SIST EN ISO 10993-6:2017
(Main)Biological evaluation of medical devices - Part 6: Tests for local effects after implantation (ISO 10993-6:2016)
Biological evaluation of medical devices - Part 6: Tests for local effects after implantation (ISO 10993-6:2016)
This part of ISO 10993 specifies test methods for the assessment of the local effects after implantation
of biomaterials intended for use in medical devices.
This part of ISO 10993 applies to materials that are
— solid and non-absorbable,
— non-solid, such as porous materials, liquids, gels, pastes, and particulates, and
— degradable and/or absorbable, which may be solid or non-solid.
The test sample is implanted into a site and animal species appropriate for the evaluation of the
biological safety of the material. These implantation tests are not intended to evaluate or determine the
performance of the test sample in terms of mechanical or functional loading. This part of ISO 10993 can
also be applied to medical devices that are intended to be used topically in clinical indications where
the surface or lining might have been breached, in order to evaluate local tissue responses.
The local effects are evaluated by a comparison of the tissue response caused by a test sample to that
caused by control materials used in medical devices whose clinical acceptability and biocompatibility
characteristics have been established. The objective of the test methods is to characterize the history
and evolution of the tissue response after implantation of a medical device/biomaterial including
final integration or absorption/degradation of the material. In particular for degradable/absorbable
materials, the degradation characteristics of the material and the resulting tissue response should be
determined.
This part of ISO 10993 does not deal with systemic toxicity, carcinogenicity, teratogenicity or
mutagenicity. However, the long-term implantation studies intended for evaluation of local biological
effects might provide insight into some of these properties. Systemic toxicity studies conducted by
implantation might satisfy the requirements of this part of ISO 10993. When conducting combined
studies for evaluating local effects and systemic effects, the requirements of both standards is to be
fulfilled.
Biologische Beurteilung von Medizinprodukten - Teil 6: Prüfungen auf lokale Effekte nach Implantationen (ISO 10993-6:2016)
Évaluation biologique des dispositifs médicaux - Partie 6: Essais concernant les effets locaux après implantation (ISO 10993-6:2016)
ISO 10993-6:2016 spécifie les méthodes d'essai pour l'évaluation des effets locaux après une implantation de biomatériaux destinés à être utilisés dans des dispositifs médicaux.
ISO 10993-6:2016 s'applique aux matériaux qui sont
- solides et non absorbables,
- non solides, comme les matériaux poreux, liquides, en gel, pâteux et particulaires, et
- dégradables et/ou absorbables, qui peuvent être solides ou non solides.
L'échantillon d'essai est implanté dans un site et dans une espèce animale appropriés à l'évaluation de la sécurité biologique du matériau. Ces essais d'implantation ne sont pas destinés à évaluer ou à déterminer les performances de l'échantillon d'essai en matière de charge mécanique ou fonctionnelle. La présente partie de l'ISO 10993 peut également être appliquée à des dispositifs médicaux destinés à une utilisation topique dans des indications cliniques où la surface ou le revêtement pourrait perdre son intégrité, afin d'évaluer les réponses tissulaires locales.
Les effets locaux sont évalués par comparaison de la réponse tissulaire induite par un échantillon d'essai avec celle induite par des matériaux de contrôle utilisés dans des dispositifs médicaux dont les caractéristiques d'acceptabilité clinique et de biocompatibilité ont été établies. L'objectif des méthodes d'essai est de caractériser l'historique et l'évolution de la réponse tissulaire après l'implantation d'un dispositif médical ou biomatériau, y compris l'intégration finale ou l'absorption/dégradation du matériau. Particulièrement pour les matériaux dégradables/absorbables, il convient de déterminer les caractéristiques de dégradation du matériau et la réponse tissulaire résultante.
ISO 10993-6:2016 ne traite pas de la toxicité systémique, de la cancérogénicité, de la tératogénicité ou de la mutagénicité. Les études d'implantation à long terme destinées à l'évaluation des effets biologiques locaux pourraient, cependant, apporter des informations sur certaines de ces propriétés. Des études de toxicité systémique effectuées par implantation pourraient répondre aux exigences de la présente partie de l'ISO 10993. Lors de la réalisation d'études combinées pour l'évaluation des effets locaux et systémiques, les exigences des deux normes appliquées doivent être satisfaites.
Biološko ovrednotenje medicinskih pripomočkov - 6. del: Preskusi, povezani z lokalnimi učinki po implantaciji (ISO 10993-6:2016)
Ta del standarda ISO 10993 določa preskusne metode za oceno lokalnih učinkov po implantaciji biomaterialov, namenjenih za uporabo v medicinskih pripomočkih.
Ta del standarda ISO 10993 se uporablja za materiale, ki:
- so trdni in niso vpojni;
- niso trdni, npr. porozni materiali, tekočine, geli, paste in delci; ter
- so razgradljivi in/ali vpojni, ki so lahko trdni ali netrdni.
Preskusni vzorec je vsajen v mesto in živalsko vrsto, primerno za ovrednotenje
biološke varnosti materiala. Ti implantacijski preskusi niso namenjeni ovrednotenju ali določanju uspešnosti preskusnih vzorcev v smislu mehanske ali funkcionalne obremenitve. Ta del standarda ISO 10993 je mogoče uporabljati tudi za medicinske pripomočke, ki so namenjeni za lokalni nanos pri kliničnih indikacijah, pri katerih je površina ali sluznica morda predrta, za ovrednotenje odzivov lokalnega tkiva.
Lokalni učinki so ovrednoteni s primerjavo odziva tkiva, ki ga povzroči preskusni vzorec, in odziva, ki ga povzroči kontrolni material, ki se uporablja v medicinskih pripomočkih, katerih lastnosti klinične sprejemljivosti in biološke združljivosti so že bile ugotovljene. Namen preskusnih metod je opredelitev zgodovine in razvoja odzivov tkiva po implantaciji medicinskega pripomočka/biomateriala, vključno s končno integracijo ali absorpcijo/degradacijo materiala. Zlasti pri razgradljivih/vpojnih materialih je treba določiti degradacijske značilnosti materiala in posledični odziv tkiva.
