Mathematical modeling of the re-epithelialization of a 3 dimensional (3d) human skin equivalent

Re-epithelialization is the dominant mode of healing in partial thickness wounds. In order to develop better strategies to monitor such wound healing, 3D HSE models and mathematical models have long been utilized to improve our understanding of epidermis formation and re-epithelialization. Using both approaches we endeavoured to generate two mathematical models of epidermis formation and one mathematical model of wound closure based on in vitro studies of epithelialization of 3D HSE models and re-epithlialization of wounded HSE models. We used immunohistochemistry to evaluate keratinocyte proliferation, differentiation and migration. The mathematical models investigated first the role of nutrient concentration (simple model of epidermis formation) and the concurrent roles of ATP, nutrient and calcium concentrations (improved model) in epidermis formation and homeostasis, to eventually lead to a two-dimensional model of wound closure. The 3D HSE model presented similar histology and immunohistochemistry as that of native skin after 11 days of culture. A complete differentiated epidermis filled the wound by day 14 after injury. Finally the contribution of basal cell proliferation in the neoepithelium has been demonstrated during wound closure. The improved mathematical model of epidermis formation produced reasonable representations with a complex cell layer dynamic, while the initial mathematical model presented the potential role of nutrient concentration in determining epidermis thickness. The model of wound closure further illustrated the critical role of nutrient concentration in the process of re-epithelialisation. The major drawback of existing wound closure models is that they neglect the differentiation and stratification; the models developed in this project innovatively integrates by both the second dimension and differentiation, and could consequently bring more insights into the regulation of epidermis homeostasis and wound repair