Studies have reported that the constituents of the wound microenvironment are likely to have critical roles in the degradation and fate of the polymeric matrix and the compounds dissolved in the wound dressing matrix. Thus, chronic wound assessment and the design of effective medical devices and drug products for wound care partly rely on an in-depth understanding of the wound microenvironment. The main aim of this review is to identify and discuss the different stages of chronic wound progression, focusing on the changes in the biochemical composition of the wound microenvironment, with particular attention given to venous leg ulcers (VLUs), as they are one of the most prevalent chronic wound aetiologies. The pathophysiology of venous ulcers is detailed, followed by a thorough review of what is known about the VLU microenvironment and its changes as a function of the evolution of the VLU. Simulating conditions for VLU are then discussed with the view of highlighting potentially relevant simulating media as a function of VLU evolution for a better assessment of biological safety, in particular medical devices intended to be in contact with these wounds.

Facial angiofibromas (FA) are one of the most obvious cutaneous manifestations of tuberous sclerosis complex. Topical rapamycin for angiofibromas has been reported as a promising treatment. Several types of vehicles have been used hitherto, but polymeric micelles and especially those made of d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) seem to have shown better skin bioavailability of rapamycin than the so far commonly used ointments. To better understand the influence of polymeric micelles on the behavior of rapamycin, we explored it through mixed polymeric micelles combining TPGS and poloxamer, evaluating stability and skin bioavailability to define an optimized formulation to effectively treat FA. Our studies have shown that TPGS improves the physicochemical behavior of rapamycin, i.e., its solubility and stability, due to a strong inclusion in micelles, while poloxamer P123 has a more significant influence on skin bioavailability. Accordingly, we formulated mixed-micelle hydrogels containing 0.1% rapamycin, and the optimized formulation was found to be stable for up to 3 months at 2–8 °C. In addition, compared to hydroalcoholic gel formulations, the studied system allows for better biodistribution on human skin.

P63 is a major transcription factor regulating skin development and homeostasis. It controls many genes involved in cell proliferation, adhesion, and early differentiation. P63 is mutated in several rare syndromes called p63-related ectodermal dysplasia syndromes (ED). The main forms are EEC and AEC syndromes due to p63 missense mutations on the DBD and SAM domains, respectively. ED patients display many developmental defects, including ectrodactyly, clef/lip palate, and ectodermal dysplasia, while AEC patients suffer from severe skin erosions that not always heal. We have previously showed that ED-derived iPSC display altered epidermal commitment. P63 belongs to the p53 gene family sharing similar structural domains. We found that ED-iPSC epidermal commitment can be rescued by a p53-reactivating compounds called PRIMA-1^MET, also named APR-246 and currently used in anticancer clinical trials. Here, we established primary epidermal culture from two AEC children (S.F. and Y.M.) suffering from persistent skin erosions at age of 9 and 15, respectively. These patients carry missense mutations on the SAM domain (I576T and I537T). We found that primary keratinocytes (KCs) isolated from these AEC patients underwent altered epidermal differentiation that was rescued by PRIMA-1^MET treatment. It prompted us to formulate the compound onto a cream that was topically applied on the right hand of one patient and on the scalp of the second patient. In both cases, the daily treatment allowed re-epithelialization of the eroded skin and a drastic loss of pain after few weeks, improving quality of life. Normally, mutant p63 exerts a dominant-negative effect, mainly through the formation of aggregate with WT p63 and p73. PRIMA-1^MET did not reduce protein aggregation while enhancing cell differentiation, suggesting that PRIMA-1^MET targets cell differentiation and not p63 activity directly. In conclusion, we propose that repurposing of the antitumoral PRIMA-1^MET compound could become a general treatment of AEC skin erosions.