ISO 10993 — Part 1 and the FDA-Modified Matrix 第 1 部分和 FDA 修改的矩阵

This guidance considers the assessment of biocompatibility to be an evaluation of the medical device in its final finished form, including sterilization, if applicable. However, sponsors should understand the biocompatibility of each device component and any interactions between components that could occur. This is particularly important when the combination of device components could mask or complicate interpretation of a biocompatibility evaluation. For example, if a metal stent has a polymer coating that may separate over time, then the results of a final device biocompatibility assessment may not fully reflect the longer-term clinical performance of the device, and biocompatibility evaluation of the stent with and without the coating may be needed. Similarly, for an in situ polymerizing and absorbable sealant, where the materials present will change over time, separate evaluations of the pre-polymerized, polymerized, and degrading sealant may be needed.

该指南认为生物相容性评估是对医疗器械在其最终成品形态下（如适用）进行评估，包括灭菌过程。然而，赞助商应了解每个器械组成部分的生物相容性以及可能发生的组分之间的相互作用。当器械组分的组合可能掩盖或使生物相容性评估的解释复杂化时，这一点尤其重要。例如，如果金属支架具有可能随时间分离的聚合物涂层，那么最终器械生物相容性评估的结果可能无法完全反映器械的长期临床表现，因此可能需要对带涂层和不带涂层的支架进行生物相容性评估。同样地，对于在体内聚合和可吸收的止血剂而言，其中材料会随时间变化，可能需要对预聚合、聚合和降解止血剂进行单独评估。

Evaluation of Local and Systemic Risks 局部和系统风险评估

Biological evaluation of medical devices is performed to determine the acceptability of any potential adverse biological response resulting from contact of the component materials of the device with the body. The device materials should not, either directly (e.g., via surface-bound chemicals or physical properties) or through the release of their material constituents: (i) produce adverse local or systemic effects; (ii) be carcinogenic; or (iii) produce adverse reproductive and/or developmental effects, unless it can be determined that the benefits of the use of that material outweigh the risks associated with an adverse biological response. Therefore, evaluation of any new device intended for human use requires information from a systematic analysis to ensure that the benefits provided by the device in its final finished form will outweigh any potential risks produced by device materials over the intended duration and use of the device in or on the exposed tissues.

医疗器械的生物学评估是为了确定器械组分材料与人体接触可能引起的任何潜在不良生物反应的可接受性。无论是直接（例如通过表面化学物质或物理特性）还是通过其材料成分的释放，器械材料都不应：(i) 产生不良的局部或全身效应；(ii) 具有致癌性；或 (iii) 产生不良的生殖和/或发育效应，除非可以确定使用该材料的益处超过与不良生物反应相关的风险。因此，对于任何新的用于人体的器械，都需要通过系统分析获得信息，以确保器械在其最终成品形态下所提供的益处将超过器械材料在预期使用期限和使用部位对暴露组织所产生的潜在风险。

When selecting the appropriate endpoints for biological evaluation of a medical device, one should consider the chemical characteristics of the device materials and the nature, degree, frequency, and duration of exposure to the body (i.e., intended use), as outlined in Attachment A. In general, the biocompatibility endpoints to be considered include: in vitro cytotoxicity; acute, subchronic and chronic toxicity; irritation; sensitization; hemocompatibility; implantation; genotoxicity; carcinogenicity; and effects on reproduction, including developmental effects. However, depending on device physical properties (e.g., surface topography, device geometry),[1] the intended use of the device, target population, and/or the nature of contact with the body, not every biocompatibility endpoint will require testing. In contrast, the biocompatibility endpoints identified in Attachment A may not be sufficient to demonstrate the safety of certain devices (e.g., devices that include submicron or nanotechnology components, see Section V.D). In addition, biocompatibility endpoints such as neurotoxicity and immunotoxicity should be considered for devices where local or end organ toxicity assessments relevant to the implant location or toxicity issues of concern would not be assessed in a traditional biocompatibility study. For example, a neurological device having direct contact with brain parenchyma and cerebrospinal fluid (CSF) may necessitate an animal implant test to evaluate its pathological and physiological effects (e.g., effects on the brain parenchyma, neurobehavioral effects and/or neurological deficits, and effects on the functional mechanisms of the choroid plexus and arachnoid villi to secrete and absorb CSF). The specific clinical application and the materials used in the manufacture of the new device will guide selection of the appropriate biocompatibility evaluations. Where available, device-specific guidance documents may include additional safety assessments to be considered within the context of a biocompatibility evaluation.

