New methods of skin sensitization testing that could eventually offer alternatives to those currently in use continue to progress despite a potentially long road to regulatory acceptance in the US.
Skin sensitization is a hypersensitivity reaction comprising two distinct phases (see Figure):
Recent investigations of the viability of in vitro methods for medical device extracts have shown early promising correlation to in vivo methods, but validation is still needed.”
An assessment of skin sensitization risk is required for all body-contacting medical devices regardless of duration of contact (established in the International Organization for Standardization (ISO) 10993 series of standards). Historically, the only acceptable method to demonstrate minimal risk of skin sensitization from medical devices has been in vivo testing. However, with the goal of the European Union (EU) to limit animal testing and the availability of recently validated in vitro methods, it is foreseeable that non-animal methods may become increasingly acceptable for justifying exemption from in vivo biocompatibility testing when bringing devices to market under the EU Medical Device Regulation (MDR). In contrast, non-animal methods likely have a longer way to go towards gaining acceptance in the US, where standard animal testing is a general requirement. Recent investigations of the viability of in vitro methods for medical device extracts have shown early promising correlation to in vivo methods, but validation is still needed, particularly in selection of appropriate extraction vehicles and exposure volumes (Svobodova et al., 2021).
Skin sensitization biocompatibility testing is detailed in ISO 10993-10 (ISO, 2021), which currently states that the risk of skin sensitization should be evaluated by in vivo methods, but that in vitro methods may be considered when scientifically validated and available. There are three validated in vivo methods for medical devices as described in ISO 10993-10:2021: the guinea pig maximization test (GPMT), murine local lymph node assay (LLNA), and occluded patch testing in guinea pigs (Buehler assay). The GPMT is the most sensitive test as it involves stimulating the immune system of test animals and direct injection of the device extract, bypassing the dermal barrier. Given its sensitivity, the GPMT is widely accepted by both the Food and Drug Administration (US FDA) and EU for all device types. In contrast, both the LLNA and Buehler assays involve only topical exposure to the test animals’ skin, and, therefore, may be less well suited than the GPMT for evaluating the safety of blood, bone, and dentin contacting devices.
There are several in vitro methods published as Organisation for Economic Co-operation and Development (OECD) test guidelines that address different events in the biological pathway to skin sensitization. Although these tests are validated for industrial chemicals and known to perform well for assessment of single chemicals, their utility in predicting skin sensitization hazard of a complex mixture (such as a medical device extract) has not yet been established.
Beyond in vivo and in vitro tests to assess skin sensitization hazard, further development of quantitative risk assessment (QRA) and dermal sensitization thresholds (DSTs) may eventually obviate the need for skin sensitization testing of low-risk devices and result in further reductions for animal testing. Using these approaches, chemicals detected under a certain threshold concentration would not be considered chemicals of concern, and chemicals detected at levels above the threshold would require further evaluation.
Gradient has derived a DST using an internal database of over 5,500 chemicals extracted from consumer products and medical devices. Based on sensitization potency data from animal studies and human data for 375 organic skin sensitizers, Gradient derived DSTs expected to be protective of 95% of extractable skin sensitizers and for devices where materials may contain strong sensitizers. In addition to thresholds, chemical specific limits may be established in accordance with QRA methods developed by the fragrance industry, which incorporate experimental data and expected exposure parameters to determine an acceptable exposure level for a product (Api et al., 2008; SCCS, 2012). While regulatory acceptance of threshold and QRA approaches still remains relatively uncertain, recent investigations into adapting skin sensitization QRA methods for extractables and leachables suggest the time has come for further consideration of such non-animal methods for addressing skin sensitization biocompatibility concerns.
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Api, AM; Basketter, DA; Cadby, PA; Cano, MF; Ellis, G; Gerberick, GF; Griem, P; McNamee, PM; Ryan, CA; Safford, B. 2008. “Dermal sensitization quantitative risk assessment (QRA) for fragrance ingredients.” Regul. Toxicol. Pharmacol. 52(1):3-23. doi: 10.1016/j.yrtph.2007.10.008.
European Commission, Health & Consumer Protection Directorate General, Scientific Committee on Consumer Safety (SCCS). 2012. “Opinion on fragrance allergens in cosmetic products.” doi: 10.2772/77628. SCCS/1459/11. 334p., June. Accessed at https://ec.europa.eu/health/scientific_committees/consumer_safety/docs/sccs_o_102.pdf.
International Organization for Standardization (ISO). 2021. “ISO 10993-10:2021: Biological evaluation of medical devices – Part 10: Tests for skin sensitization (Fourth Edition).” ISO 10993-10: 2021 (E). 56p.
Svobodova, L; Rucki, M; Vlkova, A; Kejlova, K; Jirova, D; Dvorakova, M; Kolarova, H; Kandarova, H; Pobis, P; Heinonen, T; Maly, M. 2021. “Sensitization potential of medical devices detected by in vitro and in vivo methods.” ALTEX doi: 10.14573/altex.2008142.