ASTM F2451-05(2010)
(Guide)Standard Guide for in vivo Assessment of Implantable Devices Intended to Repair or Regenerate Articular Cartilage (Withdrawn 2019)
Standard Guide for <i>in vivo</i> Assessment of Implantable Devices Intended to Repair or Regenerate Articular Cartilage (Withdrawn 2019)
SIGNIFICANCE AND USE
This guide is aimed at providing a range of in vivo models to aid in preclinical research and development of tissue engineered medical products intended for the clinical repair or regeneration of articular cartilage.
This guide includes a description of the animal models, surgical considerations, and tissue processing as well as the qualitative and quantitative analysis of tissue specimens.
The user is encouraged to utilize appropriate ASTM and other guidelines to conduct cytotoxicity and biocompatibility tests on materials or devices, or both, prior to assessment of the in vivo models described herein.
It is recommended that safety testing be in accordance with the provisions of the FDA Good Laboratory Practices Regulations 21 CFR 58.
Safety and Effectiveness studies to support IDE (Investigational Device Exemption), PMA (Premarket Approval), or 510K submissions should conform to appropriate FDA guidelines for development of medical devices.
Animal model outcomes are not necessarily predictive of human results and should, therefore, be interpreted cautiously with respect to potential applicability to human conditions.
SCOPE
1.1 This guide covers general guidelines for the in vivo assessment of implantable devices intended to repair or regenerate articular cartilage. Devices included in this guide may be composed of natural or synthetic biomaterials (biocompatible and biodegradable) or composites thereof and may contain cells or biologically active agents such as growth factors, synthetic peptides, plasmids, or cDNA.
1.2 Guidelines include a description and rationale of various animal models utilizing a range of species such as rabbit (lupine), dog (canine), pig (porcine), goat (caprine), sheep (ovine), and horse (equine). Outcome measures based on histologic, biochemical, and mechanical analyses are briefly described and referenced. The user should refer to specific test methods for additional detail.
1.3 This guide is not intended to include the testing of raw materials, preparation of biomaterials, sterilization, or packaging of product. ASTM standards for these steps are available in Reference Documents.
1.4 The values stated in SI units are to be regarded as standard. No other units of measurement are included in this standard.
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 requirements prior to use.
WITHDRAWN RATIONALE
This guide covered general guidelines for the in vivo assessment of implantable devices intended to repair or regenerate articular cartilage.
Formerly under the jurisdiction of Committee F04 on Medical and Surgical Materials and Devices, this guide was withdrawn in January 2019 in accordance with section 10.6.3 of the Regulations Governing ASTM Technical Committees, which requires that standards shall be updated by the end of the eighth year since the last approval date.
General Information
Relations
Standards Content (Sample)
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: F2451 − 05 (Reapproved 2010)
Standard Guide for
in vivo Assessment of Implantable Devices Intended to
Repair or Regenerate Articular Cartilage
This standard is issued under the fixed designation F2451; 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 Devices, and Associated Tissues and Fluids
F565 PracticeforCareandHandlingofOrthopedicImplants
1.1 This guide covers general guidelines for the in vivo
and Instruments
assessment of implantable devices intended to repair or regen-
F895 TestMethodforAgarDiffusionCellCultureScreening
erate articular cartilage. Devices included in this guide may be
for Cytotoxicity
composed of natural or synthetic biomaterials (biocompatible
F981 Practice for Assessment of Compatibility of Biomate-
and biodegradable) or composites thereof and may contain
rials for Surgical Implants with Respect to Effect of
cells or biologically active agents such as growth factors,
Materials on Muscle and Bone
synthetic peptides, plasmids, or cDNA.
F1983 Practice for Assessment of Compatibility of
1.2 Guidelinesincludeadescriptionandrationaleofvarious
Absorbable/Resorbable Biomaterials for ImplantApplica-
animal models utilizing a range of species such as rabbit
tions
(lupine), dog (canine), pig (porcine), goat (caprine), sheep
F2150 Guide for Characterization and Testing of Biomate-
(ovine), and horse (equine). Outcome measures based on
rial Scaffolds Used in Tissue-Engineered Medical Prod-
histologic, biochemical, and mechanical analyses are briefly
ucts
described and referenced. The user should refer to specific test
2.2 Other Documents:
methods for additional detail.