Ta del standarda ISO 10993 ne zajema sistemske toksičnosti, kancerogenosti, teratogenosti ali mutagenosti. Kljub temu bi dolgoročne študije o implantaciji, namenjene ovrednotenju lokalnih bioloških učinkov, lahko zagotovile vpogled v nekatere od teh lastnosti. Študije o sistemski toksičnosti, opravljene z implantacijo, morda izpolnjujejo zahteve tega dela standarda ISO 10993. Pri izvajanju kombiniranih študij za ovrednotenje lokalnih in sistemskih učinkov, morajo biti izpolnjene zahteve obeh standardov.
General Information
Relations
Related Packages
Standards Content (Sample)
SLOVENSKI STANDARD
SIST EN ISO 10993-6:2017
01-februar-2017
1DGRPHãþD
SIST EN ISO 10993-6:2009
%LRORãNRRYUHGQRWHQMHPHGLFLQVNLKSULSRPRþNRYGHO 3UHVNXVLSRYH]DQL]
ORNDOQLPLXþLQNLSRLPSODQWDFLML ,62
Biological evaluation of medical devices - Part 6: Tests for local effects after implantation
(ISO 10993-6:2016)
Biologische Beurteilung von Medizinprodukten - Teil 6: Prüfungen auf lokale Effekte nach
Implantationen (ISO 10993-6:2016)
Évaluation biologique des dispositifs médicaux - Partie 6: Essais concernant les effets
locaux après implantation (ISO 10993-6:2016)
Ta slovenski standard je istoveten z: EN ISO 10993-6:2016
ICS:
11.100.20 %LRORãNRRYUHGQRWHQMH Biological evaluation of
PHGLFLQVNLKSULSRPRþNRY medical devices
SIST EN ISO 10993-6:2017 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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SIST EN ISO 10993-6:2017
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SIST EN ISO 10993-6:2017
EN ISO 10993-6
EUROPEAN STANDARD
NORME EUROPÉENNE
December 2016
EUROPÄISCHE NORM
ICS 11.100.20 Supersedes EN ISO 10993-6:2009
English Version
Biological evaluation of medical devices - Part 6: Tests for
local effects after implantation (ISO 10993-6:2016)
Évaluation biologique des dispositifs médicaux - Partie Biologische Beurteilung von Medizinprodukten - Teil 6:
6: Essais concernant les effets locaux après Prüfungen auf lokale Effekte nach Implantationen (ISO
implantation (ISO 10993-6:2016) 10993-6:2016)
This European Standard was approved by CEN on 4 November 2016.
CEN members are bound to comply with the CEN/CENELEC Internal Regulations which stipulate the conditions for giving this
European Standard the status of a national standard without any alteration. Up-to-date lists and bibliographical references
concerning such national standards may be obtained on application to the CEN-CENELEC Management Centre or to any CEN
member.
This European Standard exists in three official versions (English, French, German). A version in any other language made by
translation under the responsibility of a CEN member into its own language and notified to the CEN-CENELEC Management
Centre has the same status as the official versions.
CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia,
Finland, Former Yugoslav Republic of Macedonia, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania,
Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey and
United Kingdom.
EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION
EUROPÄISCHES KOMITEE FÜR NORMUNG
CEN-CENELEC Management Centre: Avenue Marnix 17, B-1000 Brussels
© 2016 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 10993-6:2016 E
worldwide for CEN national Members.
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SIST EN ISO 10993-6:2017
EN ISO 10993-6:2016 (E)
Contents Page
European foreword . 3
Annex ZA (informative) Relationship between this European Standard and the essential
requirements of Directive 93/42/EEC [OJ L 169] aimed to be covered . 5
Annex ZB (informative) Relationship between this European Standard and the essential
requirements of Directive 90/385/EEC [OJ L 189] aimed to be covered . 7
2
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SIST EN ISO 10993-6:2017
EN ISO 10993-6:2016 (E)
European foreword
This document (EN ISO 10993-6:2016) has been prepared by Technical Committee ISO/TC 194
"Biological and clinical evaluation of medical devices" in collaboration with Technical Committee
CEN/TC 206 “Biological and clinical evaluation of medical devices” the secretariat of which is held by
DIN.
This European Standard shall be given the status of a national standard, either by publication of an
identical text or by endorsement, at the latest by June 2017, and conflicting national standards shall be
withdrawn at the latest by June 2017.
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. CEN [and/or CENELEC] shall not be held responsible for identifying any or all such patent
rights.
This document supersedes EN ISO 10993-6:2009.
This document has been prepared under a mandate given to CEN by the European Commission and the
European Free Trade Association, and supports essential requirements of EU Directives.
For relationship with EU Directives, see informative Annex ZA and ZB, which are integral parts of this
document.
According to the CEN-CENELEC Internal Regulations, the national standards organizations of the
following countries are bound to implement this European Standard: Austria, Belgium, Bulgaria,
Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, Former Yugoslav Republic of Macedonia,
France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta,
Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland,
Turkey and the United Kingdom.
Endorsement notice
The text of ISO 10993-6:2016 has been approved by CEN as EN ISO 10993-6:2016 without any
modification.
The following referenced documents are indispensable for the application of this document. For
undated references, the latest edition of the referenced document (including any amendments) applies.
For dated references, only the edition cited applies. However, for any use of this standard ‘within the
meaning of Annex ZA’, the user should always check that any referenced document has not been
superseded and that its relevant contents can still be considered the generally acknowledged state-of-
art.
When an IEC or ISO standard is referred to in the ISO standard text, this shall be understood as a
normative reference to the corresponding EN standard, if available, and otherwise to the dated version
of the ISO or IEC standard, as listed below.
NOTE The way in which these referenced documents are cited in normative requirements determines the
extent (in whole or in part) to which they apply.
