Mechano-biological and bio-mechanical pathways in cutaneous wound healing

Skin injuries heal through coordinated action of fibroblast-mediated extracellular matrix (ECM) deposition, ECM remodeling, and wound contraction. Defects involving the dermis result in fibrotic scars featuring increased stiffness and altered collagen content and organization. Although computational models are crucial to unravel the underlying biochemical and biophysical mechanisms, simulations of the evolving wound biomechanics are seldom benchmarked against measurements. Here, we leverage recent quantifications of local tissue stiffness in murine wounds to refine a previously-proposed systems bio-chemo-mechanobiological finite-element model. Fibroblasts are considered as the main cell type involved in ECM remodeling and wound contraction. Tissue rebuilding is coordinated by the release and diffusion of a cytokine wave, e.g. TGF-β, itself developed in response to an earlier inflammatory signal triggered by platelet aggregation. We calibrate a model of the evolving wound biomechanics through a custom-developed hierarchical Bayesian inverse analysis. Further calibration is based on published biochemical and morphological murine wound healing data over a 21-day healing period. The calibrated model recapitulates the temporal evolution of: inflammatory signal, fibroblast infiltration, collagen buildup, and wound contraction. Moreover, it enables in silico hypothesis testing, which we explore by: (i) quantifying the alteration of wound contraction profiles corresponding to the measured variability in local wound stiffness; (ii) proposing alternative constitutive links connecting the dynamics of the biochemical fields to the evolving mechanical properties; (iii) discussing the plausibility of a stretch- vs. stiffness-mediated mechanobiological coupling. Ultimately, our model challenges the current understanding of wound biomechanics and mechanobiology, beside offering a versatile tool to explore and eventually control scar fibrosis after injury. Author summary Wounds constitute a major healthcare burden, often yielding overly stiff scars that feature altered collagen content and organization. Accurate computational models have the potential to impact the understanding, treatment, and ultimately the outcome of wound healing progression by highlighting key mechanisms of new tissue formation and providing a versatile platform for hypothesis testing. However, the description of wound biomechanics has so far been based on measurements of uninjured tissue behavior, limiting our understanding of the links between wound stiffness and healing outcome. Here, we leverage recent experimental data of the local stiffness changes during murine wound healing to inform a computational model. The calibrated model also recapitulates previously-measured biochemical and morphological aspects of wound healing. We further demonstrate the relevance of the model towards understanding scar formation by evaluating the link between local changes in tissue stiffness and overall wound contraction, as well as testing hypotheses on: (i) how local tissue stiffness is linked to composition; (ii) how a fibrotic response depends on mechanobiological cues.