Development of a multiscale skin barrier model for de novo, in silico prediction

We developed a multiscale, many-cell skin barrier model. Our strategy was the integration of four distinct models that have been previously validated and described in the literature. Modeling cells as discrete elements in a continuous environment, the foundation is a three-dimensional, agent-based model of barrier formation and epidermal homeostasis. A continuum representation is used for transport of molecular species in the extracellular space and water transport, which modulates swelling of cellular agents and impacts TransEpidermal Water Loss (TEWL). Finally, we apply a system of ordinary differential equations in each basal cells to capture intracellular biomolecular processes related to cell cycle control.We employed the high-performance computing platform Biocellion. Unlike other platforms, Biocellion provides scalability across CPU threads or cluster nodes with virtually no overhead. It allows modeling at the level of detail and flexibility necessary to maintain the integrity of the underlying source models. Because we model individual cells, reactions and transport at micron length scales, and because we simulate whole tissue scales of mm and days, this model is a true three-dimensional, multiscale representation of a dynamic skin barrier.To demonstrate utility, we investigated the potential for de novo, in silico prediction of barrier response to external stimuli. For this initial case-study, we chose a strong chemical stimuli, a CDK1/CDC2 inhibitor. All parameters were found in existing sources and no training was required. The results showed the feedback from inhibitor penetration to reduced proliferation to barrier breakdown that leads to increased penetration. In addition, the simulation also predicts increases in TEWL, connecting the computational model to clinically relevant measures of human barrier function.