ASTM F981-99
(Practice)Standard Practice for Assessment of Compatibility of Biomaterials for Surgical Implants with Respect to Effect of Materials on Muscle and Bone
Standard Practice for Assessment of Compatibility of Biomaterials for Surgical Implants with Respect to Effect of Materials on Muscle and Bone
SCOPE
1.1 This practice provides a series of experimental protocols for biological assays of tissue reaction to nonabsorbable biomaterials for surgical implants. It assesses the effects of the material on animal tissue in which it is implanted. The experimental protocol is not designed to provide a comprehensive assessment of the systemic toxicity, carcinogenicity, teratogenicity, or mutagenicity of the material. It applies only to materials with projected applications in human subjects where the materials will reside in bone or soft tissue in excess of 30 days and will remain unabsorbed. Applications in other organ systems or tissues may be inappropriate and are therefore excluded. Control materials will consist of any one of the metal alloys in Specifications F67, F75, F90, F136, F138, or F562, high purity dense aluminum oxide as described in Specification F603, ultra high molecular weight polyethylene as stated in Specification F648 or USP polyethylene negative control.
1.2 This document is a combination of Practice F361-80 and Practice F469-78. The purpose, basic procedure, and method of evaluation of each type of material are similar; therefore, they have been combined.
1.3 This standard does not purport to address all of the safety problems, 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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NOTICE: This standard has either been superseded and replaced by a new version or withdrawn. Contact ASTM
International (www.astm.org) for the latest information.
Designation:F981–99
Standard Practice for
Assessment of Compatibility of Biomaterials for Surgical
Implants with Respect to Effect of Materials on Muscle and
Bone
This standard is issued under the fixed designation F 981; 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 Alloy for Surgical Implant Applications
F 86 Practice for Surface Preparation and Marking of Me-
1.1 Thispracticeprovidesaseriesofexperimentalprotocols
tallic Surgical Implants
for biological assays of tissue reaction to nonabsorbable
F 90 Specification for Wrought Cobalt-Chromium-
biomaterials for surgical implants. It assesses the effects of the
Tungsten-Nickel Alloy for Surgical Implant Applications
material on animal tissue in which it is implanted. The
F 136 Specification for Wrought Titanium-6 Aluminum-4
experimental protocol is not designed to provide a comprehen-
Vanadium ELI (Extra Low Interstitial) Alloy (UNS
sive assessment of the systemic toxicity, immune response,
R56401) for Surgical Implant Applications
carcinogenicity, teratogenicity, or mutagenicity of the material
F 138 Specification for Wrought-18 Chromium–14
since other standards deal with these issues. It applies only to
NIckel–2.5 Molybdenum Stainless Steel Bar and Wire for
materials with projected applications in humans where the
Surgical Implants (UNS S31673)
materials will reside in bone or soft tissue in excess of 30 days
F 361 Practice for Assessment of Compatibility of Metallic
and will remain unabsorbed. It is recommended that short-term
Materials for Surgical Implants with Respect to Effect of
assays, according to Practice F 763, first be performed. Appli-
Materials on Tissue
cations in other organ systems or tissues may be inappropriate
F 469 Practice for Assessment of Compatibility of Nonpo-
and are therefore excluded. Control materials will consist of
rous Polymeric Materials for Surgical Implants with Re-
any one of the metal alloys in Specifications F 67, F 75, F 90,
gard to Effect of Materials on Tissue
F 136, F 138, or F 562, high purity dense aluminum oxide as
F 562 Specification for Wrought Cobalt-35 Nickel–20
described in Specification F 603, ultra high molecular weight
Chromium-10 Molybdenum Alloy for Surgical Implant
polyethylene as stated in Specification F 648 or USP polyeth-
Applications
ylene negative control.
F 603 Specification for High-Purity Dense Aluminum Ox-
1.2 This document is a combination of Practice F 361–80
ide for Surgical Implant Application
and Practice F 469 – 78. The purpose, basic procedure, and
F 648 Specification for Ultra-High-Molecular-Weight Poly-
method of evaluation of each type of material are similar;
ethylene Powder and Fabricated Form for Surgical Im-
therefore, they have been combined.
plants
1.3 This standard does not purport to address all of the
F 763 Practice for Short-Term Screening of Implant Mate-
safety concerns, if any, associated with its use. It is the
rials
responsibility of the user of this standard to establish appro-
priate safety and health practices and determine the applica-
3. Summary of Practice
bility of regulatory limitations prior to use.
3.1 This practice describes the preparation of implants, the
2. Referenced Documents number of implants and test hosts, test sites, exposure sched-
ule, implant sterilization techniques, and methods of implant
2.1 ASTM Standards:
retrieval and tissue examination of each test site. Histological
F 67 Specification for Unalloyed Titanium for Surgical
criteria for evaluating tissue reaction are provided.