ISO-10993 Biological Evaluation of Medical Devices—Part
1.3 This guide is not intended to include the testing of raw
5: Tests for in vitro Cytotoxicity
materials, preparation of biomaterials, sterilization, or packag-
21 CFR Part 58 Good Laboratory Practice for Nonclinical
ing of product.ASTM standards for these steps are available in
Laboratory Studies
Reference Documents.
3. Terminology
1.4 The values stated in SI units are to be regarded as
standard. No other units of measurement are included in this 3.1 Definitions:
standard. 3.1.1 cartilage regeneration—the formation of articular-like
cartilage that has histologic, biochemical, and mechanical
1.5 This standard does not purport to address all of the
properties similar to that of native articular cartilage (1, 2).
safety concerns, if any, associated with its use. It is the
responsibility of the user of this standard to establish appro- 3.1.2 cartilage repair—the process of healing injured carti-
priate safety and health practices and determine the applica- lage or its replacement through cell proliferation and synthesis
bility of regulatory requirements prior to use. of new extracellular matrix (1, 2).
3.1.3 compact bone—classification of ossified boney con-
2. Referenced Documents
nective tissue characterized by the presence of osteons con-
2.1 ASTM Standards: taining lamellar bone.
F561 Practice for Retrieval and Analysis of Medical
3.1.4 femoral condyles—the anatomic site corresponding to
the distal end of the femur characterized by medial and lateral
convex surfaces that are lined by cartilage and articulate with
This guide is under the jurisdiction of ASTM Committee F04 on Medical and
the proximal tibia and medial and lateral menisci.
Surgical Materials and Devices and is the direct responsibility of Subcommittee
F04.44 on Assessment for TEMPs.
Current edition approved Sept. 1, 2010. Published November 2010. Originally
approved in 2005. Last previous edition approved in 2005 as F2451 – 05. DOI: Available fromAmerican National Standards Institute (ANSI), 25 W. 43rd St.,
10.1520/F2451-05R10. 4th Floor, New York, NY 10036.
2 4
For referenced ASTM standards, visit the ASTM website, www.astm.org, or AvailablefromU.S.GovernmentPrintingOfficeSuperintendentofDocuments,
contact ASTM Customer Service at service@astm.org. For Annual Book of ASTM 732 N. Capitol St., NW, Mail Stop: SDE, Washington, DC 20401.
Standards volume information, refer to the standard’s Document Summary page on The boldface numbers in parentheses refer to the list of references at the end of
the ASTM website. this standard.
Copyright ©ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA19428-2959. United States
F2451 − 05 (2010)
3.1.5 fibrocartilage—disorganized cartilagenous tissue hav- 4. Significance and Use
ing an abnormally high content of type I collagen.
4.1 This guide is aimed at providing a range of in vivo
3.1.6 growth plate—the anatomic location within the
models to aid in preclinical research and development of tissue
epiphyseal region of long bones corresponding to the site of
engineered medical products intended for the clinical repair or
growth of bone through endochondral bone formation. The
regeneration of articular cartilage.
growth plate in skeletally mature animals is fused.
4.2 This guide includes a description of the animal models,
3.1.7 hyaline articular cartilage—cartilagenous connective
surgical considerations, and tissue processing as well as the
tissue located in diarthrodial joints and characterized by its
qualitative and quantitative analysis of tissue specimens.
localization to articulating surfaces.
4.3 The user is encouraged to utilize appropriateASTM and
3.1.8 marrow—also called myeloid tissue; soft, gelatinous
other guidelines to conduct cytotoxicity and biocompatibility
tissue that fills the cavities of the bones. It is either red or
testsonmaterialsordevices,orboth,priortoassessmentofthe
yellow, depending upon the preponderance of vascular (red) or
in vivo models described herein.
fatty (yellow) tissue.
4.4 It is recommended that safety testing be in accordance
3.1.9 matrix—a term applied to either the exogenous im-
with the provisions of the FDA Good Laboratory Practices
planted scaffold or the endogenous extracelluar substance
Regulations 21 CFR 58.
