ASTM F1983-99(2003)
(Practice)Standard Practice for Assessment of Compatibiltiy of Absorbable/Resorbable Biomaterials for Implant Applications
Standard Practice for Assessment of Compatibiltiy of Absorbable/Resorbable Biomaterials for Implant Applications
SIGNIFICANCE AND USE
This practice is a guideline for a screening test for the evaluation of the local tissue response to materials that may be selected for implantation into the human body and which are expected to undergo degradation by absorption or resorption within three years.
This practice is similar to that for studies on candidate materials that are not resorbable, such as those specified in Practices F 763, F 981, and F 1408; however, analysis of the host response must take into account the effect of degradation and degradation products on the inflammatory response at the local tissue site and on subsequent healing of the implantation site.
The material to be tested should be in the final finished form as for intended use, including sterilization. Material/body ratios 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.
Materials that are designed for use in devices with in situ polymerization shall be introduced in a manner such that in situ polymerization occurs. Testing of individual precursor components is not recommended.
SCOPE
1.1 This practice provides experimental protocols for biological assays of tissue reactions to absorbable/resorbable biomaterials for implant applications. This practice applies only to resorbable/absorbable materials with projected clinical applications in which the materials will reside in bone or soft tissue longer than 30 days and less than three years. Other standards with designated implantation times are available to address the shorter time periods. Careful consideration should be given to the appropriateness of this practice for slowly degrading materials that will remain for longer than three years. It is anticipated that the tissue response to degrading biomaterials will be different from the response to nonresorbable materials. In many cases, a chronic inflammatory response may be observed during the degradation phase, but the local histology should return to normal after degradation; therefore, the minimal tissue response usually equated with "biocompatibility" may require long implantations.
1. 2 The time period for implant degradation will vary depending on chemical composition and implant size; therefore, the implantation times for examination of tissue response will be linked to the rate of resorption. No single implantation time is indicated in this practice.
1.3 These protocols assess the effects of the material on the animal tissue in which it is implanted. The experimental protocols do not fully assess systemic toxicity, carcinogenicity, teratogenicity, or mutagenicity of the material. Other standards are available to address these issues.
1.4 To maximize use of the animals in the study protocol, all toxicological findings should be recorded. There are some aspects of systemic toxicity, including effects of degradation products on the target organs, that can be addressed with this practice, and these effects should be documented fully.
1.5 This standard does not purport to address all of the safety concerns, if any, associated with its use. It is the responsibility of the user of this standard to establish appropriate safety and health practices and determine the applicability of regulatory limitations prior to use.
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Designation:F1983–99 (Reapproved 2003)
Standard Practice for
Assessment of Compatibility of Absorbable/Resorbable
Biomaterials for Implant Applications
This standard is issued under the fixed designation F 1983; the number immediately following the designation indicates the year of
original adoption or, in the case of revision, the year of last revision. A number in parentheses indicates the year of last reapproval. A
superscript epsilon (e) indicates an editorial change since the last revision or reapproval.
1. Scope responsibility of the user of this standard to establish appro-
priate safety and health practices and determine the applica-
1.1 This practice provides experimental protocols for bio-
bility of regulatory limitations prior to use.
logical assays of tissue reactions to absorbable/resorbable
biomaterials for implant applications. This practice applies
2. Referenced Documents
only to resorbable/absorbable materials with projected clinical
2.1 ASTM Standards:
applications in which the materials will reside in bone or soft
F 561 Practice for Analysis of Implanted Medical Devices
tissue longer than 30 days and less than three years. Other
and Associated Tissues
standards with designated implantation times are available to
F 750 PracticeforEvaluatingMaterialExtractsbySystemic
address the shorter time periods. Careful consideration should
Injection in the Mouse
be given to the appropriateness of this practice for slowly
F 763 Practice for Short-Term Screening of Implant Mate-
degrading materials that will remain for longer than three
rials
years. It is anticipated that the tissue response to degrading
F 981 Practice for Assessment of Compatibility of Bioma-
biomaterials will be different from the response to nonresorb-
terials for Surgical Implants With Respect to Effect of
ablematerials.Inmanycases,achronicinflammatoryresponse
Materials on Muscle and Bone
may be observed during the degradation phase, but the local
F 1408 Practice for Subcutaneous Screening Test for Im-
histology should return to normal after degradation; therefore,
plant Materials
the minimal tissue response usually equated with “biocompat-
F 1903 Practice for Testing for Biological Responses to
ibility” may require long implantations.
Particles in vitro
1.2 The time period for implant degradation will vary
F 1904 Practice for Testing the Biological Responses to
depending on chemical composition and implant size; there-
Particles in vivo
fore, the implantation times for examination of tissue response
F 1905 Practice for Selecting Tests for Determining the
will be linked to the rate of resorption. No single implantation
Propensity of Materials to Cause Immunotoxicity
time is indicated in this practice.
