Biological evaluation of medical devices - Part 6: Tests for local effects after implantation
1 Scope
This document specifies test methods for the assessment of the local effects after implantation of biomaterials intended for use in medical devices.
This document applies to materials that are
——solid and non-solid, such as porous materials, liquids, gels, pastes, and particulates, and
——non-absorbable, and
——degradable and/or absorbable, which may be solid or non-solid.
This document 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.
Note 1: The test sample is implanted into a site and animal species appropriate for the evaluation of the biological safety of the material. 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. 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.
These implantation tests are not intended to evaluate or determine the performance of the test sample in terms of mechanical or functional loading.
This document does not deal with systemic toxicity, carcinogenicity, teratogenicity or mutagenicity.
Note 2: The long-term implantation studies intended for evaluation of local biological effects might provide insight into some information about systemic toxicity, carcinogenicity, teratogenicity or mutagenicity. Systemic toxicity studies conducted by implantation might satisfy the requirements of this document. 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 normative documents contain provisions which, through reference in this text, constitute indispensable provisions of this document. For dated references, only the edition cited applies. For undated references, the latest edition (including any amendments) applies.
ISO 10993-1 Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process
Note: GB/T 16886.1-2022 Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process (ISO 10993-1: 2018, IDT).
ISO 10993-2 Biological evaluation of medical devices - Part 2: Animal welfare requirements
Note: GB/T 16886.2-2011 Biological evaluation of medical devices - Part 2: Animal welfare requirements (ISO 10993-2: 2006, IDT).
ISO 10993-4 Biological evaluation of medical devices - Part 4: Selection of tests for interactions with blood
Note: GB/T 16886.4-2022 Biological evaluation of medical devices - Part 4: Selection of tests for interactions with blood (ISO 10993-4:2017, IDT)
ISO 10993-12 Biological evaluation of medical devices - Part 12: Sample preparation and reference materials
Note: GB/T 16886.12-2017 Biological evaluation of medical devices - Part 12: Sample preparation and reference materials (ISO 10993-12:2012, IDT)
ISO 10993-16 Biological evaluation of medical devices - Part 16: Toxicokinetic study design for degradation products and leachables
Note: GB/T 16886.16-2021 Biological evaluation of medical devices - Part 16: Toxicokinetic study design for degradation products and leachables (ISO 10993-16:2017, IDT)
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, 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 implant sample 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 samples 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.
4.2.3 For materials used as scaffolds for tissue-engineered medical products, it may be appropriate not to use the final preparation pre-populated with cells and/or proteins, as the immune reaction of the animal to the cellular/protein components of such products and the reaction of the cells to the animal may interfere with the resulting local tissue response, making it difficult to interpret.
4.2.4 For composite materials (e.g. bone cements, dental materials), the components may be mixed before use and allowed to set before implantation. For multicomponent materials designed to be cured prior to placement, the components may be mixed before use and allowed to set before implantation. However, materials that are designed to polymerize in situ (e.g. bone cements, many dental materials) shall be introduced in a manner such that in situ polymerization occurs. The procedure used shall be documented and justified.
4.2.5 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.
Polyethylene (PE), polypropylene (PP), or polytetrafluoroethylene (PTFE) tubes are commonly used for this purpose. PE tubes can be deformed by autoclaving.
4.2.6 Evaluation shall be performed by comparing the tissue reaction to that of a similar sample/material whose clinical acceptability and biocompatibility characteristics have been established.
Note: For further guidance, see ISO 10993-12.
4.2.7 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 practical, 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.
4.2.8 For implantation studies, the amount or size of the test and control sample shall be documented.
4.3 Study design
For devices comprising/composed of two 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.
5 Test methods, general aspects
5.1 Tissue and implantation site
5.1.1 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 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 are vertical standards prescribing specific implant studies to evaluate local tissue responses, e.g. intraocular lens implant and dental usage tests. These studies can be used to satisfy the requirements in this document.
5.1.2 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, a location marker comprised of an appropriate nonabsorbable negative control (e.g. HDPE 1mm by 2mm by 5mm, PP suture, gold band, clips) may be used to identify 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
5.2.1 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.
5.2.2 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.
5.2.3 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.
5.2.4 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.
5.2.5 Before starting an animal study with degradable materials, relevant information from in vitro degradation studies should be considered. For absorbable materials, a pilot study in rodents may be considered to determine the expected rate of degradation before embarking on studies on larger animals.
5.2.6 The samples 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 into 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.
5.2.7 However, when a neuroimplantation study (see Annex D) is conducted or when the local effects after implantation are investigated as part of a systemic toxicity study by implantation, control and test samples shall not be placed in the same animal.
5.3 Test periods
5.3.1 The test period shall be determined by the likely clinical exposure time or be continued until or beyond when a steady-state with respect to the biological response has been reached. The time points selected shall be explained and justified.