3
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SIST EN ISO 10993-6:2017
EN ISO 10993-6:2016 (E)
Table 1 — Correlations between undated normative references and dated EN and ISO standards
Normative references Equivalent dated standard
as listed in Clause 2 of
EN ISO or IEC
the ISO standard
ISO 10993-1 EN ISO 10993-1:2009 ISO 10993-1:2009
ISO 10993-2 EN ISO 10993-2:2006 ISO 10993-2:2006
ISO 10993-4 EN ISO 10993-4:2009 ISO 10993-4:2002
ISO 10993-12 EN ISO 10993-12:2012 ISO 10993-12:2012
ISO 10993-16 EN ISO 10993-16:2010 ISO 10993-16:2010
NOTE This part of EN ISO 10993 refers to ISO 10993-1 which itself refers to ISO 14971. In Europe, it should
be assumed that the reference to ISO 14971 is to EN ISO 14971:2012.
4
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SIST EN ISO 10993-6:2017
EN ISO 10993-6:2016 (E)
Annex ZA
(informative)
Relationship between this European Standard and the essential
requirements of Directive 93/42/EEC [OJ L 169] aimed to be covered
This European Standard has been prepared under a Commission’s joint standardization request
M/BC/CEN/89/9 concerning harmonized standards relating to horizontal aspects in the field of medical
devices to provide one voluntary means of conforming to essential requirements of Council Directive
93/42/EEC of 14 June 1993 concerning medical devices [OJ L 169].
Once this standard is cited in the Official Journal of the European Union under that Directive,
compliance with the normative clauses of this standard given in Table ZA.1 confers, within the limits of
the scope of this standard, a presumption of conformity with the corresponding essential requirements
of that Directive and associated EFTA regulations.
NOTE 1 Where a reference from a clause of this standard to the risk management process is made, the risk
management process needs to be in compliance with Directive 93/42/EEC as amended by 2007/47/EC. This
means that risks have to be reduced ‘as far as possible’, ‘to a minimum’, ‘to the lowest possible level’, ‘minimized’
or ‘removed’, according to the wording of the corresponding essential requirement.
NOTE 2 The manufacturer’s policy for determining acceptable risk must be in compliance with Essential
Requirements 1, 2, 5, 6, 7, 8, 9, 11 and 12 of the Directive.
NOTE 3 This Annex ZA is based on normative references according to the table of references in the European
foreword, replacing the references in the core text.
NOTE 4 When an Essential Requirement does not appear in Table ZA.1, it means that it is not addressed by this
European Standard.
5
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SIST EN ISO 10993-6:2017
EN ISO 10993-6:2016 (E)
Table ZA.1 — Correspondence between this European Standard and Annex I of Directive
93/42/EEC [OJ L 169]
Essential Requirements of Clause(s)/sub-clause(s) of Remarks/Notes
Directive 93/42/EEC this EN
This part of ISO 10993 specifies
test methods for the assessment
4, 5, 6 and Annex A, Annex B,
of the local effects after
7.1 (First and second indent)
Annex C and Annex D
implantation of biomaterials
intended for use in medical
devices.
These implantation tests are not
intended to evaluate or
4, 5, 6 and Annex A, Annex B,
determine the performance of
7.2
Annex C and Annex D
the test sample in terms of
mechanical or functional
loading.
This part of ISO 10993 does not
deal with systemic toxicity,
carcinogenicity, teratogenicity or
mutagenicity. However, the long-
term implantation studies
intended for evaluation of local
biological effects may provide
insight into some of these
properties. Systemic toxicity
studies conducted by
4, 5, 6 and Annex A, Annex B,
implantation may satisfy the
7.5 (First paragraph)
Annex C and Annex D
requirements of this part of
ISO 10993. When conducting
combined studies for evaluating
local effects and systemic effects,
the requirements of this part of
ISO 10993 and ISO 10993-11
shall be fulfilled.
For ER 7.1 (first and second
indent), flammability is not
covered
General Note: Presumption of conformity depends on also complying with all relevant
clauses/subclauses of ISO 10993-1.
WARNING 1 — Presumption of conformity stays valid only as long as a reference to this European
Standard is maintained in the list published in the Official Journal of the European Union. Users of this
standard should consult frequently the latest list published in the Official Journal of the European
Union.
WARNING 2 — Other Union legislation may be applicable to the products falling within the scope of this
standard.
6
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SIST EN ISO 10993-6:2017
EN ISO 10993-6:2016 (E)
Annex ZB
(informative)
Relationship between this European Standard and the essential
requirements of Directive 90/385/EEC [OJ L 189] aimed to be covered
This European Standard has been prepared under a Commission’s joint standardization request
M/BC/CEN/89/9 concerning harmonized standards relating to horizontal aspects in the field of medical
devices to provide one voluntary means of conforming to essential requirements of Council Directive
90/385/EEC of 20 June 1990 on the approximation of the laws of the Member States relating to active
implantable medical devices [OJ L 189].
Once this standard is cited in the Official Journal of the European Union under that Directive,
compliance with the normative clauses of this standard given in Table ZB.1 confers, within the limits of
the scope of this standard, a presumption of conformity with the corresponding essential requirements
of that Directive and associated EFTA regulations.
NOTE 1 Where a reference from a clause of this standard to the risk management process is made, the risk
management process needs to be in compliance with Directive 90/385/EEC as amended by 2007/47/EC. This
means that risks have to be reduced ‘as far as possible’, ‘to a minimum’, ‘to the lowest possible level’, ‘minimized’
or ‘removed’, according to the wording of the corresponding essential requirement.
NOTE 2 The manufacturer’s policy for determining acceptable risk must be in compliance with Essential
Requirements 1, 4, 5, 8, 9 and 10 of the Directive.
NOTE 3 This Annex ZB is based on normative references according to the table of references in the European
foreword, replacing the references in the core text.
NOTE 4 When an Essential Requirement does not appear in Table ZB.1, it means that it is not addressed by this
European Standard.
7
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SIST EN ISO 10993-6:2017
EN ISO 10993-6:2016 (E)
Table ZB.1 — Correspondence between this European Standard and Annex I of Directive
90/385/EEC [OJ L 189]
Essential Requirements of Clause(s)/sub-clause(s) Remarks/Notes
Directive 90/385/EEC of this EN
This part of ISO 10993 specifies
test methods for the assessment of
the local effects after implantation
of biomaterials intended for use in
medical devices.