F 1906 Practice for Evaluation of Immune Responses in
1.3 These protocols assess the effects of the material on the
Biocompatibility Testing Using ELISATests, Lymphocyte
animal tissue in which it is implanted. The experimental
Proliferation, and Cell Migration
protocols do not fully assess systemic toxicity, carcinogenicity,
teratogenicity, or mutagenicity of the material. Other standards
3. Summary of Practice
are available to address these issues.
3.1 Under strict aseptic conditions, specimens of the final
1.4 Tomaximizeuseoftheanimalsinthestudyprotocol,all
implant form candidate material are implanted into the most
toxicological findings should be recorded. There are some
relevant anatomical tissue site in small laboratory animals,
aspects of systemic toxicity, including effects of degradation
preferably mice, rats, hamsters, or rabbits.
products on the target organs, that can be addressed with this
3.2 The use of larger animals, such as the dog, goat, or
practice, and these effects should be documented fully.
sheepmaybejustifiedbaseduponspecialconsiderationsofthe
1.5 This standard does not purport to address all of the
particular study. Choice of species also should consider the
safety concerns, if any, associated with its use. It is the
This practice is under the jurisdiction ofASTM CommitteeF04 on Medical and
Surgical Material and Devices and is the direct responsibility of Subcommittee For referenced ASTM standards, visit the ASTM website, www.astm.org, or
F04.16 on Biocompatibility Test Methods. contact ASTM Customer Service at service@astm.org. For Annual Book of ASTM
Current edition approved Nov. 1, 2003. Published December 2003. Originally Standards volume information, refer to the standard’s Document Summary page on
approved in 1999. Last previous edition approved in 1999 as F 1983 – 99. the ASTM website.
Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959, United States.
F1983–99 (2003)
availability of historical data on biological responses of these mens shall not be used for biocompatibility testing. Other
animals to similar devices to aid in analysis and comparison of methods of following the degradation are acceptable. The
data obtained. target organs of the metabolism and excretion of the products
3.3 All animal studies must be done in a facility approved should be identified. It is recommended that acute systemic
byanationallyrecognizedorganizationandinaccordancewith studies with material extracts according to Practice F 750 be
all appropriate regulations. completed prior to the initiation of the implantation study.
4. Significance and Use 6. Implant Specimens
4.1 This practice is a guideline for a screening test for the 6.1 Design of the Implant—Specimens may be made from
evaluation of the local tissue response to materials that may be the final finished form candidate material in configurations
selected for implantation into the human body and which are specific for the animal study.As described in 4.3, the material/
expected to undergo degradation by absorption or resorption host ratio should be available and referrable to ultimate use in
within three years. the human with material/body mass ratios of 1X, 10X, and
4.2 This practice is similar to that for studies on candidate 50X, if applicable, recommended. Relevant configurations of
materials that are not resorbable, such as those specified in implant specimens, such as cylinders, flat cloth, amorphous
Practices F 763, F 981, and F 1408; however, analysis of the gels, and polymerizable liquids may be used.
host response must take into account the effect of degradation 6.2 The use of positive and negative controls is not required
and degradation products on the inflammatory response at the in this practice; however, the implantation of the candidate
local tissue site and on subsequent healing of the implantation material must be accompanied by the use of an implanted
site. markerorotherpermanentmethod,suchasatemplate,tomark
4.3 The material to be tested should be in the final finished the implant site to allow identification of the implant site at the
form as for intended use, including sterilization. Material/body various time periods. A sham surgical site, or a sham surgical
ratios should be relevant to that of intended device use. animal, is necessary.
Material surface area or mass to body mass ratios of 1X, 10X, 6.3 The material used shall be in its final finished form and
and 50X if applicable, are recommended. sterilized as indicated for its ultimate use. It shall be handled
4.4 Materials that are designed for use in devices with in for implantation in a manner analogous to that for intended
situpolymerizationshallbeintroducedinamannersuchthatin final use, for example, special forceps, special cannulas or
situ polymerization occurs. Testing of individual precursor needles, special syringes, and so forth.
components is not recommended. 6.4 The candidate material shall be described thoroughly to
facilitate development of a suitable implant application proto-
5. Test Animals and Sites
col. The absorption, distribution, metabolism, and excretion of
5.1 Choice of test animal shall take into consideration the
the material and its degradation products should be described.
normal life span of the animal and the length of the implanta-
The information shall include, but is not limited to, the
tion study. Small laboratory animals are preferred. The strain,
following:
sex, age, and origin of the animals used should be noted. If
6.4.1 Expected method of degradation, for example, hy-
larger animals are used, justification for their use should be
drolysis, enzymatic, phagocytosis, and so forth.
provided.Thesourceoftheanimals,species/strain,weight,age
6.4.2 Expected nonresorbable degradation products, for ex-
(where known or approximate if not known), general health,
ample, fibrils, particles from composites.
and boarding conditions should be recorded. Animal use and
6.4.3 Expected rate of degradation.
care regulations must be followed.
