1、Designation: F1983 14Standard Practice forAssessment of Selected Tissue Effects of AbsorbableBiomaterials for Implant Applications1This standard is issued under the fixed designation F1983; the number immediately following the designation indicates the year oforiginal adoption or, in the case of rev
2、ision, the year of last 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 provides experimental protocols for bio-logical assays of tissue reactions to absorba
3、ble biomaterials forimplant applications. This practice applies only to absorbablematerials with projected clinical applications in which thematerials will reside in bone or soft tissue longer than 30 daysand less than three years. Other standards with designatedimplantation times are available to a
4、ddress shorter time peri-ods. Careful consideration should be given to the appropriate-ness of this practice for slowly degrading materials that willremain for longer than three years. It is anticipated that thetissue response to degrading biomaterials will be different fromthe response to nonabsorb
5、able materials. In many cases, achronic inflammatory response may be observed during thedegradation phase, but the local histology should return tonormal after absorption; therefore, the minimal tissue responseusually equated with “biocompatibility” may require longimplantations.1.2 The time period
6、for implant absorption will vary de-pending on chemical composition implant size, implantlocation, and test subject species; therefore, the implantationtimes for examination of tissue response will be linked to therate of absorption. No single implantation time is indicated inthis practice.1.3 These
7、 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 maximize use of th
8、e 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 does not p
9、urport 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:2
10、F561 Practice for Retrieval and Analysis of MedicalDevices, and Associated Tissues and FluidsF750 Practice for Evaluating Material Extracts by SystemicInjection in the MouseF763 Practice for Short-Term Screening of Implant Materi-alsF981 Practice for Assessment of Compatibility of Biomate-rials for
11、Surgical Implants with Respect to Effect ofMaterials on Muscle and BoneF1408 Practice for Subcutaneous Screening Test for ImplantMaterialsF1903 Practice for Testing For Biological Responses toParticles In VitroF1904 Practice for Testing the Biological Responses toParticles in vivoF1905 Practice For
12、Selecting Tests for Determining thePropensity of Materials to Cause Immunotoxicity (With-drawn 2011)3F1906 Practice for Evaluation of Immune Responses InBiocompatibility Testing Using ELISATests, LymphocyteProliferation, and Cell Migration (Withdrawn 2011)33. Summary of Practice3.1 Under strict asep
13、tic conditions, specimens of the sterilefinal implant form candidate material are implanted into themost relevant anatomical tissue site in small laboratoryanimals, preferably mice, rats, hamsters, or rabbits.1This practice is under the jurisdiction of ASTM CommitteeF04 on Medical andSurgical Materi
14、als and Devices and is the direct responsibility of SubcommitteeF04.16 on Biocompatibility Test Methods.Current edition approved Nov. 1, 2014. Published January 2015. Originallyapproved in 1999. Last previous edition approved in 2008 as F1983 99 (2008).DOI: 10.1520/F1983-14.2For referenced ASTM stan
15、dards, 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 Summary page onthe ASTM website.3The last approved version of this historical standard is referenced onwww.astm.org.Co
16、pyright ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States13.2 The use of larger animals, such as the dog, goat, orsheep may be justified based upon special considerations of theparticular study. Choice of species also should consider theavailabil
17、ity of historical data on biological responses of theseanimals to similar devices to aid in analysis and comparison ofthe data obtained.3.3 All animal studies shall be done in a facility approvedby a nationally recognized organization and in accordance withall appropriate regulations.4. Significance
18、 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 implantation into the human body and which areexpected to undergo absorption within three years.4.2 This practice is similar to that for studies on candid
19、atematerials that are not absorbable, such as those specified inPractices F763, F981, and F1408; however, analysis of the hostresponse must take into account the effect of degradation anddegradation products on the inflammatory response at the localtissue site and on subsequent healing of the implan
20、tation site.4.3 The material to be tested should be in the final finishedform as for intended use, including sterilization. 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 Ma
21、terials that are designed for use in devices with insitu polymerization shall be introduced in a manner such that insitu polymerization occurs. Testing of individual precursorcomponents is not recommended.5. Test Animals and Sites5.1 Choice of test animal shall take into consideration thenormal life
22、 span of the animal and the length of the implanta-tion study. Small laboratory animals are preferred. The strain,sex, age, 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
23、(where known or approximate if not known), general health,and boarding conditions should be recorded. Animal use andcare regulations shall 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 separ
24、ate tissue blocks are preparedeasily for each implant and that the biological reactions do notoverlap or interfere with each other. Implants may be placedbilaterally in soft tissue, including muscle. Bilateral implanta-tion into bone should be considered carefully and justificationgiven. In general,
