ASTM F1983-23

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Designation: F1983 − 14 F1983 − 23
Standard Practice for
Assessment of Selected Tissue Effects of Absorbable
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
1.1 This practice provides experimental protocols for biological assays of tissue reactions to absorbable biomaterials for implant
applications. This practice applies only to 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 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 nonabsorbable materials. In many cases, a chronic inflammatory response may be observed
during the degradation phase, but the local histology should return to normal after absorption; therefore, the minimal tissue
response usually equated with “biocompatibility”biocompatibility may require long implantations.
1.2 The time period for implant absorption will vary depending on chemical compositioncan depend on variables of chemical
composition, implant size, implant location, and test subject species; therefore, the implantation times for examination of tissue
response will be linked to animal models. Therefore, the selected time points for assessing tissue effects may be selected based
on the rate of absorption. 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
They do not fully assess systemic toxicity, carcinogenicity, teratogenicity, reproductive and development toxicity, 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 different organs and tissues downstream
of or surrounding the target site, can be addressed with this practice, and these effects should be documented fully. practice.
1.5 Because animal models are not identical to human biology, this practice cannot account for all potential biological hazards,
for example the effect of the oligosaccharide a-Gal (Gala 1,3-Galb1-4GlcNAc-R), known as the “a-Gal” epitope present in
xenogeneic materials on humans. See ISO 22442.
1.6 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 healthsafety, health, and environmental practices and determine
the applicability of regulatory limitations prior to use.
1.7 This international standard was developed in accordance with internationally recognized principles on standardization
established in the Decision on Principles for the Development of International Standards, Guides and Recommendations issued
by the World Trade Organization Technical Barriers to Trade (TBT) Committee.
This practice is under the jurisdiction of ASTM Committee F04 on Medical and Surgical Materials and Devices and is the direct responsibility of Subcommittee F04.16
on Biocompatibility Test Methods.
Current edition approved Nov. 1, 2014April 1, 2023. Published January 2015April 2023. Originally approved in 1999. Last previous edition approved in 20082014 as
F1983 – 99 (2008).F1983 – 14. DOI: 10.1520/F1983-14.10.1520/F1983-23.
Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States
F1983 − 23
2. Referenced Documents
2.1 ASTM Standards:
F561 Practice for Retrieval and Analysis of Medical Devices, and Associated Tissues and Fluids
F750 Practice for Evaluating Acute Systemic Toxicity of Material Extracts by Systemic Injection in the Mouse
F763 Practice for Short-Term Intramuscular Screening of Implantable Medical Device Materials
F981 Practice for Assessment of Compatibility of Biomaterials for Surgical Implants with Respect to Effect of Materials on
Muscle and Insertion into Bone
F1408 Practice for Subcutaneous Screening Test for Implant Materials
F1635 Test Method for in vitro Degradation Testing of Hydrolytically Degradable Polymer Resins and Fabricated Forms for
Surgical Implants
F1903 Practice for Testing for Cellular Responses to Particles in vitro
F1904 Practice for Testing the Biological Responses to Particles in vivo
F1905F2902 Practice For Selecting Tests for Determining the Propensity of Materials to Cause ImmunotoxicityGuide for
Assessment of Absorbable Polymeric Implants (Withdrawn 2011)
F1906F3268 PracticeGuide for Evaluation ofin vitro Immune Responses In Biocompatibility Testing Using ELISA Tests,
Lymphocyte Proliferation, and Cell MigrationDegradation Testing of Absorbable Metals (Withdrawn 2011)
2.2 ISO Standards:
ISO 10993-6 Biological evaluation of medical devices—Part 6: Tests for local effects after implantation
ISO 10993-9 Biological evaluation of medical devices—Part 9: Framework for identification and quantification of potential
degradation products
ISO 10993-11 Biological evaluation of medical devices—Part 11: Tests for systemic toxicity
ISO 10993-18 Biological evaluation of medical devices—Part 18: Chemical characterization of medical device materials within
a risk management process
ISO/TS 10993-19 Biological evaluation of medical devices—Part 19: Physico-chemical, morphological and topographical
characterization of materials
ISO 13781 Implants for surgery—Homopolymers, copolymers and blends on poly(lactide)—In vitro degradation testing
ISO/TS 17137 Cardiovascular implants and extracorporeal systems—Cardiovascular absorbable implants
ISO 22442 Medical devices utilizing animal tissues and their derivatives
ISO/TS 37137-1 Biological evaluation of absorbable medical devices—Part 1: General requirements
3. Terminology
3.1 Definitions:
3.1.1 final finished form—a device or device component that includes all manufacturing processes for the “to be marketed” device
including packaging and sterilization, if applicable.
