ASTM F1408-1997(2002)e1 Standard Practice for Subcutaneous Screening Test for Implant Materials《植入材料的皮下筛选试验》.pdf

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1、Designation: F 1408 97 (Reapproved 2002)e1Standard Practice forSubcutaneous Screening Test for Implant Materials1This standard is issued under the fixed designation F 1408; the number immediately following the designation indicates the year oforiginal adoption or, in the case of revision, the year o

2、f last revision. A number in parentheses indicates the year of last reapproval. Asuperscript epsilon (e) indicates an editorial change since the last revision or reapproval.e1NOTEFootnote 3 was editorially corrected in November 2002.1. Scope1.1 This practice covers a short-term testing method toscre

3、en the subcutaneous tissue reaction to metallic or otherimplant candidate 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 practi

4、ce, along with other appropriate biologicaltests (including other 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 andpreparatio

5、ns of known materials.1.3 This experimental protocol is not designed to provide acomprehensive assessment of the systemic toxicity, carcinoge-nicity, teratogenicity, or mutagenicity of the material.1.4 The values stated in SI units are to be regarded as thestandard.1.5 This standard does not purport

6、 to address 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:F 67 Sp

7、ecification for Unalloyed Titanium for SurgicalImplant Applications (UNS R50250, UNS R50400, UNSR50550, UNS R50700)2F 75 Specification for Cobalt-28Chromium-6MolybdenumAlloy Castings and Casting Alloy for Surgical Implants(UNS R30075)2F 86 Practice for Surface Preparation and Marking of Me-tallic Su

8、rgical Implants2F 136 Specification for Wrought Titanium-6Aluminum-4Vanadium ELI (Extra Low Interstitial) Alloy for SurgicalImplant Applications (UNS R56401)2F 138 Specification for Wrought 18Chromium-14Nickel-2.5Molybdenum Stainless Steel Bar and Wire for SurgicalImplants (UNS S31673)2F 648 Specifi

9、cation for Ultra-High-Molecular-Weight Poly-ethylene Powder and Fabricated Form for Surgical Im-plants2F 763 Practice for Short-Term Screening of Implant Mate-rials2F 981 Practice for Assessment of Compatibility of Bio-materials for Surgical Implants With Respect to Effect ofMaterials on Muscle and

10、Bone23. Summary of Practice3.1 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 t

11、issue envelope. On histologicsections 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 mater

12、ials thatmay be selected for implantation in the human body. This testmay be performed prior to longterm testing (for example,Practice F 981) to eliminate unsuitable candidate materialsearly and to save further animal testing.4.2 This practice may be used to detect toxic effects ofmaterials in gener

13、al (see Appendix X1). 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 F 763 should be considered as a shortterm tes

14、t method.4.3 The suggested implant specimens are cylindrical. Aspecial grooved type of cylinder may be used (see Fig. X2.1 ofAppendix X2) to allow tissue interlocking that could keep theimplant in place and minimize tissue irritation through motionat the interface that otherwise could contribute to

15、increased1This practice is under the jurisdiction of ASTM Committee F-4 on Medical andSurgical Materials and Devices and is the direct responsibility of SubcommitteeF04.16 on Biocompatibility Test Methods.Current edition approved November 10, 1997. Published June 1998. Originallypublished as F 1408

16、- 92. Last previous edition F 1408 - 92 (1996).2Annual Book of ASTM Standards, Vol 13.01.1Copyright ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959, United States.variance of the results. In case ungrooved cylinders are used(see Fig. X1.2 of Appendix X2), pro

17、bable motion at theimplant/tissue interface must be taken into account. Controlcylinders should 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

18、 to comparethe effect of different surface structures or conditions of thesame material or to 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 othe

19、r suitable testanimals (for example, rats).5.2 The implant specimens of control and candidate 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 s

20、uitable animals are used,more than one test specimen may be implanted, but theimplants should 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 t

21、he neck in one animal.6. Implant Specimens6.1 Specimen DesignCylinders of 7 mm length and 4 mmdiameter 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 inc