5.3.2 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 population after 9 weeks to 12 weeks. Implantation in bone tissue may need longer observation periods before a steady-state is reached.
5.3.3 For absorbable materials, the test period shall be related to the estimated degradation time of the test product at a clinically relevant implantation site. 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, study duration should extend up to or beyond the point of complete absorption. 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, as a minimum, the following time points:
a) early time frame (where there is no or minimal degradation)——For absorbable materials, usually a study interval of between 1 week and 2 weeks post-implantation should be used to assess the early tissue response.
b) mid time frame (when degradation is taking place)——Subsequent study intervals for absorbable devices should be guided by 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 may require multiple assessment time points, with intervals targeted in accordance with the expected pattern of degradation.
c) when a device with multiple materials with differing absorption rates is implanted, implant intervals reflecting the degradation profile of those components should be included.
d) 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 absorption, the overall data collected should be sufficient to allow characterization of the local effects after implantation if:
——the affected tissue’s response, structure, and function have achieved an acceptable steady-state condition, and
——the absorbable material and/or its degradation products are in a state of limited visually-identifiable presence.
Foreword i
Introduction iii
1 Scope
2 Normative references
3 Terms and definitions
4 Common provisions for implantation test methods
5 Test methods, general aspects
6 Test report
Annex A (Normative) Test methods for implantation in subcutaneous tissue
Annex B (Normative) Test method for implantation in muscle
Annex C (Normative) Test method for implantation in bone
Annex D (Normative) Test methods for implantation in brain tissue
Annex E (Informative) Examples of evaluation of local biological effects after implantation
Bibliography
医疗器械生物学评价 第6部分：植入后局部反应试验
1 范围
本文件规定了用于评估医疗器械所用生物材料植入后局部反应的试验方法。
本文件适用于下列材料：
——固形和非固形材料，如多孔材料、液体、胶状、膏状和颗粒材料，
——非吸收性材料，和
——可降解和/或可吸收性固形或非固形材料。
本文件也适用于评价临床上预期用于局部损伤表面或损伤内表面的医疗器械产生的局部组织反应。
注1：将试验样品植入适宜种属的动物和部位以评价材料的生物学安全性，其目的为表征医疗器械/生物材料植入后组织反应的进程和演变，包括材料最终的组织整合或吸收/降解，尤其对可降解/可吸收性材料，确定材料的降解特性以及所产生的组织反应。通过比较试验样品与已确立临床可接受性和生物相容性的医疗器械所用对照材料产生的组织反应，对局部反应进行评价。