4. Summary of Practice
3.1 Under strict aseptic conditions, specimens of the sterile final implant form candidate material are implanted into the most
relevant anatomical tissue site in small laboratory animals, preferably mice, rats, hamsters, or rabbits.
4.1 The Under strict aseptic conditions, sterile test articles (for example, final device) are implanted into a relevant animal model
and at a clinically relevant anatomical tissue site. However, for screening candidate materials, testing in a clinically relevant animal
model and anatomical tissue site may not be necessary. Small laboratory animals such as mice, rats, hamsters, or rabbits are
preferred. In addition, the use of larger animals, such as the dog, goat, pig, or sheep may be justified based upon special
considerations of the particular study. Choice of species also should the animal model should also consider the availability of
historical data on biological responses of these animals to similar devices to aid in analysis and comparison of the data obtained.
4.2 All animal studies shall be done in a facility approved by a nationally recognized organization and in accordance with all
appropriate regulations.
For referenced ASTM standards, visit the ASTM website, www.astm.org, or contact ASTM Customer Service at service@astm.org. For Annual Book of ASTM Standards
volume information, refer to the standard’s Document Summary page on the ASTM website.
Available from American National Standards Institute (ANSI), 25 W. 43rd St., 4th Floor, New York, NY 10036, http://www.ansi.org.
FDA Biocompatibility Guidance, “Use of International Standard ISO 10993-1, ‘Biological evaluation of medical devices—Part 1: Evaluation and testing within a risk
management process’” (https://www.fda.gov/media/85865/download).
F1983 − 23
5. Significance and Use
5.1 This practice is a guideline for a screening test for the evaluation of the of candidate materials or assessment of local tissue
response to materials that may be selected for implantation into the human body and absorbable medical devices which are
expected to undergo complete absorption within three years.
5.2 This practice is similar to thatthose for studies on candidate materials or medical devices that are not absorbable, such as those
specified in Practices F763, F981, and F1408; 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. site, as well as the potential for adverse distal tissue effects.
5.3 The material to be tested For testing of absorbable medical devices, the test article for implantation 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 packaging and sterilization (if applicable). Configurations specific to the animal study may be needed. The test article’s
surface-area-to-body mass or mass-to-body mass ratios within the animal model should be established by calculating based on
surface-area-to-body mass or mass-to-body mass ratios in humans during the device’s intended clinical use. Worst-case clinical
dose should be considered in the study design. For implantation studies incorporating evaluation of both local tissue responses and
systemic toxicity, exaggerated material surface area or mass to body mass ratios of 1X, 10X, and 50X if applicable, are
recommended. mass-to-body mass ratios (for example, a 2X to 10X safety factor to assess implant safety for regulatory
submissions) compared to clinical use (for example, largest device size, maximum number of devices) should be considered, unless
otherwise justified. For example, implantation of exaggerated doses may not be feasible in the selected animal model. For some
devices, additional animal group(s) for exaggerated conditions should be considered if dose response information is needed.
Additionally, for some devices, exaggerated dose at a specific implantation site can also be used to evaluate local tissue responses.
5.4 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 Additional testing of individual precursor components is not recommended.or partially polymerized
materials may be needed in some cases (for example, if testing of the final implant indicates an adverse response or incomplete
polymerization).
6. Test Animals and SitesAnimal Model
6.1 Choice of test animal The choice of animal model shall take into consideration the normal life span of the animal animal, the
clinical use conditions, device absorption kinetics, and the length of the implantation study. Small laboratory animals are preferred.
study, and shall be justified. The strain, sex, age, and origin weight, origin, and general health of the animals used should be noted.
If larger animals are used, justification for their use should be provided. 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 recorded.
5,6,7,8,9
Institutional and government animal use and care policies and regulations shall be followed.
6.2 The number of implant sites shall depend on the size of the implant and the animal. The distance between implants shall be
sufficient so that separate tissue blocks are prepared easily for each implant and that the local biological reactions do not overlap
or interfere with each other. Implants may be placed bilaterally in soft tissue, including muscle. Bilateral implantation into bone
should be considered carefully and justification given. In general, mice, rats, hamsters, and other similarly sized rodents small
laboratory animal species should receive no more than one implant on each side. Larger animals, including rabbits, may receive
up to five implants on each side. When the implant is composed of a collection of particles, pellets, and so forth, each collection
is considered one implant site.
