ASTM F1904-2014 Standard Practice for Testing the Biological Responses to Particles in vivo《测试体内颗粒生物反应的标准实施规程》.pdf

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1、Designation: F1904 98 (Reapproved 2008)F1904 14Standard Practice forTesting the Biological Responses to Particles in vivo1This standard is issued under the fixed designation F1904; the number immediately following the designation indicates the year oforiginal adoption or, in the case of revision, th

2、e 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 covers the production of wear debrisparticles and degradation products from implanted material

3、s that may leadto a cascade of biological responses resulting in damage to adjacent and remote tissues. In order to ascertain the role of particlesin stimulating such responses, the nature of the responses, and the consequences of the responses, established protocols are needed.This is an emerging,

4、rapidly developing area and the information gained from standard protocols is necessary to interpretresponses. Some of the procedures listed here may, on further testing, not prove to be predictive of clinical responses to particulatedebris. However, only the use of standard protocols will establish

5、 which are useful techniques. Since there are many possible andestablished ways of determining responses, a single standard protocol is not stated. However, this recommended practice indicateswhich necessary information should be supplied with test results. For laboratories without established proto

6、cols, recommendationsare given and indicated with an *.asterisk (*).1.2 This standard is not designed to provide a comprehensive assessment of the systemic toxicity, carcinogenicity,teratogenicity, or mutagenicity of the material.1.3 This standard does not purport to address all of the safety concer

7、ns, if any, associated with its use. It is the responsibilityof the user of this standard to establish appropriate safety and health practices and determine the applicability of regulatorylimitations prior to use.2. Referenced Documents2.1 ASTM Standards:2F561 Practice for Retrieval and Analysis of

8、Medical Devices, and Associated Tissues and FluidsF619 Practice for Extraction of Medical PlasticsF748 Practice for Selecting Generic Biological Test Methods for Materials and DevicesF1877 Practice for Characterization of Particles3. Summary of Practice3.1 Biological responses to particles testing m

9、ay be done using specimens from animals being tested according to in accordancewith the Practice F748 matrix for irritation and sensitivity, or for implantation. Blood, organs, or tissues from the animals may beused. Procedures according toIf particles were implanted during the testing procedures or

10、 generated during the experimental F561may be used to assess the cellular response.time period, the response to those particles may form a part of the overall investigationof response to particles. Blood, organs, or tissues from the animals may be used.3.2 Biological responses to particles may be te

11、sted using the actual particulate materials or extracts according to in accordancewith Practice F619. The increased surface area of small particles may enhance the amount of extracted substances but, since theresponse to particles may be related to the physical size, shape and composition, the use o

12、f only extracts will not completelyaddress the question of the impact of particle formation on the tissue response and actual implantation or other testing of particlesshould be included as a part of the characterization of tissue response when particle generation is likely during actual usage. Thes

13、ematerials or extracts may be used in in vivo tests or for the in vitro tests. Particles generated by other methods may also be used.The method of generation mustshall be described.1 This practice is under the jurisdiction of ASTM Committee F04 on Medical and Surgical Materials and Devices and is th

14、e direct responsibility of Subcommittee F04.16on Biocompatibility Test Methods.Current edition approved Aug. 1, 2008March 1, 2014. Published August 2008May 2014. Originally approved in 1998. Last previous edition approved in 20032008 asF1904 98 (2003).(2008). DOI: 10.1520/F1904-98R08.10.1520/F1904-1

15、4.2 For referencedASTM standards, visit theASTM website, www.astm.org, or contactASTM Customer Service at serviceastm.org. For Annual Book of ASTM Standardsvolume information, refer to the standards Document Summary page on the ASTM website.This document is not an ASTM standard and is intended only

16、to provide the user of an ASTM standard an indication of what changes have been made to the previous version. Becauseit may not be technically possible to adequately depict all changes accurately, ASTM recommends that users consult prior editions as appropriate. In all cases only the current version

17、of the standard as published by ASTM is to be considered the official document.Copyright ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States14. Significance and Use4.1 This practice is to be used to help assess the biocompatibility of materials use

18、d in medical devices. It is designed to test theeffect of particles from the materials on the host tissues.4.2 The appropriateness of the methods should be carefully considered by the user since not all materials or applications needto be tested by this practice. The validity of these studies in pre

