1、Designation: F 1983 99 (Reapproved 2003)Standard Practice forAssessment of Compatibility of Absorbable/ResorbableBiomaterials for Implant Applications1This standard is issued under the fixed designation F 1983; the number immediately following the designation indicates the year oforiginal adoption o
2、r, in the case of revision, the year of 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.1. Scope1.1 This practice provides experimental protocols for bio-logical assays of tissu
3、e reactions to absorbable/resorbablebiomaterials for implant applications. This practice appliesonly to resorbable/absorbable materials with projected clinicalapplications in which the materials will reside in bone or softtissue longer than 30 days and less than three years. Otherstandards with desi
4、gnated implantation times are available toaddress the shorter time periods. Careful consideration shouldbe given to the appropriateness of this practice for slowlydegrading materials that will remain for longer than threeyears. It is anticipated that the tissue response to degradingbiomaterials will
5、 be different from the response to nonresorb-able materials. In many cases, a chronic inflammatory responsemay be observed during the degradation phase, but the localhistology should return to normal after degradation; therefore,the minimal tissue response usually equated with “biocompat-ibility” ma
6、y require long implantations.1.2 The time period for implant degradation will varydepending on chemical composition and implant size; there-fore, the implantation times for examination of tissue responsewill be linked to the rate of resorption. No single implantationtime is indicated in this practic
7、e.1.3 These protocols assess the effects of the material on theanimal tissue in which it is implanted. The experimentalprotocols do not fully assess systemic toxicity, carcinogenicity,teratogenicity, or mutagenicity of the material. Other standardsare available to address these issues.1.4 To maximiz
8、e use of the animals in the study protocol, alltoxicological findings should be recorded. There are someaspects of systemic toxicity, including effects of degradationproducts on the target organs, that can be addressed with thispractice, and these effects should be documented fully.1.5 This standard
9、 does not purport 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
10、Standards:2F 561 Practice for Analysis of Implanted Medical Devicesand Associated TissuesF 750 Practice for Evaluating Material Extracts by SystemicInjection in the MouseF 763 Practice for Short-Term Screening of Implant Mate-rialsF 981 Practice for Assessment of Compatibility of Bioma-terials for S
11、urgical Implants With Respect to Effect ofMaterials on Muscle and BoneF 1408 Practice for Subcutaneous Screening Test for Im-plant MaterialsF 1903 Practice for Testing for Biological Responses toParticles in vitroF 1904 Practice for Testing the Biological Responses toParticles in vivoF 1905 Practice
12、 for Selecting Tests for Determining thePropensity of Materials to Cause ImmunotoxicityF 1906 Practice for Evaluation of Immune Responses inBiocompatibility Testing Using ELISA Tests, LymphocyteProliferation, and Cell Migration23. Summary of Practice3.1 Under strict aseptic conditions, specimens of
13、the finalimplant form candidate material are implanted into the mostrelevant anatomical tissue site in small laboratory animals,preferably mice, rats, hamsters, or rabbits.3.2 The use of larger animals, such as the dog, goat, orsheep may be justified based upon special considerations of theparticula
14、r study. Choice of species also should consider the1This practice is under the jurisdiction of ASTM CommitteeF04 on Medical andSurgical Material and Devices and is the direct responsibility of SubcommitteeF04.16 on Biocompatibility Test Methods.Current edition approved Nov. 1, 2003. Published Decemb
15、er 2003. Originallyapproved in 1999. Last previous edition approved in 1999 as F 1983 99.2For 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
16、ary page onthe ASTM website.1Copyright ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959, United States.availability of historical data on biological responses of theseanimals to similar devices to aid in analysis and comparison ofdata obtained.3.3 All animal s
17、tudies must be done in a facility approvedby a nationally recognized organization and in accordance withall appropriate regulations.4. Significance and Use4.1 This practice is a guideline for a screening test for theevaluation of the local tissue response to materials that may beselected for implant
18、ation into the human body and which areexpected to undergo degradation by absorption or resorptionwithin three years.4.2 This practice is similar to that for studies on candidatematerials that are not resorbable, such as those specified inPractices F 763, F 981, and F 1408; however, analysis of theh
19、ost response must take into account the effect of degradationand degradation products on the inflammatory response at thelocal tissue site and on subsequent healing of the implantationsite.4.3 The material to be tested should be in the final finishedform as for intended use, including sterilization.
