ASTM F1635-16

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Designation: F1635 − 11 F1635 − 16
Standard Test Method for
in vitro Degradation Testing of Hydrolytically Degradable
Polymer Resins and Fabricated Forms for Surgical
Implants
This standard is issued under the fixed designation F1635; 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 test method covers in vitro degradation of hydrolytically degradable polymers (HDP) intended for use in surgical
implants.
1.2 The requirements of this test method apply to HDPs in various forms:
1.2.1 Virgin polymer resins, or
1.2.2 Any form fabricated from virgin polymer such as a semi-finished component of a finished product, a finished product,
which may include packaged and sterilized implants, or a specially fabricated test specimen.
1.3 This test method provides guidance for mechanical loading or fluid flow, or both, when relevant to the device being
evaluated. The specifics of loading type, magnitude, and frequency for a given application are beyond the scope of this test method.
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
limitations prior to use.
2. Referenced Documents
2.1 ASTM Standards:
D638 Test Method for Tensile Properties of Plastics
D671 Test Method for Flexural Fatigue of Plastics by Constant-Amplitude-of-Force (Withdrawn 2002)
D695 Test Method for Compressive Properties of Rigid Plastics
D747 Test Method for Apparent Bending Modulus of Plastics by Means of a Cantilever Beam
D790 Test Methods for Flexural Properties of Unreinforced and Reinforced Plastics and Electrical Insulating Materials
D882 Test Method for Tensile Properties of Thin Plastic Sheeting
D1708 Test Method for Tensile Properties of Plastics by Use of Microtensile Specimens
D1822 Test Method for Tensile-Impact Energy to Break Plastics and Electrical Insulating Materials
D2857 Practice for Dilute Solution Viscosity of Polymers
F748 Practice for Selecting Generic Biological Test Methods for Materials and Devices
2.2 Other Referenced Standard:ISO Standards:
ISO 31–8 Physical Chemistry and Molecular Physics - Part 8: Quantities and Units
ISO 10993–1 Biological Evaluation of Medical Devices—Part 1 Evaluation and Testing
ISO 10993–9 Biological Evaluation of Medical Devices—Part 9 Framework for Identification and Quantification of Potential
Degradation Products
NIST Special Publication SP811ISO 13781 Guide for the Use of the International System of Units (SI)Poly(L-lactide) resins and
fabricated forms for surgical implants – In vitro degradation testing
This test method is under the jurisdiction of ASTM Committee F04 on Medical and Surgical Materials and Devices and is the direct responsibility of Subcommittee
F04.15 on Material Test Methods.
Current edition approved March 1, 2011Dec. 1, 2016. Published March 2011January 2017. Originally approved in 1995. Last previous edition approved in 20042011 as
F1635 – 04a.F1635 – 11. DOI: 10.1520/F1635-11.10.1520/F1635-16.
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.
The last approved version of this historical standard is referenced on www.astm.org.
Available from American National Standards Institute (ANSI), 25 W. 43rd St., 4th Floor, New York, NY 10036, http://www.ansi.org.
Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States
F1635 − 16
2.3 NIST Standard:
NIST Special Publication SP811 Guide for the Use of the International System of Units (SI)
3. Terminology
3.1 Definitions:
3.1.1 absorbable, adj—in the body—an initially distinct foreign material or substance that either directly or through intended
degradation can pass through or be assimilated by cells and/or tissue.
NOTE 1—See Appendix X2 for a discussion regarding the usage of absorbable and other related terms.
3.1.2 hydrolytically degradable polymer (HDP)—any polymeric material in which the primary mechanism of chemical
degradation in the body is by hydrolysis (water reacting with the polymer resulting in cleavage of the chain).
3.1.3 resin—any polymer that is a basic material for plastics.
4. Summary of Test Method
4.1 Samples of polymer resins, semi-finished components, finished surgical implants, or specially designed test specimens
fabricated from those resins are placed in buffered saline solution at physiologic temperatures. Samples are periodically removed
and tested for various material or mechanical properties at specified intervals. The required test intervals vary greatly depending
on the specific polymeric composition. For example, poly(l-lactide) and poly(e-caprolactone) degrade very slowly and can require
two or more years for complete degradation. Polymers based substantially on glycolide can completely degrade in two to three
months depending on the exact composition and on the size of the specimen. Degradation time is also strongly affected by
specimen size, polymer molar mass, and crystallinity.
NOTE 2—The term molecular weight (abbreviated MW) is obsolete and should be replaced by the SI (Système Internationale) equivalent of either
relative molecular mass (M ), which reflects the dimensionless ratio of the mass of a single molecule to an atomic mass unit [see ISO 31–8], or molar
r
mass (M), which refers to the mass of a mole of a substance and is typically expressed as grams/mole. For polymers and other macromolecules, use of
the symbols M ,M , and M continue, referring to mass-average molar mass, number-average molar mass, and z-average molar mass, respectively. For
w n z
more information regarding proper utilization of SI units, see NIST Special Publication SP811.
