1、Designation: F981 04 (Reapproved 2016)Standard Practice forAssessment of Compatibility of Biomaterials for SurgicalImplants with Respect to Effect of Materials on Muscle andInsertion into Bone1This standard is issued under the fixed designation F981; the number immediately following the designation
2、indicates the year of originaladoption or, in the case of revision, the year of last revision. A number in parentheses indicates the year of last reapproval. A superscriptepsilon () indicates an editorial change since the last revision or reapproval.1. Scope1.1 This practice provides a series of exp
3、erimental protocolsfor biological assays of tissue reaction to nonabsorbablebiomaterials for surgical implants. It assesses the effects of thematerial on animal tissue in which it is implanted. Theexperimental protocol is not designed to provide a comprehen-sive assessment of the systemic toxicity,
4、immune response,carcinogenicity, teratogenicity, or mutagenicity of the materialsince other standards deal with these issues. It applies only tomaterials with projected applications in humans where thematerials will reside in bone or soft tissue in excess of 30 daysand will remain unabsorbed. It is
5、recommended that short-termassays, according to Practice F763, first be performed. Appli-cations in other organ systems or tissues may be inappropriateand are therefore excluded. Control materials will consist ofany one of the metal alloys in Specifications F67, F75, F90,F136, F138,orF562, high puri
6、ty dense aluminum oxide asdescribed in Specification F603, ultra high molecular weightpolyethylene as stated in Specification F648 or USP polyeth-ylene negative control.1.2 This practice is a combination of Practice F361 andPractice F469. The purpose, basic procedure, and method ofevaluation of each
7、 type of material are similar; therefore, theyhave been combined.1.3 The values stated in SI units are to be regarded asstandard. No other units of measurement are included in thisstandard.1.4 This standard does not purport to address all of thesafety concerns, if any, associated with its use. It is
8、 theresponsibility of the user of this standard to establish appro-priate safety and health practices and determine the applica-bility of regulatory limitations prior to use.2. Referenced Documents2.1 ASTM Standards:2F67 Specification for Unalloyed Titanium, for Surgical Im-plant Applications (UNS R
9、50250, UNS R50400, UNSR50550, UNS R50700)F75 Specification for Cobalt-28 Chromium-6 MolybdenumAlloy Castings and Casting Alloy for Surgical Implants(UNS R30075)F86 Practice for Surface Preparation and Marking of Metal-lic Surgical ImplantsF90 Specification for Wrought Cobalt-20Chromium-15Tungsten-10
10、Nickel Alloy for Surgical Implant Applica-tions (UNS R30605)F136 Specification for Wrought Titanium-6Aluminum-4Vanadium ELI (Extra Low Interstitial)Alloy for SurgicalImplant Applications (UNS R56401)F138 Specification for Wrought 18Chromium-14Nickel-2.5Molybdenum Stainless Steel Bar and Wire for Sur
11、gicalImplants (UNS S31673)F361 Practice for Assessment of Compatibility of MetallicMaterials for Surgical Implants with Respect to Effect ofMaterials on Tissue (Withdrawn 1987)3F469 Practice for Assessment of Compatibility of Nonpo-rous Polymeric Materials for Surgical Implants withRegard to Effect
12、of Materials on Tissue (Withdrawn1986)3F562 Specification for Wrought 35Cobalt-35Nickel-20Chromium-10Molybdenum Alloy for Surgical ImplantApplications (UNS R30035)F603 Specification for High-Purity Dense Aluminum Oxidefor Medical ApplicationF648 Specification for Ultra-High-Molecular-Weight Poly-eth
13、ylene Powder and Fabricated Form for Surgical Im-plants1This practice is under the jurisdiction ofASTM Committee F04 on Medical andSurgical Materials and Devices and is the direct responsibility of SubcommitteeF04.16 on Biocompatibility Test Methods.Current edition approved April 1, 2016. Published
14、June 2016. Originallyapproved in 1986. Last previous edition approved in 2010 as F981 04(2010). DOI:10.1520/F0981-04R16.2For 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
15、 to the standards Document Summary page onthe ASTM website.3The last approved version of this historical standard is referenced onwww.astm.org.Copyright ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States1F763 Practice for Short-Term Screening of I
16、mplant Materi-als3. Summary of Practice3.1 This practice describes the preparation of implants, thenumber of implants and test hosts, test sites, exposureschedule, implant sterilization techniques, and methods ofimplant retrieval and tissue examination of each test site.Histological criteria for eva
17、luating tissue reaction are provided.4. Significance and Use4.1 This practice covers a test protocol for comparing thelocal tissue response evoked by biomaterials, from whichmedical implantable devices might ultimately be fabricated,with the local tissue response elicited by control materialscurrent