在选择医疗器械的生物学评估合适终点时，应考虑器械材料的化学特性以及与人体的接触性质、程度、频率和持续时间（即预期使用），如附件 A 所述。一般而言，应考虑的生物相容性终点包括：体外细胞毒性；急性、亚慢性和慢性毒性；刺激性；致敏性；血液相容性；植入性；基因毒性；致癌性；以及对生殖的影响，包括发育效应。然而，根据器械的物理特性（例如表面形貌、器械几何形状）、器械的预期使用、目标人群和/或与人体接触的性质，不是每个生物相容性终点都需要进行测试。相反，附件 A 中确定的生物相容性终点可能不足以证明某些器械的安全性（例如包含亚微米或纳米技术组分的器械，请参见第 V.D 节）。此外，对于需要评估与植入位置相关的局部或终末器官毒性以及相关的毒性问题的器械，还应考虑神经毒性和免疫毒性等生物相容性终点，这些无法在传统的生物相容性研究中进行评估。例如，与脑实质和脑脊液（CSF）直接接触的神经器械可能需要进行动物植入测试，以评估其对脑实质、神经行为以及脉络丛和蜘蛛膜对分泌和吸收 CSF 的功能机制的病理和生理影响。具体的临床应用和新器械制造中使用的材料将指导选择适当的生物相容性评估。如有相关的器械特定指南文件，可能包括在生物相容性评估范围内考虑的其他安全评估。

Some devices are made of materials that have been well characterized both chemically and physically in the published literature and/or have a long history of safe use in legally US-marketed medical devices. It may not be necessary to conduct testing for all or a portion of the biocompatibility endpoints suggested in the FDA matrix of this guidance. For example, if the sponsor is able to document the use of a particular material (e.g., 316L stainless steel) in a legally-marketed predicate device or a legally-marketed device with comparable tissue exposure, and is able to explain why manufacturing is not expected to adversely impact biocompatibility, additional testing may not be necessary to address some or all of the biocompatibility endpoints recommended for consideration in Attachment A. Sponsors may also leverage information from existing marketing applications to support a rationale that the biocompatibility of the device has been established.[2] Refer to Section III, Risk Management for Biocompatibility Evaluations, for additional information on how to use prior information in lieu of new testing. Also, refer to Attachment F, Component and Device Documentation Examples, for additional information on comparisons to a legally-marketed device.

某些器械采用的材料在已发表的文献中在化学和物理上都得到了充分的表征，并且在美国市场上合法销售的医疗器械中已经有了长期安全使用的历史。可能不需要针对 FDA 指南中建议的所有或部分生物相容性终点进行测试。例如，如果赞助商能够记录在合法销售的前体器械或具有可比组织暴露的合法销售器械中使用某种特定材料（例如 316L 不锈钢），并且能够解释为什么制造不会对生物相容性产生不利影响，那么可能不需要进行额外的测试来处理在附件 A 中建议考虑的一些或全部生物相容性终点。赞助商还可以利用现有的市场申请信息来支持设备生物相容性已经得到验证的合理性。有关如何使用先前信息以代替新测试的更多信息，请参考第 III 节的风险管理部分。此外，请参考附件 F 中的组件和设备文档示例，了解与合法销售器械的比较的更多信息。

B.FDA Use of ISO 10993-1 FDA 使用 ISO 10993-1 标准

The International Organization for Standardization (ISO), in an effort to harmonize biocompatibility testing, developed a standard for biological evaluation of medical devices (ISO 10993). The scope of this multi-part standard is to evaluate the effects of medical device materials on the body. The first part of this standard,"Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process,"provides a framework in which to plan biological evaluation of medical devices, and if needed, guidance for selecting tests to evaluate the biological response to medical devices. Most of the other parts of the ISO 10993 standard series discuss appropriate methods to conduct biological tests that may be identified when following Part 1 of the standard. With the 2009 revision of the ISO 10993-1 standard, the focus of the document changed from how to determine which biocompatibility tests to conduct, to an approach that considers existing information prior to determining if biocompatibility testing is needed.

