ASTM F1983-99(2008)
(Practice)Standard Practice for Assessment of Compatibility of Absorbable/Resorbable Biomaterials for Implant Applications
Standard Practice for Assessment of Compatibility 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 2008)
Standard Practice for
Assessment of Compatibility of Absorbable/Resorbable
Biomaterials for Implant Applications
This standard is issued under the fixed designation F1983; 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 (´) 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
F561 Practice for Retrieval and Analysis of Medical
tissue longer than 30 days and less than three years. Other
Devices, and Associated Tissues and Fluids
standards with designated implantation times are available to
F750 Practice for Evaluating Material Extracts by Systemic
address the shorter time periods. Careful consideration should
Injection in the Mouse
be given to the appropriateness of this practice for slowly
F763 Practice for Short-Term Screening of Implant Materi-
degrading materials that will remain for longer than three
als
years. It is anticipated that the tissue response to degrading
F981 Practice for Assessment of Compatibility of Biomate-
biomaterials will be different from the response to nonresorb-
rials 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
F1408 Practice for Subcutaneous Screening Test for Implant
histology should return to normal after degradation; therefore,
Materials
the minimal tissue response usually equated with “biocompat-
F1903 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
F1904 Practice for Testing the Biological Responses to
depending on chemical composition and implant size;
Particles in vivo
therefore, the implantation times for examination of tissue
F1905 Practice For Selecting Tests for Determining the
response will be linked to the rate of resorption. No single
Propensity of Materials to Cause Immunotoxicity (With-
implantation time is indicated in this practice.
drawn 2011)
1.3 These protocols assess the effects of the material on the F1906 Practice for Evaluation of Immune Responses In
animal tissue in which it is implanted. The experimental
BiocompatibilityTestingUsingELISATests,Lymphocyte
protocols do not fully assess systemic toxicity, carcinogenicity, Proliferation, and Cell Migration (Withdrawn 2011)
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
practice, and these effects should be documented fully.
3.2 The use of larger animals, such as the dog, goat, or
sheep may be justified based upon special considerations of the
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
1 2
This practice is under the jurisdiction ofASTM CommitteeF04 on Medical and For referenced ASTM standards, visit the ASTM website, www.astm.org, or
Surgical Materials and Devices and is the direct responsibility of Subcommittee contact ASTM Customer Service at service@astm.org. For Annual Book of ASTM
F04.16 on Biocompatibility Test Methods. Standards volume information, refer to the standard’s Document Summary page on
Current edition approved Aug. 1, 2008. Published August 2008. Originally the ASTM website.
approved in 1999. Last previous edition approved in 2003 as F1983 – 99 (2003). The last approved version of this historical standard is referenced on
DOI: 10.1520/F1983-99R08. www.astm.org.
Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States
F1983 − 99 (2008)
availability of historical data on biological responses of these prediction may be done by radio-labeling the material and
animals to similar devices to aid in analysis and comparison of following the loss of radioactivity; however, radioactive speci-
data obtained. mens shall not be used for biocompatibility testing. Other
methods of following the degradation are acceptable. The
3.3 All animal studies must be done in a facility approved
target organs of the metabolism and excretion of the products
byanationallyrecognizedorganizationandinaccordancewith
should be identified. It is recommended that acute systemic
all appropriate regulations.
studies with material extracts according to Practice F750 be
completed prior to the initiation of the implantation study.
4. Significance and Use
4.1 This practice is a guideline for a screening test for the
6. Implant Specimens
evaluation of the local tissue response to materials that may be
6.1 Design of the Implant—Specimens may be made from
selected for implantation into the human body and which are
the final finished form candidate material in configurations
expected to undergo degradation by absorption or resorption
specific for the animal study.As described in 4.3, the material/
within three years.
host ratio should be available and referrable to ultimate use in
4.2 This practice is similar to that for studies on candidate
the human with material/body mass ratios of 1X, 10X, and
materials that are not resorbable, such as those specified in
50X, if applicable, recommended. Relevant configurations of
PracticesF763,F981,andF1408;however,analysisofthehost
implant specimens, such as cylinders, flat cloth, amorphous
response must take into account the effect of degradation and
gels, and polymerizable liquids may be used.
degradation products on the inflammatory response at the local
6.2 The use of positive and negative controls is not required
tissue site and on subsequent healing of the implantation site.
in this practice; however, the implantation of the candidate
4.3 The material to be tested should be in the final finished
material must be accompanied by the use of an implanted
form as for intended use, including sterilization. Material/body
markerorotherpermanentmethod,suchasatemplate,tomark
ratios should be relevant to that of intended device use.
the implant site to allow identification of the implant site at the
Material surface area or mass to body mass ratios of 1X, 10X,
various time periods. A sham surgical site, or a sham surgical
and 50X if applicable, are recommended.
animal, is necessary.
4.4 Materials that are designed for use in devices with in
6.3 The material used shall be in its final finished form and
situpolymerizationshallbeintroducedinamannersuchthatin
sterilized as indicated for its ultimate use. It shall be handled
situ polymerization occurs. Testing of individual precursor
for implantation in a manner analogous to that for intended
components is not recommended.
final use, for example, special forceps, special cannulas or
needles, special syringes, and so forth.
