1、Designation: F 1635 04aStandard Test Method forin vitro Degradation Testing of Hydrolytically DegradablePolymer Resins and Fabricated Forms for SurgicalImplants1This standard is issued under the fixed designation F 1635; the number immediately following the designation indicates the year oforiginal
2、adoption or, in the case of revision, the year of last revision. A number in parentheses indicates the year of last reapproval. Asuperscript epsilon (e) indicates an editorial change since the last revision or reapproval.1. Scope1.1 This test method covers in vitro degradation of hydro-lytically deg
3、radable polymers (HDP) intended for use insurgical implants.1.2 The requirements of this test method apply to HDPs invarious forms:1.2.1 Virgin polymer resins, or1.2.2 Any form fabricated from virgin polymer such as asemi-finished component of a finished product, a finishedproduct, which may include
4、 packaged and sterilized implants,or a specially fabricated test specimen.1.3 This test method has no provisions for mechanicalloading, fluid flow, or other dynamic challenges.1.4 This standard does not purport to address all of thesafety concerns, if any, associated with its use. It is theresponsib
5、ility of the user of this standard to establish appro-priate safety and health practices and determine the applica-bility of regulatory limitations prior to use.2. Referenced Documents2.1 ASTM Standards:2D 638 Test Method for Tensile Properties of PlasticsD 671 Test Method for Flexural Fatigue of Pl
6、astics byConstant-Amplitude-of-Force3D 695 Test Method for Compressive Properties of RigidPlasticsD 747 Test Method for Apparent Bending Modulus ofPlastics by Means of a Cantilever BeamD 790 Test Method for Flexural Properties of Unreinforcedand Reinforced Plastics and Electrical Insulating Material
7、sD 882 Test Method for Tensile Properties of Thin PlasticSheetingD 1708 Test Method for Tensile Properties of Plastics byUse of Microtensile SpecimensD 1822 Test Method for Tensile-Impact Energy to BreakPlastics and Electrical Insulating MaterialsD 2857 Test Method for Dilute Solution Viscosity of P
8、oly-mersF 748 Practice for Selecting Generic Biological Test Meth-ods for Materials and Devices2.2 Other Referenced Standard:ISO 10993-9:1999 Biological Evaluation of MedicalDevicesPart 9 Framework for Identification and Quan-tification of Potential Degradation Products43. Terminology3.1 Definitions
9、:3.1.1 resinany polymer that is a basic material for plas-tics.53.1.2 hydrolytically degradable polymer (HDP)any poly-meric material in which the primary mechanism of chemicaldegradation in the body is by hydrolysis (water reacting withthe polymer resulting in cleavage of the chain).4. Summary of Te
10、st Method4.1 Samples of polymer resins, semi-finished components,finished surgical implants, or specially designed test specimensfabricated from those resins are placed in buffered salinesolution at physiologic temperatures. Samples are periodicallyremoved and tested for various material or mechanic
11、al prop-erties at specified intervals. The required test intervals varygreatly depending on the specific polymeric composition. Forexample, poly(l-lactide) and poly(e-caprolactone) degrade veryslowly and can require two or more years for completedegradation. Polymers based substantially on glycolide
12、 cancompletely degrade in two to three months depending on the1This test method is under the jurisdiction of ASTM Committee F04 on Medicaland Surgical Materials and Devices and is the direct responsibility of SubcommitteeF04.15 on Material Test Methods.Current edition approved Oct. 1, 2004. Publishe
13、d October 2004. Originallyapproved in 1995. Last previous edition approved in 2004 as F 1635 04.2For referenced ASTM standards, visit the ASTM website, www.astm.org, orcontact ASTM Customer Service at serviceastm.org. For Annual Book of ASTMStandards volume information, refer to the standards Docume
14、nt Summary page onthe ASTM website.3Withdrawn.4Available from American National Standards Institute (ANSI), 25 W. 43rd St.,4th Floor, New York, NY 10036.5Polymer Technology Dictionary, Tony Whelan ed., Chapman once per week is generally practicaland suggested. In cases where no prior knowledge of th
15、edegradation rate is available, it is suggested that the pH betested at least daily until a baseline is established. Thisincreased sampling frequency may need to be repeated duringperiods of elevated mass loss (that is, pH change).8. Sample and Test Specimen8.1 All test samples shall be representati
16、ve of the materialunder evaluation.8.1.1 For most HDP resins, inter-lot variations in the mo-lecular weight and residual monomer content can be signifi-cant. Since these factors can strongly affect degradation rates,molecular weight (or inherent viscosity) and residual monomercontent of the source r
17、esin and fabricated test parts need to beunderstood.8.1.2 Where evaluation aims allow, it is recommended thatsamples comparing variations in design be produced from thesame material lot (or batch) and under the same fabricationconditions.8.1.3 When testing for inter-lot variability in degradationrat
