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1、A Reference number ISO 15814:1999(E) INTERNATIONAL STANDARD ISO 15814 First edition 1999-11-15 Implants for surgery Copolymers and blends based on polylactide In vitro degradation testing Implants chirurgicaux Copolymres et mlanges base de polylactide Essais de dgradation in vitro Copyright Internat
2、ional Organization for Standardization Provided by IHS under license with ISO Licensee=NASA Technical Standards 1/9972545001 Not for Resale, 04/22/2007 19:56:59 MDTNo reproduction or networking permitted without license from IHS -,-,- ISO 15814:1999(E) ISO 1999 All rights reserved. Unless otherwise
3、specified, no part of this publication may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying and microfilm, without permission in writing from the publisher. International Organization for Standardization Case postale 56 CH-1211 Genve 20 Switzerl
4、and Internetisoiso.ch Printed in Switzerland ii ContentsPage 1 Scope1 2 Normative references1 3 Terms and definitions .2 4 Degradation methods2 4.1 General.2 4.2 Apparatus and reagents.2 4.3 Control of the buffer solution3 4.4 Degradation test3 5 Mechanical tests3 5.1 General.3 5.2 Procedures4 6 Phy
5、sicochemical tests 5 6.1 Loss of substance mass5 6.2 Determination of the limiting viscosity.6 7 Test termination.6 8 Test report6 Annex A (informative) Accelerated degradation test8 Copyright International Organization for Standardization Provided by IHS under license with ISO Licensee=NASA Technic
6、al Standards 1/9972545001 Not for Resale, 04/22/2007 19:56:59 MDTNo reproduction or networking permitted without license from IHS -,-,- ISOISO 15814:1999(E) iii Foreword ISO (the International Organization for Standardization) is a worldwide federation of national standards bodies (ISO member bodies
7、). The work of preparing International Standards is normally carried out through ISO technical committees. Each member body interested in a subject for which a technical committee has been established has the right to be represented on that committee. International organizations, governmental and no
8、n-governmental, in liaison with ISO, also take part in the work. ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of electrotechnical standardization. International Standards are drafted in accordance with the rules given in the ISO/IEC Directives, Par
9、t 3. Draft International Standards adopted by the technical committees are circulated to the member bodies for voting. Publication as an International Standard requires approval by at least 75 % of the member bodies casting a vote. International Standard ISO 15814 was prepared by Technical Committee
10、 ISO/TC 150, Implants for surgery, Subcommittee SC 1, Materials. Annex A of this International Standard is for information only. Copyright International Organization for Standardization Provided by IHS under license with ISO Licensee=NASA Technical Standards 1/9972545001 Not for Resale, 04/22/2007 1
11、9:56:59 MDTNo reproduction or networking permitted without license from IHS -,-,- Copyright International Organization for Standardization Provided by IHS under license with ISO Licensee=NASA Technical Standards 1/9972545001 Not for Resale, 04/22/2007 19:56:59 MDTNo reproduction or networking permit
12、ted without license from IHS -,-,- INTERNATIONAL STANDARD ISOISO 15814:1999(E) 1 Implants for surgery Copolymers and blends based on polylactide In vitro degradation testing 1 Scope This International Standard is applicable to copolymers and/or blends based on polylactide, in bulk or processed forms
13、, used for the manufacture of surgical implants. This International Standard describes methods for the determination of chemical and mechanical changes in the properties of these copolymers and/or blends under in vitro degradation testing conditions. The test methods specified in this International
14、Standard are intended to determine the degradation rate and the changes in material properties of polylactide-based copolymers and/or blends with various comonomers (for example glycolid, trimethylene carbonate, -caprolactone) in vitro. These in vitro methods cannot be used to predict definitely the
15、 behaviour of these materials under in vivo conditions. The purpose of this International Standard is to compare and/or evaluate materials or processing conditions. 2 Normative references The following normative documents contain provisions which, through reference in this text, constitute provision
16、s of this International Standard. For dated references, subsequent amendments to, or revisions of, any of these publications do not apply. However, parties to agreements based on this International Standard are encouraged to investigate the possibility of applying the most recent editions of the nor