18、ly accepted for the fabrication of surgical devices. Thematerials may include metals (and metal alloys), dense alumi-num oxide, and polyethylene that are standardized on the basisof acceptable, well recognized, long-term response. The con-trols consistently produce cellular reaction and wound healin
19、gto a degree that has been found to be acceptable to the host.5. Test Hosts and Sites5.1 Rats (acceptable strains such as Fischer 344), NewZealand White rabbits, and other small laboratory animals maybe used as test hosts for soft tissue implant response. It issuggested that the rats be age and sex
20、matched. Rabbits orlarger animals may be used as test hosts for bone implants.When larger animals such as dogs, goats, or sheep are used, thedecision should be based upon special considerations of theparticular implant material or study.5.2 The sacro-spinalis, paralumbar, gluteal muscles, and thefem
21、ur or tibia can serve as the test site for implants. However,the same site must be used for test and material implants in allthe animal species.5.3 There shall be a minimum of four animals at eachsacrifice interval for a total of twelve animals per study. Iflarger animals are used, in which a greate
22、r number of implantsmay be placed, at least two animals shall be sacrificed at eachtime period.6. Implant Specimens6.1 FabricationEach implant shall be made in a cylindri-cal shape with hemispherical ends (see 6.3 and 6.4 for sizes).If the ends are not hemispherical, this shall be reported. Eachimpl
23、ant shall be fabricated, finished, and its surface cleaned ina manner appropriate for its projected application in humansubjects in accordance with Practice F86. If the specimens areporous, the method of preparation of the porous specimensshall be representative of the contemplated human implantappl
24、ication and shall yield a specimen with characteristic poresize, pore volume, and pore interconnection diameter. Thechoice between using solid core specimens with porous coat-ings and specimens that are porous throughout shall be adecision of the investigator and shall be reported.6.2 Reference meta
25、llic specimens shall be fabricated inaccordance with 6.1 from materials such as the metal alloys inSpecifications F67, F75, F90, F138,orF562, ceramic inSpecification F603, or polymers such as in Specification F648polyethylene or USP Negative Control Plastic. If the testmaterials are porous, consider
26、ation should be given to usingporous specimens for reference specimens. Alternatively, non-porous reference specimens may be used.6.3 Suggested Sizes and Shapes of Implants for Insertion inMuscle:6.3.1 The implants shall be cylindrical in shape and mayrange from 1 mm to 6 mm in diameter and from 10
27、mm to 20mm in length depending upon the relative size of the speciesunder study.6.3.2 The dimensions used shall be reported in accordancewith 8.1.6.3.3 Depending upon the particular device application,other sample shapes may be used. For instance, an investigatormight wish to test the biocompatibili
28、ty of a new material forscrews in the form of a screw. If an alternative specimen shapeis used, this should be reported in accordance with 8.1.6.4 Sizes and Shapes of Implants for Insertion in Bone:6.4.1 Implant diameters for use in bone shall be approxi-mately equal to the cortex thickness. Implant
29、 lengths shallallow them to reside in one cortex and the medulla withoutexcessive protrusion beyond the periosteum.6.4.2 The dimensions used shall be reported in accordancewith 8.1.6.5 Number of Test and Control Implants:6.5.1 In each rat, due to size, there may be two implants; onetest and one cont
30、rol material implant.6.5.2 In each rabbit, due to size, there may be six implants;four test and two control material implants.6.5.3 In larger animals, there may be twelve implants; eighttest material and four control material implants.6.5.4 In rabbits or larger animals, at least sixteen testmaterial
31、s and eight materials shall be tested at each timeperiod.6.6 Conditioning:6.6.1 Remove all surface contaminants with appropriatesolvents and rinse all test and control implants in distilled waterprior to sterilization. It is recommended that the implantmaterials be processed and cleaned in the same
32、way the finalproduct will be.6.6.2 Clean, package, and sterilize all implants in the sameway as used for human implantation.6.6.3 After final preparation and sterilization, handle the testand control implants with great care to ensure that they are notscratched, damaged, or contaminated in any way p
33、rior toinsertion.6.6.4 Report all details of conditioning in accordance with8.1.6.7 Implantation PeriodInsert all implants into each ani-mal at the same surgical session for implantation periods of 12,26, and 52 weeks.7. Procedure7.1 Implantation (Muscle):F981 04 (2016)27.1.1 Place material implants
