Medical Device safety is of paramount importance to consumers and medical professionals. All medical devices must be minimally tested for acute toxicity, dermal irritation, dermal sensitization and genotoxicity. To test for these potential adverse effects, medical devices are incubated in polar (saline) and non-polar (sesame oil or similar) solvents and extracted under specified conditions according to ISO 10993 Part 12 standards. These extracts, which tend to have low concentrations of potentially toxic molecules, are evaluated for toxicity in a variety of models. The current method for assessing dermal irritation, the rabbit skin irritation test (Draize test), is expensive and time consuming. The Organization for Economic Cooperation and Development (OECD) adopted an updated test guideline 439 in July of 2015. This test provides an in vitro method for irritation assessment in chemicals and cosmetic products using reconstructed human epidermis. In 2013, scientists at CeeTox Inc. in Kalamazoo, Michigan collaborated with scientists at Medtronic Inc. in Minneapolis, Minnesota to determine if the OECD 439 test could be adapted in order to apply to these dilute medical device extracts. A publication in 2013 (Coleman et al.) demonstrated that irritancy potential even pertaining to low levels of irritating molecules in medical device extracts could be detected using the reconstructed human epidermis model after 24 hour exposure time.
When Cyprotex acquired Ceetox in 2014, scientists at Medtronic were working to gain International Organization for Standardization (ISO) acceptance of the new in vitro medical device irritation test. Cyprotex in Kalamazoo, along with 30 other labs, began a large scale validation study of the test. The validation study is unique in that simulated medical device polymers were prepared at multiple labs and are impregnated with known irritants and non-irritants. The simulated medical device polymers were shipped to Cyprotex and the other participating labs with instructions for extraction in 0.9% saline and sesame oil for 72 hours at 37°C. Extracts were applied to reconstructed tissues and incubated overnight (18 hours). After the overnight incubation the tissues were rinsed and assayed for viability using MTT. Medical devices were blinded and tested in three separate rounds. While Cyprotex in Kalamazoo has completed its work on the simulated medical devices, the final data from all labs in not expected to be fully collected until the end of August 2016. Analysis of the data is expected to take some time, but it is hoped that this new methodology will soon be adopted by ISO as a replacement for the rabbit irritation test.
Cyprotex’s collaboration with Medtronic was furthered once again in 2014 when simulated medical devices were used in the SenCeeTox® model for dermal sensitisation. The promising results of the study (Coleman et al., 2015) suggest that the SenCeeTox® model, also performed with reconstructed human epidermis, could be a replacement for the murine local lymph node assay (LLNA) or Guinea pig maximisation test (GPMT), the current models used to assess dermal sensitisation.
Casas JW, Lewerenz GM, Rankin EA, Willoughby JA Sr, Blakeman LC, McKim JM Jr, Coleman KP (2013) In vitro human skin irritation test for evaluation of medical device extracts. Toxicol In Vitro. 27(8): 2175-83
Coleman KP, McNamara LR., Grailer TP., Willoughby JA., Keller DJ., Patel P, Thomas S, and Dilworth C (2015) Evaluation of an in vitro human dermal sensitization test for use with medical device extracts. Applied In Vitro Toxicology 1(2): 118-130