18、e (for example, for process validation purposes), a minimumof three resin lots should be used.8.2 If a test is intended to be representative of actualperformance in vivo, specimens shall be packaged and steril-ized in a manner consistent with that of the final device.Unsterilized control specimens m
19、ay be included for compara-tive purposes showing the effects of sterilization.9. Procedure9.1 Test A, Weight Loss:9.1.1 Test samples, in either resin or fabricated form, shallbe weighed to a precision of 0.1 % of the total sample weightprior to placement in the physiological solution. Samples shallb
20、e dried to a constant weight before initial weighing (see Note2 and X1.8). Drying conditions, including final relative humid-ity (if applicable), shall be reported and may include the use ofa desiccator, partial vacuum, or elevated temperatures (seeNote 3).9.1.2 Test samples shall be fully immersed
21、in the physi-ological solution for a specified period of time as discussed in4.1 (for example, 1 week, 2 weeks, and so forth).9.1.3 Upon completion of the specified time period, eachsample shall be removed, gently rinsed with sufficient distilledwater to remove saline, placed in a tared container, a
22、nd dried toa constant weight (see Note 2 and X1.8). The weight shall berecorded to a precision of 0.1 % of the original total sampleweight.NOTE 2Drying to a constant weight may be quantified as less than0.1 % weight change over a period of 48 h, or less than 0.05 % change in24 h if the balance used
23、is capable of such precision. Section X1.8provides additional information.NOTE 3Elevated temperatures may be used to assist drying of thesample provided that the temperature used does not induce material orchemical changes in the sample. Vacuum drying with a dry gas purge canalternately be used with
24、out concern for material degradation. The dryingconditions used for the samples prior to aging and for the samplesretrieved at each test interval shall be identical. The actual dryingconditions used are to be reported.9.1.4 After weighing, the samples shall not be returned tothe physiological soluti
25、on and shall be retired from the study.9.2 Test B, Molecular Weight:9.2.1 Prior to placement of samples in the physiologicalsolution, determine the inherent viscosity (logarithmic viscos-ity number) of representative samples using Test MethodD 2857 in a solvent appropriate for the test polymer and a
26、t atemperature sufficient to allow adequate solubility and tem-perature control. For example, poly(l-lactide) IV should bedetermined in chloroform at 25C. The sample dilution ratio(mg/cm3) and test temperature shall be reported. Alternativemeans of molecular weight determination such as size exclu-s
27、ion chromatography may be used when feasible.9.2.2 Test samples shall be fully immersed in the physi-ological solution for the specified period of time (for example,1 week, 3 weeks, 52 weeks, and so forth).9.2.3 Samples shall be removed at each specified timeperiod throughout the duration of the tes
28、t, dried as in 9.1.1, andtested for inherent viscosity as above. For polymers thatundergo very rapid degradation the molecular weight maychange significantly during the drying procedure, causing anoverestimate of the degradation rate. Therefore the user shouldexercise caution in interpretation of th
29、is data. This caution doesnot generally apply to mass loss measurements, since contin-ued degradation after the samples are placed in tared containerswill not affect the sample mass unless the degradation productsare volatile. For rapidly degrading HDP materials, alternativeprocedures such as vacuum
30、 drying should be considered.9.3 Test C, Mechanical Testing:9.3.1 Determine the appropriate mechanical properties ofrepresentative samples of resin or fabricated forms usingtensile, compressive, torque, bending or other appropriatemechanical tests prior to placement of the samples in thephysiologica
31、l solution (time zero). Relevant ASTM test meth-ods may include one or more of the following:Test Method D 638Test Method D 671Test Method D 695Test Method D 747Test Method D 790Test Method D 882Test Method D 1708Test Method D 18229.3.2 Fully immerse test samples in the physiological solu-tion at 37
32、C for the specified period of time (for example, 1week, 2 weeks, and so forth).9.3.3 Remove samples at each specified time periodthroughout the duration of the test and retest using theoriginally selected mechanical test methods and conditions.Unless otherwise deemed relevant, samples should be test
33、ed ina non-dried or wet condition. Section X1.9 provides additionalinformation. Testing conditions, wet versus dry, testing tem-perature, and so forth, should be reported.9.3.4 Unless specifically germane to the testing scheme,samples shall be retired after the completion of each test.9.4 Other Test
