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Significance and Use
4.1 This guide covers animal implantation methods and analysis of the explanted DBM-containing material to determine whether a material or substance possesses osteoinductive potential, as defined by its ability to cause bone to form in vivo at a site that would otherwise not support bone formation, that is, heterotopically in a skeletal muscle implant site. For in vitro evaluation see Test Method F2131 for in vitro assessment of rhBMP 2.
4.2 The test methods described here may be suitable for defining product specifications, cGMP lot release testing, research evaluation, regulatory submission, and so forth, but a positive outcome should not be presumed to indicate that the product will be osteoinductive in a human clinical application. At present, the only direct assays to assess new bone formation are in vivo, since the property of bone conduction or induction can only be assessed in a heterotopic or orthotopic site in a living animal. When these products are implanted in an orthotopic site, osteogenic factors already present at the implantation site may contribute to and enhance bone formation in conjunction with the osteoconductive nature of the product. Thus, orthotopic implantation of products may result in bone formation by acting on existing bone forming cells and not by causing mesenchymal stem cells to become osteochondroprogenitor cells. In contrast, when these products are implanted in a heterotopic site, no native osteogenic factors are present to contribute to or enhance bone formation. Thus, heterotopic implantation of products will only result in new bone formation by causing mesenchymal stem cells to become osteochondroprogenitor cells. In vitro assays have been described and some believe they may correlate to the results obtained from in vivo assays. However such in vitro assays measure only some of the biochemical marker(s) associated with in vivo bone formation and are therefore only indirect assays for osteoinductive activity or the capacity to promote new bone formation. Many factors or combination of factors contribute to osteoblast progenitor cells differentiating and/or proliferating into bone forming cells in vitro that are both osteoinductive and osteoconductive when they are implanted in vivo. Thus, only an in vivo assay method currently directly considers the many potential factors involved in new bone formation induced by DBM containing biomaterials. The qualification of a DBM or DBM-containing material should also encompass product characterization such as that described in Appendix X1.
1.1 This guide covers general guidelines to evaluate the effectiveness of DBM-containing products intended to cause and/or promote bone formation when implanted or injected in vivo. This guide is applicable to products that may be composed of one or more of the following components: natural biomaterials (such as demineralized bone), and synthetic biomaterials (such as calcium sulfate, glycerol, and reverse phase polymeric compounds) that act as additives, fillers, and/or excipients (radioprotective agents, preservatives, and/or handling agents) to make the demineralized bone easier to manipulate. It should not be assumed that products evaluated favorably using this guidance will form bone when used in a clinical setting. The primary purpose of this guide is to facilitate the equitable comparison of unique bone-forming products in in vivo heterotopic models of osteoinductivity. The purpose of this guide is not to exclude other established methods.
1.3 This standard does not purport to address all of the safety concerns, if any, associated with the use of DBM-containing bone-forming/promoting products. It is the responsibility of the user of this standard to establish appropriate safety and health practices involved in the development of said products in accordance with applicable regulatory guidance documents and in implementing this guide to evaluate the bone-forming/promoting capabilities of the product.
2. Referenced Documents (purchase separately) The documents listed below are referenced within the subject standard but are not provided as part of the standard.
D1193 Specification for Reagent Water
D5056 Test Method for Trace Metals in Petroleum Coke by Atomic Absorption
E508 Test Method for Determination of Calcium and Magnesium in Iron Ores by Flame Atomic Absorption Spectrometry
F565 Practice for Care and Handling of Orthopedic Implants and Instruments
F895 Test Method for Agar Diffusion Cell Culture Screening for Cytotoxicity
F981 Practice for Assessment of Compatibility of Biomaterials for Surgical Implants with Respect to Effect of Materials on Muscle and Bone
F1854 Test Method for Stereological Evaluation of Porous Coatings on Medical Implants
F2131 Test Method for In Vitro Biological Activity of Recombinant Human Bone Morphogenetic Protein-2 (rhBMP-2) Using the W-20 Mouse Stromal Cell Line
F2721 Guide for Pre-clinical in vivo Evaluation in Critical Size Segmental Bone Defects
Federal Documents21CFR1270 Human Tissue Intended for Transplantation 21CFR1271 Human Cells, Tissues, and Cellular and Tissue-Based Products 21CFR58 Good Laboratory Practice for Nonclinical Laboratory Studies 21CFR610.12 General Biological Products Standards--General Provisions--Sterility 21CFR820 Quality System Regulation ContainerandClosureI in Lieu of Sterility Testing as a Component of the Stability Protocol for Sterile Products, FDA Guidance Document EligibilityDetermina Guidance for Industry GuidanceforthePrepar Guidance for Industry and/or for FDA Reviewers/Staff and/or Compliance Q1EEvaluationofStabi FDA Guidance for Industry
AAMI/ISO DocumentsAAMI/ISO22442-01 Medical Devices Utilizing Animal Tissues and their Derivatives--Part 1: Application of Risk Management AAMI/ISO22442-03 Medical Devices Utilizing Animal Tissues and their Derivatives--Part 3: Validation of the Elimination and/or Inactivation of Viruses and Transmissible Spongiform Encephalopathy (TSE) Agents AAMITIR17 Compatibility of Materials Subject to Sterilization
ICS Number Code 07.080 (Biology. Botany. Zoology); 11.100.99 (Other standards related to laboratory medicine)