5. Test Animals and Sites
6.4 The candidate material shall be described thoroughly to
5.1 Choice of test animal shall take into consideration the
facilitate development of a suitable implant application proto-
normal life span of the animal and the length of the implanta-
col. The absorption, distribution, metabolism, and excretion of
tion study. Small laboratory animals are preferred. The strain,
the material and its degradation products should be described.
sex, age, and origin of the animals used should be noted. If
The information shall include, but is not limited to, the
larger animals are used, justification for their use should be
following:
provided.Thesourceoftheanimals,species/strain,weight,age
6.4.1 Expected method of degradation, for example,
(where known or approximate if not known), general health,
hydrolysis, enzymatic, phagocytosis, and so forth.
and boarding conditions should be recorded. Animal use and
6.4.2 Expected nonresorbable degradation products, for
care regulations must be followed.
example, fibrils, particles from composites.
5.2 The number of implant sites shall depend on the size of
6.4.3 Expected rate of degradation.
the implant and the animal. The distance between implants
6.4.4 Expected target organ effects where known or
shall be sufficient so that separate tissue blocks are prepared
expected, for example, eliminated in kidney, stored in liver,
easily for each implant and sufficient that the biological
stored in spleen or lymph nodes.
reactions do not overlap or interfere with each other. Implants
6.5 For each time period, at least six rodents shall be used
may be placed bilaterally in soft tissue, including muscle.
with either single or bilateral implants. For the larger animals,
Bilateral implantation into bone should be considered carefully
at least four animals shall be used per time period. It is
and justification given. In general, mice, rats, hamsters, and
recommended that additional animals be included in the initial
other similarly sized rodents should receive no more than one
protocol to accommodate any unexpected changes in degrada-
implant on each side. Larger animals, including rabbits, may
tion rates of the material.
receive up to five implants on each side. When the implant is
composedofacollectionofparticles,pellets,andsoforth,each
7. Procedure
collection is considered one implant site.
7.1 Implantation:
5.3 Before embarking on studies in large animals, it is
recommended that a pilot study in rodents be undertaken to 7.1.1 Implant the specimen under sterile conditions in
determineexpectedrateofdegradationandthedistributionand anesthetized animals. Where possible, implant the specimen
metabolism of the degradation products. When feasible, initial using a trochar method to avoid the need for an incision. If an
F1983 − 99 (2008)
incision is needed, insert the implant as far from the incision tion. The additional animals recommended in 6.5 may be used
site as possible. Close the insertion site with a suitable suture for this purpose of additional euthanasia times.
material. 7.3.2 At euthanasia, record the general appearance of the
skin at the implantation site; then, carefully expose the region
7.1.1.1 A sham site or sham animal with the identical
of the initial implantation. This is facilitated by the use of a
implantation procedure, but not the test material, should be
template and skin marker at surgery. If a marker suture is used,
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
7.1.2 The implantation site must be marked in manner
of the material. The use of gross photography should be
suitable for identification of the site at the designated time
considered carefully since it may aid in maintaining an
periods. The use of a permanent skin marker and a template
adequate permanent record. Remove the intact tissue envelope
marking the placement of the specimen and the sham site is
around the marker or template and extend beyond any identi-
recommended. Specimens that are radiopaque may have serial
fiable remaining candidate material. If the candidate material is
radiographs to identify the location. The implantation of a
not evident at the site, extend the explanation site to include
nonabsorbable marker material such as a monofilament, non-
several mm of normal tissue on all sides of the marker material
absorbable suture attached to the specimen or embedded in the
or template mark. If any abnormal tissue is observed
gelorliquidalsoisacceptable.Ifanimplantedmarkermaterial
elsewhere, this shall be removed for further examination.
is used with the specimen, this marker material shall be
Transfer the tissue specimen as soon as possible into a fixing
included in the sham site. The test specimen site and the sham
agent suitable for further histologic processing. The use of
site shall be marked.
alcohol, formaldehyde, or glutaraldehyde is recommended, but
7.1.3 Keep the animals in standard housing according to
otheragents,suchasfreezing,maybeconsidered.Referenceto
currentanimalprotectionrequirements.Theindividualanimals
Practices F561, F981, and F1408 is encouraged for processing
should be marked for identification.
procedures.
7.2 Post-Operative Care:
7.3.3 Although systemic toxicity is not addressed specifi-
7.2.1 Care of the animals shall be in accordance with
cally in this practice, examination of target organs should be
accepted standards as outlined in Guide for Care and Use of
conducted to maximize use of the animal. After the implanta-
Laboratory Animals according to the local and national gov-
tion site is harvested, the abdominal and thoracic viscera
ernment ordinances in an approved facility.
should be examined. The liver, spleen, kidney, local lymph
7.2.2 Carefully observe each animal during the specified nodes, gonads, and lung should be retained in fixative in case
time period and record any abnormal clinical findings. of future need. If any abnormalities are noted, the specimen
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 F1903 and F1904.
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 processe
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