20、 Material/bodyratios should be relevant to that of intended device use.Material surface area or mass to body mass ratios of 1X, 10X,and 50X if applicable, are recommended.4.4 Materials that are designed for use in devices with insitu polymerization shall be introduced in a manner such that insitu po
21、lymerization occurs. Testing of individual precursorcomponents is not recommended.5. Test Animals and Sites5.1 Choice of test animal shall take into consideration thenormal life span of the animal and the length of the implanta-tion study. Small laboratory animals are preferred. The strain,sex, age,
22、 and origin of the animals used should be noted. Iflarger animals are used, justification for their use should beprovided. The source of the animals, species/strain, weight, age(where known or approximate if not known), general health,and boarding conditions should be recorded. Animal use andcare re
23、gulations must be followed.5.2 The number of implant sites shall depend on the size ofthe implant and the animal. The distance between implantsshall be sufficient so that separate tissue blocks are preparedeasily for each implant and sufficient that the biologicalreactions do not overlap or interfer
24、e with each other. Implantsmay be placed bilaterally in soft tissue, including muscle.Bilateral implantation into bone should be considered carefullyand justification given. In general, mice, rats, hamsters, andother similarly sized rodents should receive no more than oneimplant on each side. Larger
25、 animals, including rabbits, mayreceive up to five implants on each side. When the implant iscomposed of a collection of particles, pellets, and so forth, eachcollection is considered one implant site.5.3 Before embarking on studies in large animals, it isrecommended that a pilot study in rodents be
26、 undertaken todetermine expected rate of degradation and the distribution andmetabolism of the degradation products. When feasible, initialprediction may be done by radio-labeling the material andfollowing the loss of radioactivity; however, radioactive speci-mens shall not be used for biocompatibil
27、ity testing. Othermethods of following the degradation are acceptable. Thetarget organs of the metabolism and excretion of the productsshould be identified. It is recommended that acute systemicstudies with material extracts according to Practice F 750 becompleted prior to the initiation of the impl
28、antation study.6. Implant Specimens6.1 Design of the ImplantSpecimens may be made fromthe final finished form candidate material in configurationsspecific for the animal study. As described in 4.3, the material/host ratio should be available and referrable to ultimate use inthe human with material/b
29、ody mass ratios of 1X, 10X, and50X, if applicable, recommended. Relevant configurations ofimplant specimens, such as cylinders, flat cloth, amorphousgels, and polymerizable liquids may be used.6.2 The use of positive and negative controls is not requiredin this practice; however, the implantation of
30、 the candidatematerial must be accompanied by the use of an implantedmarker or other permanent method, such as a template, to markthe implant site to allow identification of the implant site at thevarious time periods. A sham surgical site, or a sham surgicalanimal, is necessary.6.3 The material use
31、d shall be in its final finished form andsterilized as indicated for its ultimate use. It shall be handledfor implantation in a manner analogous to that for intendedfinal use, for example, special forceps, special cannulas orneedles, special syringes, and so forth.6.4 The candidate material shall be
32、 described thoroughly tofacilitate development of a suitable implant application proto-col. The absorption, distribution, metabolism, and excretion ofthe material and its degradation products should be described.The information shall include, but is not limited to, thefollowing:6.4.1 Expected method
33、 of degradation, for example, hy-drolysis, enzymatic, phagocytosis, and so forth.6.4.2 Expected nonresorbable degradation products, for ex-ample, fibrils, particles from composites.6.4.3 Expected rate of degradation.6.4.4 Expected target organ effects where known or ex-pected, for example, eliminate
34、d in kidney, stored in liver,stored in spleen or lymph nodes.6.5 For each time period, at least six rodents shall be usedwith either single or bilateral implants. For the larger animals,at least four animals shall be used per time period. It isrecommended that additional animals be included in the i
