Biocompatibility refers to the ability of a medical device to perform its intended function in contact with the body without eliciting adverse reactions or compromising normal tissue functions. Internationally recognized guidelines for evaluating biocompatibility are outlined in the ISO 10993 standard series, which requires manufacturers to assess all relevant biological risks.
While the assessment does include a review of existing safety data, some additional testing according to ISO 10993 is typically required to demonstrate the biological safety of new medical devices and to bring them to market in the EU, the US, and other major markets.
Measurlabs offers a comprehensive selection of accredited and GLP-certified biocompatibility tests, helping manufacturers comply with the EU Medical Device Regulation (MDR) and FDA 510(k) premarket submission requirements. Our experts can also help select an appropriate testing strategy for your device.
Book a free kick-off meeting with our experts to discuss your biocompatibility testing needs.
The ISO 10993 standard family
The general principles for conducting a biocompatibility evaluation are outlined in Part 1 of ISO 10993, which also emphasizes the importance of creating a structured biological evaluation plan (BEP) to document any biological risks inherent to the device, as well as the ways in which they are addressed.1 Some of the subsequent parts provide further guidance on specific aspects of the evaluation, such as animal welfare or sample preparation, while others describe concrete test methods for evaluating different biological effects.
Table 1 provides an overview of selected ISO 10993 standards and the device types they typically apply to. More information on each test, along with indicative pricing, can be found by clicking the standard numbers.
Table 1: Overview of selected ISO 10993 biocompatibility tests
Standard | Scope | Applicable devices* |
All new medical devices in direct or indirect body contact** | ||
Sensitization | All new medical devices in direct or indirect body contact** | |
Irritation | All new medical devices in direct or indirect body contact** | |
Chemical characterization | All new medical devices in direct or indirect body contact | |
Toxicological risk assessment | Devices found to release chemicals above the specified safety thresholds during chemical characterization | |
Genotoxicity, carcinogenicity, and reproductive toxicity | Devices with prolonged or long-term contact with any tissue except intact skin. Devices that contact circulating blood (any duration).*** | |
Hemocompatibility | Devices in direct or indirect contact with blood | |
ISO 10993-6 | Local effects after implantation/tissue contact | Implantable devices and other devices in prolonged or long-term direct contact with tissues other than intact skin. Devices in indirect long-term contact with the blood path*** |
Ethylene oxide sterilization residuals | Devices sterilized with ethylene oxide | |
Systemic toxicity (acute, subacute, or chronic) | Devices in prolonged or long-term contact with mucosal membranes and in contact of any duration with other tissues except intact skin*** |
* These are examples of the types of devices that typically require testing. The final decision on whether or not testing is necessary to address any given biocompatibility endpoint depends on several factors, including device characteristics and pre-existing safety data documented in the biological evaluation plan.
** Together, these tests are commonly known as the “Big Three” in biocompatibility testing.
*** Contact duration definitions: limited (≤24 h), prolonged (24 h–30 days), long-term (>30 days)
Formulating a biocompatibility testing strategy
As shown in Table 1, the extent of biocompatibility testing recommended by ISO 10993-1 depends on the nature of the medical device, including the type of body contact (e.g., intact skin vs. blood/tissue) and contact duration (limited, prolonged, or long-term). More rigorous testing is needed when devices come into contact with blood or internal tissues for an extended period. Correspondingly, devices that only contact intact skin for a limited time require fewer tests.
In terms of test method selection, ISO 10993-1:2025 states that non-animal methods, such as chemical analyses and in vitro assays, should be prioritized when they yield equally robust results to in vivo tests.2 In practice, the market area will dictate the extent to which testing can be conducted using non-animal methods, as the FDA still commonly requires in vivo testing to assess irritation and sensitization.3 In the EU, in vitro tests are often sufficient for low-risk devices.