These implantation tests are not
intended to evaluate or determine
the performance of the test sample
in terms of mechanical or
functional loading.
This part of ISO 10993 does not
deal with systemic toxicity,
4, 5, 6 and Annex A,
carcinogenicity, teratogenicity or
9 (only first and second
Annex B, Annex C and
mutagenicity. However, the long-
indent)
Annex D
term implantation studies intended
for evaluation of local biological
effects may provide insight into
some of these properties. Systemic
toxicity studies conducted by
implantation may satisfy the
requirements of this part of
ISO 10993. When conducting
combined studies for evaluating
local effects and systemic effects,
the requirements of this part of
ISO 10993 and ISO 10993-11 shall
be fulfilled.
General Note: Presumption of conformity depends on also complying with all relevant
clauses/subclauses of ISO 10993-1.
WARNING 1 — Presumption of conformity stays valid only as long as a reference to this European
Standard is maintained in the list published in the Official Journal of the European Union. Users of this
standard should consult frequently the latest list published in the Official Journal of the European
Union.
WARNING 2 — Other Union legislation may be applicable to the products falling within the scope of this
standard.
8
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SIST EN ISO 10993-6:2017
INTERNATIONAL ISO
STANDARD 10993-6
Third edition
2016-12-01
Biological evaluation of medical
devices —
Part 6:
Tests for local effects after
implantation
Évaluation biologique des dispositifs médicaux —
Partie 6: Essais concernant les effets locaux après implantation
Reference number
ISO 10993-6:2016(E)
©
ISO 2016
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SIST EN ISO 10993-6:2017
ISO 10993-6:2016(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2016, Published in Switzerland
All rights reserved. Unless otherwise specified, no part of this publication may be reproduced or utilized otherwise in any form
or by any means, electronic or mechanical, including photocopying, or posting on the internet or an intranet, without prior
written permission. Permission can be requested from either ISO at the address below or ISO’s member body in the country of
the requester.
ISO copyright office
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Tel. +41 22 749 01 11
Fax +41 22 749 09 47
copyright@iso.org
www.iso.org
ii © ISO 2016 – All rights reserved
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SIST EN ISO 10993-6:2017
ISO 10993-6:2016(E)
Contents Page
Foreword .iv
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 2
4 Common provisions for implantation test methods . 2
5 Test methods, general aspects. 4
6 Test report . 9
6.1 General . 9
6.2 Test laboratory . 9
6.3 Implant samples . 9
6.4 Animals and implantation . 9
6.5 Retrieval and histological procedure .10
6.6 Macroscopic and microscopic evaluation .10
6.7 Final evaluation .10
Annex A (normative) Test methods for implantation in subcutaneous tissue .11
Annex B (normative) Test method for implantation in muscle .13
Annex C (normative) Test method for implantation in bone .15
Annex D (normative) Test method for implantation in brain tissue .18
Annex E (informative) Examples of evaluation of local biological effects after implantation .23
Bibliography .27
© ISO 2016 – All rights reserved iii
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SIST EN ISO 10993-6:2017
ISO 10993-6:2016(E)
Foreword
ISO (the International Organization for Standardization) is a worldwide federation of national standards
bodies (ISO member bodies). 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 non-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.
The procedures used to develop this document and those intended for its further maintenance are
described in the ISO/IEC Directives, Part 1. In particular the different approval criteria needed for the
different types of ISO documents should be noted. This document was drafted in accordance with the
editorial rules of the ISO/IEC Directives, Part 2 (see www.iso.org/directives).
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of
any patent rights identified during the development of the document will be in the Introduction and/or
on the ISO list of patent declarations received (see www.iso.org/patents).
Any trade name used in this document is information given for the convenience of users and does not
constitute an endorsement.
For an explanation on the meaning of ISO specific terms and expressions related to conformity
assessment, as well as information about ISO’s adherence to the WTO principles in the Technical
Barriers to Trade (TBT) see the following URL: Foreword - Supplementary information
The committee responsible for this document is ISO/TC 194, Biological and clinical evaluation of medical
devices.
This third edition cancels and replaces the second edition (ISO 10993-6:2007), which has been
technically revised with the following changes:
a) addition of guidance on biological evaluation of absorbable medical devices;
b) new Annex D.
ISO 10993 consists of the following parts, under the general title Biological evaluation of medical devices:
— Part 1: Evaluation and testing within a risk management process
— Part 2: Animal welfare requirements
— Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity
— Part 4: Selection of tests for interactions with blood
— Part 6: Tests for local effects after implantation
— Part 7: Ethylene oxide sterilization residuals
— Part 9: Framework for identification and quantification of potential degradation products
— Part 10: Tests for irritation and skin sensitization
— Part 11: Tests for systemic toxicity
— Part 12: Sample preparation and reference materials
— Part 13: Identification and quantification of degradation products from polymeric medical devices
— Part 14: Identification and quantification of degradation products from ceramics
iv © ISO 2016 – All rights reserved
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SIST EN ISO 10993-6:2017
ISO 10993-6:2016(E)
— Part 15: Identification and quantification of degradation products from metals and alloys
— Part 16: Toxicokinetic study design for degradation products and leachables
— Part 17: Establishment of allowable limits for leachable substances
— Part 18: Chemical characterization of materials
— Part 19: Physico-chemical, morphological and topographical characterization of materials [Technical
specification]
— Part 20: Principles and methods for immunotoxicology testing of medical devices [Technical
specification]
— Part 33: Guidance on tests to evaluate genotoxicity — Supplement to ISO 10993-3 [Technical Report]
The following parts are under preparation:
— Part 5: Tests for in vitro cytotoxicity
© ISO 2016 – All rights reserved v
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SIST EN ISO 10993-6:2017
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SIST EN ISO 10993-6:2017
INTERNATIONAL STANDARD ISO 10993-6:2016(E)
Biological evaluation of medical devices —
Part 6:
Tests for local effects after implantation
1 Scope
This part of ISO 10993 specifies test methods for the assessment of the local effects after implantation
of biomaterials intended for use in medical devices.
