ASTM F981-04(2010)
(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
SIGNIFICANCE AND USE
This practice covers a test protocol for comparing the local tissue response evoked by biomaterials, from which medical implantable devices might ultimately be fabricated, with the local tissue response elicited by control materials currently accepted for the fabrication of surgical devices. The materials may include metals (and metal alloys), dense aluminum oxide, and polyethylene that are standardized on the basis of acceptable long-term well-characterized long-term response. The controls consistently produce cellular reaction and wound healing to a degree that has been found to be acceptable to the host.
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, immune response, carcinogenicity, teratogenicity, or mutagenicity of the material since other standards deal with these issues. It applies only to materials with projected applications in humans where the materials will reside in bone or soft tissue in excess of 30 days and will remain unabsorbed. It is recommended that short-term assays, according to Practice F763, first be performed. 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 practice is a combination of Practice and Practice . The purpose, basic procedure, and method of evaluation of each type of material are similar; therefore, they have been combined.
1.3 The values stated in SI units are to be regarded as standard. No other units of measurement are included in this standard.
1.4 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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Standards Content (Sample)
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Designation: F981 − 04(Reapproved 2010)
Standard Practice for
Assessment of Compatibility of Biomaterials for Surgical
Implants with Respect to Effect of Materials on Muscle and
Bone
ThisstandardisissuedunderthefixeddesignationF981;thenumberimmediatelyfollowingthedesignationindicatestheyearoforiginal
adoption or, in the case of revision, the year of last revision.Anumber in parentheses indicates the year of last reapproval.Asuperscript
epsilon (´) indicates an editorial change since the last revision or reapproval.
1. Scope 2. Referenced Documents
2.1 ASTM Standards:
1.1 Thispracticeprovidesaseriesofexperimentalprotocols
F67 Specification for Unalloyed Titanium, for Surgical Im-
for biological assays of tissue reaction to nonabsorbable
plant Applications (UNS R50250, UNS R50400, UNS
biomaterials for surgical implants. It assesses the effects of the
R50550, UNS R50700)
material on animal tissue in which it is implanted. The
F75 Specification for Cobalt-28 Chromium-6 Molybdenum
experimental protocol is not designed to provide a comprehen-
Alloy Castings and Casting Alloy for Surgical Implants
sive assessment of the systemic toxicity, immune response,
(UNS R30075)
carcinogenicity, teratogenicity, or mutagenicity of the material
F86 Practice for Surface Preparation and Marking of Metal-
since other standards deal with these issues. It applies only to
lic Surgical Implants
materials with projected applications in humans where the
F90 Specification for Wrought Cobalt-20Chromium-
materials will reside in bone or soft tissue in excess of 30 days
15Tungsten-10NickelAlloy for Surgical ImplantApplica-
and will remain unabsorbed. It is recommended that short-term
tions (UNS R30605)
assays, according to Practice F763, first be performed. Appli-
F136 Specification for Wrought Titanium-6Aluminum-
cations in other organ systems or tissues may be inappropriate
4Vanadium ELI (Extra Low Interstitial)Alloy for Surgical
and are therefore excluded. Control materials will consist of
Implant Applications (UNS R56401)
any one of the metal alloys in Specifications F67, F75, F90,
F138 Specification for Wrought 18Chromium-14Nickel-
F136, F138,or F562, high purity dense aluminum oxide as
2.5Molybdenum Stainless Steel Bar and Wire for Surgical
described in Specification F603, ultra high molecular weight
Implants (UNS S31673)
polyethylene as stated in Specification F648 or USP polyeth-
F361 Practice for Assessment of Compatibility of Metallic
ylene negative control.
Materials for Surgical Implants with Respect to Effect of
1.2 This practice is a combination of Practice F361 and
Materials on Tissue (Withdrawn 1987)
Practice F469. The purpose, basic procedure, and method of
F469 Practice for Assessment of Compatibility of Nonpo-
evaluation of each type of material are similar; therefore, they
rous Polymeric Materials for Surgical Implants with
have been combined.
Regard to Effect of Materials on Tissue (Withdrawn
1986)
1.3 The values stated in SI units are to be regarded as
F562 Specification for Wrought 35Cobalt-35Nickel-
standard. No other units of measurement are included in this
20Chromium-10Molybdenum Alloy for Surgical Implant
standard.
Applications (UNS R30035)
1.4 This standard does not purport to address all of the
F603 Specification for High-Purity Dense Aluminum Oxide
safety concerns, if any, associated with its use. It is the
for Medical Application
responsibility of the user of this standard to establish appro-
F648 Specification for Ultra-High-Molecular-Weight Poly-
priate safety and health practices and determine the applica-
ethylene Powder and Fabricated Form for Surgical Im-
bility of regulatory limitations prior to use.
plants
1 2
ThispracticeisunderthejurisdictionofASTMCommitteeF04onMedicaland 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 June 1, 2010. Published September 2010. Originally the ASTM website.
approved in 1986. Last previous edition approved in 2004 as F981 – 04. DOI: The last approved version of this historical standard is referenced on
10.1520/F0981-04R10. www.astm.org.
Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States
F981 − 04 (2010)
F763 Practice for Short-Term Screening of Implant Materi- Specifications F67, F75, F90, F138,or F562, ceramic in
als Specification F603, or polymers such as in Specification F648
polyethylene or USP Negative Control Plastic. If the test
3. Summary of Practice
materials are porous, consideration should be given to using
3.1 This practice describes the preparation of implants, the porous specimens for reference specimens. Alternatively, non-
number of implants and test hosts, test sites, exposure
porous reference specimens may be used.
schedule, implant sterilization techniques, and methods of
6.3 Suggested Sizes and Shapes of Implants for Insertion in
implant retrieval and tissue examination of each test site.
Muscle:
Histologicalcriteriaforevaluatingtissuereactionareprovided.
6.3.1 The implants shall be cylindrical in shape and may
range from 1 mm to 6 mm in diameter and from 10 mm to 20
4. Significance and Use
mm in length depending upon the relative size of the species
4.1 This practice covers a test protocol for comparing the
under study.
local tissue response evoked by biomaterials, from which
6.3.2 The dimensions used shall be reported in accordance
medical implantable devices might ultimately be fabricated,
with 8.1.
with the local tissue response elicited by control materials
6.3.3 Depending upon the particular device application,
currently accepted for the fabrication of surgical devices. The
other sample shapes may be used. For instance, an investigator
materials may include metals (and metal alloys), dense alumi-
might wish to test the biocompatibility of a new material for
num oxide, and polyethylene that are standardized on the basis
screws in the form of a screw. If an alternative specimen shape
ofacceptablelong-termwell-characterizedlong-termresponse.
is used, this should be reported in accordance with 8.1.
The controls consistently produce cellular reaction and wound
6.4 Sizes and Shapes of Implants for Insertion in Bone:
healing to a degree that has been found to be acceptable to the
host. 6.4.1 Implant diameters for use in bone shall be approxi-
mately equal to the cortex thickness. Implant lengths shall
5. Test Hosts and Sites
allow them to reside in one cortex and the medulla without
5.1 Rats (acceptable strains such as Fischer 344), New
excessive protrusion beyond the periosteum.
ZealandWhite rabbits, and other small laboratory animals may 6.4.2 The dimensions used shall be reported in accordance
be used as test hosts for soft tissue implant response. It is
with 8.1.
suggested that the rats be age and sex matched. Rabbits or
6.5 Number of Test and Control Implants:
larger animals may be used as test hosts for bone implants.
6.5.1 Ineachrat,duetosize,theremaybetwoimplants;one
Whenlargeranimalssuchasdogs,goats,orsheepareused,the
each test and control material implant.
decision should be based upon special considerations of the
6.5.2 In each rabbit, due to size, there may be six implants;
particular implant material or study.
four test materials and two control material implants.
5.2 The sacro-spinalis, paralumbar, gluteal muscles, and the
6.5.3 In larger animals, there may be twelve implants; eight
femur or tibia can serve as the test site for implants. However,
test materials and four control material implants.
the same site must be used for test and material implants in all
6.5.4 In rabbits or larger animals, there shall be tested at
the animal species.
least sixteen test material implants and eight control material
implants at each time period.
5.3 There shall be a minimum of four animals at each
sacrifice interval for a total of twelve animals per study. If
6.6 Conditioning:
larger animals are used, in which a greater number of implants
6.6.1 Remove all surface contaminants with appropriate
can be placed, there shall be at least two animals sacrificed at
solventsandrinsealltestandcontrolimplantsindistilledwater
each time period.
prior to sterilization. It is recommended that the implant
materials be processed and cleaned in the same way the final
6. Implant Specimens
product will be.
6.1 Fabrication—Each implant shall be made in a cylindri-
6.6.2 Clean, package, and sterilize all implants in the same
cal shape with hemispherical ends (see 6.3 and 6.4 for sizes).
way as used for human implantation.