17、mative documents indicated below. For undated references, the latest edition of the normative document referred to applies. Members of ISO and IEC maintain registers of currently valid International Standards. ISO 178:1993, Plastics Determination of flexural properties. ISO 180:1993, Plastics Determ
18、ination of Izod impact strength. ISO 527-1:1993, Plastics Determination of tensile properties Part 1: General principles. ISO 527-2:1993, Plastics Determination of tensile properties Part 2: Test conditions for moulding and extrusion plastics. ISO 537:1989, Plastics Testing with the torsion pendulum
19、. ISO 604:1993, Plastics Determination of compressive properties. ISO 1184:1993, Plastics Determination of tensile properties of films. ISO 1628-1:1998, Plastics Determination of the viscosity of polymers in dilute solution using capillary viscometers Part 1: General. ISO 1805:1973, Fishing nets Det
20、ermination of breaking load and knot breaking load of netting yarns. ISO 2062:1993, Textiles Yarns from packages Determination of single-end breaking force and elongation at break. Copyright International Organization for Standardization Provided by IHS under license with ISO Licensee=NASA Technical
21、 Standards 1/9972545001 Not for Resale, 04/22/2007 19:56:59 MDTNo reproduction or networking permitted without license from IHS -,-,- ISO 15814:1999(E) ISO 2 ISO 3696:1987, Water for analytical laboratory use Specification and test methods. ISO 5081:1977, Textiles Woven fabrics Determination of brea
22、king strength and elongation (Strip method). ISO/TR 10993-9:1994, Biological evaluation of medical devices Part 9: Framework for identification and quantification of potential degradation products. ISO 13781:1997, Poly(L-lactide) resins and fabricated forms for surgical implants In vitro degradation
23、. ISO 14130:1997, Fibre-reinforced plastic composites Determination of apparent interlaminar shear strength by short-beam method. 3 Terms and definitions For the purposes of this International Standard, the terms and definitions given in ISO 13781, ISO/TR 10993-9 and the following apply. 3.1 copolym
24、er polymeric material which consists of different monomer units 3.2 blend polymeric material which consists of different polymers mixed intensively together 3.3 resorption loss of morphology and loss of mass 4 Degradation methods 4.1 General The initial values for the following tests shall be determ
25、ined directly before starting the degradation test (time zero). The tests shall be carried out on the degraded samples at each test period. 4.2 Reagents and apparatus 4.2.1 Soaking solution (phosphate buffer solution; Srensen buffer) For the in vitro degradation study, the test sample shall be immer
26、sed in a ”Srensen” buffer solution (pH 7,4) consisting of potassium dihydrogenphosphate and disodium hydrogenphosphate in analytical water Grade 2 in accordance with ISO 3696. a) 1/15 mol/l KH2PO4:9,078 g KH2PO4 per litre H2O b) 1/15 mol/l Na2HPO4:11,876 g Na2HPO4 2H2O per litre H2O Prepare the solu
27、tion by mixing 18,2 % (volume fraction) from solution a) and 81,8 % (volume fraction) from solution b). No other additives shall be used for the solution. Copyright International Organization for Standardization Provided by IHS under license with ISO Licensee=NASA Technical Standards 1/9972545001 No
28、t for Resale, 04/22/2007 19:56:59 MDTNo reproduction or networking permitted without license from IHS -,-,- ISOISO 15814:1999(E) 3 Salts used for the preparation of the buffer solution shall be of analytical grade and dried to constant mass. The minimum volume of the buffered solution used shall be
29、10 ml. The ratio of the volume, in millilitres, of buffer solution to the test sample mass, in grams, shall be greater than 30:1. The buffer capacity shall be equal or greater than the maximum calculated acid concentration. The test sample shall be completely immersed in the soaking solution. 4.2.2
30、Inert plastic or glass container (e.g. bottle, jar, vial, etc.) capable of holding the test sample for each material and time period and the required volume of soaking solution. Each container shall be sealed against loss of solution by evaporation and to prevent microbial contamination. 4.2.3 Const
31、ant-temperature bath or oven capable of maintaining the sample containers at degradation temperature (37 1) C at any place for the specified test duration (for example circulating-air dryer). 4.2.4 pH-Meter, for controlling the pH value. 4.2.5 Analytical balance with an accuracy of 0,1 mg. 4.3 Contr
32、ol of the buffer solution 4.3.1 Changes in pH value The pH value shall be measured in two different containers at each test period. In extended test periods, the pH value shall be measured additionally in at least two containers every four weeks. If in one container the pH value has shifted beyond t