This part of ISO 10993 applies to materials that are
— solid and non-absorbable,
— non-solid, such as porous materials, liquids, gels, pastes, and particulates, and
— degradable and/or absorbable, which may be solid or non-solid.
The test sample is implanted into a site and animal species appropriate for the evaluation of the
biological safety of the material. These implantation tests are not intended to evaluate or determine the
performance of the test sample in terms of mechanical or functional loading. This part of ISO 10993 can
also be applied to medical devices that are intended to be used topically in clinical indications where
the surface or lining might have been breached, in order to evaluate local tissue responses.
The local effects are evaluated by a comparison of the tissue response caused by a test sample to that
caused by control materials used in medical devices whose clinical acceptability and biocompatibility
characteristics have been established. The objective of the test methods is to characterize the history
and evolution of the tissue response after implantation of a medical device/biomaterial including
final integration or absorption/degradation of the material. In particular for degradable/absorbable
materials, the degradation characteristics of the material and the resulting tissue response should be
determined.
This part of ISO 10993 does not deal with systemic toxicity, carcinogenicity, teratogenicity or
mutagenicity. However, the long-term implantation studies intended for evaluation of local biological
effects might provide insight into some of these properties. Systemic toxicity studies conducted by
implantation might satisfy the requirements of this part of ISO 10993. When conducting combined
studies for evaluating local effects and systemic effects, the requirements of both standards is to be
fulfilled.
2 Normative references
The following documents, in whole or in part, are normatively referenced in this document and are
indispensable for its application. For dated references, only the edition cited applies. For undated
references, the latest edition of the referenced document (including any amendments) applies.
ISO 10993-1, Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk
management process
ISO 10993-2, Biological evaluation of medical devices — Part 2: Animal welfare requirements
ISO 10993-4, Biological evaluation of medical devices — Part 4: Selection of tests for interactions with blood
ISO 10993-12, Biological evaluation of medical devices — Part 12: Sample preparation and reference
materials
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SIST EN ISO 10993-6:2017
ISO 10993-6:2016(E)
ISO 10993-16, Biological evaluation of medical devices — Part 16: Toxicokinetic study design for
degradation products and leachables
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 10993-1, ISO 10993-2,
ISO 10993-12, ISO 10993-16 and the following apply.
3.1
absorb/absorption
action of a non-endogenous (foreign) material or substance, or its decomposition products passing
through or being assimilated by cells and/or tissue over time
3.2
degradation
decomposition of a material
[SOURCE: ISO 10993-9:2009, 3.1]
3.3
degradation product
any intermediate or final by-product which results from the physical, metabolic, and/or chemical
decomposition of a material or substance
[SOURCE: ISO/TR 37137:2014, 2.2, modified]
3.4
degrade
to physically, metabolically, and/or chemically decompose a material or substance
[SOURCE: ISO/TR 37137:2014, 2.3]
3.5
biomaterial
material or substance intended to interface with biological systems to evaluate, treat, augment or
replace any tissue, organ or function of the body.
[SOURCE: European Society Biomaterials Conference II]
4 Common provisions for implantation test methods
4.1 General
It is important that the study be planned in sufficient detail such that all relevant information can be
extracted from the use of each animal and each study (see ISO 10993-2, ISO 10993-11 and ISO 10993-16).
All animal studies shall be performed in a facility approved by a nationally recognized organization and
in accordance with all appropriate regulations dealing with laboratory animal welfare to comply with
the requirements of ISO 10993-2. These studies shall be performed under good laboratory practices or
other recognized, quality assurance systems.
The provisions of this Clause shall apply to the test methods specified in Annex A, Annex B, Annex C,
and Annex D.
4.2 Preparation of samples for implantation
4.2.1 Test sample and reference or control material preparation shall be in accordance with ISO 10993-
12. The implant size and shape shall be documented and justified. Test samples for various implant sites
are described in Annex A, Annex B, Annex C, and Annex D. Physical characteristics (such as form, density,
2 © ISO 2016 – All rights reserved
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SIST EN ISO 10993-6:2017
ISO 10993-6:2016(E)
hardness, surface) can influence the character of the tissue response to the test material and shall be
recorded and taken into account when the response is characterized. Control articles should be matched
as closely as reasonably possible for physical characteristics.
4.2.2 Each im
...
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Biological evaluation of medical devices - Part 6: Tests for local effects after implantation
(ISO/DIS 10993-6:2014)
Biologische Beurteilung von Medizinprodukten - Teil 6: Prüfungen auf lokale Effekte nach
Implantationen (ISO/DIS 10993-6:2014)
Évaluation biologique des dispositifs médicaux - Partie 6: Essais concernant les effets
locaux après implantation (ISO/DIS 10993-6:2014)
Ta slovenski standard je istoveten z: prEN ISO 10993-6
ICS:
11.100.20 %LRORãNRRYUHGQRWHQMH Biological evaluation of
PHGLFLQVNLKSULSRPRþNRY medical devices
oSIST prEN ISO 10993-6:2015 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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oSIST prEN ISO 10993-6:2015
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oSIST prEN ISO 10993-6:2015
DRAFT INTERNATIONAL STANDARD
ISO/DIS 10993-6
ISO/TC 194 Secretariat: DIN
Voting begins on: Voting terminates on:
2014-10-16 2015-03-16
Biological evaluation of medical devices —
Part 6:
Tests for local effects after implantation
Évaluation biologique des dispositifs médicaux —
Partie 6: Essais concernant les effets locaux après implantation
ICS: 11.100.20
ISO/CEN PARALLEL PROCESSING
This draft has been developed within the International Organization for
Standardization (ISO), and processed under the ISO lead mode of collaboration
as defined in the Vienna Agreement.
This draft is hereby submitted to the ISO member bodies and to the CEN member
bodies for a parallel five month enquiry.
Should this draft be accepted, a final draft, established on the basis of comments
received, will be submitted to a parallel two-month approval vote in ISO and
THIS DOCUMENT IS A DRAFT CIRCULATED
formal vote in CEN.
