ASTM F2884-2012 Standard Guide for Pre-clinical in vivo Evaluation of Spinal Fusion《临床前体外评价脊柱融合的标准指南》.pdf

1、Designation: F2884 12Standard Guide forPre-clinical in vivo Evaluation of Spinal Fusion1This standard is issued under the fixed designation F2884; the number immediately following the designation indicates the year oforiginal adoption or, in the case of revision, the year of last revision. A number

2、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 for the pre-clinicalin vivo assessment of tissue-engineered medical products(TEMPs) intended to repair or

3、 regenerate bone in an interbodyand/or posterolateral spinal environment. TEMPs included inthis guide may be composed of, but are not limited to, naturalor synthetic biomaterials or composites thereof, and maycontain cells or biologically active agents such as growthfactors, synthetic peptides, plas

4、mids, or cDNA. The modelsdescribed in this document represent a stringent test of amaterials ability to induce and/or augment bone growth in thespinal environment.1.2 While clinically TEMPs may be combined with hard-ware for initial stabilization or other purposes, the focus of thisguide is on the a

5、ppropriateness of the animal model chosen andevaluation of the TEMP induced repair and as such does notfocus on issues of hardware.1.3 Guidelines include a description and rationale of variousanimal models for the in vivo assessment of the TEMP. Theanimal models utilize a range of species including

6、rat (murine),rabbit (lapine), dog (canine), goat (caprine), pig (porcine),sheep (ovine), and non-human primate (primates). Outcomemeasures include in vivo assessments based on radiographic,histologic, CT imaging as well as subsequent in vitro assess-ments of the repair, including histologic analyses

7、 and mechani-cal testing. All methods are described briefly and referenced.The user should refer to specific test methods for additionaldetail.1.4 This guide is not intended to include the testing of rawmaterials, preparation of biomaterials, sterilization, or packag-ing of the product. ASTM standar

8、ds for these steps areavailable in Referenced Documents (Section 2).1.5 The use of any of the methods included in this guidemay not produce a result that is consistent with clinicalperformance in one or more specific applications.1.6 Other pre-clinical methods may also be appropriate andthis guide i

9、s not meant to exclude such methods. The materialmust be suitable for its intended purpose. Additional biologicaltesting in this regard would be required.1.7 The values stated in SI units are to be regarded asstandard. No other units of measurement are included in thisstandard.1.8 The values stated

10、in inch-pound units are to be regardedas standard. The values given in parentheses are mathematicalconversions to SI units that are provided for information onlyand are not considered standard.2. Referenced Documents2.1 ASTM Standards:2F561 Practice for Retrieval and Analysis of Medical De-vices, an

11、d Associated Tissues and FluidsF565 Practice for Care and Handling of Orthopedic Im-plants and InstrumentsF895 Test Method for Agar Diffusion Cell Culture Screen-ing for CytotoxicityF981 Practice for Assessment of Compatibility of Biomate-rials for Surgical Implants with Respect to Effect ofMaterial

12、s on Muscle and BoneF1983 Practice for Assessment of Compatibility ofAbsorbable/Resorbable Biomaterials for Implant Applica-tionsF2150 Guide for Characterization and Testing of Biomate-rial Scaffolds Used in Tissue-Engineered Medical Products2.2 Other StandardsISO 10993 Biological Evaluation of Medi

13、cal TEMPsPart5: Tests for in vitro Cytotoxicity321 CFR Part 58 Good Laboratory Practice for NonclinicalLaboratory Studies41This guide is under the jurisdiction of ASTM Committee F04 on Medical andSurgical Materials and Devices and is the direct responsibility of SubcommitteeF04.44 on Assessment for

14、TEMPs.Current edition approved April 1, 2012. Published April 2012. DOI: 10.1520/F288412.2For 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 Summ

15、ary page onthe ASTM website.3Available from American National Standards Institute (ANSI), 25 W. 43rd St.,4th Floor, New York, NY 10036, http:/www.ansi.org.4Available from U.S. Government Printing Office Superintendent of Documents,732 N. Capitol St., NW, Mail Stop: SDE, Washington, DC 20401, http:/w

16、ww.access.gpo.gov.1Copyright ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959, United States.21 CFR 610.12 General Biological Product Standards Sterility43. Terminology3.1 Definitions:3.1.1 bone regenerationthe formation of bone that hashistologic, biochemical

17、, and mechanical properties similar tothat of native bone.3.1.2 bone remodelinga lifelong process where old boneis removed from the skeleton (a sub-process called boneresorption) and new bone is added (a sub-process called boneformation).3.1.2.1 DiscussionThese processes also control the re-shaping

