<p>The mechanical behavior of tissues at the macroscale is tightly coupled to cellular activity at the microscale and tuned by microstructure at the mesoscale. Dermal wound healing is a prominent example of a complex system in which multiscale mechanics regulate restoration of tissue form and function. In cutaneous wound healing, a fibrin matrix is populated by fibroblasts migrating in from a surrounding tissue made mostly out of collagen. Fibroblasts both respond to mechanical cues such as fiber alignment and stiffness as well as exert active stresses needed for wound closure. </p> <p>To model wound healing mechanobiology, we first develop a multiscale model with a two-way coupling between a microscale cell adhesion model and a macroscale tissue mechanics model. Starting from the well-known model of adhesion kinetics proposed by Bell, we extend the formulation to account for nonlinear mechanics of fibrin and collagen and show how this nonlinear response naturally captures stretch-driven mechanosensing. We then embed the new nonlinear adhesion model into a custom finite element implementation of tissue mechanical equilibrium. Strains and stresses at the tissue level are coupled with the solution of the microscale adhesion model at each integration point of the finite element mesh. In addition, solution of the adhesion model is coupled with the active contractile stress of the cell population. The multiscale model successfully captures the mechanical response of biopolymer fibers and gels, contractile stresses generated by fibroblasts, and stress-strain contours observed during wound healing. We anticipate this framework will not only increase our understanding of how mechanical cues guide cellular behavior in cutaneous wound healing, but will also be helpful in the study of mechanobiology, growth, and remodeling in other tissues. </p> <p>Next, we develop another multiscale model with a bidirectional coupling between a microscale cell adhesion model and a mesoscale microstructure mechanics model. By mimicking the generation of fibrous network in experiment, we established a discrete fiber network model to simulate the microstructure of biopolymer gels. We then coupled the cell adhesion model to the discrete model to obtain the solution of microstructure equilibrium. This multiscale model was able to recover the volume loss of fibrous gels and the contraction from cells in the networks observed in experiment. We examined the influence of RVE size, stiffness of single fibers and stretch of the gels. We expect this work will help bridge the activity of cell to the microstructure and then to the tissue mechanics especially in wound healing. We hope this work will provide more rigorous understanding in the study of mechanobiology.</p> <p>At last, we established a computational model to accurately capture the mechanical response of fibrin gels which is a naturally occurring protein network that forms a temporary structure to enable remodeling during wound healing and a common tissue engineering scaffold due to the controllable structural properties. We formulated a strategy to quantify both the macroscale (1–10 mm) stress-strain response and the deformation of the mesoscale (10–1000 microns) network structure during unidirectional tensile tests. Based on the experimental data, we successfully predict the strain fields that were observed experimentally within heterogenous fibrin gels with spatial variations in material properties by developing a hyper-viscoelastic model with non-affined evolution under stretching. This model is also potential to predict the macroscale mechanics and mesoscale network organization of other heterogeneous biological tissues and matrices.</p>