19、dicting the human response is not known at this time and studiessuch as those described here are needed.4.3 AbbreviationAbbreviations Used:4.3.1 LPSCDLipopolysaccharide (endotoxin).Cluster differentiation.4.3.2 LALDNALimulus amebocyte lysate.Deoxyribonucleic acid.4.3.3 PCREDSPolymerase chain reactio

20、n.Energy dispersive X-ray spectroscopy.4.3.4 CDEUCluster differentiation. Endotoxin unit.4.3.5 HLAHuman leukocyte antigens.4.3.6 LALLimulus amebocyte lysate.4.3.7 LPSLipopolysaccharide (endotoxin).4.3.8 RNARibonucleic acid.5. Responses from In Vivo Systems5.1 ParticlesDefine the nature of the partic

21、les used:5.1.1 Source,5.1.2 Chemistry,5.1.3 Size (mean and range),5.1.4 Shape,5.1.5 Surface charge (if known),5.1.6 Method of sterilization,5.1.7 If the presence of bacterial lipopolysaccharide (LPS) was determined, specify how this was done and the sensitivity of themethod. (LAL testing with a sens

22、itivity of at least 0.06 EU is recommended),5.1.8 Concentration of particles used as weight, or number, or surface area/implant, and5.1.9 Polystyrene particles, spherical, 1 to 5 m in size shouldmay be used as a reference particle.particles.5.1.10 Practice F1877 may be useful in defining the nature

23、of the particles.5.2 Biological SystemOne or more of these sites should be used:5.2.1 Air Pouch Model This is an emerging a model to simulate synovial tissue.The volume of air and the time allowed beforeintroduction of the particles should be specified. This model needs to be validated for length of

24、 time of implantation and relevanceto other in vivo systems.5.2.2 CagesCages made of porous materials such as stainless steel mesh or porous teflon can be implanted with a test materialinside the cage. These may be implanted subcutaneously or intraperitoneally. The material and the implant location

25、chosen shouldbe specified. The fluid accumulating in the cage can be sampled at various time intervals. The time intervals mustshall be specified.The cage and contained material is removed at the termination of the experiment (specify the time chosen) and evaluated for celladhesion, cell type, and p

26、roducts. Fluid containing a large number of red blood cells should be discarded since it represents blood,not cage fluid.5.2.3 Bone Implant ChamberThis is a modification of the cage system and allows determination of the effect of particles andthe resulting biological response on bone remodeling5.2.

27、4 Direct Injection Intraperitoneal, intravenous, intramuscular, and subcutaneous are the favored routes. The end useapplication should govern the route of injection and the organ or tissue utilized in this test. Inhalation may be suitable for someend use applications.5.2.5 Other MethodsThe use of ot

28、her biological systems, animal models,or methods of implantation may be appropriate,depending upon the intended use of the material.5.2.6 Examination of tissue at implant retrieval from animal models or clinical conditions is dealt with in Practice F561, andPractice F1877. may be used to describe th

29、e morphology of the particles that may be present in or extracted from those tissues.Some of the procedures defined here are also applicable to these tissues.5.2.7 All sites used in these studies should be carefully evaluated for infection and inflammation at the termination of the study.The presenc

30、e of infection or inflammation will have a major impact on the outcome since it stimulates many responses.5.2.8 Control AnimalsIn the conduct of testing with any of the above described models, appropriate control animals whoreceive any vehicles, carriers, other treatments received by the experimenta

31、l models, to control for the effects of factors other thanthe presence of the particles, should be included as well.5.3 Biological Response DeterminedResponseOne or more of the following:following should be performed:5.3.1 Cell accumulation at the site of the particles should be evaluated for the re

32、lative number and type of cells. Standardparaffin or plastic embedded sections are usually sufficient to identify acute inflammatory cells, lymphocytes, macrophages, foreignF1904 142body giant cells, osteoclasts, osteoblasts, osteocytes, eosinophils, etc. But in some cases special histological proce

33、dures, orimmunohistochemical stains such as those described in Practice F561, or flow cytometry may be needed to confirm the identityof lymphocytes and macrophages.An evaluation scale of 0 to 5 with 0 being no cell response, 1 being accumulation of a few cells,2 being a mild response with some cell

