbsorbable/Resorbable Biomaterials for Implant Applica-tionsF 2148 Practice for Evaluation of Delayed Contact Hyper-sensitivity Using the Murine Local Lymph Node Assay(LLNA)2.2 ISO Standards:4ISO 10993-1 Biological Evaluation of Medical DevicesPart
21、1: Evaluation and TestingISO 10993-3Part 3 Tests for Genotoxicity, Carcinogenic-ity and Reproductive ToxicityISO 10993-9Part 9 Framework for Identification andQuantification of Potential Degradation ProductsISO 10993-10 Biological Evaluation of Medical DevicesPart 10: Tests for Irritation and Delaye
22、d-Type Hypersen-sitivityISO 10993-17Part 17 Methods for Establishment of Al-lowable Limits for Leachable Substances Using Health-Based Risk AssessmentISO 13408-1: 1998 Aseptic Processing of Health CareProductsPart 1: General Requirements2.3 EN (European Norm) Documents:5EN 12442-1 Animal Tissues and
23、 their Derivatives Utilizedin the Manufacture of Medical DevicesPart 1: Analysisand Management of RiskEN 12442-2Part 2 Controls on Sourcing, Collection andHandlingEN 12442-3Part 3 Validation of the Elimination and/orInactivation of Virus and Transmissible Agents2.4 U. S. Pharmacopeia Documents:6Unit
24、ed States Pharmacopeia (USP), Edition XXIV (24)USP 24/NF 19 Viral Safety Evaluation of BiotechnologyProducts Derived from Cell Lines of Human or AnimalOrigin2.5 Code of Federal Regulations:7Code of Federal Regulations, Title 21, Part 820Federal Register Vol. 43, No. 141, Friday, July 21, 1978Human C
25、ells, Tissues and Cellular and Tissue-Based Prod-ucts, Establishment Registration and Listing. 21 CFRParts 207, 807, and 1271Federal Register/Vol. 66, No. 13, Jan 19, 2001/Rules andRegulations, page 5447Suitability Determination for Donors of Human Cell andTissue-based Products, 21 CFR 1271 Part C,
26、ProposedRuleCurrent Good Tissue Practice for Manufacturers of HumanCellular and Tissue-Based Products, Inspection and En-forcement. Proposed Rule. Federal Register/Vol. 66, No.5/January 8, 2001/Proposed Rules, pages 1552-1559Guidance for Screening and Testing of Donors of HumanTissue Intended for Tr
27、ansplantation, Availability. FederalRegister/Vol. 62, No. 145/July 29, 1997/NoticesDraftGuidance for Preclinical and Clinical Investigations ofUrethral Bulking Agents used in the Treatment of UrinaryIncontinence. November 29, 1995. (ODE/DRARD/ULDB), Document No. 850Guidance for Industry and for FDA
28、Reviewers, MedicalDevices Containing Materials Derived from AnimalSources (Except for In Vitro Diagnostic Devices), Novem-ber 6, 1998, U.S. Department of Health and HumanServices, Food and Drug Administration, Center for De-vices and Radiological HealthCFR 610.13(b), Rabbit Pyrogen Assay2.6 ICH Docu
29、ments:8International Conference on Harmonization (1997) Guid-ance for Industry M3 Nonclinical Safety Studies for theConduct of Human Clinical Trials for Pharmaceuticals 62FR 62922International Conference on Harmonization (1996) Guide-line for Industry S2A Specific Aspects of RegulatoryGenotoxicity T
30、ests for Pharmaceuticals. 61 FR 18199International Conference on Harmonization (1997) Guid-ance for Industry S2B Genotoxicity: A Standard Batteryfor Genotoxicity Testing of Pharmaceuticals 62 FR 62472International Conference on Harmonization (1994) Guide-line for Industry S5A Detection of Toxicity t
31、o Reproduc-tion for Medicinal Products. 59 FR 487464Available from International Organization for Standardization (ISO), 1 rue deVaremb, Case postale 56, CH-1211, Geneva 20, Switzerland.5Available from European Committee for Standardization, CEN ManagementCentre 36, rue de Stassart B-1050 Brussels,
32、Belgium.6Available from U.S. Pharmacopeia (USP), 12601 Twinbrook Pkwy., Rockville,MD 20852.7Available from U.S. Government Printing Office Superintendent of Documents,732 N. Capitol St., NW, Mail Stop: SDE, Washington, DC 20401.8ICH Secretariat, c/o IFPMA, 30 rue de St-Jean, P.O. Box 758, 1211 Genev
33、a 13,Switzerland.F 2212 02 (2007)e12International Conference on Harmonization (1996) Guid-ance for Industry S5B Detection of Toxicity to Reproduc-tion for Medicinal Products: Addendum on Toxicity toMale Fertility. 61 FR 15360International Conference on Harmonization (1996) Guide-line for Industry S1
34、A The Need for Long-term RodentCarcinogenicity Studies of Pharmaceuticals. 61 FR 8153International Conference on Harmonization (1998) Guid-ance for Industry S1B Testing for Carcinogenicity ofPharmaceuticals. 63 FR 8983International Conference on Harmonization (1995) Guide-line for Industry S1C Dose
35、Selection for CarcinogenicityStudies of Pharmaceuticals. 60 FR 11278International Conference on Harmonization (1997)S1C(R) Guidance for Industry Addendum to Dose Selec-tion for Carcinogenicity Studies of Pharmaceuticals: Ad-dition of a Limit Dose and Related Notes. 62 FR 64259International Conferenc