6.3 Before embarking on studies in large animals, it is recommended that a pilot study Scientifically established analytical
methods should in vitro or in rodents be undertaken to determine the expected rate of degradation and assist in the selection of
study periods in long-term animal studies. During analysis of study results, the distribution and metabolism of the degradation
products should be determined by available analytical methods, such as massbe used in the identification and quantification of
degradation products (ISO 10993-9, ISO 10993-18, ISO 10993-19, ISO 13781, Test Method F1635spectrometry. Alternatively,,
Animal Welfare Act, 7 U.S.C. § 2131 et seq., as amended. 2013.
Animal Welfare Regulations, 9 CFR Chapter 1, Subchapter A, Parts 1, 2, and 3. 2004.
Health Research Extension Act of 1985, Public Law 99-158 November 20, 1985.
Office of Laboratory Animal Welfare, National Institutes of Health. Public Health Service Policy on Humane Care and Use of Laboratory Animals, Bethesda, MD, 2015.
National Research Council, Guide for the Care and Use of Laboratory Animals: Eighth Edition. Washington, DC, The National Academies Press; 2011.
F1983 − 23
Guide F2902prediction may, Guide F3268be done by radio-labeling the material and following the loss of radioactivity; however,
radioactive specimens shall not be used for biocompatibility testing. Other methods of characterizing the absorption are acceptable.
The target organs of the metabolism and excretion of the products should be identified. It is recommended that acute systemic
studies with material extracts according to Practice). Literature information (if available) on the fate of the absorbable material’s
degradation products can be used to address their absorption, distribution, metabolism, and excretion (ADME) and identify the
potential organs involved. Literature evaluations should focus on all degradation products, including those from major
compositional components as well as any other constituents with known or suspected toxicities, at F750 be completed prior to the
initiation of the implantation study.the amounts present that could impact tissue response.
NOTE 1—A pilot study in vitro or in small animals may be undertaken to assess the rate of degradation which can potentially be used to select estimated
time points for evaluating degradation in large animal studies.
NOTE 2—In some cases where degradation products or metabolites of the candidate material are not known or well established, it may be possible to assess
the quantitation and distribution of degradation products or metabolites using in vivo radio-labeling methods following administration of radio-labeled
parent material for ADME assessments. However, if radio-labeling is used, a justification should be included to explain why radio-labeling is not expected
to impact ADME results.
7. Implant Specimens Test Article and Implant Placement Considerations
7.1 Design of the Implant—Test Article—Specimens may be made from theMay be devices in their final finished form candidate
materialor made from candidate materials in configurations specific for the animal study. Photograph(s) of the implant articles
should be taken prior to implantation. As described in 4.35.3, the material/host ratio should be available and referrable to ultimate
use in the human selected based on clinical use, with material/body mass ratios of 1X, 10X, and 50X, if applicable, recommended.
2X and 10X, if applicable. Relevant configurations of implant specimens,articles, such as cylinders, flat cloth,cloths, amorphous
gels, and polymerizable liquids may be used. used for material screening studies.
7.2 The implantation site of the absorbable device or candidate material shall be described and recorded with anatomic landmarks
and include adequate means to identify the specific implant sites, including during and after advanced stages of degradation. Such
means of site identification may include use of an implanted non-absorbable marker or other permanent method, such as a template.
7.3 The implantation site of the candidate material shall be accompanied by the use of an implanted marker or other permanent
method, such as a template, to mark the implant site to allow identification of the implant site at the various time periods. In
additional animals, control materials shall be implanted by the same techniques, to allow the Control materials shall be implanted
using the same placement techniques as the test material to allow the comparison of the tissue response. When assessing systemic
endpoints, it is essential that separate groups of animals be used for test and comparator groups. A sham surgical site, or a sham
surgical animal, is necessary.Choice of control devices/materials with established biocompatibility and clinical relevance shall
adhere to the following selection priority with appropriate consideration for clinical best practice, availability, and dimensional
suitability for the intended implantation site:
(1) Absorbable device/material with similar expected absorption profile.
(2) Absorbable device/material with different absorption profile or non-absorbable device/material.