22、reased proportionally. If it isimpossible to prepare specimens of this kind, the specimenconfiguration 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 us

23、e as control materials include those given in Specifica-tions F 67, F 75, F 136, and F 138. However, for specificapplications any metal of known compatibility and standard-ized as implant material may be employed as control materialfor comparison. To study adverse tissue reactions, a non-compatible

24、material like copper may be used as a positivecontrol material. A suitable polymeric control material like thepolyethylene USP negative control plastic, RS, or UHMWPE(see Specification F 648) may be used.6.3 Specimen SurfaceThe surface of specimens fromprospective implant materials should be treated

25、 in the samemanner as the implant intended for clinical application in thehuman patient. Depending 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 m

26、aterial. Forpreparation of metallic materials Practice F 86 should beconsidered.6.4 Numbers of Test 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 larg

27、er test hosts, atleast four animals should be used per material and time period.6.5 ConditioningThe 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 surfa

28、ce alterations andcontamination and should be handled with non-metallic for-ceps when appropriate. 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 a

29、nimals. The incision site is remote from theimplantation site to prevent infection around the implant. 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 cl

30、ose the tunnel withthree stitches with a thread of a non-metallic suture material toprevent moving 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 curren

31、t animal protection requirements.Keep mice up to three or four weeks in individual cages.7.2 Post-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

32、 ofassay, and report any abnormal clinical findings.7.2.2 If infection or injury of the test implant 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 i

33、t and determine the cause of death. Replace the animalif the cause of death is unrelated to the test 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 a

34、nimals after one, three, and nine weeks.If longer time intervals are of interest, mice may be kept 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 surroundin

35、g the implant.Remove 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 possible ina fixing agent that does not interfere with the implant materialand its probable degradation products.8.

36、 Histologic Evaluation8.1 Histological Preparation:3The Guide for Care and Use of Laboratory Animals, Institute of LaboratoryAnimal Research Publication. Available from National Academy Press, 500 FifthSt., NW, Lockbox 285, Washington, DC 20055.F 1408 97 (2002)e128.1.1 In general, standard laborator

37、y practices for histologi-cal preparation of the implant/tissue specimens and staining areused.8.1.2 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 tech

38、niques must be employed for the preparationof histologic slides. Before sectioning, hard metals may beremoved by an electrochemical technique. In this case, afterembedding, one cuts the sample longitudinally through theimplant and dissolves the implant parts electrochemically,providing that the elec

39、trochemical procedure does not mark-edly alter the contacting tissues embedded in the plastics. Theempty 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 co

40、nsidered. Where possible,the material may be dissolved after embedding, thus preservingthe interface, 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 ev

41、aluations the cutting geometry inrelation to the cylinder must be considered. The implantorientation 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

42、this techniquethe tissue layers closest to the implant are usually destroyed.8.1.5 If such conventional 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 histolog

43、ic sections of the surroundingtissues from the candidate- and control-material implants arecompared, 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

44、 implant are usually used forevaluation.8.1.7 The counted cell populations at defined distances fromthe 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, mater

45、ial condi-tion, fabrication, surface condition, and modifications of therecommended shape and size of implants.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 t

46、han mice areused. Comment on age, sex, and strain of animals, insertiontechniques, and special diet. Any 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 tes

47、t implants, as well as the grossappearance of the tissues surrounding the implants. The num-ber of implants 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.1

48、0. Keywords10.1 biocompatibility; mice; orthopaedic medical devices;short-term tissue screening; subcutaneous tissue screening;tissue compatibility; toxicity/toxicologyAPPENDIXES(Nonmandatory Information)X1. RATIONALEX1.1 This practice complements existing ASTM standardson in vivo biocompatibility t

49、esting of prospective implantmaterials. The two particular related standards, Practices F 981and F 763, 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 subcutaneous implants(for example, in plastic or tumor surgery) or for implants forfracture treatment that are usually in contact with subcutaneoustissues (for example, midface, hand, tibia), muscles, fasciae,tendo