34、ing:F 1635 04a39.4.1 The characterization of other material properties anduse of other test methods (for example, thermal propertiesmeasured using Differential Scanning Calorimetry) may alsobe performed at each test interval. Conditioning and testingparameters, as well as test results, should all be
35、 recorded andreported.9.4.2 The degradation products of the HDP under investi-gation may be analyzed. ISO 10993-9 provides guidelines foridentification and quantification of degradation products.9.4.3 Biological response to HDP materials or their degra-dation products may be investigated. Practice F
36、 748 providesguidelines for the selection of in vitro and in vivo biocompat-ibility tests for medical devices and materials.10. Test Termination10.1 Testing of samples shall be terminated when one ormore of the following has occurred:10.1.1 A predetermined end point has been reached, that is,elapsed
37、 time (for example, 2 years), percent weight loss,minimum inherent viscosity, percent strength loss, and so forth.10.1.2 Sample integrity has been compromised by theprogression of degradation or by mechanical damage to thepoint that meaningful and reliable data may no longer beobtained.10.1.3 The so
38、aking solution temperature or pH has driftedoutside of the ranges specified in Section 6. Any sampleproperties obtained since the last in-range temperature and pHmeasurements shall be considered invalid and so noted in thestudy report (see X1.4).11. Report11.1 Report the following information:11.1.1
39、 Test material description, batch or lot number anddimensions (as appropriate).11.1.2 Solution composition and preparation procedures.11.1.3 Measurements of solution temperature and pH withtime, if applicable.11.1.4 Sample weights expressed as an average percentageloss, initial and subsequent by tim
40、e period.11.1.5 Inherent viscosity, initial and subsequent by timeperiod.11.1.6 Mechanical properties (tensile strength, compressivestrength, stiffness, elongation at break, and so forth) appropri-ate for tests performed, at time zero and at each time period.11.1.7 Other material properties measured
41、.11.1.8 Reason(s) for test termination.12. Precision12.1 Intralaboratory and interlaboratory reproducibility hasnot been systematically determined.13. Keywords13.1 absorbable; bioabsorbable; degradation; in vitro; hy-drolytically degradable polymer; hydrolysis; PLA, poly(l-lacticacid); poly(d-lactid
42、e); poly(d,l-lactide); PGA, poly(glycolide);poly(caprolactone); poly(p-dioxanone); surgical implantAPPENDIX(Nonmandatory Information)X1. RATIONALEX1.1 With the development of absorbable polymers for usein implantable devices, there is a need to define standardtesting methods that aid in characterizi
43、ng material and me-chanical properties with time in a simulated physiologicalenvironment. This test method is intended only as a frameworkfor assessing degradation of implant materials and devices.X1.1.1 This test method is written for use in characterizinghydrolytically degradable polymer resins an
44、d devices. Giventhe wide variety of bioabsorbable polymer compositions cur-rently available or under investigation, it is incumbent upon theresearcher to show through reference or experimentation thatother degradation mechanisms are not dominant for the mate-rial and the intended use. For example, c
45、ertain bio-polymers(for example, collagen based materials such as gelatin) areknown to degrade in vivo primarily by enzymatic attack and theuse of this method would give a serious underestimation of thedegradation rate. It has also been hypothesized that enzymaticdegradation may play a role in the d
46、egradation of somesynthetic polymers. in vitro studies have shown that in suffi-cient concentration certain enzymes (for example, esterases)may increase degradation rates of specific polymers withsusceptible bonds. However, when comparisons have beenmade between in vitro and in vivo degradation rate
47、s ofequivalent samples of hydrolytically degradable polymersunder unloaded conditions, the results have consistently shownthat in vivo acceleration of degradation is either not present oris within the error of measurement.6X1.2 It is recognized that the use of test coupons orspecimens in forms other
48、 than final implant configurations maybe helpful in assessing relevant polymer properties. For ex-ample, rectangular or round rods may be necessary to measureflexural properties, while a screw geometry may be required toevaluate the performance of a specific implantable device.However, specimen size
49、, surface area, and process consider-ations must be addressed in order to relate in vitro degradationof test specimens to in vivo behavior of implant devices.X1.3 The pH level specified for the buffered saline solution(that is, 7.4 6 0.2) was selected on the basis of informationreceived from two consultants to the Task Group that this rangeof pH values was representative of that found in human bloodand extra-cellular fluid. For devices intended for use inapplications where the fluid environment has a different pH(for example, urethral stents exposed to urine), a different pHF 16