5. Significance and Use
5.1 This test method is intended to help assess the degradation rates (that is, the mass loss rate) and changes in material or
structural properties, or both, of HDP materials used in surgical implants. Polymers that are known to degrade primarily by
hydrolysis include but are not limited to homopolymers and copolymers of l-lactide, d-lactide, d,l-lactide glycolide, caprolactone,
and p-dioxanone.
5.2 This test method may not be appropriate for all types of implant applications or for all known absorbable polymers. The
user is cautioned to consider the appropriateness of the test method in view of the materials being tested and their potential
application (see X1.1.1).
5.3 Since it is well known that mechanical loading can increase the degradation rate of absorbable polymers, the presence and
extent of such loading needs to be considered when comparing in vitro behavior with that expected or observed in vivo.
5.3.1 Mechanically Unloaded Hydrolytic Evaluation—Conditioning of a hydrolysable device under mechanically unchallenged
hydrolytic conditions at 37°C in buffered saline is a common means to obtain a first approximation of the degradation profile of
an absorbable material or device. It does not necessarily represent actual in vivo service conditions, which can include mechanical
loading in a variety of forms (for example. static tensile, cyclic tensile, shear, bending, and so forth). If the performance of a device
under its indicated use includes loading, hydrolytic aging alone is NOT sufficient to fully characterize the device.
5.3.2 Mechanically Loaded Hydrolytic Evaluation—The objective of loading is to approximate (at 37°C in buffered saline) the
actual expected device service conditions so as to better understand potential physicochemical changes that may occur. Such testing
can be considered as necessary if loading can be reasonably expected under in vivo service conditions. When feasible, test
specimens should be loaded in a manner that simulates in vivo conditions, both in magnitude and type of loading. Clinically
relevant cyclic load tests may include testing to failure or for a specified number of cycles followed by testing to evaluate
physicochemical properties.
5.3.2.1 Static Loading—It is notable that for some polymeric materials it has been shown that a constant load results in the same
failure mechanism (for example, creep) and is the worst case when compared to a cyclic load (where the maximum amplitude of
the cyclic load is equal to the constant load). Thus, in specific cases it may be acceptable to simplify the test by using a constant
load even when the anticipated in vivo loading is cyclic. It is encumbent upon the user of this test method to demonstrate through
experiment or specific reference that this simplification is applicable to the polymer under investigation and does not alter the
Available from National Institute of Standards and Technology (NIST), 100 Bureau Dr., Stop 1070, Gaithersburg, MD 20899-1070, at http://physics.nist.gov/cuu/Units/
bibliography.html.
Polymer Technology Dictionary, Tony Whelan ed., Chapman & Hall, 1994.
Handbook of Biodegradable Polymers, A.J. Domb ed., Harwood Academic Publishers, 1997.
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failure mode of the test specimen. If such evidence is not available ,it is necessary to recognize that static loading and cyclic
loading are measuring different material properties and are not comparable. Using one to replace the other could lead to
misinterpretation of the results.
NOTE 3—Caution must be taken to ensure that fixturing does not introduce artifactual performace or degradation issues, or both. An example is the
use of rigid foam block, which restricts swelling & expansion and can elevate pull out strength test results from sample compression within the block.
Additionally, restricted perfusion due to the closed cell nature of the foam can result in concentration of acidic byproducts that result in accelerated
degradation when compared to a normally perfused and buffered in vivo condition.
NOTE 4—When performing degradation testing under load, it may be necessary to consider and monitor polymer creep during testing, which may be
significant.
5.4 Absorbable devices subjected to flow conditions (for example, vascular stents, particularly those with a drug eluting
component) may degrade more rapidly than the same device maintained under static degradation test conditions. When it is feasible
to estimate the flow conditions that an implant will be subjected to in vivo and replicate them in vitro the degradation study should
be conducted under flow conditions. However, details regarding appropriate flow modeling are beyond the scope of this test
method.
5.5 Sterilization of HDP materials should be expected to cause changes in molar mass or structure, or both, of the polymers.
This can affect the initial mechanical and physical properties of a material or device, as well as its subsequent rate of degradation.
Therefore, if a test is intended to be representative of actual performance in vivo, specimens shall be packaged and sterilized in
a manner consistent with that of the final device. Non-sterilized specimens may be included for comparative purposes.
6. Materials and Apparatus
6.1 Physiologic Soaking Solution—A phosphate-buffered saline (PBS) solution shall be used. The pH of the solution shall be
maintained at 7.4 6 0.2 (see X1.3) unless it is determined through documented literature or self-advised study that the pH should
be different due to the physiological conditions of the intended application (this may require use of an alternate buffer system).