FOR COMMENT AND APPROVAL. IT IS
THEREFORE SUBJECT TO CHANGE AND MAY
NOT BE REFERRED TO AS AN INTERNATIONAL
STANDARD UNTIL PUBLISHED AS SUCH.
To expedite distribution, this document is circulated as received from the
IN ADDITION TO THEIR EVALUATION AS
committee secretariat. ISO Central Secretariat work of editing and text
BEING ACCEPTABLE FOR INDUSTRIAL,
composition will be undertaken at publication stage.
TECHNOLOGICAL, COMMERCIAL AND
USER PURPOSES, DRAFT INTERNATIONAL
STANDARDS MAY ON OCCASION HAVE TO
BE CONSIDERED IN THE LIGHT OF THEIR
POTENTIAL TO BECOME STANDARDS TO
WHICH REFERENCE MAY BE MADE IN
Reference number
NATIONAL REGULATIONS.
ISO/DIS 10993-6:2014(E)
RECIPIENTS OF THIS DRAFT ARE INVITED
TO SUBMIT, WITH THEIR COMMENTS,
NOTIFICATION OF ANY RELEVANT PATENT
RIGHTS OF WHICH THEY ARE AWARE AND TO
©
PROVIDE SUPPORTING DOCUMENTATION. ISO 2014
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oSIST prEN ISO 10993-6:2015
ISO/DIS 10993-6:2014(E)
Copyright notice
This ISO document is a Draft International Standard and is copyright-protected by ISO. Except as
permitted under the applicable laws of the user’s country, neither this ISO draft nor any extract
from it may be reproduced, stored in a retrieval system or transmitted in any form or by any means,
electronic, photocopying, recording or otherwise, without prior written permission being secured.
Requests for permission to reproduce should be addressed to either ISO at the address below or ISO’s
member body in the country of the requester.
ISO copyright office
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Tel. + 41 22 749 01 11
Fax + 41 22 749 09 47
E-mail copyright@iso.org
Web www.iso.org
Reproduction may be subject to royalty payments or a licensing agreement.
Violators may be prosecuted.
ii © ISO 2014 – All rights reserved
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oSIST prEN ISO 10993-6:2015
ISO/DIS 10993-6:2014(E)
Contents Page
Foreword .iv
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 2
4 Common provisions for implantation test methods . 2
4.1 General . 2
4.2 Preparation of samples for implantation . 2
4.3 Study design . 3
5 Test methods, general aspects. 3
5.1 Tissue and implantation site . 3
5.2 Animals . 4
5.3 Test periods . 4
5.4 Surgery and testing conditions . 6
5.5 Evaluation . 6
6 Test report . 8
6.1 General . 8
6.2 Test laboratory . 8
6.3 Implant samples . 8
6.4 Animals and implantation . 9
6.5 Retrieval and histological procedure . 9
6.6 Macroscopic and microscopic evaluation . 9
6.7 Final evaluation . 9
Annex A (normative) Test methods for implantation in subcutaneous tissue .10
Annex B (normative) Test method for implantation in muscle .12
Annex C (normative) Test method for implantation in bone .14
Annex D (normative) Test method for implantation in central nervous system (neural) tissue .17
Annex E (normative) Examples of evaluation of local biological effects after implantation .22
Bibliography .26
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oSIST prEN ISO 10993-6:2015
ISO/DIS 10993-6:2014(E)
Foreword
ISO (the International Organization for Standardization) is a worldwide federation of national standards
bodies (ISO member bodies). 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 non-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.
The procedures used to develop this document and those intended for its further maintenance are
described in the ISO/IEC Directives, Part 1. In particular the different approval criteria needed for the
different types of ISO documents should be noted. This document was drafted in accordance with the
editorial rules of the ISO/IEC Directives, Part 2, see www.iso.org/directives.
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of any
patent rights identified during the development of the document will be in the Introduction and/or on
the ISO list of patent declarations received, see www.iso.org/patents.
Any trade name used in this document is information given for the convenience of users and does not
constitute an endorsement.
The committee responsible for this document is ISO/TC 194.
The major technical changes are the following:
a)
b)
c)
d)
e)
ISO 10993 consists of the following parts, under the general title Biological evaluation of medical devices:
Part 1: Evaluation and testing within a risk management system
Part 2: Animal welfare requirements
Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity
Part 4: Selection of tests for interactions with blood
Part 5: Tests for in vitro cytotoxicity
Part 6: Tests for local effects after implantation
Part 7: Ethylene oxide sterilization residuals
Part 9: Framework for identification and quantification of potential degradation products
Part 10: Tests for irritation and delayed-type hypersensitivity
Part 11: Tests for systemic toxicity
Part 12: Sample preparation and reference materials
Part 13: Identification and quantification of degradation products from polymeric medical devices
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oSIST prEN ISO 10993-6:2015
ISO/DIS 10993-6:2014(E)
Part 14: Identification and quantification of degradation products from ceramics
Part 15: Identification and quantification of degradation products from metals and alloys
Part 16: Toxicokinetic study design for degradation products and leachables
Part 17: Establishment of allowable limits for leachable substances
Part 18: Chemical characterization of materials
Part 19: Physico-chemical, morphological and topographical characterization of materials (Technical
specification)
Part 20: Principles and methods for immunotoxicology testing of medical devices (Technical specification)
Part 33: Supplement to ISO 10993-3:— Guidance on tests to evaluate genotoxicity [Technical Report]
The following definitions apply in understanding how to implement an ISO International Standard and
other normative ISO deliverables (TS, PAS, IWA).
— “shall” indicates a requirement
— “should” indicates a recommendation
— “may” is used to indicate that something is permitted
— “can” is used to indicate that something is possible, for example, that an organization or individual
is able to do something
In 3.3.1 of the ISO/IEC Directives, Part 2 (sixth edition, 2011) defines a requirement as an “expression
in the content of a document conveying criteria to be fulfilled if compliance with the document is to be
claimed and from which no deviation is permitted.”
In 3.3.2 of the ISO/IEC Directives, Part 2 (sixth edition, 2011) defines a recommendation as an
“expression in the content of a document conveying that among several possibilities one is recommended
as particularly suitable, without mentioning or excluding others, or that a certain course of action is
preferred but not necessarily required, or that (in the negative form) a certain possibility or course of
action is deprecated but not prohibited.”