If the ends are not hemispherical, this shall be reported. Each
6.6.3 Afterfinalpreparationandsterilization,handlethetest
implant shall be fabricated, finished, and its surface cleaned in
and control implants with great care to ensure that they are not
a manner appropriate for its projected application in human
scratched, damaged, or contaminated in any way prior to
subjects in accordance with Practice F86. If the specimens are
insertion.
porous, the method of preparation of the porous specimens
6.6.4 Report all details of conditioning in accordance with
shall be representative of the contemplated human implant
8.1.
application and shall yield a specimen with characteristic pore
6.7 Implantation Period—Insert all implants into each ani-
size, pore volume, and pore interconnection diameter. The
mal at the same surgical session for implantation periods of 12,
choice between using solid core specimens with porous coat-
26, and 52 weeks.
ings and specimens that are porous throughout shall be a
decision of the investigator and shall be reported.
7. Procedure
6.2 Reference metallic specimens shall be fabricated in
accordance with 6.1 from materials such as the metal alloys in 7.1 Implantation (Muscle):
F981 − 04 (2010)
7.1.1 Placematerialimplantsintheparavertebralmusclesin layer of tissue surrounding the implant. If less than a 4-mm
such a manner that they are directly in contact with muscle thick layer of tissue is removed, report in accordance with 8.1.
tissue.
7.5 Postmortem Observations—In accordance with standard
7.1.2 Introduce material implants in larger animals by the
laboratory practice, perform a necropsy on all animals that are
technique of making an implantation site in the muscle by
sacrificed for the purposes of the assay or die during the assay
using a hemostat to separate the muscle fibers. Then insert the
period. Establish the status of the health of the experimental
implant using plastic-tipped forceps or any tool that is non-
animal during the period of the assay. Report as described in
abrasive to avoid damage to the implant.
Section 8.
7.1.3 Introduce material implants using sterile technique.
7.6 Histological Procedure:
Sterile disposable needles or hypodermic tubing and trochar
7.6.1 Tissue Sample Preparation—Prepare appropriate
may be used to implant the material implants into the paraver-
blocks from each implantation site and indicate the orientation
tebral muscles along the spine. In rats, insert a negative control
of the axis of the femur relative to the axis of the implant (for
implant on one side of the spine and a test material implant on
bone implants). Also indicate the orientation of the implant
the other side. In rabbits, implant one negative control material
relative to the axis of rotation of the femoral condyles.
oneachsideofthespineandimplanttwotestmaterialsoneach
7.6.1.1 Process the excised tissue block containing either a
side of the spine. If larger diameter specimens are used, an
test implant or control implant for histopathological examina-
alternative implantation technique is that described in 7.1.2.
tion and such other studies as are appropriate. Cut the sample
7.2 Implantation (Femur)—Expose the lateral cortex of
midway from end to end into appropriate size and in the
each rabbit femur and drill undersized pilot holes through the
appropriate orientation for each study. Transfer, or record, or
lateral cortex using the technique and instrument appropriate
both, the orientational details noted in 7.6.1 to each part of the
for the procedure. Final reaming of the holes should be
sample. Record the gross appearance of the implant and the
performed by hand to yield holes which are smaller than the
tissue. If the sample is porous, it is imperative that sectioning
implant specimens by 0.1 mm or less. Into each one of these
procedures be used that maintain the implant within its tissue
holes, insert one of the implants by finger pressure. Then close
envelope to allow the evaluation of tissue within the pores.
the wound.
Such procedures may include ground section preparation.
7.6.1.2 If special stains are deemed necessary, prepare
NOTE 1—Caution should be taken to minimize the motion of the
additional sections and make appropriate observations.
implant in the tissue to prevent the effects of motion on the desired result.
7.7 Histopathological Observations—Compare the amount
7.3 Postoperative Care:
of tissue reaction adjacent to the test implant to that adjacent to
7.3.1 All animal studies must be done in a facility approved
a similar location and orientation on the control implant with
byanationallyrecognizedorganizationandinaccordancewith
respect to thickness of scar, presence of inflammatory or other
all appropriate regulations.
cell types, presence of particles, and such other indications of
7.3.2 Carefully observe each animal during the period of
interactionoftissueandmaterialasmightoccurwiththeactual
assay and report any abnormal findings.
material under test. A suggested method for the evaluation of
7.3.3 Infection or injury of the test implant site may
tissue response after implantation is Turner, et al. (1).Ifa
invalidatetheresults.Thedecisiontoreplacetheanimalsothat
porous sample is being tested, the evaluation of the tissue
the total number of retrieved implants will be as represented in
reaction must include areas within the pores of the test and
the schedule shall be dependent upon the design of the study.
control samples at similar locations.
7.3.4 Ifananimaldiespriortotheexpecteddateofsacrifice,
7.7.1 Suggested Method for Tissue Response Evaluation:
perform a necropsy in accordance with the procedure in 7.4 to
7.7.1.1 A suggested format with tissue response and cell
determine the cause of death. Replacement of the animal to the
accumulation to be evaluated and a scoring range of 0 to 3 is
study shall be dependent upon the design of the study. Include
shown in Table 1.
the
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