NOTE 3—Absorbable device/material controls that possess a different degradation rate than the test implant may require retrieval at additional intervals
to allow assessment of tissue response at an equivalent stage in the control material’s degradation/absorption process. Use of an absorbable device/material
with an absorption profile different from the test implant may not allow a bilateral implantation and additional animals may be used for the implantation
of the control device/material.
(3) Sham sites / sham animals—A sham surgical site (to assess local effects), or a sham surgical animal (to assess local and
systemic effects) may be helpful. If a sham site or sham animal is used, the same implantation procedure without the test or control
should be used.
NOTE 4—Such sites may be used to assess the impact of surgical procedures but may not enable a direct comparison of tissue responses to the ongoing
presence of an implant (absorbable or nonabsorbable).
7.3.1 The material/host (material surface area or mass-to-body mass) ratio of any control material should be comparable to the
material/host ratio used for the test implant as described in 5.3. The selection of the control shall be justified. Guidance regarding
considerations prior to commencing an in vivo study of absorbable materials can be found in the following standards:
(1) Guide F2902—For absorbable polymeric devices, this standard describes the manufacturing, characterization, packaging,
sterilization, and biocompatibility aspects and the related testing that should be considered prior to undertaking in vivo evaluations.
(2) ISO 10993-6—Provides absorbable-specific considerations when evaluating a material’s biological safety through
implantation, which includes guidance for selecting appropriate animal retrieval intervals (see Clause 5 of ISO 10993-6:2016).
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(3) ISO/TS 17137—Provides recommendations on in vitro and in vivo assessments of absorbable (test or control) implants (see
the stages of degradation depicted in Figure 2 and the supporting discussions contained within subclauses 5.1, 5.3, 5.4, and 5.6
in ISO/TS 17137:2021).
(4) ISO/TS 37137-1—Provides supplemental absorbable-specific considerations when biologically evaluating a device in
accordance with the ISO 10993 series.
7.3.2 If assessing systemic endpoints as part of the implantation study, it is essential that separate groups of animals be used for
test and control groups.
7.4 The material used shall be in its final finished form and sterilized as indicated for its ultimate use. It shall be handled for
implantation in a manner analogous to that for intended final use, foruse (for example, special forceps, special cannulas or needles,
special syringes, and so forth.forth).
NOTE 5—If this method is used for material research, testing for endotoxin prior to implantation should be considered.
7.5 The candidate material shall be described thoroughly to facilitate development of a suitable implant application protocol. The
absorption, distribution, metabolism, and excretion ADME of the material and its degradation products should be described. The
information shall include, but is not limited to, the following:
7.5.1 Expected method of degradation, formechanism of degradation (for example, hydrolysis, enzymatic, phagocytosis, and so
forth. forth).
7.5.2 Expected nonabsorbable degradation products, forproducts (for example, fibrils, particles from composites.composites).
7.5.3 Expected stages and rate of degradation.
7.5.4 Expected target organ effects where known or expected, for (for example, eliminated in the kidney, stored in the liver, stored
in the spleen or lymph nodes.nodes).
7.6 For each time period, at least six rodents small laboratory animals shall be used with either single or bilateral implants. For
the larger animals, unilateral or bilateral implants to assess local responses per test and control groups. For larger animals,
including rabbits, at least four animals shall be used per time period. period per test and control group. It is recommended that
additional animals be included in the initial protocol to accommodate any unexpected changesprotocol to address assessment of
systemic responses (for example, per ISO 10993-11) and to accommodate any differences in in vitro and in vivo degradation rates
of the material.
8. Procedure
8.1 Implantation:
8.1.1 Implant the specimen under sterile conditions in anesthetized animals. Where possible, implant the specimentest and control
under aseptic conditions in animals that are under surgical plane of anesthesia. For screening studies with subcutaneous
implantations, place the articles using a trochar method to avoid the need for an incision. If an incision is needed, insert the implant
as far from the incision site as possible. Close the insertion site with a suitable suture material.
7.1.1.1 A sham site or sham animal with the identical implantation procedure, but not the test material, should be included in the
protocol. If animals are to be used as part of a systemic toxicity study, the sham shall be a separate animal.
8.1.2 The implantation site shall be described and recorded with anatomic landmarks and shall be marked in a manner suitable
for identification of the site at the designated time periods. The use of a permanent skin marker and a template marking the
placement of the specimentest and the shamcontrol/sham site i
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