国际标准化组织（ISO）为了协调生物相容性测试，制定了医疗器械生物评价的标准（ISO 10993）。这个多部分标准的范围是评估医疗器械材料对人体的影响。该标准的第一部分，《医疗器械的生物评价-第 1 部分：在风险管理流程中的评估和测试》，提供了一个框架来规划医疗器械的生物评价，以及在需要时选择评估医疗器械生物反应的测试的指导。ISO 10993 标准系列的其他大部分部分讨论了在遵循该标准的第一部分时可能确定的进行生物测试的适当方法。

With the advancement of scientific knowledge regarding the basic mechanisms of tissue responses, FDA agrees with the ISO 10993-1:2009 revision focus on minimizing the “number and exposure of test animals by giving preference to chemical constituent testing and in vitro models, in situations where these methods yield equally relevant information to that obtained from in vivo models.”[3] For FDA submissions, biocompatibility information for the device in its final finished form, either developed through the risk management process or from biocompatibility testing (using both in vitro and in vivo models), and/or adequate chemical characterization in conjunction with supplementary biocompatibility information that adequately address the biocompatibility risks of the device should be provided.

随着对组织反应基本机制的科学知识的进一步了解，FDA 同意 ISO 10993-1：2009 修订版本的重点是通过优先考虑化学成分测试和体外模型来减少“测试动物的数量和接触次数，在这些方法产生与体内模型获得的信息同等相关的情况下”。对于 FDA 的提交，应提供设备在其最终成品形式中的生物相容性信息，无论是通过风险管理流程开发的还是通过生物相容性测试（使用体外和体内模型），以及充分的化学表征信息，以及足够解决设备生物相容性风险的补充生物相容性信息。

ISO 10993-1 uses an approach to biocompatibility evaluation that is very similar to the original Tripartite Biocompatibility Guidance (G87-1)[4], including the same seven general principles.

ISO 10993-1 采用了与原始的三方生物相容性指南（G87-1）[4:1]非常相似的生物相容性评估方法，包括相同的七个基本原则。

  1. The selection of material(s) to be used in device manufacture and its biocompatibility evaluation should initially take into account the likelihood of direct or indirect tissue contact and any available information for the materials of manufacture, for example, chemical formulation for each component material, including adhesives, known and suspected impurities, and constituents associated with processing.

    在设备制造过程中，选择要使用的材料及其生物相容性评估应首先考虑与组织直接或间接接触的可能性，以及有关制造材料的任何可用信息，例如每个组件材料的化学配方，包括粘合剂、已知和疑似杂质以及与加工相关的成分。

    For the purposes of submission to the FDA, in situations where details pertaining to the materials of manufacture may be proprietary information held by the material supplier, a master file for the material component(s) may assist in determining the formulation of some components of the final device (see Attachment B). However, this information alone may not be sufficient to establish the biocompatibility of the device. Currently there is no standard established for the content or completeness of a device master file. Because the information in a master file may be specific to the material and may not address device fabrication, the information contained in master files may be insufficient to address all of the characterization or biocompatibility questions that pertain to the medical device in its final finished form.

    对于提交给 FDA 的目的，在制造材料的详细信息可能是材料供应商持有的专有信息的情况下，有关材料组分的主文件可能有助于确定最终设备的某些组件的配方（见附件 B）。然而，仅凭这些信息可能不足以确定设备的生物相容性。目前还没有为设备主文件的内容或完整性建立标准。由于主文件中的信息可能特定于材料，并且可能不涉及设备制造，主文件中包含的信息可能不足以解决与医疗器械最终成品相关的所有特性或生物相容性问题。

  2. The material(s) of manufacture, the device in its final finished form, and possible leachable chemicals or degradation products should be considered for their relevance to the overall biocompatibility evaluation of the device.

    在设备的整体生物相容性评估中，应考虑到制造材料、最终成品设备以及可能溶出的化学物质或降解产物的相关性。

  3. Endpoints relevant to the biocompatibility evaluation should take into account the nature, degree, frequency, duration, and conditions of exposure of the device materials to the body. This principle may lead to the categorization of devices that would facilitate the selection of appropriate endpoints for inclusion in the overall biocompatibility evaluation.

    与生物相容性评估相关的终点应考虑到设备材料与人体接触的性质、程度、频率、持续时间和条件。该原则可能导致对设备进行分类，以便在整体生物相容性评估中选择适当的终点。

  1. Any in vitro or in vivo biological safety experiments or tests should be conducted in accordance with recognized Good Laboratory Practice (GLP) regulations [5] including, but not limited to, the assignment of competent trained staff in the conduct of biocompatibility testing.