Implant Applications
F 75 SpecificationforCastCobalt-Chromium-Molybdenum
4. Significance and Use
4.1 This practice covers a test protocol for comparing the
local tissue response evoked by biomaterials, from which
This practice is under the jurisdiction ofASTM Committee F-4 on Medical and
Surgical Materials and Devices and is the direct responsibility of Subcommittee
F04.16 on Biocompatibility.
Current edition approved May 10, 1999. Published August 1999. Originally
published as F 981 – 86. Last previous edition F 981 – 93. Discontinued—See 1986 Annual Book of ASTM STandards, Vol 13.01.
2 4
Annual Book of ASTM Standards, Vol 13.01. Discontinued—See 1987 Annual Book of ASTM STandards, Vol 13.01.
Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959, United States.
NOTICE: This standard has either been superseded and replaced by a new version or withdrawn. Contact ASTM
International (www.astm.org) for the latest information.
F981–99
medical implantable devices might ultimately be fabricated, 6.3.3 Depending upon the particular device application,
with the local tissue response elicited by control materials other sample shapes may be used. For instance, an investigator
currently accepted for the fabrication of surgical devices. The might wish to test the biocompatibility of a new material for
materials may include metals (and metal alloys), dense alumi- screws in the form of a screw. If an alternative specimen shape
num oxide, and polyethylene that are standardized on the basis is used, this should be reported in accordance with 8.1.
ofacceptablelong-termwell-characterizedlong-termresponse. 6.4 Sizes and Shapes of Implants for Insertion in Bone:
The controls consistently produce cellular reaction and wound 6.4.1 Implant diameters for use in bone shall be approxi-
healing to a degree that has been found to be acceptable to the mately equal to the cortex thickness. Implant lengths shall
host. allow them to reside in one cortex and the medulla without
excessive protrusion beyond the periosteum.
5. Test Hosts and Sites
6.4.2 The dimensions used shall be reported in accordance
5.1 Rats (acceptable strains such as Fischer 344), New
with 8.1.
ZealandWhite rabbits, and other small laboratory animals may
6.5 Number of Test and Control Implants:
be used as test hosts for soft tissue implant response. It is
6.5.1 Ineachrat,duetosize,theremaybetwoimplants;one
suggested that the rats be age and sex matched. Rabbits or
each test and control material implant.
larger animals may be used as test hosts for bone implants. 6.5.2 In each rabbit, due to size, there may be six implants;
When larger animals such as dogs, goats, or sheep are used, the
four test materials and two control material implants.
decision should be based upon special considerations of the 6.5.3 In larger animals, there may be twelve implants; eight
particular implant material or study.
test materials and four control material implants.
5.2 The sacro-spinalis, paralumbar, gluteal muscles, and the 6.5.4 In rabbits or larger animals, there shall be tested at
femur or tibia can serve as the test site for implants. However,
least sixteen test material implants and eight control material
the same site must be used for test and material implants in all implants at each time period.
the animal species.
6.6 Conditioning:
5.3 There shall be a minimum of four animals at each
6.6.1 Remove all surface contaminants with appropriate
sacrifice interval for a total of twelve animals per study. If
solventsandrinsealltestandcontrolimplantsindistilledwater
larger animals are used, in which a greater number of implants
prior to sterilization. It is recommended that the implant
can be placed, there shall be at least two animals sacrificed at
materials be processed and cleaned in the same way the final
each time period.
product will be.
6.6.2 Clean, package, and sterilize all implants in the same
6. Implant Specimens
way as used for human implantation.
6.1 Fabrication— Each implant shall be made in a cylin-
6.6.3 Afterfinalpreparationandsterilization,handlethetest
drical shape with hemispherical ends (see 6.3 and 6.4 for
and control implants with great care to ensure that they are not
sizes). If the ends are not hemispherical, this shall be reported.
scratched, damaged, or contaminated in any way prior to
Each implant shall be fabricated, finished, and its surface
insertion.
cleaned in a manner appropriate for its projected application in
6.6.4 Report all details of conditioning in accordance with
human subjects in accordance with Practice F86.Ifthe
8.1.
specimens are porous, the method of preparation of the porous
6.7 Implantation Period—Insert all implants into each ani-
specimens shall be representative of the contemplated human
mal at the same surgical session for implantation periods of 12,
implant application and shall yield a specimen with character-
26, and 52 weeks.
isticporesize,porevolume,andporeinterconnectiondiameter.
7. Procedure
The choice between using solid core specimens with porous
coatings and specimens that are porous throughout shall be a 7.1 Implantation (Muscle):
decision of the investigator and shall be reported. 7.1.1 Placematerialimplantsintheparavertebralmusclesin
6.2 Reference metallic specimens shall be fabricated in such a manner that they are directly in contact with muscle
accordance with 6.1 from materials such as the metal alloys in tissue.
