Development of Sensitive In Vitro Protocols for the Biocompatibility Testing of Medical Devices and Pharmaceuticals Intended for Contact with the Eyes: Acute Irritation and Phototoxicity Assessment.

This study introduces a novel in vitro methodology that employs the 3-D reconstructed tissue model, EpiOcular, to assess the irritation and phototoxicity potential of medical devices and drugs in contact with the eye. Our study evaluated diverse test materials, including medical devices, ophthalmological solutions and an experimental drug (cemtirestat), for their potential to cause eye irritation and phototoxicity. The protocols used in this study with the EpiOcular tissue model were akin to those used in the ultra-mildness testing of cosmetic formulations, which is challenging to predict with standard in vivo rabbit tests. To design these protocols, we leveraged experience gained from the validation project on the EpiDerm skin irritation test for medical devices (ISO 10993-23:2021) and the OECD TG 498 method for photo-irritation testing. The predictions were based on the tissue viability and inflammatory response, as determined by IL-1α release. By developing and evaluating these protocols for medical devices, we aimed to expand the applicability domain of the tests referred to in ISO 10993-23. This will contribute to the standardisation and cost-effective safety evaluation of ophthalmic products, while reducing reliance on animal testing in this field. The findings obtained from the EpiOcular model in the photo-irritation test could support its implementation in the testing strategies outlined in OECD TG 498.

The "Big Three" in biocompatibility testing of medical devices: implementation of alternatives to animal experimentation-are we there yet?

Biocompatibility testing ensures the safety of medical devices by assessing their compatibility with biological systems and their potential to cause harm or adverse reactions. Thus, it is a critical part of the overall safety evaluation process for medical devices. Three primary types of biocompatibility tests-cytotoxicity, irritation, and sensitisation assessment-are standard for nearly all medical devices. However, additional biocompatibility tests, such as genotoxicity, systemic toxicity, hemocompatibility, and implantation studies, may also be necessary, depending on the device's nature and intended use. The testing is partly conducted in vitro, but the industry still heavily relies on animal experiments. Compared to other industrial sectors, implementing alternatives in medical device biocompatibility testing has been notably slower. This delay can be attributed to the absence of specific validation processes tailored to medical devices and the resulting hesitation regarding the predictive capacity of these alternative methods despite their successful applications in other domains. This review focuses on the progress and obstacles to implementing new approach methodologies in the areas of cytotoxicity, irritation and sensitisation testing of medical devices. While challenges persist in adopting these innovative methods, the trend towards embracing alternatives remains robust. This trend is driven by technological advancements, ethical considerations, and growing industrial interest and support, all collectively contributing to advancing safer and more effective medical devices.

Sensitization potential of medical devices detected by in vitro and in vivo methods.

Medical devices must be tested before marketing in accordance with ISO EN 10993-10 in order to avoid skin sensi­tization. This standard predominantly refers to the in vivo test but does not exclude the use of in vitro methods that have been sufficiently technically and scientifically validated for medical device testing. It is foreseen that, due to the complexity of the sensitization endpoint, a combination of several methods will be needed to address all key events occurring in the sensitization process. The objective of this pilot study was to evaluate the sensitization potential of selected medical devices using a combination of in chemico (DPRA, OECD TG 442C) and in vitro (LuSens, OECD TG 442D) methods in comparison with the in vivo (LLNA DA, OECD TG 442A) method and to suggest a possible testing strategy for the safety assessment of medical device extracts. Overall, one of the 42 tested samples exhibited positive results in all employed test methods, while 33 samples were predicted as non-sensitizing in all three performed methods. This study demonstrated good agreement between in vitro and in vivo results regarding non-sensitizing samples; however, some discrepancies in positive classification were recorded. A testing strategy is suggested in which negative results are accepted and any positive results in the in chemico or in vitro tests are followed up with a third in vitro test and evaluated in accordance with the "2 out of 3 approach". This strategy may reduce and replace animal use for testing the sensitization potential of medical devices.