Mechanobiological wound model for improved design and evaluation of collagen dermal replacement scaffolds

Skin wounds are among the most common and costly medical problems experienced. Despite the myriad of treatment options, such wounds continue to lead to displeasing cosmetic outcomes and also carry a high burden of loss-of-function, scarring, contraction, or nonhealing. As a result, the need exists for new therapeutic options that rapidly and reliably restore skin cosmesis and function. Here we present a new mechanobiological computational model to further the design and evaluation of next-generation regenerative dermal scaffolds fabricated from polymerizable collagen. A Bayesian framework, along with microstructure and mechanical property data from engineered dermal scaffolds and autograft skin, were used to calibrate constitutive models for collagen density, fiber alignment and dispersion, and stiffness. A chemo-bio-mechanical finite element model including collagen, cells, and representative cytokine signaling was adapted to simulate no-fill, dermal scaffold, and autograft skin outcomes observed in a preclinical animal model of full-thickness skin wounds, with a focus on permanent contraction, collagen realignment, and cellularization. Finite element model simulations demonstrated wound cellularization and contraction behavior that was similar to that observed experimentally. A sensitivity analysis suggested collagen fiber stiffness and density are important scaffold design features for predictably controlling wound contraction. Finally, prospective simulations indicated that scaffolds with increased fiber dispersion (isotropy) exhibited reduced and more uniform wound contraction while supporting cell infiltration. By capturing the link between multi-scale scaffold biomechanics and cell-scaffold mechanochemical interactions, simulated healing outcomes aligned well with preclinical animal model data. STATEMENT OF SIGNIFICANCE: Skin wounds continue to be a significant burden to patients, physicians, and the healthcare system. Advancing the mechanistic understanding of the wound healing process, including multi-scale mechanobiological interactions amongst cells, the collagen scaffolding, and signaling molecules, will aide in the design of new skin restoration therapies. This work represents the first step towards integrating mechanobiology-based computational tools with in vitro and in vivo preclinical testing data for improving the design and evaluation of custom-fabricated collagen scaffolds for dermal replacement. Such an approach has potential to expedite development of new and more effective skin restoration therapies as well as improve patient-centered wound treatment.