1、Designation: F2529 13Standard Guide forin vivo Evaluation of Osteoinductive Potential for MaterialsContaining Demineralized Bone (DBM)1This standard is issued under the fixed designation F2529; the number immediately following the designation indicates the year oforiginal adoption or, in the case of
2、 revision, the year of last revision. A number in parentheses indicates the year of last reapproval. Asuperscript epsilon () indicates an editorial change since the last revision or reapproval.1. Scope1.1 This guide covers general guidelines to evaluate theeffectiveness of DBM-containing products in
3、tended to causeand/or promote bone formation when implanted or injected invivo. This guide is applicable to products that may be com-posed of one or more of the following components: naturalbiomaterials (such as demineralized bone), and synthetic bio-materials (such as calcium sulfate, glycerol, and
4、 reverse phasepolymeric compounds) that act as additives, fillers, and/orexcipients (radioprotective agents, preservatives, and/or han-dling agents) to make the demineralized bone easier to ma-nipulate. It should not be assumed that products evaluatedfavorably using this guidance will form bone when
5、 used in aclinical setting. The primary purpose of this guide is tofacilitate the equitable comparison of unique bone-formingproducts in in vivo heterotopic models of osteoinductivity. Thepurpose of this guide is not to exclude other establishedmethods.1.2 The values stated in SI units are to be reg
6、arded asstandard. No other units of measurement are included in thisstandard.1.3 This standard does not purport to address all of thesafety concerns, if any, associated with the use of DBM-containing bone-forming/promoting products. It is the respon-sibility of the user of this standard to establish
7、 appropriatesafety and health practices involved in the development of saidproducts in accordance with applicable regulatory guidancedocuments and in implementing this guide to evaluate thebone-forming/promoting capabilities of the product.2. Referenced Documents2.1 ASTM Standards:2D1193 Specificati
8、on for Reagent WaterD5056 Test Method for Trace Metals in Petroleum Coke byAtomic AbsorptionE508 Test Method for Determination of Calcium and Mag-nesium in Iron Ores by Flame Atomic Absorption Spec-trometryF565 Practice for Care and Handling of Orthopedic Implantsand InstrumentsF895 Test Method forA
9、gar Diffusion Cell Culture Screeningfor CytotoxicityF981 Practice for Assessment of Compatibility of Biomate-rials for Surgical Implants with Respect to Effect ofMaterials on Muscle and BoneF1854 Test Method for Stereological Evaluation of PorousCoatings on Medical ImplantsF2131 Test Method forIn Vi
10、tro Biological Activity of Re-combinant Human Bone Morphogenetic Protein-2(rhBMP-2) Using the W-20 Mouse Stromal Cell LineF2721 Guide for Pre-clinical in vivo Evaluation in CriticalSize Segmental Bone Defects2.2 Federal Documents:321 CFR 58 Good Laboratory Practice for Nonclinical Labo-ratory Studie
11、s21 CFR 820 Quality System Regulation21 CFR 1270 Human Tissue Intended for Transplantation21 CFR 1271 Human Cells, Tissues, and Cellular andTissue-Based Products21 CFR 610.12 General Biological Products StandardsGeneral ProvisionsSterilityQ1E Evaluation of Stability Data, FDA Guidance for Indus-tryC
12、ontainer and Closure Integrity Testing in Lieu of SterilityTesting as a Component of the Stability Protocol forSterile Products, FDA Guidance DocumentEligibility Determination for Donors of Human Cells,Tissues, and Cellular and Tissue-Based Products, Guid-ance for IndustryGuidance for the Preparatio
13、n of a Premarket NotificationApplication for a Surgical Mesh, Guidance for Industryand/or for FDA Reviewers/Staff and/or Compliance1This test method is under the jurisdiction ofASTM Committee F04 on Medicaland Surgical Materials and Devices and is the direct responsibility of SubcommitteeF04.44 on A
14、ssessment for TEMPs.Current edition approved Feb. 1, 2013. Published August 2013. DOI: 10.1520/F252913.2For 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
15、 Document Summary page onthe ASTM website.3Available from Food and Drug Administration (FDA), 10903 New HampshireAve., Silver Spring, MD 20993-0002, http:/www.fda.gov.Copyright ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States12.3 AAMI/ISO Docume
16、nts:4AAMI TIR 17 Compatibility of Materials Subject to Steril-izationAAMI/ISO 22442-01 Medical Devices Utilizing AnimalTissues and their DerivativesPart 1:Application of RiskManagementAAMI/ISO 22442-03 Medical Devices Utilizing AnimalTissues and their DerivativesPart 3: Validation of theElimination
17、and/or Inactivation of Viruses and Transmis-sible Spongiform Encephalopathy (TSE) Agents2.4 ANSI/AAMI/ISO Documents:5ANSI/AAMI/ISO 11137 Parts 13 Sterilization of HealthCare ProductsRadiationANSI/AAMI/ISO 10993 Biological Evaluation of MedicalProducts2.5 ICH Documents:6ICH Harmonised Tripartite Guid
18、eline Q5C Quality of Bio-technological ProductsStability Testing ofBiotechnological/Biological ProductsICH Harmonised Tripartite Guideline Q5A(R1) Viral SafetyEvaluation of Biotechnology Products Derived from CellLines of Human or Animal Origin2.6 USP Document:7United States Pharmacopeia Chapter 3.
