The synergistic effect of corticosteroids and 5-fluorouracil (5-FU) for the treatment of pathological scarring is widely documented. While topical administration can be a painless, convenient way to convey the two active ingredients, physical enhancement techniques such as microneedling are required to deepen their skin penetration and achieve therapeutic effects. A novel approach to keloid and scar treatment is given by microincision, i.e., micrometric-sized columnar perforations which allow the drugs to diffuse into the skin and promote tissue proliferation in a more physiological structure. Combining the delivery of triamcinolone acetonide (TAC) and 5-FU with microincision is an innovative approach that could improve the speed and efficacy of regenerative treatments. This study evaluated the effectiveness of the skin treatment with a device combining microincisions and photobiomodulation, in the skin permeation of a combination of TAC and 5-FU. Increasing treatment times (4, 6, and 8 min) led to higher drug penetration compared to intact skin, with a more noticeable effect for 5-FU compared to TAC. Specifically, all treatment durations were significantly more effective (p < 0.05) than the control for 5-FU, while TAC showed less variation between treatments. Moreover, it was shown that in-vitro the permeation improvement given by the red-light treatment was mainly due to the mechanical massage which pushed the actives into the microchannels created by the treatment. The application of prolonged skin microincision times ensured much higher skin permeation of both TAC and 5-FU compared to microneedling on healthy excised skin.
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