    一切体外或体内的生物安全实验或测试应按照公认的良好实验室规范（GLP）法规进行[5:1]，包括但不限于指定经过专业培训的员工进行生物相容性测试。

    For the purposes of submission to the FDA, if information on these types of nonclinical laboratory studies [6] is provided, a statement that all such studies have been conducted in compliance with applicable requirements in the Good Laboratory Practice regulation in 21 CFR 58 should also be provided. If any such study was not conducted in compliance with such regulation (e.g., for supporting historical data included with a regulatory submission), a statement detailing how the study complies with each part of the GLP regulations must be provided, with an explanation of how, without an independent audit, the Agency can be assured that all of the data reported in the results represent all data obtained (e.g., the results are reported unbiased and the data not selected for inclusion).

    对于提交给 FDA 的目的，如果提供了关于这些非临床实验室研究[6:1]的信息，还应提供一个声明，说明所有这些研究都符合 21 CFR 58 良好实验室规范法规的适用要求。如果任何这样的研究未按照该法规进行（例如用于支持监管提交的历史数据），必须提供一份详细说明，说明该研究如何符合 GLP 法规的每个部分，并解释在没有独立审计的情况下，机构如何确保所报告的所有数据都代表所获得的所有数据（例如，结果报告无偏差，数据未选取以进行包含）。

  2. When test data are provided , complete experimental data , complete to the extent that an independent conclusion could be made, should be submitted to the reviewing authority.

    在提供测试数据时，应提交完整的实验数据，完整到足以得出独立结论的程度，以供审查机构使用。

    For the purposes of submission to the FDA, if testing is conducted according to a recognized standard that does not require data reporting, submission of the test data is not required.

    对于提交给 FDA 的目的，如果测试是根据不需要数据报告的公认标准进行的，则不需要提交测试数据。

  3. Any change in chemical composition, manufacturing process, physical configuration (e.g., size, geometry, surface properties) or intended use of the device should be evaluated with respect to possible changes in biocompatibility and the need for additional biocompatibility testing.

    设备的化学成分、制造工艺、物理结构（例如尺寸、几何形状、表面特性）或预期用途的任何变化都应评估其对生物相容性可能造成的影响，并评估是否需要进行额外的生物相容性测试。

  4. The biocompatibility evaluation performed in accordance with this guidance should be considered in conjunction with information obtained from other nonclinical tests, clinical studies, and postmarket experiences for a safety assessment that incorporates all available relevant information.

    根据本指南进行的生物相容性评估应与从其他非临床测试、临床研究和市场后经验中获得的信息结合考虑，以进行安全评估，并纳入所有可用的相关信息。

The FDA-Modified Matrix FDA 修改后的矩阵

Like ISO 10993-1:2009, this guidance also uses a tabular format (matrix) to outline the recommendations for biological effects evaluation based on the various factors discussed above for biocompatibility information to be submitted in support of an IDE or marketing application.

与 ISO 10993-1:2009 一样，本指南也使用表格格式（矩阵）来概述基于上述各种因素的生物效应评估建议，以支持 IDE 或营销申请提交的生物相容性信息。

Unlike G95-1, the matrix in this guidance consists of a single table. Attachment A, Evaluation Endpoints for Consideration, includes biocompatibility endpoints for consideration recommended by ISO 10993-1:2009, and additional endpoints FDA recommends for consideration as previously identified in G95-1. Some of the endpoints in this table (chronic toxicity, carcinogenicity, reproductive/developmental toxicity and degradation) are not included as separate columns in Annex A of ISO 10993-1:2009, but were included in previous revisions of ISO 10993-1, as well as G95-1. In addition, we have added a column for material-mediated pyrogenicity, which is included as a subset of acute systemic toxicity in ISO 10993-1:2009. Attachment D is a biocompatibility evaluation flow chart explaining when additional biocompatibility evaluations may be needed, and is slightly revised from the prior version in G95-1. Additional evaluations beyond those recommended in ISO 10993-1 may be requested to fully characterize the biocompatibility profile, if novel materials or manufacturing processes are used (i.e., materials or processes that have not previously been used in a legally US-marketed medical device with the same type and duration of contact).

