ASTM F1408-1997(2013) Standard Practice for Subcutaneous Screening Test for Implant Materials《植入材料的皮下筛选试验的标准实施规程》.pdf

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1、Designation: F1408 97 (Reapproved 2013)Standard Practice forSubcutaneous Screening Test for Implant Materials1This standard is issued under the fixed designation F1408; the number immediately following the designation indicates the year oforiginal adoption or, in the case of revision, the year of la

2、st 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 practice covers a short-term testing method toscreen the subcutaneous tissue reaction to metallic or otherimplant c

3、andidate materials in small laboratory animals. Thematerial may be dense or porous. The tissue reactions will beevaluated in comparison to those evoked by control materialsthat are accepted as clinical implant materials.1.2 This practice, along with other appropriate biologicaltests (including other

4、 ASTM test methods), may be used toassess the biocompatibility of candidate materials for use in thefabrication of devices for clinical application. It may be alsoapplied to evaluate the effect of special surface textures andpreparations of known materials.1.3 This experimental protocol is not desig

5、ned to provide acomprehensive assessment of the systemic toxicity,carcinogenicity, teratogenicity, or mutagenicity of the material.1.4 The values stated in SI units are to be regarded asstandard. No other units of measurement are included in thisstandard.1.5 This standard does not purport to address

6、 all of thesafety concerns, if any, associated with its use. It is 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

7、 for Unalloyed Titanium, for Surgical Im-plant Applications (UNS R50250, 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 Imp

8、lantsF136 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 SurgicalImplants (UNS S31673)F648 Specification for Ultra

9、-High-Molecular-Weight Poly-ethylene Powder and Fabricated Form for Surgical Im-plantsF763 Practice for Short-Term Screening of Implant Materi-alsF981 Practice for Assessment of Compatibility of Biomate-rials for Surgical Implants with Respect to Effect ofMaterials on Muscle and Bone3. Summary of Pr

10、actice3.1 Under strict aseptic conditions, specimens of the candi-date and control materials are implanted subcutaneously in theneck of mice (or other suitable animals). After one, three, andnine weeks the animals are anesthetized and the test samplesare excised with an intact tissue envelope. On hi

11、stologicsections the tissue reactions to the candidate materials arecompared with the tissue response to clinically acceptedcontrol materials.4. Significance and Use4.1 This practice is a guideline for a short-term screeningtest for the evaluation of the tissue response to materials thatmay be selec

12、ted for implantation in the human body. This testmay be performed prior to longterm testing (for example,Practice F981) to eliminate unsuitable candidate materialsearly and to save further animal testing.4.2 This practice may be used to detect toxic effects ofmaterials in general (see Appendix X1).

13、However, it is particu-larly suitable for the testing of materials that are intended tohave contact with subcutaneous tissues or soft tissues ingeneral. For materials intended to be inserted specifically intomuscle tissues, Practice F763 should be considered as a shortterm test method.4.3 The sugges

14、ted implant specimens are cylindrical. Aspecial grooved type of cylinder may be used (see Fig. X2.1 of1This 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.Cur

15、rent edition approved Oct. 1, 2013. Published October 2013. Originallyapproved in 1992. Last previous edition approved in 2008 as F1408 - 97 (2008).DOI: 10.1520/F1408-97R13.2For referenced ASTM standards, visit the ASTM website, www.astm.org, orcontact ASTM Customer Service at serviceastm.org. For A

16、nnual Book of ASTMStandards volume information, refer to the standards Document Summary page onthe ASTM website.Copyright ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States1Appendix X2) to allow tissue interlocking that could keep theimplant in pl

17、ace and minimize tissue irritation through motionat the interface that otherwise could contribute to increasedvariance of the results. In case ungrooved cylinders are used(see Fig. X1.2 of Appendix X2), probable motion at theimplant/tissue interface must be taken into account. Controlcylinders shoul

18、d be shaped like the test cylinders.4.4 The type of surface preparation of the specimens canaffect the tissue reaction, therefore the preparation procedureshould be noted in the report. The test may be used to comparethe effect of different surface structures or conditions of thesame material or to