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oSIST prEN ISO 10993-6:2015
DRAFT INTERNATIONAL STANDARD ISO/DIS 10993-6:2014(E)
Biological evaluation of medical devices —
Part 6:
Tests for local effects after implantation
1 Scope
This part of ISO 10993 specifies test methods for the assessment of the local effects after implantation
of biomaterials intended for use in medical devices.
This part of ISO 10993 applies to materials that are:
— solid and non- absorbable;
— degradable and/or absorbable;
— non-solid, such as porous materials, liquids, gels, pastes and particulates.
The test sample is implanted into a site and animal species appropriate for the evaluation of the
biological safety of the material. These implantation tests are not intended to evaluate or determine the
performance of the test sample in terms of mechanical or functional loading. This part of ISO 10993 may
also be applied to medical devices that are intended to be used topically in clinical indications where the
surface or lining may have been breached, in order to evaluate local tissue responses.
The local effects are evaluated by a comparison of the tissue response caused by a test sample to that
caused by control materials used in medical devices of which the clinical acceptabilit y and biocompatibilit y
characteristics have been established. The objective of the test methods is to characterize the history
and evolution of the tissue response after implantation of a medical device/biomaterial including final
integration or absorption/degradation of the material. In particular for degradable/absorbable materials
the degradation characteristics of the material and the resulting tissue response should be determined.
This part of ISO 10993 does not deal with systemic toxicity, carcinogenicity, teratogenicity or mutagenicity.
However, the long-term implantation studies intended for evaluation of local biological effects may
provide insight into some of these properties. Systemic toxicity studies conducted by implantation may
satisfy the requirements of this part of ISO 10993. When conducting combined studies for evaluating
local effects and systemic effects, the requirements of both standards shall be fulfilled.
2 Normative references
The following documents, in whole or in part, are normatively referenced in this document and are
indispensable for its application. For dated references, only the edition cited applies. For undated
references, the latest edition of the referenced document (including any amendments) applies.
ISO 10993-1:2009, Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk
management process
ISO 10993-2, Biological evaluation of medical devices — Part 2: Animal welfare requirements
ISO 10993-11, Biological evaluation of medical devices — Part 11: Tests for systemic toxicity
ISO 10993-12, Biological evaluation of medical devices — Part 12: Sample preparation and reference
materials
ISO 10993-16, Biological evaluation of medical devices — Part 16: Toxicokinetic study design for degradation
products and leachables
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ISO/DIS 10993-6:2014(E)
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 10993-1, ISO 10993-2,
ISO 10993-12, ISO 10993-16 and the following apply.
3.1
absorb
in biomaterials, action of a non-endogenous (foreign) material or substance passing through or being
assimilated by cells and/or tissue over time
3.2
degradation
decomposition of a material
[SOURCE: ISO 10993-9:1999, definition 3.1]
3.3
degradation product
any intermediate or final result from the physical, metabolic, and/or chemical decomposition
of a material or substance
[SOURCE: ISO/TR 37137:2014, definition 2.2]
3.4
degrade
to physically, metabolically, and/or chemically decompose a material or substance
[SOURCE: ISO/TR 37137:2014, definition 2.3]
3.5
biomaterial
material intended to interface with biological systems to evaluate, treat, augment or replace any tissue,
organ or function of the body
[SOURCE: European Society Biomaterials Conference II]
4 Common provisions for implantation test methods
4.1 General
It is important that the study be planned in sufficient detail such that all relevant information can be
extracted from the use of each animal and each study (see ISO 10993-2, ISO 10993-11 and ISO 10993-16).
All animal studies shall be performed in a facility approved by a nationally recognized organization and
in accordance with all appropriate regulations dealing with laboratory animal welfare. These studies
shall be performed under good laboratory practices or other recognized quality assurance systems, and
comply with the requirements of ISO 10993-2.
The provisions of this clause shall apply to the test methods specified in Annex A, Annex B, Annex C, and
Annex D.
4.2 Preparation of samples for implantation
Test sample and reference or control material preparation shall be in compliance with ISO 10993-12.
The implant size and shape shall be documented and justified. Test samples for various implant sites are
described in Annex A, Annex B, Annex C, and Annex D. Physical characteristics (such as form, density,
hardness, surface) can influence the character of the tissue response to the test material and shall be
recorded and taken into account when the response is characterized.
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Each implant shall be manufactured, processed, cleaned of contaminants and sterilized by the method
intended for the final product and this shall be confirmed in the study documentation. After final
preparation and sterilization, the implant specimens shall be handled aseptically and in such a way as
to ensure that they are not damaged or contaminated in any way prior to or during implantation.
For materials used as scaffolds for tissue-engineered medical products, it may be appropriate not to
use the final preparation pre-populated with cells, as the immune reaction of the animal to the cellular
components of such products and the reaction of the cells to the animal, may interfere with the resulting
local tissue response.
For composite materials (e.g. bone cements, dental materials) the components may be mixed before
use and allowed to set before implantation. However, materials that are designed for use in devices
with in situ polymerization shall be introduced in a manner such that in situ polymerization occurs. The
procedure used shall be documented and justified.
Non-solid materials (including powders) may be contained in open-ended cylindrical tubes for the
purpose of testing for local effects after implantation (see ISO 10993-12 for the selection of materials for
tubes). Prepare the test material according to the manufacturer’s instructions and insert the material
into the tube until level with the end, taking care not to contaminate the outer surface of the tube with
the test material; if contamination occurs the sample shall not be implanted. Avoid entrapment of air
in the tube and ensure that the end surfaces of the inserted material in the tube and the tube ends are
smooth.
NOTE 1 Polyethylene (PE), polypropylene (PP) or polytetrafluoroethylene (PTFE) tubes are commonly used
for this purpose. PE tubes can be deformed by autoclaving. PTFE tubes are difficult to section in the microtome,
and substitution by PE or PP tubes of the same dimensions can be preferable when the tubes are to remain in the
tissue blocks during sectioning.