6.4.4 Expected target organ effects where known or ex-
5.2 The number of implant sites shall depend on the size of
pected, for example, eliminated in kidney, stored in liver,
the implant and the animal. The distance between implants
stored in spleen or lymph nodes.
shall be sufficient so that separate tissue blocks are prepared 6.5 For each time period, at least six rodents shall be used
easily for each implant and sufficient that the biological
with either single or bilateral implants. For the larger animals,
reactions do not overlap or interfere with each other. Implants at least four animals shall be used per time period. It is
may be placed bilaterally in soft tissue, including muscle.
recommended that additional animals be included in the initial
Bilateral implantation into bone should be considered carefully
protocol to accommodate any unexpected changes in degrada-
and justification given. In general, mice, rats, hamsters, and
tion rates of the material.
other similarly sized rodents should receive no more than one
7. Procedure
implant on each side. Larger animals, including rabbits, may
receive up to five implants on each side. When the implant is 7.1 Implantation:
composedofacollectionofparticles,pellets,andsoforth,each 7.1.1 Implant the specimen under sterile conditions in
collection is considered one implant site. anesthetized animals. Where possible, implant the specimen
5.3 Before embarking on studies in large animals, it is using a trochar method to avoid the need for an incision. If an
recommended that a pilot study in rodents be undertaken to incision is needed, insert the implant as far from the incision
determineexpectedrateofdegradationandthedistributionand site as possible. Close the insertion site with a suitable suture
metabolism of the degradation products. When feasible, initial material.
prediction may be done by radio-labeling the material and 7.1.1.1 A sham site or sham animal with the identical
following the loss of radioactivity; however, radioactive speci- implantation procedure, but not the test material, should be
F1983–99 (2003)
included in the protocol. If animals are to be used as part of the site of the marker suture shall be noted. Record the color
systemic toxicity study, the sham must be a separate animal. and consistency of the tissues in the region of the original site
of the material. The use of gross photography should be
7.1.2 The implantation site must be marked in manner
considered carefully since it may aid in maintaining an
suitable for identification of the site at the designated time
adequate permanent record. Remove the intact tissue envelope
periods. The use of a permanent skin marker and a template
around the marker or template and extend beyond any identi-
marking the placement of the specimen and the sham site is
fiableremainingcandidatematerial.Ifthecandidatematerialis
recommended. Specimens that are radiopaque may have serial
not evident at the site, extend the explanation site to include
radiographs to identify the location. The implantation of a
several mm of normal tissue on all sides of the marker material
nonabsorbable marker material such as a monofilament, non-
or template mark. If any abnormal tissue is observed else-
absorbable suture attached to the specimen or embedded in the
where, this shall be removed for further examination. Transfer
gelorliquidalsoisacceptable.Ifanimplantedmarkermaterial
is used with the specimen, this marker material shall be the tissue specimen as soon as possible into a fixing agent
suitable for further histologic processing. The use of alcohol,
included in the sham site. The test specimen site and the sham
site shall be marked. formaldehyde, or glutaraldehyde is recommended, but other
agents, such as freezing, may be considered. Reference to
7.1.3 Keep the animals in standard housing according to
Practices F 561, F 981, and F 1408 is encouraged for process-
currentanimalprotectionrequirements.Theindividualanimals
ing procedures.
should be marked for identification.
7.3.3 Although systemic toxicity is not addressed specifi-
7.2 Post-Operative Care:
cally in this practice, examination of target organs should be
7.2.1 Care of the animals shall be in accordance with
conducted to maximize use of the animal. After the implanta-
accepted standards as outlined in Guide for Care and Use of
tion site is harvested, the abdominal and thoracic viscera
Laboratory Animals according to the local and national gov-
should be examined. The liver, spleen, kidney, local lymph
ernment ordinances in an approved facility.
nodes, gonads, and lung should be retained in fixative in case
7.2.2 Carefully observe each animal during the specified
of future need. If any abnormalities are noted, the specimen
time period and record any abnormal clinical findings.
should be subjected to histologic examination. If the release of
7.2.3 If infection or accidental injury of the test implant site
particles is anticipated, then the target organs shall be pro-
occurs, record the information and process the implant site and
cessed in an appropriate manner to preserve the particles as
tissues and organs as described in 7.3 and 8.1. Record the data
discussed in Practices F 1903 and F 1904.
in the results, but do not use the data in the final analysis of
7.3.4 It is recommended that tissues from the target organs
results from the other animals. A replacement animal may be
listed in 7.3.3 be processed for histologic analysis since the
added, if desired.
data may be useful in evaluation of systemic toxicity.Although
7.2.4 If an animal dies before the scheduled termination,
this practice does not substitute for systemic toxicity studies
record the information and process the implant site and tissues
(see Practice F 750), remote organs should be collected and
and organs as described in 7.3 and 8.1. Record the data, but do
assessed for toxicological findings to maximize use of the
not use the data in t
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