与 G95-1 不同，本指南中的矩阵由一个单独的表格组成。附件 A“考虑的评估终点”包括 ISO 10993-1:2009 推荐的考虑生物相容性终点，以及 FDA 推荐的其他终点，这些终点在 G95-1 中已经提及。本表格中的一些终点（慢性毒性、致癌性、生殖/发育毒性和降解）在 ISO 10993-1:2009 的附录 A 中并未列为单独的列，但在之前的版本中以及 G95-1 中被包含进去。此外，我们还添加了一个用于材料介导的致热原性的列，该列作为 ISO 10993-1:2009 中急性全身毒性的一个子集。附件 D 是一张生物相容性评估流程图，解释了何时可能需要额外的生物相容性评估，并与 G95-1 中的先前版本略有修改。如果使用了新材料或制造工艺（即以前未在合法销售的同类型和接触持续时间的美国医疗器械中使用的材料或工艺），可能会要求进行超出 ISO 10993-1 推荐的额外评估，以充分描述生物相容性特征。

If the device has multiple types of exposure, you should include information to address each exposure category identified for the device, [7] even though testing may not be necessary for every exposure category, in your overall biocompatibility assessment. For example, a pacemaker may include both a pulse generator that is implanted subcutaneously and leads that are implanted within the cardiovasculature. Therefore, we have considered these devices to be classified as both tissue contact and blood contact devices for the evaluation of biocompatibility.

如果设备存在多种类型的接触，您应包含有关设备所识别的每个接触类别的信息[7:1]，即使并非每个接触类别都需要进行测试，在您的整体生物相容性评估中也要考虑到。例如，起搏器可能包括植入皮下的脉冲发生器和植入心血管内的引导线。因此，我们认为这些设备在生物相容性评估中既属于组织接触设备，也属于血液接触设备。

In general, FDA agrees with the framework established in ISO 10993-1 for identification of the nature and duration of contact (e.g., cumulative effects with repeat use).[8] However, FDA has made several modifications to the evaluations identified in that standard for the reasons outlined in Section IV.D and Attachment A.

总体而言，FDA 认同 ISO 10993-1 中建立的用于识别接触性质和持续时间（例如，重复使用的累积效应）的框架[8:1]。然而，出于第 IV.D 节和附件 A 所列原因，FDA 对该标准中确定的评估进行了若干修改。

Endpoint Assessment 终点评估

As described in Attachments A and C, sponsors should evaluate each biocompatibility endpoint and whether there is a need for additional testing. All biological effects included in the matrix may not be relevant for all devices. Thus, the modified matrix is only a framework for the selection of endpoints for consideration and not a checklist of required biocompatibility testing. A scientific rationale to support the use of previously collected information in lieu of additional biocompatibility testing should be included with the submission for each endpoint identified in Attachment A. Chemical formulation and processing information may not always be needed for all medical device submissions; however, this information may assist the sponsor to support justifications for waiving testing for any recommended endpoints.

如附件 A 和 C 所述，赞助商应评估每个生物相容性终点，并确定是否需要进行额外的测试。矩阵中包含的所有生物效应可能并不适用于所有设备。因此，修改后的矩阵仅是用于选择需要考虑的终点的框架，而不是必需的生物相容性测试清单。对于附件 A 中确定的每个终点，在提交时应包含支持使用先前收集的信息代替额外生物相容性测试的科学理据。化学配方和加工信息可能并非对所有医疗器械提交都是必需的；然而，这些信息可能有助于赞助商为豁免任何推荐终点的测试提供理由。

ISO 10993-1:2009, Clause 4.1 states that “Evaluation may include both a study of relevant preclinical and clinical experience and actual testing. Such an evaluation might result in the conclusion that no testing is needed if the material has a demonstrable safe history of use in a specified role and physical form that is equivalent to that of the device under design.”[9] To conclude that no additional biocompatibility testing is needed, the sponsor should provide evidence that for each material, the type and duration of tissue contact, physical form, formulation, processing, component interactions, and storage conditions are the same as for the comparator device(s), or the comparator device is demonstrated to be “worst case” compared to the proposed device. In cases where there are differences, such differences should be explained and justified as to how prior data are applicable to support a biocompatibility assessment of the medical device in its final finished form. In vivo animal data and/or clinical data may be of limited utility (as discussed previously in Section III) if specific biocompatibility endpoints are not included as part of the data collected for these studies.