34、 in the paravertebral muscles insuch a manner that they are directly in contact with muscletissue.7.1.2 Introduce material implants in larger animals by thetechnique of making an implantation site in the muscle byusing a hemostat to separate the muscle fibers. Then insert theimplant using plastic-ti
35、pped forceps or any tool that is non-abrasive to avoid damage to the implant.7.1.3 Introduce material implants using sterile technique.Sterile disposable needles or hypodermic tubing and trocharmay be used to implant the material implants into the paraver-tebral muscles along the spine. In rats, ins
36、ert a negative controlimplant on one side of the spine and a test material implant onthe other side. In rabbits, implant one negative control materialon each side of the spine and implant two test materials on eachside of the spine. If larger diameter specimens are used, analternative implantation t
37、echnique is that described in 7.1.2.7.2 Implantation (Femur)Expose the lateral cortex ofeach rabbit femur and drill undersized pilot holes through thelateral cortex using the technique and instrument appropriatefor the procedure. Final reaming of the holes should beperformed by hand to yield holes w
38、hich are smaller than theimplant specimens by 0.1 mm or less. Into each one of theseholes, insert one of the implants by finger pressure. Then closethe wound.NOTE 1Caution should be taken to minimize the motion of theimplant in the tissue to prevent the effects of motion on the desired result.7.3 Po
39、stoperative Care:7.3.1 All animal studies shall be done in a facility approvedby a nationally recognized organization and in accordance withall appropriate regulations.7.3.2 Carefully observe each animal during the period ofassay and report any abnormal findings.7.3.3 Infection or injury of the test
40、 implant site mayinvalidate the results. The decision to replace the animal so thatthe total number of retrieved implants will be as represented inthe schedule shall be dependent upon the design of the study.7.3.4 If an animal dies prior to the expected date of sacrifice,perform a necropsy in accord
41、ance with the procedure in 7.4 todetermine the cause of death. Replacement of the animal to thestudy shall be dependent upon the design of the study. Includethe animal in the assay of data if the cause of death is relatedto the procedure or test material.7.4 Sacrifice and Implant Retrieval:7.4.1 Eut
42、hanize animals by a humane method at the inter-vals specified in 6.7.NOTE 2The necropsy periods start at 12 weeks because it is assumedthat acceptable implant data has been received for earlier periods fromshort term implant testing according to Practice F763. If the 90-daysacrifice period has been
43、utilized under Practice F763, that group need notbe repeated under this protocol, and thus, the 12-week group may beeliminated.7.4.2 At necropsy, record any gross abnormalities of coloror consistency observed in the tissue surrounding the implant.Remove each implant with an intact envelope of surrou
44、ndingtissue. Include in the tissue sample a minimum of a 4-mm thicklayer of tissue surrounding the implant. If less than a 4-mmthick layer of tissue is removed, report in accordance with 8.1.7.5 Postmortem ObservationsIn accordance with standardlaboratory practice, perform a necropsy on all animals
45、that aresacrificed for the purposes of the assay or die during the assayperiod. Establish the status of the health of the experimentalanimal during the period of the assay. Report as described inSection 8.7.6 Histological Procedure:7.6.1 Tissue Sample PreparationPrepare appropriateblocks from each i
46、mplantation site and indicate the orientationof the axis of the femur relative to the axis of the implant forbone implants. Also indicate the orientation of the implantrelative to the axis of rotation of the femoral condyles.7.6.1.1 Process the excised tissue block containing either atest implant or
47、 control implant for histopathological examina-tion and such other studies as are appropriate. Cut the samplemidway from end to end into appropriate size and in theappropriate orientation for each study. Transfer, or record, orboth, the orientational details noted in 7.6.1 to each part of thesample.
48、 Record the gross appearance of the implant and thetissue. If the sample is porous, it is imperative that sectioningprocedures be used that maintain the implant within its tissueenvelope to allow the evaluation of tissue within the pores.Such procedures may include ground section preparation.7.6.1.2
49、 If special stains are deemed necessary, prepareadditional sections and make appropriate observations.7.7 Histopathological ObservationsCompare the amountof tissue reaction adjacent to the test implant to that adjacent toa similar location and orientation on the control implant withrespect to thickness of scar, presence of inflammatory or othercell types, presence of particles, and such other indications ofinteraction of tissue and material as might occur with the actualmaterial under test. A suggested method for the evaluation oftissue response after implantation is Turner,