(otherwise known as extracellular matrix) derived from the
4.5 Safety and Effectiveness studies to support IDE (Inves-
host.
tigational Device Exemption), PMA (Premarket Approval), or
3.1.10 patella—the bone of the knee joint which articulates
510K submissions should conform to appropriate FDA guide-
within the trochlear groove of the femur.
lines for development of medical devices.
3.1.11 residence time—the time at which an implanted
4.6 Animal model outcomes are not necessarily predictive
material (synthetic or natural) can no longer be detected in the
of human results and should, therefore, be interpreted cau-
host tissue.
tiously with respect to potential applicability to human condi-
3.1.12 skeletal maturity—the age at which the epiphyseal
tions.
plates are fused.
3.1.13 subchondral plate—the margin of compact bone in
5. Animal Models
direct apposition to the articular cartilage.
NOTE 1—This section provides a description of the options to consider
in determining the appropriate animal model and cartilage defect size and
3.1.14 synovial fluid—the fluid secreted by synovium pro-
location.
viding lubrication and nutrition to the joint surfaces.
5.1 Joint Size and Load:
3.1.15 synovium—the epithelial lining of synovial joint
5.1.1 A high proportion of hyaline cartilage injuries in
cavities that produce synovial fluid.
humans occur in the knee joint predominantly in the medial
3.1.16 tidemark—the anatomic site in articular cartilage
compartment (that is, medial femoral condyle and tibial pla-
corresponding to the margin between cartilage and the under-
teau). Accordingly, the knee joint is commonly used for
lying calcified cartilage.
assessing cartilage repair/regeneration in animal models.
3.1.17 trabecular bone—classification of ossified boney
5.1.2 The knee is a complex diarthrodial joint involving
connective tissue characterized by spicules surrounded by
primarily two separate articulations; femoropatellar and femo-
marrow space.
rotibial.The articular surfaces of the distal femur and proximal
3.1.18 trochlear groove—the anatomic site on the distal end tibia are incongruent and contain wedge shaped fibrocartilag-
of the femur corresponding to the region of articulation with enous menisci separating the articular surfaces. Contact be-
the patella. tween the cartilage of the femoral condyles and that of the
TABLE 1 Animal Models for the Assessment of Cartilage Repair
Critical
Cartilage Thickness
Breed Age of Weight at Defect Sites Size Defect
Species at Femoral
Commonly Used Adult Eqivalancy Adult Equivalancy Commonly Used (Diameter
Condyle (mm)
in mm)
A
Rabbit (Lupus or New Zealand White 9 months 3–4 kg FC, TG, TP, P 0.25–0.75 3
Lupine)
B
Dog (Canine) Mongrel, Beagle >1–2 years 15–30 kg FC, TG, P 1.3 —
B
Pig (Porcine) Minipig 10 months– 20–40 kg FC, TG — —
1 year
B
Goat (Caprine) Spanish, Dairy, Boer 2–3 years 40–70 kg FC, TG, TP, P 1.5–2 —
Cross
B
Sheep (Ovine) Suffolk or Texel 2–3 years 35–80 kg FC, TG 1.7 7
B
Horse (Equine) Mixed, 2–4 years 400–500 kg FC, TG, RC 2–3 9
Thoroughbred,
Quarter Horse
A
small animal.
B
large animal; FC, femoral condyle; TG, trochlear groove; TP, tibial plateau; P, Patella; RC, radial carpal.
F2451 − 05 (2010)
tibial plateau occurs at the innermost central region of each 5.2.1 Exposure of implants to extreme and highly variable
medial and lateral meniscus. Mechanical load is distributed mechanical forces as a result of jumping, running,
directlyfromthefemurtothetibiaaswellasindirectlythrough hyperextension, or hyperflexion of the joint can lead to
the menisci. The patella articulates with the femoral condyle increased variability in outcome measures.
within the trochlear groove.