19、Terminology3.1 Definitions:3.1.1 additiveingredients that may be used to preserve theproduct, provide radioprotection, and/or act as bulk fillerand/or binding agent.3.1.1.1 DiscussionIt has no intended mode of action, suchas causing cells to transform lineage, once implanted.3.1.2 biologically activ
20、e carriera component added to aDBM-containing bone forming product that results in a physi-ological and/or biochemical transformation in the implant siteindependent of other constituents in the bone forming product.3.1.2.1 DiscussionThe transformation may be desirable oruntoward. A biologically acti
21、ve carrier may also contribute tothe physical or chemical properties/characteristics of that boneforming product.3.1.3 bonehard connective tissue of the skeletal system invertebrates comprised of collagen, growth factors, and aninorganic rigid matrix containing calcium, phosphate and otherminerals,
22、and various cellular elements, including osteoblasts,osteocytes, osteoclasts, and hematopoietic cells.3.1.3.1 DiscussionBone is made up of cortical and can-cellous bone tissue. It serves as the point of attachment formuscles and tendons and is load-bearing.3.1.4 bone forming product (containing DBM)
23、as used inthis guide, a DBM-containing bone forming product may becomprised of multiple components including, but not restrictedto, demineralized bone, growth factors, differentiation factors,osteoprogenitor cells, mesenchymal stem cells, biologicallyactive carrier(s), and/or non-biologically active
24、 carrier(s).3.1.5 bone marrowtissue located in the cancellous portionand cavities (medullary canal) of most bones.3.1.5.1 DiscussionBone marrow is highly vascular andoccurs in two forms: white/yellow marrow, comprised mostlyof adipose cells located primarily in the long bones, and redmarrow, which p
25、rimarily produces and contains pluripotentstems cells and red blood cells, platelets and white blood cellsderived from them. In adults, red marrow is located primarilyin the flat bones.3.1.6 bone tissuethe tissue component of a bone com-prised of a mineralized collagenous matrix formed and main-tain
26、ed through the action of osteoblastic cells and osteocytesremodeled through the action of osteoclasts.3.1.7 cartilageconnective tissue that is a major constitu-ent of the embryonic and young vertebrate skeleton, largelyreplaced with bone and bone marrow bone with maturation.3.1.7.1 DiscussionIt is c
27、omprised mostly of Type II col-lagen and proteoglycans and found in joints, the outer ear,bronchi, and larynx. There are three major types of cartilage:hyaline cartilage, which is adapted for joint surfaces by virtueof its smoothness and ability to withstand compression;fibrocartilage, found in the
28、outer ear, nose, and meniscus; andelastic cartilage, found in the outer ear and epiglottis. Cartilageis also formed by the action of bone morphogenetic protein(s)(BMPs) in concert with other peptide factors on mesenchymalstem cells.3.1.8 cortical bonethin superficial layer of compact bonetissue that
29、 constitutes the primary load-bearing component of abone.3.1.9 demineralized bonebone tissue wherein the averagemineral content, typically measured as calcium, is less than orequal to 8 % by dry weight.3.1.9.1 DiscussionAs used in this guide, dry weightmeans lacking significant or measurable residua
30、l moisture(50 % of emptyspace, fibrous connective tissue, skeletal muscle, excipient,additive and/or filler, and so forth, shall not be counted even ifthey contain new bone. Because a square with 50 bone mayonly contain “one chondrocyte,” by eliminating squares with30% new bone forming elementspasse
31、s test.10. Quantitative AssessmentValidity and Maintenanceof Validity for Lot Release Testing (Recommended)10.1 The histopathologists assessment shall be verifiedevery 4 to 6 months by one of two methods: (1) Visualizationand judging of the percent new bone forming elements on aminimum of 20 slides
32、evaluated by another histopathologist,encompassing the full range of bone formation not seen beforeor (2) Randomly reevaluating 1 % of the slides they assessedover the preceding 4 to 6 months and comparing both sets ofresults. The histopathologist should score an 85 % or better, byeither assessment
33、modality, to continue to perform lot releaseassessment for bone forming products. If the histopathologistfails the assessment, s/he shall be retrained and retested on anew set of slides that have been previously evaluated. Within aproject the histopathologist shall be blind as to the test articles,a
34、ny applicable controls, and the requesting institution/company.11. Examples of New Bone Forming Elements11.1 Bone induction is defined as the presence of newlyformed bone at the implant site. Newly formed bone shall bedefined as the presence of one or more of the following boneforming elements: chon