18、or replacement of bone during growth and followinginjuries. Remodeling responds to functional demands andmuscle attachments. As a result bone is added where neededand removed where it is not required.3.1.3 bone repairprocess of healing injured bone throughcell proliferation and synthesis of new extr

19、acellular matrix.3.1.4 cancellous bone(also known as trabecular, orspongy, bone), a type of osseous tissue with a low apparentdensity and strength but very high surface area, that fills theinner cavity of long bones.3.1.4.1 DiscussionThe orientation of the trabecular boneis such that the trabecular

20、“struts” tend to follow the lines ofstress to which the bones are normally subjected. The externallayer of cancellous bone contains red bone marrow where theproduction of blood cellular components (known as he-matopoiesis) takes place. Cancellous bone is also where mostof the arteries and veins of b

21、one organs are found.3.1.5 compact boneclassification of ossified bony connec-tive tissue characterized by the presence of osteon-containinglamellar bone; lamellar bone is highly organized in concentricsheets.3.1.6 cortical boneone of the two main types of osseoustissue; cortical bone is dense and f

22、orms the surface of bones.3.1.7 endochondral ossificationone of the two main typesof bone formation, where a cartilaginous matrix forms first andis subsequently replaced by osseous tissue.3.1.7.1 DiscussionEndochondral ossification is respon-sible for much of the bone growth in vertebrate skeletons,

23、especially in long bones.3.1.7.2 DiscussionThe other main mechanism for boneformation is intramembraneous ossification, where osseoustissue is formed directly, without cartilaginous precursor; itoccurs mainly in the formation of flat bones (skull).3.1.8 growth platethe anatomic location within theep

24、iphyseal region of long bones corresponding to the site ofgrowth through endochondral bone formation.3.1.8.1 DiscussionThe growth plate in skeletally matureanimals is fused.3.1.9 interbody spine fusiona method of obtaining spinalfusion that involves placing bone graft between adjacentvertebra in the

25、 area usually occupied by the intervertebral disc.3.1.10 marrowsoft, gelatinous tissue that fills the cavitiesof the bones. It is either red or yellow, depending upon thepreponderance of hematopoietic (red) or fatty (yellow) tissue.3.1.10.1 DiscussionRed marrow is also called myeloidtissue.3.1.11 ma

26、trixa term applied to either the exogenousimplanted scaffold or the endogenous extracelluar substance(otherwise known as extracellular matrix) derived from thehost.3.1.12 posterolateral spine fusiona method of obtainingspinal fusion that involves placing bone graft in the “gutter” inthe posterolater

27、al portion of the spine between the transverseprocess and the spinous process.3.1.12.1 DiscussionPosterolateral spine fusion is alsoknown as posterolateral gutter spine fusion.3.1.13 remodelinga lifelong process where old bone isremoved from the skeleton (bone resorption) and new bone isadded (bone

28、formation).3.1.14 residence timetime at which an implanted material(synthetic or natural) can no longer be detected in the hosttissue.3.1.15 skeletal maturitythe age at which the epiphysealplates are fused.3.1.15.1 DiscussionIn rodents, skeletally mature animalsare characterized by defined gonads.3.

29、1.16 spinal fusionalso known as spondylosyndesis, is asurgical technique used to combine two or more vertebrae.3.1.16.1 DiscussionSupplementary bone tissue (either au-tograft or allograft) is often used in conjunction with the bodysnatural osteoblastic processes. This procedure is used primarilyto e

30、liminate the pain caused by abnormal motion of thevertebrae by immobilizing the vertebrae themselves. Spinalfusion is done most commonly in the lumbar region of thespine, but it is also used to treat cervical and thoracic problems.3.1.17 trabecular bonebony connective tissue character-ized by spicul

31、es surrounded by marrow space.3.1.18 vertebrathe vertebral column (singular: vertebra)are the individual irregular bones that make up the spinalcolumn (also known as ischis)a flexuous and flexible col-umn.3.1.18.1 DiscussionThere are normally thirty-three (33)vertebrae in humans, including the five

32、that are fused to formthe sacrum (the others are separated by intervertebral discs)and the four coccygeal bones which form the tailbone. Theupper three regions comprise the remaining 24, and aregrouped under the names cervical (7 vertebrae), thoracic (12vertebrae) and lumbar (5 vertebrae), according