ISO 10993-1:2009 第 4.1 条规定：“评估可以包括相关的临床前和临床经验研究以及实际测试。如果材料在指定角色和物理形式下具有可证明的安全使用历史，与设计中的设备相等，那么这样的评估可能会得出不需要进行测试的结论。”[9:1] 为了得出不需要额外生物相容性测试的结论，赞助商应提供证据，证明每种材料的组织接触类型和持续时间、物理形式、配方、加工、组件相互作用和存储条件与比较设备相同，或证明比较设备相对于拟议设备来说是“最坏情况”。在存在差异的情况下，应解释和证明这些差异如何适用于支持最终成品形式的医疗器械的生物相容性评估。如果特定生物相容性终点不作为这些研究所收集数据的一部分，那么在体动物数据和/或临床数据可能具有有限的用途（如前面第 III 节所讨论）。

  1. For example, a material may be selected to provide a certain stiffness required for the device to perform appropriately (i.e., device characteristic), but may also have other material characteristics that could impact the biological response to the device (e.g., hydrophilic or hydrophobic surface).
    例如，可能会选择一种材料以提供器械所需的特定刚度（即器械特性），但该材料还可能具有其他特性，可能会影响对器械的生物反应（例如亲水或疏水表面）。 ↩︎

  2. For the purposes of a biocompatibility evaluation, leveraging information from other marketing applications could be appropriate in support of 510(k)s, PMAs, De Novos, HDEs, and initiation of IDEs.
    为了进行生物相容性评估，利用其他市场申请的信息可能适用于支持 510(k)、PMA、De Novo、HDE 和 IDE 的启动。 ↩︎

  3. ISO 10993-1:2009 “Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk management process.” ↩︎

  4. In 1986, FDA, Health and Welfare Canada, and Health and Social Services UK issued the Tripartite Biocompatibility Guidance for Medical Devices. FDA subsequently issued General Program Memorandum G87-1 “Tripartite Biocompatibility Guidance” (April 24, 1987). This Guidance was used by FDA reviewers, as well as by manufacturers of medical devices until 1995, to select appropriate tests to evaluate the adverse biological responses to medical devices. FDA then issued Blue Book Memorandum G95-1 "Use of International Standard ISO-10993, “Biological Evaluation of Medical Devices Part-1: Evaluation and Testing,” (May 1, 1995). The final version of this guidance supersedes both G87-1 and G95-1.
    1986 年，FDA、加拿大卫生福利部和英国卫生及社会服务部发布了三方医疗器械生物相容性指南。FDA 随后发布了《G87-1 三方生物相容性指南》（1987 年 4 月 24 日）。这个指南被 FDA 的审核人员以及医疗器械制造商用于选择适当的测试方法来评估医疗器械的不良生物反应，直到 1995 年。FDA 随后发布了《G95-1 国际标准 ISO-10993 的使用，《医疗器械生物评价第 1 部分：评估和测试》（1995 年 5 月 1 日）。本指南的最终版本取代了 G87-1 和 G95-1。 ↩︎ ↩︎

  5. FDA does not recognize ISO/IEC 17025 “General requirements for the competence of testing and calibration laboratories.”
    FDA 不承认 ISO/IEC 17025《测试和校准实验室的能力的一般要求》。 ↩︎ ↩︎

  6. See definition of nonclinical laboratory study at 21 CFR 58.3(d).
    参见 21 CFR 58.3(d)对非临床实验室研究的定义。 ↩︎ ↩︎

  7. We encourage sponsors to contact the appropriate Center and review division if there is a question about the appropriate evaluations for a particular device type.
    如果对特定设备类型的适当评估存在疑问，我们鼓励赞助商与适当的中心和审查部门联系。 ↩︎ ↩︎

  8. See ISO 10993-1:2009, Clause 5.2 “Categorization by nature of body contact” and Clause 5.3"Categorization by duration of contact."
    参见 ISO 10993-1:2009，第 5.2 节“按接触性质分类”和第 5.3 节“按接触持续时间分类”。 ↩︎ ↩︎

  9. See ISO 10993-1:2009, Section 4 “General principles applying to biological evaluation of medical devices,” Clause 4.1.
    参见 ISO 10993-1:2009，第 4 节“适用于医疗器械生物评价的一般原则”，第 4.1 条。 ↩︎ ↩︎