35、nitialprotocol to accommodate any unexpected changes in degrada-tion rates of the material.7. Procedure7.1 Implantation:7.1.1 Implant the specimen under sterile conditions inanesthetized animals. Where possible, implant the specimenusing a trochar method to avoid the need for an incision. If anincis
36、ion is needed, insert the implant as far from the incisionsite as possible. Close the insertion site with a suitable suturematerial.7.1.1.1 A sham site or sham animal with the identicalimplantation procedure, but not the test material, should beF 1983 99 (2003)2included in the protocol. If animals a
37、re to be used as part ofsystemic toxicity study, the sham must be a separate animal.7.1.2 The implantation site must be marked in mannersuitable for identification of the site at the designated timeperiods. The use of a permanent skin marker and a templatemarking the placement of the specimen and th
38、e sham site isrecommended. Specimens that are radiopaque may have serialradiographs to identify the location. The implantation of anonabsorbable marker material such as a monofilament, non-absorbable suture attached to the specimen or embedded in thegel or liquid also is acceptable. If an implanted
39、marker materialis used with the specimen, this marker material shall beincluded in the sham site. The test specimen site and the shamsite shall be marked.7.1.3 Keep the animals in standard housing according tocurrent animal protection requirements. The individual animalsshould be marked for identifi
40、cation.7.2 Post-Operative Care:7.2.1 Care of the animals shall be in accordance withaccepted standards as outlined in Guide for Care and Use ofLaboratory Animals according to the local and national gov-ernment ordinances in an approved facility.7.2.2 Carefully observe each animal during the specifie
41、dtime period and record any abnormal clinical findings.7.2.3 If infection or accidental injury of the test implant siteoccurs, record the information and process the implant site andtissues and organs as described in 7.3 and 8.1. Record the datain the results, but do not use the data in the final an
42、alysis ofresults from the other animals. A replacement animal may beadded, if desired.7.2.4 If an animal dies before the scheduled termination,record the information and process the implant site and tissuesand organs as described in 7.3 and 8.1. Record the data, but donot use the data in the final a
43、nalysis of results from the otheranimals. If the death is related to anesthesia, a replacementanimal may be selected.7.3 Euthanasia and Implant Retrieval:7.3.1 Euthanasia method shall be according to the recom-mended method for the particular animal species according tolocal and government regulatio
44、ns. Euthanasia times shall bebased on expected degradation rate of the material. The initialeuthanasia interval shall be when there is expected to be a 50 %loss of mass or release of 50 % of the degradation products.Additional euthanasia times shall include expected 100 % lossof mass, and when compl
45、ete healing and return to normalhistology is anticipated. It is permissible to establish euthanasiatimes during the study period if at the established time periodexpected loss has not occurred, for example, if 50 % loss hasnot occurred when expected, then the euthanasia time for 50 %loss shall again
46、 be estimated. Euthanasia at this additional timeperiod is needed. The additional time frames should beadvanced to accommodate this slower than expected degrada-tion. The additional animals recommended in 6.5 may be usedfor this purpose of additional euthanasia times.7.3.2 At euthanasia, record the
47、general appearance of theskin at the implantation site; then, carefully expose the regionof the initial implantation. This is facilitated by the use of atemplate and skin marker at surgery. If a marker suture is used,the site of the marker suture shall be noted. Record the colorand consistency of th
48、e tissues in the region of the original siteof the material. The use of gross photography should beconsidered carefully since it may aid in maintaining anadequate permanent record. Remove the intact tissue envelopearound the marker or template and extend beyond any identi-fiable remaining candidate
49、material. If the candidate material isnot evident at the site, extend the explanation site to includeseveral mm of normal tissue on all sides of the marker materialor template mark. If any abnormal tissue is observed else-where, this shall be removed for further examination. Transferthe tissue specimen as soon as possible into a fixing agentsuitable for further histologic processing. The use of alcohol,formaldehyde, or glutaraldehyde is recommended, but otheragents, such as freezing, may be considered. Reference toPractices F 561, F 981, and F 1408 is encouraged for process-ing proc