本文件不适用于预期评价或测定试验样品在机械或功能负荷方面的性能的植入试验。
本文件不涉及全身毒性、致癌性、致畸性或致突变性。
注2：用来评价局部生物学反应的长期植入研究可能提供全身毒性、致癌性、致畸性或致突变性方面的一些信息。通过植入进行的全身毒性研究可能满足本文件的要求。当进行联合研究来评价局部反应和全身反应时，两个文件的要求都要满足。
2 规范性引用文件
下列文件中的内容通过文中的规范性引用而构成本文件必不可少的条款。其中，注日期的引用文件，仅该日期对应的版本适用于本文件；不注日期的引用文件，其最新版本(包括所有的修改单)适用于本文件。
ISO 10993-1 医疗器械生物学评价 第1部分：风险管理过程中的评价与试验(Biological evaluation of medical devices—Part 1：Evaluation and testing within a risk management process)
注：GB/T 16886.1—2022 医疗器械生物学评价 第1部分：风险管理过程中的评价与试验(ISO 10993-1：2018，IDT)。
ISO 10993-2 医疗器械生物学评价 第2部分：动物福利要求(Biological evaluation of medical devices—Part 2：Animal welfare requirements)
注：GB/T 16886.2—2011 医疗器械生物学评价 第2部分：动物福利要求(ISO 10993-2：2006，IDT)。
ISO 10993-4 医疗器械生物学评价 第4部分：与血液相互作用试验选择(Biological evaluation of medical devices—Part 4：Selection of tests for interactions with blood)
注：GB/T 16886.4—2022 医疗 器械生物学评价 第4部分：与血液相互作用试验选择(ISO 10993-4：2017，IDT)。
ISO 10993-12 医疗器械生物学评价 第12部分：样品制备与参照材料(Biological evaluation of medical devices—Part 12：Sample preparation and reference materials)
注：GB/T 16886.12—2017 医疗器械生物学评价 第12部分：样品制备与参照材料(ISO 10993-12：2012，IDT)。
ISO 10993-16 医疗器械生物学评价 第16部分：降解产物与可沥滤物毒代动力学研究设计(Biological evaluation of medical devices—Part 16：Toxicokinetic study design for degradation products and leachables)
注：GB/T 16886.16—2021 医疗器械生物学评价 第16部分：降解产物与可沥滤物毒代动力学研究设计(ISO 10993-16：2017，IDT)。
3 术语和定义
ISO 10993-1、ISO 10993-2、ISO 10993-12和ISO 10993-16界定的以及下列术语和定义适用于本文件。
3.1
吸收/吸收性 absorb/absorption
某一非内源性(外部的)材料或物质，或其分解产物逐步通过细胞和/或组织或被细胞和/或组织同化的作用。
3.2
降解 degradation
材料的分解。
[来源：ISO 10993-9：2009，3.1]
3.3
降解产物 degradation product
某一材料或物质由于物理、代谢和/或化学分解而产生的所有中间或最终副产物。
[来源：ISO/TR 37137：2014，2.2，有修改]
3.4
(使)降解 degrade
将某一材料或物质通过物理、代谢和/或化学途径进行分解。
[来源：ISO/TR 37137：2014，2.3]
3.5
生物材料 biomaterial
预期与生物系统相互作用的材料或物质，用于评价、治疗、填充或替代任何人体组织、器官或功能。
[来源：欧洲学会生物材料会议]
4 植入试验方法通则
4.1 总则
充分详细地设计试验方案非常重要，这样能从所用的每只动物和每项研究中获得全部相关信息(见ISO 10993-2、ISO 10993-11和ISO 10993-16)。
所有的动物研究均应在经国家认可机构认可的实验室内进行，并应遵守与实验动物福利有关的全部适用法规，以符合ISO 10993-2的要求，这些研究应在良好实验室质量管理规范或其他经批准的质量保证体系的控制下进行。
附录A、附录B、附录C和附录D中规定的试验方法均应采用本章的规定。
4.2 植入样品的制备
4.2.1 应按照ISO 10993-12制备试验样品和参照或对照材料。植入样品的尺寸和形状应形成文件并进行论证。附录A、附录B、附录C和附录D中给出了各种植入部位的试验样品。物理特性(例如形态密度、硬度、表面)可能影响试验材料组织反应的性质，因此应予以记录并在表征组织反应时考虑这些因素。对照材料宜与试验样品具有尽可能相近的物理特性。
4.2.2 应根据最终产品预期所用方法对每个植入样品进行加工、处理、清洗污染物和灭菌，并应在研究文件中进行确认。植入样品在最终制备和灭菌后，应进行无菌操作，以保证植入样品在植入前和植入时不会以任何方式被损坏或污染。
4.2.3 对于用于组织工程医疗产品的支架材料，可能不宜使用预先装有细胞和/或蛋白质的最终产品，因为动物对这种产品细胞/蛋白质成分产生的免疫反应，以及细胞对动物产生的反应可能会干扰局部组织反应，造成结果难以解释。
4.2.4 对于复合材料(如骨水泥、牙科材料)，在使用之前可能要混合组分，并在植入前进行固化。设计为在放置前固化的多组分材料，可在使用前进行组分混合并在植入前进行固化。但设计用于原位聚合的材料(例如骨水泥、许多牙科材料) ，应以在原位聚合的方式予以植入。应对所使用的步骤形成文件并进行论证。
