Thermo‐Mechanical Fractional Injury Enhances Skin Surface‐ and Epidermis‐ Protoporphyrin IX Fluorescence: Comparison of 5‐Aminolevulinic Acid in Cream and Gel Vehicles

Background and Objectives Thermo‐mechanical fractional injury (TMFI) impacts the skin barrier and may increase cutaneous drug uptake. This study investigated the potential of TMFI in combination with 5‐aminolevulinic acid (ALA) cream and gel formulations to enhance Protoporphyrin IX (PpIX) fluorescence at the skin surface and in the skin. Study Design/Materials and Methods In healthy volunteers ( n  = 12) a total of 144 test areas were demarcated on the upper back. Test areas were randomized to (i) TMFI (6 milliseconds, 400 µm at a single pass) or no pretreatment and (ii) 20% ALA in cream or gel formulations. Skin surface PpIX fluorescence was quantified by PpIX fluorescence photography and photometry in 30‐minute intervals until 3 hours. PpIX fluorescence microscopy quantified separate PpIX fluorescence in the epidermis, and in superficial‐, mid‐, and deep‐ dermis from punch biopsies sampled after 3 hours of ALA incubation. Local skin reactions (LSR) and pain intensities (numerical rating scale 0–10) were evaluated immediately, at 3 hours and 14 days after the intervention. Results TMFI exposure before photosensitizer application significantly increased skin surface PpIX fluorescence, both for ALA cream (TMFI‐ALA‐cream 7848 arbitrary units [AU] vs. ALA‐cream 5441 AU, 3 hours, P  < 0.001) and ALA gel (TMFI + ALA‐gel 4591 AU vs. ALA‐gel 3723 AU, 3 hours, P  < 0.001). The TMFI‐mediated increase in PpIX fluorescence was similar for ALA‐cream and ‐gel formulations ( P  = 0.470) at the skin surface. In the epidermis , PpIX fluorescence intensities increased from combination treatment with TMFI and ALA‐cream (TMFI + ALA‐cream 421 AU vs. ALA‐cream 293 AU, P  = 0.034) but not from combination with TMFI and ALA‐gel (TMI + ALA‐gel 264 AU vs. ALA‐gel 261 AU, P  = 0.791). Dermal fluorescence intensities (superficial‐, mid‐, or deep dermis) were unaffected by TMFI pretreatment in both ALA‐cream and ALA‐gel exposed skin ( P  = 0.339). ALA‐cream generally induced higher PpIX fluorescence intensities than ALA‐gel (skin surface P  < 0.001 and epidermis P  < 0.03). TMFI induced low pain intensities (median 3) and mild LSR that were resolved at 14 days follow‐up. Conclusion Given the present study design, TMFI, in combination with the standardized application of 20% ALA cream and gel formulations, significantly enhanced skin surface PpIX fluorescence compared to no pretreatment. Additionally, TMFI increased epidermal PpIX fluorescence combined with 20% ALA cream vehicle. Thus, TMFI pretreatment and formulation characteristics exert influence on PpIX fluorescence intensities in normal skin. Lasers Surg. Med. © 2020 Wiley Periodicals LLC