33、 to the regionsthey occupy. This number is sometimes increased by anadditional vertebra in one region, or it may be diminished inone region, the deficiency often being supplied by an additionalvertebra in another. The number of cervical vertebrae is,however, very rarely increased or diminished. Each

34、 vertebra iscomposed of a body anteriorly and a neural arch posteriorly.The arch encloses an opening, the vertebral foramen, whichhelps to form a canal in which the spinal cord is housed.Protruding from the posterior extreme of each neural arch is aspinous process and extending from the lateral edge

35、s of eacharch are transverse processes. These bony elements serve asimportant sites of attachment of deep back muscles. The neuralarch of each vertebrae is divided into component parts by theseprocesses. The parts of the neural arch between the spinous andtransverse processes are known as the lamina

36、e and the parts ofthe arch between the transverse processes and the body are theF2884 122pedicles. At the point where the laminae and pedicles meet,each vertebra contains two superior articular facets and twoinferior articular facets. The former pair of facets form articu-lations, which are synovial

37、 joints, with the two inferiorarticular facets of the vertebra immediately above (or the skull,in the case of the first cervical vertebra). The pedicle of eachvertebra is notched at its superior and inferior edges. Togetherthe notches from two contiguous vertebra form an opening, theintervertebral f

38、oramen, through which spinal nerves pass.3.1.19 vertebral bodythe largest part of a vertebra, and isapproximately cylindrical in shape.3.1.19.1 DiscussionIts upper and lower surfaces are flat-tened and rough, and give attachment to the intervertebralfibrocartilages, and each presents a rim around it

39、s circumfer-ence. In front, the body is convex from side to side and concavefrom above downward. Behind, it is flat from above downwardand slightly concave from side to side. Its anterior surfacepresents a few small apertures, for the passage of nutrientvessels. On the posterior surface is a single

40、large, irregularaperture, or occasionally more than one, for the exit of thebasi-vertebral veins from the body of the vertebra.4. Significance and Use4.1 This guide is aimed at providing a range of in vivomodels to aid in preclinical research and development oftissue-engineered medical products (TEM

41、Ps) intended for theclinical repair or regeneration of bone in the spine.4.2 This guide includes a description of the animal models,surgical considerations, and tissue processing as well as thequalitative and quantitative analysis of tissue specimens.4.3 The user is encouraged to utilize appropriate

42、 ASTM andother guidelines to conduct cytotoxicity and biocompatibilitytests on materials, TEMPs, or both, prior to assessment of thein vivo models described herein.4.4 It is recommended that safety testing be in accordancewith the provisions of the FDA Good Laboratory PracticesRegulations 21 CFR 58.

43、4.5 Safety and effectiveness studies to support regulatorysubmissions (for example, Investigational Device Exemption(IDE), PremarketApproval (PMA), 510K, Investigational NewDrug (IND), or Biologics License Application (BLA) submis-sions in the U.S.) should conform to appropriate guidelines ofthe reg

44、ulatory bodies for development of medical devices,biologics, or drugs.4.6 Animal model outcomes are not necessarily predictiveof human results and should, therefore, be interpreted cau-tiously with respect to potential applicability to human condi-tions.5. Animal ModelsNOTE 1This section provides a

45、description of the options to considerin determining the appropriate animal model and fusion location.NOTE 2Research using these models needs to be conducted inaccordance with governmental regulations appropriate to the locale andguidelines for the care and use of laboratory animals. Study protocols

46、should be developed after consultation with the institutional attendingveterinarian, and need appropriate review and approval by the institutionalanimal care and use committee prior to study initiation.5.1 Defect Considerations:5.1.1 Spinal fusion is typically performed on a patient whohas sustained

47、 trauma in order to stabilize the spine, to relievea neural deficit related to bony stenosis or to treat degenerativedisc disease. A high proportion of injuries in humans occur inthe spine. Accordingly, defects created in the spine are com-monly used for assessing spinal bone repair/regeneration ina

48、nimal models.5.1.2 Defects may be created surgically in both the inter-body and posterolateral spinal locations. For the purpose of thisguide, defects created in both spinal regions will be described.5.1.3 Significant variability exists between animal specieswith respect to the size and weight of th

49、e animal, anatomy, andgait thereby influencing kinetics, range of motion, and me-chanical forces on defects. These factors influence bonearchitecture and structure. These factors play a significant rolein the response to injury or disease of bone. The user shouldconsider carefully the animal model that is appropriate for thestage of investigation of an implanted TEMPs. Table A isprovided to give guidance for the selection of animal modelsand the relevancy of their results.5.1.4 Mechanical load has been shown to affect bone repair.The intermitten