Evaluation shall be performed by comparing to the tissue reaction to that of a similar sample/material
of which the clinical acceptability and biocompatibility characteristics have been established.
NOTE 2 For further guidance, see ISO 10993-12.
The physical characteristics such as shape, and especially the surface condition of the control(s), shall
be as similar to that of the implant test samples as is practically possible, with any deviations being
explained and justified. When the test material is contained in a tube, the control shall be of the same
material as the tube and have the same diameter as the outer diameter of the tube. The choice of the
control rod or tube shall be documented and justified.
For implantation studies the amount or size of the test and control article shall be documented.
4.3 Study design
For devices comprised of 2 or more different materials, the test articles should be of similar composition
or multiple implants may be needed e.g. if a device is made of HDPE and titanium then the test article
should be made of HDPE and titanium or separate HDPE and titanium coupons should be implanted
5 Test methods, general aspects
5.1 Tissue and implantation site
The test sample shall be implanted into the tissues most relevant to the intended clinical use of the
material. The justification for the choice of sample numbers, tissue and implantation sites shall be
documented. Test methods for various implantation sites are given in Annex A, Annex B, Annex C, and
Annex D. If other implantation sites are chosen, the general scientific principles behind the test methods
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oSIST prEN ISO 10993-6:2015
ISO/DIS 10993-6:2014(E)
described in Annex A, Annex B, Annex C, and Annex D shall still be adhered to and the justification
provided.
NOTE For some devices there may be vertical standards prescribing specific implant studies to evaluate
[47] [12]
local responses, e.g. intraocular lens implant and dental usage tests . These studies may be used to satisfy
the requirements in ISO 10993-6.
For absorbable materials, the implantation site shall be marked in a manner suitable for identification
of the site at the end of the designated time periods. The use of a non-invasive permanent skin marker
and/or a template marking the placement of the sample is recommended for short-term study intervals
only. In most circumstances an appropriate non-absorbable negative control (e.g. HDPE 1 mm by 2 mm
by 5 mm, PP suture, gold band) may be used as a marker for the location of the implant site. These
location markers can be removed without inducing artefacts to the test article-tissue interface prior to
histology processing.
Exceptionally, a sham surgical procedure might be used to evaluate the impact of the procedure on the
tissue involved; in these cases the specific justification shall be provided.
5.2 Animals
All aspects of animal care and accommodation shall be in accordance with ISO 10993-2. In general, small
laboratory animals such as mice, rats, hamsters or rabbits are preferred.
The use of larger animals may be justified based upon special scientific considerations of the particular
biomaterial under study, or if needed to accommodate implant size with whole device testing.
Select an animal species in line with the principles set out in ISO 10993-2, giving due consideration to
the size of the implant test samples, the number of implants per animal, the intended duration of the test
in relation to the expected lifespan of the animals, as well as potential species’ differences regarding
biological response
For short-term testing, animals such as rodents or rabbits are commonly used. For long-term testing,
animals such as rodents, rabbits, dogs, sheep, goats, pigs and other animals with a relatively long life
expectancy are suitable.
Before starting an animal study with degradable materials, relevant information from in vitro degradation
studies should be considered. For biodegradable materials a pilot study in rodents may be considered to
determine the expected rate of degradation before embarking on studies on larger animals.
The specimens of test and control materials shall be implanted under the same conditions in animals of
the same species and of the same age, sex and strain in corresponding anatomical sites. The number and
size of implants inserted in an animal depends on the size of the species and the anatomical location.
Whenever possible, the reference control and the test samples should be implanted into the same animal.
However, when the local effects after implantation are investigated as part of a systemic toxicity study
by implantation, control and test samples should not be placed in the same animal.
5.3 Test periods
The test period shall be determined by the likely clinical exposure time or be continued until or beyond
a steady-state has been reached with respect to the biological response. The time points selected shall
be explained and justified.
For non-absorbable materials the short-term responses are normally assessed from 1 week up to 4 weeks
and the long-term responses in tests exceeding 12 weeks. The local biological response to implanted
materials depends both on the properties of the materials and on the response to the associated trauma
of surgery. The tissue configuration in the vicinity of an implant changes with the time elapsed after
surgery. During the first two weeks after implantation the reaction due to the surgical procedure itself
may be difficult to distinguish from the tissue reaction evoked by the implant. In muscle and connective
tissue, depending on the species, and the severity of the surgical trauma, a steady-state is seen in the cell
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population after 9 weeks to 12 weeks. Implantation in bone tissue may need longer observation periods
before a steady-state is reached. In general, it is expected that experiments that go up to or beyond the
point of absorption are needed for the evaluation of degradable materials.
For absorbable materials the test period shall be related to the estimated degradation time of the test
product. When determining the time points for sample evaluation, an estimation of the degradation
time shall be made. This can be accomplished in vitro by real-time or accelerated degradation studies
or in certain circumstances by mathematical modelling. In general, experiments that extend up to or
beyond the point of absorption are needed. The evaluation period for absorbable materials will depend
in part on the degradation rate of the materials. Study intervals should span a significant portion of the
degradation time frame for the implant, and shall include the following minimum time points:
a) Early Time Frame (Where there is no or minimal degradation) — For absorbable materials, usually
a study interval of between 1 and 2 weeks post-implantation should be evaluated to assess the early
tissue response.
b) Mid Time Frame (When degradation is taking place) — Subsequent study intervals for absorbable
devices should be selected based on the degradation profile of the specific absorbable material.
The target interval should allow assessment of histological response when the tissue response is
expected to be most pronounced (e.g. substantial structural disruption and/or fragmentation of
the device is most likely to occur). Implants with longer-term degradation profiles might require
additional assessment time points, with intervals targeted in accordance with the expected pattern
of degradation.
When a device with multiple materials with differing absorption rates is implanted, implant intervals
reflecting the degradation profile of those components should be included.
c) Late Time Frame (When the implant is essentially absorbed) — This interval is targeted to observe
when minimal amounts of the absorbable component remain at the implant site.
Gross and microscopic evaluation after complete implant absorption is highly desirable. However, in the
absence of complete a
...
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