19、assess the effect of various treatments ofmodifications of a material.5. Test Animals and Sites5.1 Mice of an established strain, (preferably females), areused as test hosts. The test may be adapted to other suitable testanimals (for example, rats).5.2 The implant specimens of control and candidate

20、mate-rials are inserted subcutaneously in the neck of the host.5.3 One implant is inserted per mouse. Therefore, thenumber of animals is identical with the number of testspecimens. If rats or other larger suitable animals are used,more than one test specimen may be implanted, but theimplants should

21、never be allowed to come in contact with eachother. If animals other than mice are large enough, cylinders ofthe candidate and control material may be implanted separatelyat the right and the left side of the neck in one animal.6. Implant Specimens6.1 Specimen DesignCylinders of 7 mm length and 4 mm

22、diameter are prepared for implantation in mice. Special speci-mens with two grooves are designed corresponding to thefigures in Appendix X2. If larger animal hosts are used, theimplant dimensions may be increased proportionally. If it isimpossible to prepare specimens of this kind, the specimenconfi

23、guration used must be described fully in the report.Implant specimens from the candidate and control materialshould always have the same dimensions.6.2 Selection of Control MaterialsRecommended metalsfor use as control materials include those given in Specifica-tions F67, F75, F136, and F138. Howeve

24、r, for specific appli-cations any metal of known compatibility and standardized asimplant material may be employed as control material forcomparison. To study adverse tissue reactions, a non-compatible material like copper may be used as a positivecontrol material. A suitable polymeric control mater

25、ial like thepolyethylene USP negative control plastic, RS, or UHMWPE(see Specification F648) may be used.6.3 Specimen SurfaceThe surface of specimens from pro-spective implant materials should be treated in the samemanner as the implant intended for clinical application in thehuman patient. Dependin

26、g on the particular issue, the controlspecimens should have either a surface condition as it isnormally used for clinical applications or a surface conditionmost similar to that of the tested candidate material. Forpreparation of metallic materials Practice F86 should beconsidered.6.4 Numbers of Tes

27、t and Control ImplantsPer each timeperiod, at least six implant specimens of each candidate andcontrol material should be evaluated in mice (one per mouse).If more than one specimen is implanted in larger test hosts, atleast four animals should be used per material and time period.6.5 ConditioningTh

28、e cleaning, sterilization, and packag-ing should be the same as used for implantation in the humanpatient. After surface preparation and sterilization the implantspecimens should be protected from surface alterations andcontamination and should be handled with non-metallic for-ceps when appropriate.

29、 When plastified forceps are used, besure that no plastic material is transferred to the implantsurface.7. Procedure7.1 Implantation:7.1.1 Implant the specimens under sterile conditions inanesthetized animals. The incision site is remote from theimplantation site to prevent infection around the impl

30、ant. Inmice, makea1cmlong incision above the sacrum and preparea subcutaneous tunnel toward the neck.7.1.2 Push the implant through the tunnel and position at theneck. In some distance of the implant close the tunnel withthree stitches with a thread of a non-metallic suture material toprevent moving

31、 of the implant. Then close the incision. (Do notplace the implant directly underneath the incision to avoidinfection.)7.1.3 Keep the individually marked animals in standardcages that comply with current animal protection requirements.Keep mice up to three or four weeks in individual cages.7.2 Post-

32、Operative CareCare of the animals should be inaccordance with accepted standards as outlined in the Guidefor the Care and Use of Laboratory Animals.37.2.1 Carefully observe each animal during the period ofassay, and report any abnormal clinical findings.7.2.2 If infection or injury of the test impla

33、nt site invalidatesthe results, replace the animal so that the number of retrievedimplants will be at least that of the schedule.7.2.3 If an animal dies prior to the expected date of sacrifice,autopsy it and determine the cause of death. Replace the animalif the cause of death is unrelated to the te

34、st procedure or the testmaterial. Include the test animal in the assay of data if thecause of death is related to the procedure or test material.7.3 Sacrifice and Implant Retrieval:7.3.1 Sacrifice the animals after one, three, and nine weeks.If longer time intervals are of interest, mice may be kept