Limited excursions outside of the specified pH range are tolerable provided the time weighted average pH after buffer
replenishment is maintained within this range (see X1.3.1). The ionic concentration should be in the physiological range for the
intended application (for example, a solution that contains 0.1 M phosphate buffer and 0.1 M NaCl would be appropriate for most
tissue or blood contact devices). The solution-to-HDP mass ratio shall be as high as practical. Although there is some experience
with ratios as low as 20:1, the The experimenter is cautioned that at lower ratios (that is, less buffering capacity) the solution pH
may change more quickly. To provide adequate buffer capacity, solution-to-HDP mass ratio is recommended to be greater than
30:1. In accordance with 9.1.3 and X1.4, aging/testing is to be terminated if the solution temperature or pH are allowed to drift
outside of the specified ranges. Higher solution/specimen ratios (for example, 100:1) will be more likely to facilitate maintenance
of stable aging conditions.
6.1.1 Over the course of the study, the pH of the soaking solution should be monitored frequently and the solution shall be
changed periodically in order to maintain the pH within the acceptable limits. Refer to X1.5 for additional information.
6.1.2 Other physiologic solutions, such as bovine serum, may be substituted provided the solution is properly buffered. An
anti-microbial additive should be used to inhibit the growth of microorganisms in the solution during the test period but the
investigator must demonstrate through literature reference or experimentation that the chosen antimicrobial does not affect the
degradation rate. Section X1.6 provides additional information. The appropriate MSDS should always be consulted concerning
toxicity, safe use, and disposal of such additives.
6.2 Sample Container—A self-contained, inert container (bottle, jar, vial, and so forth) capable of holding the test sample and
the required volume of physiologic soaking solution (see X1.7). Multiple samples may be stored in the same container provided
that suitable sample separation is maintained to allow fluid access to each sample surface and to preclude sample-to-sample
contact. Each container must be sealable against solution loss by evaporation.
6.3 Constant Temperature Bath or Oven—An aqueous bath or heated air oven capable of maintaining the samples and containers
at physiologic temperatures, 37 6 2°C,1°C, for the specified testing periods.
6.4 pH Meter—A pH metering device sensitive in the physiological range (pH 6 to pH 8) with a precision of 0.02 or better.
6.5 Balance—A calibrated weighing device capable of measuring the weightmass of a sample to a precision of 0.1 % of its
initial weight.mass. A balance having precision to 0.05 % or 0.01 % will facilitate establishment of an appropriate specimen drying
period.
6.6 Other—Additional equipment as deemed appropriate by the specific test method.
7. Sampling
7.1 WeightMass Loss—A minimum of three samples shall be tested per time period.
7.2 Molar Mass—A minimum of three samples shall be tested per time period.
7.3 Mechanical Testing—A minimum of six samples shall be tested per time period.
NOTE 5—Statistical significance may require more than the minimum number of samples to be tested.
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7.4 Solution Temperature and pH—Soaking solutions shall be tested on a periodic basis throughout the test duration. The
required test period is dependent on the degradation rate of the test polymer, the solution/specimen mass ratio, and the solution’s
buffering capacity; once per week is generally practical and suggested. In cases where no prior knowledge of the degradation rate
is available, it is suggested that the pH be tested at least daily until a baseline is established. This increased sampling frequency
may need to be repeated during periods of elevated mass loss (that is, pH change).
8. Sample and Test Specimen
8.1 All test samples shall be representative of the material under evaluation.
8.1.1 For most HDP resins, inter-lot variations in the molar mass and residual monomer content can be significant. Since these
factors can strongly affect degradation rates, molar mass (or inherent viscosity) and residual monomer content of the source resin
and fabricated test parts need to be understood.
8.1.2 Where evaluation aims allow, it is recommended that samples comparing variations in design be produced from the same
material lot (or batch) and under the same fabrication conditions.
8.1.3 When testing for inter-lot variability in degradation rate (for example, for process validation purposes), a minimum of
three resin lots should be used.
8.2 If a test is intended to be representative of actual performance in vivo, specimens shall be packaged and sterilized in a
manner consistent with that of the final device. Unsterilized control specimens may be included for comparative purposes showing
the effects of sterilization.
9. Procedure
9.1 Test A, WeightMass Loss:
9.1.1 Test samples, in either resin or fabricated form, shall be weighed to a precision of 0.1 % of the total sample weightmass
prior to placement in the physiological solution. Samples shall be dried to a constant weightmass before initial weighing (see Note
6 and X1.8). Drying conditions, including final relative humidity (if applicable), shall be reported and may include the use of a
desiccator, partial vacuum, or elevated temperatures (see Note 7).
9.1.2 Test samples shall be fully immersed in the physiological solution for a specified period of time as discussed in 4.1 (for
example, 1 week, 2 weeks, and so forth).
9.1.3 Upon completion of the specified time period, each sample shall be removed, gently rinsed with sufficient distilled water
to remove saline, placed in a tared container, and dried to a constant weightmass (see Note 6 and X1.8). The weight shall
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