25、 mice, rats, hamsters, and other similarlysized rodents should receive no more than one implant on eachside. Larger animals, including rabbits, may receive up to fiveimplants on each side. When the implant is composed of acollection of particles, pellets, and so forth, each collection isconsidered o
26、ne implant site.5.3 Before embarking on studies in large animals, it isrecommended that a pilot study in vitro or in rodents beundertaken to determine the expected rate of degradation andassist in the selection of study periods in long-term animalstudies. During analysis of study results, the distri
27、bution andmetabolism of the degradation products should be determinedby available analytical methods, such as mass spectrometry.Alternatively, prediction may be done by radio-labeling thematerial and following the loss of radioactivity; however,radioactive specimens shall not be used for biocompatib
28、ilitytesting. Other methods of characterizing the absorption areacceptable. The target organs of the metabolism and excretionof the products should be identified. It is recommended thatacute systemic studies with material extracts according toPractice F750 be completed prior to the initiation of the
29、implantation 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 materi
30、al/body 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 implantation site of the candidate material shall beaccompanied by the use of an implanted mark
31、er or otherpermanent method, such as a template, to mark the implant siteto allow identification of the implant site at the various timeperiods. In additional animals, control materials shall beimplanted by the same techniques, to allow the comparison ofthe tissue response. When assessing systemic e
32、ndpoints, it isessential that separate groups of animals be used for test andcomparator groups. A sham surgical site, or a sham surgicalanimal, is necessary.6.3 The material used shall be in its final finished form andsterilized as indicated for its ultimate use. It shall be handledfor implantation
33、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 described thoroughly tofacilitate development of a suitable implant application proto-col. The absorption, distribution, m
34、etabolism, 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 of degradation, for example,hydrolysis, enzymatic, phagocytosis, and so forth.6.4.2 Expected nonabsorbable degradation pro
35、ducts, forexample, fibrils, particles from composites.6.4.3 Expected rate of degradation.6.4.4 Expected target organ effects where known orexpected, for example, eliminated in the kidney, stored in theliver, stored in the spleen or lymph nodes.6.5 For each time period, at least six rodents shall be
36、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 initialF1983 142protocol to accommodate any unexpected changes in degrada-tion rates of the material.7. Procedure7.1 I
37、mplantation: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 anincision is needed, insert the implant as far from the incisionsite as possible. Close the insertion site with a
38、suitable suturematerial.7.1.1.1 A sham site or sham animal with the identicalimplantation procedure, but not the test material, should beincluded in the protocol. If animals are to be used as part of asystemic toxicity study, the sham shall be a separate animal.7.1.2 The implantation site shall be m
39、arked in a 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 the sham site isrecommended. Specimens that are radiopaque may have serialradiographs to identify the location. The impla
40、ntation 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 marker materialis used with the specimen, this marker material shall beincluded in the sham site. The test specimen sit
41、e 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 identification.7.2 Post-Operative Care:7.2.1 Care of the animals shall be in accordance withaccepted standards as outlined in G
42、uide 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 specifiedtime period and record any abnormal clinical findings.7.2.3 If infection or accidental injury of the test implant site
43、occurs, 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 analysis ofresults from the other animals. A replacement animal may beadded, if desired.7.2.4 If an animal dies before th
44、e 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 analysis of results from the otheranimals. If the death is related to anesthesia, a replacementanimal may be selected.7.
45、3 Euthanasia and Implant Retrieval:7.3.1 The euthanasia method shall be the one recommendedfor the particular animal species according to local andgovernment regulations. Euthanasia times shall be based on theexpected degradation rate of the material. The initial euthana-sia interval shall be when t
46、here is expected to be a 50 % loss ofmass or release of 50 % of the degradation products.Additionaleuthanasia times shall include expected 100 % loss of mass,and when complete healing and return to normal histology isanticipated. It is permissible to establish euthanasia timesduring the study period
47、 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 be estimated. Euthanasia at this additional timeperiod is needed. The additional time frames should beadvanced to accommodate t
48、his 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 general appearance of theskin at the implantation site; then, carefully expose the regionof the initial implantation. This is fa
49、cilitated 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 the 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 material. If the candidate material isnot evident at the site, extend the explanation site to includeseveral mm of n
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