35、 up to24 weeks. Examine and report the status of the health of theanimals prior to euthanasia.7.3.2 At sacrifice, record any gross abnormalities of color orconsistency observed on the tissues surrounding the implant.3The Guide for Care and Use of Laboratory Animals, Institute of LaboratoryAnimal Res

36、earch Publication. Available from National Academy Press, 500 FifthSt., NW, Lockbox 285, Washington, DC 20055.F1408 97 (2013)2Remove each implant with an intact tissue envelope. If thetissue envelope was damaged during the excision, such shouldbe reported. Transfer the tissue specimen as soon as pos

37、sible ina fixing agent that does not interfere with the implant materialand its probable degradation products.8. Histologic Evaluation8.1 Histological Preparation:8.1.1 In general, standard laboratory practices for histologi-cal preparation of the implant/tissue specimens and staining areused.8.1.2

38、If the implant/tissue interface is to be studied, embed-ding of the intact tissue envelope with the implant in situ usinghard plastics is preferred. Appropriate microtomes or cuttingand grinding techniques must be employed for the preparationof histologic slides. Before sectioning, hard metals may b

39、eremoved by an electrochemical technique. In this case, afterembedding, one cuts the sample longitudinally through theimplant and dissolves the implant parts electrochemically,providing that the electrochemical procedure does not mark-edly alter the contacting tissues embedded in the plastics. Theem

40、pty space may be filled with plastic material to protect theoriginal contacting surface during sectioning.If the implant material is a ceramic or calcified material,other procedures may need to be considered. Where possible,the material may be dissolved after embedding, thus preservingthe interface,

41、 and allowing standard histologic procedures. Ifthe material cannot be dissolved after embedding, the use ofthick sections and grinding to desired thickness may bepreferable.8.1.3 For quantitative evaluations the cutting geometry inrelation to the cylinder must be considered. The implantorientation

42、and cutting geometry shall be reported.8.1.4 If techniques described under 8.1.2 are not available,conventional (for example, paraffin) embedding and standardmicrotomy may be employed. However, with this techniquethe tissue layers closest to the implant are usually destroyed.8.1.5 If such convention

43、al technique is used, the tissueenvelope should be opened before or after exposure to afixative and the condition of the implant surface and the tissuebed shall be reported.8.1.6 The stained histologic sections of the surroundingtissues from the candidate- and control-material implants arecompared,

44、and their characteristics are reported. The compari-son should be made between the same cylinder sections. Withgrooved implants the center portions between the grooves andthe flat top surfaces of the implant are usually used forevaluation.8.1.7 The counted cell populations at defined distances fromt

45、he implant interface, and the thickness of the tissue capsulamay be parameters for quantitative evaluation.9. Report9.1 Report the following information:9.1.1 ImplantsDescribe implant material, materialcondition, fabrication, surface condition, and modifications ofthe recommended shape and size of i

46、mplants.9.1.2 ConditioningDescribe cleaning, handling, and ster-ilization techniques employed.9.1.3 Hosts and ImplantationReport type of test host andnumber of implants inserted, if other animals than mice areused. Comment on age, sex, and strain of animals, insertiontechniques, and special diet. An

47、y pathologic signs shall bediagnosed and reported. If test animals are lost the cause ofdeath should be noted.9.2 Include a description of retrieval technique, observa-tions made on control and test implants, as well as the grossappearance of the tissues surrounding the implants. The num-ber of impl

48、ants tested per time interval should be stated.9.3 Report the observation of each histological examination.The techniques employed for the preparation of the histologicsections shall be described.10. Keywords10.1 biocompatibility; mice; orthopaedic medical devices;short-term tissue screening; subcut

49、aneous tissue screening;tissue compatibility; toxicity/toxicologyF1408 97 (2013)3APPENDIXES(Nonmandatory Information)X1. RATIONALEX1.1 This practice complements existing ASTM standardson in vivo biocompatibility testing of prospective implantmaterials. The two particular related standards, Practices F981and F763, provide only procedures for long term testing inmuscle and bone and short term testing in muscles, respec-tively. Thus, a short term subcutaneous screening test isdesirable for the assessment of the tissue response to materialsintended to be used either for typical