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While cellular and signalling mechanisms of wound repair have been extensively studied, the principles of epidermal\u2010dermal interactions and their effects on wound healing outcomes are only partially understood. To gain new insight into the effects of epidermal\u2010dermal interactions, we developed a multiscale, hybrid mathematical model of skin wound healing. The model takes into consideration interactions between epidermis and dermis across the basement membrane via diffusible signals, defined as activator and inhibitor. Simulations revealed that epidermal\u2010dermal interactions are critical for proper extracellular matrix deposition in the dermis, suggesting these signals may influence how wound scars form. Our model makes several theoretical predictions. First, basal levels of epidermal activator and inhibitor help to maintain dermis in a steady state, whereas their absence results in a raised, scar\u2010like dermal phenotype. Second, wound\u2010triggered increase in activator and inhibitor production by basal epidermal cells, coupled with fast re\u2010epithelialization kinetics, reduces dermal scar size. Third, high\u2010density fibrin clot leads to a raised, hypertrophic scar phenotype, whereas low\u2010density fibrin clot leads to a hypotrophic phenotype. Fourth, shallow wounds, compared to deep wounds, result in overall reduced scarring. Taken together, our model predicts the important role of signalling across dermal\u2010epidermal interface and the effect of fibrin clot density and wound geometry on scar formation. This hybrid modelling approach may be also applicable to other complex tissue systems, enabling the simulation of dynamic processes, otherwise computationally prohibitive with fully discrete models due to a large number of variables.<\/jats:p>","DOI":"10.1111\/exd.13909","type":"journal-article","created":{"date-parts":[[2019,2,26]],"date-time":"2019-02-26T04:00:29Z","timestamp":1551153629000},"page":"493-502","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["A multiscale hybrid mathematical model of epidermal\u2010dermal interactions during skin wound healing"],"prefix":"10.1111","volume":"28","author":[{"given":"Yangyang","family":"Wang","sequence":"first","affiliation":[{"name":"NSF\u2010Simons Center for Multiscale Cell Fate Research University of California, Irvine  Irvine California"},{"name":"Center for Complex Biological Systems University of California, Irvine  Irvine California"},{"name":"Department of 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