Specifications F 67, F 75, F 90, F 138, or F 562, ceramic in 7.1.2 Introduce material implants in larger animals by the
Specification F 603, or polymers such as in Specification F 648 technique of making an implantation site in the muscle by
polyethylene or USP Negative Control Plastic. If the test using a hemostat to separate the muscle fibers. Then insert the
materials are porous, consideration should be given to using implant using plastic-tipped forceps or any tool that is non-
porous specimens for reference specimens. Alternatively, non- abrasive to avoid damage to the implant.
porous reference specimens may be used. 7.1.3 Introduce material implants using sterile technique.
6.3 Suggested Sizes and Shapes of Implants for Insertion in Sterile disposable needles or hypodermic tubing and trochar
Muscle: may be used to implant the material implants into the paraver-
6.3.1 The implants shall be cylindrical in shape and may tebral muscles along the spine. In rats insert a negative control
range from 1 mm to 6 mm in diameter and from 10 mm to 20 implant on one side of the spine and a test material implant on
mm in length depending upon the relative size of the species the other side. In rabbits implant one negative control material
under study. oneachsideofthespineandimplanttwotestmaterialsoneach
6.3.2 The dimensions used shall be reported in accordance side of the spine. If larger diameter specimens are used, an
with 8.1. alternative implantation technique is that described in 7.1.2.
NOTICE: This standard has either been superseded and replaced by a new version or withdrawn. Contact ASTM
International (www.astm.org) for the latest information.
F981–99
7.2 Implantation (Femur)—Expose the lateral cortex of both, the orientational details noted in 7.6.1 to each part of the
each rabbit femur and drill undersized pilot holes through the sample. Record the gross appearance of the implant and the
lateral cortex using the technique and instrument appropriate tissue. If the sample is porous, it is imperative that sectioning
for the procedure. Final reaming of the holes should be procedures be used that maintain the implant within its tissue
performed by hand to yield holes which are smaller than the envelope to allow the evaluation of tissue within the pores.
implant specimens by 0.1 mm or less. Into each one of these Such procedures may include ground section preparation.
holes, insert one of the implants by finger pressure. Then close 7.6.1.2 If special stains are deemed necessary, prepare
the wound. additional sections and make appropriate observations.
7.7 Histopathological Observations—Compare the amount
NOTE 1—Caution should be taken to minimize the motion of the
of tissue reaction adjacent to the test implant to that adjacent to
implant in the tissue to prevent the effects of motion on the desired result.
a similar location and orientation on the control implant with
7.3 Postoperative Care:
respect to thickness of scar, presence of inflammatory or other
7.3.1 All animal studies must be done in a facility approved
cell types, presence of particles, and such other indications of
by a nationally recognized organization and in accordance with
interactionoftissueandmaterialasmightoccurwiththeactual
all appropriate regulations.
material under test. A suggested method for the evaluation of
7.3.2 Carefully observe each animal during the period of 5
tissue response after implantation is Turner, et al. (1).Ifa
assay and report any abnormal findings.
porous sample is being tested, the evaluation of the tissue
7.3.3 Infection or injury of the test implant site may
reaction must include areas within the pores of the test and
invalidatetheresults.Thedecisiontoreplacetheanimalsothat
control samples at similar locations.
the total number of retrieved implants will be as represented in
7.7.1 Suggested Method for Tissue Response Evaluation:
the schedule shall be dependent upon the design of the study.
7.7.1.1 A suggested format with tissue response and cell
7.3.4 Ifananimaldiespriortotheexpecteddateofsacrifice,
accumulation to be evaluated and a scoring range of 0 to 3 is
perform a necropsy in accordance with the procedure in 7.4 to
shown in Table 1.
determine the cause of death. Replacement of the animal to the
7.7.1.2 The scoring system of 0 to 3 is based upon the
study shall be dependent upon the design of the study. Include
observationofhighpowerfields(400–500X)andanaverageof
the animal in the assay of data if the cause of death is related
five fields.
to the procedure or test material.
Tissue Response/Cell Score
7.4 Sacrifice and Implant Retrieval:
Accumulation
7.4.1 Euthanize animals by a humane method at the inter-
1–5 0.5
vals specified in 6.7.
6–15 1
16–25 2
NOTE 2—The necropsy periods start at 12 weeks because it is assumed
26 or more 3
that acceptable implant data has been received for earlier periods from
short term implant testing according to Practice F 763. If the 90–day
7.7.1.3 The necrosis and/or degeneration score is deter-
sacrificeperiodhasbeenutilizedunderPracticeF 763,thatgroupneednot
mined using the same range of 0 to 3, as follows:
be repeated under this protocol, and thus, the 12-week group may be
eliminated.
7.4.2 At necropsy, record any gross abnormalities of color
or consistency observed in the tissue surrounding the implant.
The boldface numbers in parentheses refer to the list of references at the end
Remove each implant with an intact envelope of surrounding
of this standard.
...
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