36、e on Harmonization (ICH) Q1AICH Harmonized Tripartite Guidance for Stability Testingof New Drug Substances and Products (September 23,1994)U.S. Food and Drug Administration (FDA and Committeefor Proprietary Medicinal Products (CPMP), 1998 Inter-national Conference on Harmonization (ICH), Quality ofB
37、iotechnological Products: Viral Safety Evaluation ofBiotechnology Products Derived from Cell Lines of Hu-man or Animal Origin, Consensus Guideline ICH ViralSafety Document: Step 52.7 FDA Documents:9FDA Guideline on Validation of the Limulus AmebocyteTest as an End-Product Endotoxin Test for Human an
38、dAnimal Parenteral Drugs, Biological Products and Health-care Products, DHHS, December 1987U.S. Food and Drug Administration (FDA) Center forBiologics Evaluation and Research (CBER), 1993 Pointsto Consider in the Characterization of Cell Lines Used toproduce BiologicalsU.S. Food and Drug Administrat
39、ion (FDA) Center forBiologics Evaluation and Research (CBER), 1997 Pointsto Consider in the Manufacture and Testing of MonoclonalAntibody Products for Human Use, 94D-0259FDA Interim Guidance for Human and Veterinary DrugProducts and Biologicals, Kinetic LAL techniques,DHHS, July 15, 19912.8 AAMI Doc
40、uments:10ANSI/AAMI/ISO 11737-1: 1995 Sterilization of MedicalDevicesMicrobiological MethodsPart 1: Estimationof Bioburden on ProductANSI/AAMI/ISO 11737-2: 1998 Sterilization of MedicalDevicesMicrobiological MethodsPart 2: Tests of Ste-rility Performed in the Validation of a Sterilization ProcessAAMI
41、 TIR No. 19-1998 Guidance for ANSI/AAMI/ISO10993-7: 1995, Biological Evaluation of MedicalDevicesPart 7: Ethylene Oxide Sterilization ResidualsAAMI/ISO 14160-1998 Sterilization of Single-Use MedicalDevices Incorporating Materials of Animal OriginValidation and Routine Control of Sterilization by Liq
42、uidChemical SterilantsAAMI ST67/CDV-2: 1999 Sterilization of MedicalDevicesRequirements for Products Labeled “Sterile”2.9 Other References:Draft Guidance for Preclinical and Clinical Investigations ofUrethral BulkingAgents Used in the Treatment of UrinaryIncontinence, November 29, 1995. (ODE/DRARD/U
43、LDB), Document No. 850.113. Terminology3.1 Definitions:3.1.1 adventitious agents, nan unintentionally introducedmicrobiological or other infectious contaminant. In the produc-tion of TEMPs, these agents may be unintentionally introducedinto the process stream or the final product, or both.3.1.2 bioc
44、ompatibility, na material may be consideredbiocompatible if the materials perform with an appropriate hostresponse in a specific application (22).3.1.3 collagen, nType I collagen is a member of a familyof structural proteins found in animals. Type I collagen is partof the fibrillar group of collagen
45、s. It derives from the COL1A1and COL1A2 genes, which express the alpha chains of thecollagen. All collagens have a unique triple helical structureconfiguration of three polypeptide units known as alpha-chains. Proper alignment of the alpha chains of the collagenmolecule requires a highly complex enz
46、ymatic and chemicalinteraction in vivo. As such, preparation of the collagen byalternate methods may result in improperly aligned alphachains and, putatively, increase the immunogenicity of thecollagen. Collagen is high in glycine, L-alanine, L-proline, and4-hydroxyproline, low in sulfur, and contai
47、ns no L-tryptophan.Natural, fibrillar Type I collagen is normally soluble in diluteacids and alkalis. When heated (for example, above approxi-mately 40C), collagen is denatured to single alpha chains(gelatin). At each end of the chains are short non-helicaldomains called telopeptides, which are remo
48、ved in somecollagen preparations. Through non-covalent interactions withsites on adjacent helixes, fibrillogenesis is achieved. Subse-quently, non-reducible cross links are formed. Type I collagencan be associated with Type III and Type V collagen and alsowith the other non-collagenous proteins like
49、 elastin and otherstructural molecules like glycosaminoglycans and complexlipoproteins and glycoproteins.3.1.4 degradation, nchange in chemical, physical, ormolecular structure or appearance (that is, gross morphology)of material.3.1.5 endotoxin, na high-molecular-weight lipopolysac-charide (LPS) complex associated with the cell wall ofgram-negative bacteria that is pyrogenic in humans.3.1.5.1 DiscussionThough endotoxins are pyrogens, notall pyrogens are endotoxins.9Available from the Food and DrugAdministration, 5600 Fishers Ln., Rockville,MD 20857.10Associa