4.2.5 非固形材料(包括粉剂)可装在两端开口的圆柱形管内用于植入后局部反应试验(见ISO 10993-12中给出的管材选择)。按照制造商的使用说明书制备试验材料，将材料装入管内直至与端口平齐，谨慎操作防止试验材料污染管的外表面；如出现污染不应植入样品。避免空气进入管内，并确保装入管内的材料端口面和管的端口均光滑。
聚乙烯(PE)、聚丙烯(PP)或聚四氟乙烯(PTFE)管常用于本试验。PE管经高压蒸汽处理可能会变形。
4.2.6 应通过与已确立临床可接受性和生物相容性的类似样品/材料的组织反应进行比较来进行评价。
注：详细指南见ISO 10993-12。
4.2.7 对照品的物理特性如形状，特别是表面状况，如实际可行应与植入试验样品相似，任何差异都应说明并论证。如试验材料装入管内，对照品应是与管相同的材料，直径与管的外径相同。对照棒材或管的选择应形成文件并论证。
4.2.8 对于植入研究，应对试验和对照样品的数量或尺寸形成文件记录。
4.3 研究设计
对于包含两种或多种不同材料/由两种或多种不同材料组成的器械，试验样品宜具有相似组分或可能需要多个植入物，例如，如果某一器械由高密度聚乙烯(HDPE)和钛组成，那么试验样品宜由HDPE和钛组成。
5 试验方法的基本要求
5.1 组织与植入部位
5.1.1 试验样品应植入与材料预期临床应用最相关的组织，对样品数量、组织和植入部位的选择理由应形成文件。附录A、附录B、附录C和附录D给出了各种植入部位的试验方法。如选择其他植入部位，仍应遵循附录A、附录B、附录C和附录D给出试验方法的基本科学原理，并进行论证。
注：对于某些器械，具有给出特定植入研究的产品标准来评价局部组织反应，例如，人工晶状体植入物和牙科应用试验。这些研究可用于满足本文件的要求。
5.1.2 对于可吸收性材料，应采用一种适当的方式标记植入部位，用于在特定的时间段结束时识别该部位。推荐仅在间隔较短的研究中使用非侵入持久性的皮肤标记和/或模板标记样品植入位置。在大多数情况下，可采用适宜的非吸收性阴性对照(例如，HDPE 1 mm×2 mm×5 mm，PP缝合线、金线、夹)组成的位置标记物来标记植入位置。这些位置标志物可以在组织学处理之前，在不影响试验样品组织接触面的情况下被移除。
特殊情况下，可采用假手术步骤来评价手术步骤对有关组织的影响；这种情况应提供具体的论证。
5.2 动物
5.2.1 动物管理和饲养应完全执行ISO 10993-2。一般情况下首选小型实验动物，比如小鼠、大鼠、仓鼠或兔。
5.2.2 基于研究中针对具体生物材料的特殊科学考虑，可论证使用较大型动物，或者如果需要调整植入物尺寸，以进行完整器械试验。
5.2.3 动物种属的选择符合ISO 10993-2规定的原则，适当考虑植入试验样品的尺寸、每只动物植入物的数量、根据动物预期寿命确定的试验周期，以及动物种属可能存在的生物学反应差异性。
5.2.4 对于短期试验，通常使用啮齿类动物或兔。对于长期试验，适宜使用啮齿动物、兔、犬、绵羊、山羊、猪及平均寿命相对较长的其他动物。
5.2.5 在开始可降解材料的动物研究之前，宜考虑体外降解研究的相关信息。对于可吸收性材料，在开展较大型动物研究之前，宜先采用啮齿动物进行预试验，以测定材料的预期降解率。
5.2.6 应在同样条件下将试验和对照材料样品植入相同年龄、性别和品系的同一种属动物的对应解剖部位，根据动物种属体型大小和解剖位置情况，确定植入物的数量和尺寸。在可能的情况下，参照/对照样品和试验样品宜植入同一只动物。
5.2.7 然而，当进行神经植入研究(见附录D)，或植入后局部反应是作为通过植入进行全身毒性试验的一部分而被研究时，则不应将对照样品和试验样品植入同一只动物。
5.3 试验周期
5.3.1 应根据临床可能接触时间，或是持续至相应生物学反应达到或超过某一稳定状态的时间，来确定试验周期。所选择的时间点应进行说明和论证。
5.3.2 对于非吸收性材料，短期反应评估一般为1周至4周，长期反应评估则一般超过12周。植入材料的局部生物学反应与材料特性和手术创伤反应有关，术后植入物周围组织结构的改变随时间而变化。植入后的最初2周，可能很难将外科手术所致的反应与植入物引起的组织反应区分开来。在肌肉和结缔组织中，植入后9周至12周时细胞群呈稳定状态，这取决于动物种属和手术创伤的严重程度。在骨组织中，则可能需要较长的观察期才能达到稳定状态。
5.3.3 对于可吸收性材料，试验周期应与试验产品在临床相关植入部位估计的降解时间相关。确定样品评价时间点时，应估算降解时间。这可以通过体外实时或加速降解试验来实现，也可以在某些情况下通过数学模型方法来实现。一般情况下，研究周期宜涵盖或超过材料的完全吸收终点。可吸收性材料的评价周期将部分依赖于材料的降解速率。研究间隔宜跨越植入物降解时间框架的重要部分，并应至少包括下列时间点：
a)早期时间框架(无或微量降解)——对于可吸收性材料，通常宜使用植入后1周和2周之间的一个时间点来评估早期组织反应。
b)中期时间框架(发生降解时)——宜根据特定可吸收性材料的降解特性来指导选择可吸收器械的后续的研究时间间隔。目标时间间隔宜允许评估预期最明显的组织学反应(例如，最有可能发生实质性结构紊乱和/或器械碎裂)。降解时间较长的植入物可能需要多个评估时间点，并根据预期的降解模式确定目标间隔。
c)当植入含有不同吸收速率的复合材料时，植入时间间隔宜包含反映这些组分降解特征的时间间隔。
d)末期时间框架(当植入物基本被吸收时)——该时间间隔是为了在可吸收性组分在植入部位有微量残余时进行观察。
植入物完全吸收后的大体和显微学评价非常重要。然而，在没有完全吸收情况下，如果满足以下条件，则收集到的全部资料宜足以表征植入后的局部反应：
——受影响组织的反应、结构和功能已经达到了一个可接受的稳定状态，和
——可吸收性材料和/或其降解产物处于一种肉眼难以发现的状态。