5.2.2 Care should be used to reduce stress or other factors
that cause behaviors associated with rapid or extreme, or both,
5.1.3 Significant variability exists between animal species
movements of joints.
withrespecttotheweightoftheanimal,jointanatomy,andgait
thereby influencing joint kinetics, range of motion, and me-
5.3 Gender:
chanical forces on joint surfaces. These factors influence the
5.3.1 Due to the impact of circulating steroids on cartilage
thicknessanddistributionofarticularcartilagewithinthejoints
and bone metabolism and regeneration, the choice of gender
as well as macromolecular content, distribution, and collagen
should be considered.Animals in lactation should not be used.
architecture. These factors play a significant role in the
5.3.2 It is recommended that the gender be the same within
responsetoinjuryordiseaseofarticularcartilage(seeTable1).
the cohort.
The user should consider carefully the animal model that is
5.4 Age:
appropriate for the stage of investigation of an implanted
device (3).
5.4.1 Bone and cartilage undergo dynamic changes in me-
tabolism and remodeling during growth. Due to the impact of
5.1.4 Mechanical load has been shown to affect cartilage
these physiologic processes on tissue repair, the age of a
repair.Amongstthemechanobiologicalfactors,theintermittent
particular species should be chosen to exceed the age of
hydrostatic pressure and shear stresses play an important role
skeletal maturity. The cohorts should have fused epiphyseal
in modulating cartilage development, and maintenance as well
growth plates. Skeletal maturity varies between species and
as cartilage degeneration (4, 5).The impact of mechanical load
can be generally determined radiographically if necessary.
extent or duration on the implanted device, surrounding native
5.4.2 Older animals have a higher propensity for osteopenia
articular cartilage, and underlying bone varies depending on
the anatomic site and the position of the joint (6). The defect and degenerative joint diseases such as osteoarthritis, and have
a decreased capacity to repair articular cartilage defects. If
site chosen to evaluate implants should, therefore, factor the
impact of mechanical load on the performance of the implant. specific conditions are considered important for the intended
device assessment, then an appropriate model should be used.
5.1.5 It is suggested that the gait and stance of a particular
5.4.3 The mesenchymal stem cell pool, growth factor
species be considered when factoring the extent of exposure of
responsiveness, and metabolic activity of cells generally de-
the implant site to stress during standing and motion.
creases with age (7). Thus, reparative processes that are
5.1.6 The extent of compressive and shear forces in the
dependent on the number and activity of native cells may be
femoral condyles, trochlear groove, and tibial plateau differ
partially compromised in older animals.
significantlyasdodifferinganatomicsitesofthesamearticular
surface.
5.5 Study Duration:
5.1.7 It is recommended that an appropriate species and
5.5.1 The length of the study depends on the stage of device
anatomic site be chosen having articular surfaces and thickness
development, the species used, the size of the defect, and
sufficiently large to adequately investigate and optimize the
composition and design of implant.
formulation, design, dimensions, and associated instrumenta-
5.5.2 In small animals, small defects implanted for 6 to 8
tion envisaged for human use.
weeksprovideinformationregardingresidencetimeofimplant
5.1.8 Larger animals are more appropriate for studying and fixation device as well as the type of repair.
repairinjointsthathavegreaterarticularcartilagesurfaceareas
5.5.3 Using larger animals, study periods of 8 to 12 weeks
andathicknessthatmorecloselyapproximatesthatofhumans.
are limited to providing information regarding the
5.1.9 Larger defect dimensions generally require a method biocompatibility, early cellular responsiveness, and the persis-
of fixation to secure the implant and thereby reduce implant tence and condition of the implant within the defect.
dislocation. The method of implant immobilization can nega-
5.5.4 Periods of 6 to 12 months are generally necessary to
tivelyimpactboththesurroundinghosttissueandrepairtissue.
gain confidence in the extent of success in the repair or
Accordingly, the difference in the design of the test device in
regeneration of articular cartilage based on histologic and
smallanimalswhichgenerallydonotrequirefixationshouldbe
biochemical outcome measures, including the interface with
factored into the interpretation of results with respect to
adjacent cartilage and subchondral bone, as well as the
predictability of outcomes in larger animal models and humans
opposing articular surface.
requiring fixation.
5.6 Rabbit Model—The fe
...
Questions, Comments and Discussion
Ask us and Technical Secretary will try to provide an answer. You can facilitate discussion about the standard in here.