35、droblasts, chondrocytes, osteoblasts,osteocytes, cartilage, new bone, and bone marrow. Figs. 2-4illustrate a typical histological preparation of an explant fromthe implantation of DBM in a nude mouse. In Fig. 2, new boneis clearly visible as pockets of chondrocytes that have thepotential to form bon
36、e at some later time. In addition, there isnewly formed bone, bone marrow, and implant DBM that hasbeen “recellularized.”12. Keywords12.1 animal model; athymic; bioassay; demineralized bone;osteoconductive; osteoinductiveFIG. 2 H Blue implant DBM; Yellow new bone; Orange connective tissue; Red chond
37、rocytes; Green skeletal muscle)F2529 139FIG. 3 Histomorphometry of Newly Formed Bone and Implant Bone (Black progenitor cells and the adipocytes are clear vacuolescontained inside the progenitor cell region; Blue implant DBM; Yellow new bone; Orange connective tissue; Red chondrocytes)FIG. 4 Example
38、 of an Ossicle or Newly Formed Bone Surrounding Bone Marrow (Black progenitor cells; Blue implant DBM; Yellow new bone; Orange connective tissue; Red chondrocytes)F2529 1310APPENDIXES(Nonmandatory Information)X1. CHARACTERIZATIONINTRODUCTIONThis appendix is provided to provide example guidance on ho
39、w to control some potential sourcesof inter-lot and intra-lot variability.X1.1 Excipient/Additive/Filler CharacterizationX1.1.1 Excipients, additives, and fillers can be added to aid,for example, handling, radioprotection, and bulking. However,they are not intended to cause cells to transform lineag
40、e butthey may possess osteoconductive properties. Every effortshould be made to use materials that meet at least one of thecriteria listed below. Items on the FDAlist of items “GenerallyRegarded as Safe (GRAS)” should not be presumed to be safefor use in bone forming products and their safety and ef
41、ficacymust be determined within the specific product and place(s) ofintended use.X1.1.1.1 United States Pharmacopeia (USP).X1.1.1.2 American Chemical Society (ACS).X1.1.1.3 Ultra pure, 99 %.X1.1.1.4 FDA Master File.X1.1.1.5 Water Type II of Specification D1193 1199.X1.1.2 Additionally, excipients, a
42、dditives and fillers shouldbe characterized for their intended purpose, the quality of thesource material, and function in the product by means such as:X1.1.2.1 pH physiological, if applicable.X1.1.2.2 Characterization of set times, if applicable.X1.1.2.3 Radioprotective capabilities.X1.1.2.4 Preser
43、vation capabilities.X1.1.2.5 Bulking agent characteristics such as viscosity.F2529 1311X1.2 Demineralized Bone CharacterizationX1.2.1 The various attributes described below have beendemonstrated in the literature (see Bibliography) to affect theperformance of DBM:X1.2.2 Particle/Fiber SizeA specific
44、ation that details theacceptable parameters for particle size distribution or fiberdimensions, or both is recommended. The method used togenerate and/or partition particles and/or fibers should bevalidated to meet the written specification reproducibly. Onereason for this validation is that the part
45、icle/fiber size distribu-tion may impact the reproducibility of the demineralizationprocess and its ability to meet the manufacturers residualweight percent calcium specification at the least. If it is notpossible to validate the sizing process, then a written rationaleshould be constructed that add
46、resses why the inability tovalidate this process does not negatively affect the form, fit orfunction of the bone forming product.X1.2.3 Weight Percent Residual CalciumThe averageweight percent residual calcium in each lot of DBM post-demineralization should be determined prior to being mixedwith an
47、excipient. The weight percent residual calcium must beless than or equal to eight percent per theAmericanAssociationof Tissue Banks standards for DBM. The method used todetermine the weight percent calcium shall be validated to beaccurate and precise such that potential interfering substancespresent
48、 in the DBM have been demonstrated not to interferewith the accurate determination of the calcium content in theDBM. For instance, the phosphate component of DBM is aknown interfering substance in atomic absorption spectros-copy; this can be overcome with the use of lanthanum (TestMethod E508 and Te
49、st Method D5056). Additionally, thereshould be a validated sampling plan that addresses how manysamples, from how many locations must be obtained andassessed to statistically ensure that the entire lot of DBM meetsthe manufacturers calcium specification.X1.2.4 Residual MoistureThe American Association ofTissue Banks has established the six percent criterion forfreeze-dried products. For products in which the DBM isfreeze-dried and provided separately from the excipient or as afreeze-dried product, the residual mois
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