34、accumulation, 3 being a moderate response, 4 being a large response, and 5 being a severeresponse is recommended. It should also be noted whether the response is focal or diffuse.5.3.1.1 Transport of particles to relevant draining organs and histologic responses in these organs should be determined,

35、especially when direct injection is used. The relevant organs would be spleen, liver, kidney, and kidney. In some cases the lung.cases, the lung may also be an appropriate draining organ when it is reasonable to suspect that particles could enter the venousreturn portion of the vascular system. The

36、draining nodes should be harvested if identifiable. Some types of debrisparticles aredistinctive (for example, carbon fibers), but lymph nodes and lung commonly contain particles and bits of birefringent stuffmaterialthat may be confused with particles used in the experiment. Light microscopy with a

37、nd without polarized light can be suggestiveof particle migration, but other methods,methods (for example, EDAX,EDS) may be necessary to confirm the composition of themigrating particles. Organs from control animals should also be evaluated.5.3.2 Soluble Cell Products ElaboratedThis is a rapidly eme

38、rging area of technology. Histochemical and immunohistochemi-cal techniques can be used to great advantage in these studies. Reliable reagents, kits, or hybridization protocols are available todetect the following products IL- 1, IL-2, IL-4, IL-6, IL-10, PGE2, TNF, cellular products such as cytokine

39、s, prostaglandins,immunoglobulins, as well as the lymphocyte CD markers and some HLA markers. It is not necessary to measure all of thesepossible cellular products and the selection should be based on whether there is emphasis on the macrophage response or the ofmacrophages or other cells involved i

40、n the non-specific immune response, or on the specific immune response.NOTE 1The identification and study of reactive cellular products is a rapidly expanding field and any listing of specific products from which to choosewould necessarily become obsolete quickly. An immunologist should be consulted

41、 to assist in the selection of substances for which testing should beperformed.5.3.3 WhereWhen other products from the cellular response are being detected, they should be specified and the method usedspecified.5.4 Effects of the particles on other systems such as bone remodeling, chondrocyte functi

42、on, cartilage repair, and synovial tissuefunction and repair are also important studies. The methods used should be fully described.6. Report Section and Data Analysis6.1 The histologic response should be compared to that of normal tissues with no particles and to that of tissues receiving thepolyst

43、yrene reference particle. particles, if used as reference particles. This may be done by counting, by digitization, by cellanalyzer, or by estimation in the field of view. In some circumstances circumstances, the presence or absence of marker or responsewill suffice. In some circumstances circumstan

44、ces, the quantitation of the response may be obtained with data on responses suchas Ca+Ca+ released, enyzyme levels.enzyme levels, DNA or RNA levels, etc.6.2 The report should include a description of the methods used, route of administration and source of the particles, and otherdetails of the expe

45、rimental protocol sufficient to allow the results to be interpreted in the context of the testing methods used.7. Keywords7.1 biocompatibility; biological response; in vivo; interleukins; particlesAPPENDIX(Nonmandatory Information)X1. RATIONALEX1.1 The primary purpose of this practice is to describe

46、 methodologies to determine the biological response to particles using invivo responses.X1.2 It is well recognized that the biological responses to particles could be different from those to solid materials. The interactionof the particles with cells in the tissue,tissues, notably macrophages and ot

47、her phagocytic cells, is a key to the final biologicalresponse.X1.3 The interaction of particles with host tissuetissues has been an active research area for many years. Many investigators havedeveloped procedures for doing these studies. This practice is intended to delineate the information necess

48、ary for interpretation ofthe results from these various studies and to describe methodology appropriate for those investigators developing such studies.F1904 143X1.4 The interaction of the biological system with particles will lead to the accumulation of various cells whichthat may producesoluble me

49、diators whichthat influence the progression of the biological response and the immune response. It is unknown at thistime which of these responses are favorable and which are unfavorable to the host. immune response. Studies such as the onesdescribed here are needed to determine the importance of these responsesthis response in the biocompatibility and biocompatibilitytesting of materials.X1.5 This practice was revised in 2014 to incorporate new information and update some of the information originally includedin the 1998 version.ASTM International t