33、he limits, measure the value in all containers and adjust to pH 7,4 0,3 using 0,1 mol/l NaOH solution. 4.3.2 Clouding of buffer solution Clouding of the buffer solution may indicate contamination with microorganisms. Discard the test sample if any clouding is visible which cannot be related directly
34、 to the material itself or its degradation products. It is recommended that the containers and soaking solutions be sterilized in order to avoid contamination with microorganisms. 4.4 Degradation test 4.4.1 Temperature The test sample shall be maintained at physiological temperature of (37 1) C. 4.4
35、.2 Test period The test samples shall be completely immersed in the soaking solution. For materials intended to degrade over a short time, remove the test samples from the soaking solutions at the following numbers of weeks after time zero: 2, 4, 8, 16 and 26. For materials intended to degrade over
36、a long time, remove the test samples from the soaking solutions on at least six occasions, including at 6, 12, 26, 39 and 52 weeks after time zero. 5 Mechanical tests 5.1 General Each test sample shall be used for one mechanical test only. During all test periods, do not agitate the solution. To pre
37、vent slippage of the test sample in the grips, carefully dry the surfaces to be gripped, using e.g. a paper towel. At least three test samples shall be tested at each period. Copyright International Organization for Standardization Provided by IHS under license with ISO Licensee=NASA Technical Stand
38、ards 1/9972545001 Not for Resale, 04/22/2007 19:56:59 MDTNo reproduction or networking permitted without license from IHS -,-,- ISO 15814:1999(E) ISO 4 For statistical analysis, at least six samples at each test period are required. NOTE Mechanical properties change with temperature. The glass trans
39、ition temperature of amorphous or semicrystalline polymers depends on the content of water in the material. Drying of test samples, especially of fibre-reinforced and/or degraded materials, may affect the properties. 5.2 Test procedures 5.2.1 Conditioning of the test sample The type of conditioning
40、used shall be given in the test report. a) Type A: Soak the samples in analytical grade water for 60 min 3 min at a temperature of 37 C 1 C. Carry out the mechanical tests in a water bath at 37 C 1 C. b) Type B: Soak the samples in the solution for 60 min 3 min. Carry out mechanical tests at room te
41、rmperature (22 C 1 C) 10 min after removal from the solution. 5.2.2 Test periods For materials intended to degrade in a short time, at least seven test periods are required, including those at the following number of weeks after time zero: 2, 4, 8, 16 and 26. For materials intended to degrade in a l
42、ong time, at least seven test periods are required, including those at the following number of weeks after time zero: 6, 12, 26 and 52. 5.2.3 Test method Select the test methods to simulate the intended loading conditions of the device, taking into account the shape of the test sample. Determine the
43、 mechanical properties using one of the test procedures given in Table 1. The test method to be used shall be specified by the parties submitting the sample. The test parameters to be determined shall be those specified in the appropriate standard listed in Table 1, those specified by the parties su
44、bmitting the sample, or such other parameters as shall be determined by the test house, provided that in each case the selection of these parameters is justified and reported. NOTE 1As the shape and the structure of the test sample may have a strong influence on the degradation kinetics, where appli
45、cable the test sample should be comparable to the final products in shape and structure. NOTE 2Other test methods for specific structures (e.g. cellular plastics) or specific requirements (e.g. tensile creep) may be used, if applicable. Table 1 Test methods FormTest methods Rigid material ISO 178 IS
46、O 180 ISO 527-1, ISO 527-2 ISO 537 ISO 604 ISO 14130 Film, foil, sheet ISO 1184 Fibres, textiles ISO 2062 ISO 1805 ISO 5081 Copyright International Organization for Standardization Provided by IHS under license with ISO Licensee=NASA Technical Standards 1/9972545001 Not for Resale, 04/22/2007 19:56:
47、59 MDTNo reproduction or networking permitted without license from IHS -,-,- ISOISO 15814:1999(E) 5 6 Physicochemical tests 6.1 Loss of substance mass 6.1.1 Apparatus 6.1.1.1 Balance, a calibrated mass device capable of measuring the mass of the test sample to an accuracy of 1 % of the total sample
48、mass. 6.1.1.2 Desiccator containing a desiccant to absorb moisture for drying the test samples. For example, silica gel beads containing an indicator can be used. 6.1.1.3 Vacuum pump, capable of producing a vacuum of at least 5 kPa (50 mbar) in the desiccator. 6.1.1.4 An appropriate apparatus for the separation of the debris produced during the degradation study. This may involve an inert filter, a temperature-controlled c