Example 1: Elastic bandage for the EU market
Elastic bandages for supporting a sprain come into contact with intact skin only, which means that chemical characterization followed by cytotoxicity, sensitization, and irritation testing is typically sufficient. For the EU market, it may be possible to perform all tests using non-animal methods, although method selection needs to be justified – particularly for skin sensitization, where in vitro and in chemico alternatives are not currently listed on an equal footing with in vivo methods in ISO 10993-10.4
The following is an example test sequence that avoids animal testing for an elastic bandage intended for the EU market:
Chemical characterization using two solvents (polar and non-polar) under exaggerated extraction conditions, followed by a toxicological risk assessment
Cytotoxicity testing on device extracts prepared in a serum-supplemented cell culture medium using the quantitative neutral red uptake (NRU) method
Sensitization testing using two non-animal methods that cover different key events in the sensitization adverse outcome pathway (AOP), for example, the ARE-Nrf2 luciferase assay and the human cell line activation test (h-CLAT)
Irritation testing on polar and non-polar device extracts using a reconstructed human epidermis (RhE) model
Example 2: Knee implant for the US market
Knee implants are intended for long-term (>30 days) use in direct contact with bone and tissue, which means that they require an extensive biocompatibility evaluation using both in vitro and in vivo test methods. The following is an example test sequence for a knee implant intended for the US market, following FDA guidance on the use of ISO 10993-1:5
Chemical characterization using exhaustive extraction conditions with polar, semi-polar, and non-polar solvents to identify extractables and potential degradation products, followed by a toxicological risk assessment
Cytotoxicity testing on device extracts prepared in a serum-supplemented culture medium using the NRU method
Sensitization testing using the guinea pig maximization test (GPMT), which is the FDA-recommended method for devices that contact deep tissues6
Irritation/intracutaneous reactivity test in rabbits using intradermally injected polar and non-polar device extracts
Implantation and chronic systemic toxicity assessment with histopathological evaluation of local tissue response and systemic toxicity endpoints, typically in rabbits
Genotoxicity testing using a bacterial reverse mutation assay (Ames test) and a mouse lymphoma assay (MLA), which together detect a broad spectrum of genotoxins
The example test sequences above are illustrative, and the actual biocompatibility tests required for a similar device may differ depending on factors such as chemical composition, physical configuration, and intended patient group. A biological evaluation plan should be in place before testing begins, as it determines which tests and methods are required for the specific device.
All biocompatibility tests in one place
Measurlabs is a trusted partner for all your biocompatibility testing needs, offering everything from the biological evaluation plan (BEP) to all ISO 10993 tests and the biological evaluation report (BER) to summarize the findings. Testing according to additional standards, such as ISO 18562 (breathing gas pathways), ISO 11737-1 (bioburden), and ISO 11737-2 (sterility), is also available.
With experience in tailoring test plans to both EU and FDA requirements, our experts can help you select the most appropriate methods for your device and market area. Fill in the form below to start planning your project with us.
References
1 See section 5, “Biological evaluation plan” of ISO 10993-1:2025.
2 Section 4.4, "Animal welfare" of ISO 10993-1:2025
3 The FDA does not recognize the clauses and annexes of ISO 10993-10 and ISO 10993-23 that describe in vitro methods. See more: Partial recognition of ISO 10993-10 and ISO 10993-23 on the FDA-recognized consensus standard database.
4 The informative Annex C of ISO 10993-10:2021 discusses several non-animal methods for skin sensitization testing, but notes that any single assay on its own may not be sufficient to address all the sensitization pathways. Instead, it may be necessary to perform several assays and/or combine test results with prior information, e.g., chemical characterization results.
5 FDA Guidance for Industry: Use of International Standard ISO 10993-1, "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process", September 2023
6 See Section B. Sensitization in the FDA Guidance on Use of International Standard ISO 10993-1. The agency states that test chemicals may not penetrate the skin sufficiently in the local lymph node assay (LLNA), which is otherwise the preferred method according to ISO 10993-10:2021 due to animal welfare considerations and the ability to provide “objective quantitative data” (section 6.1 of the standard).