Mechanobiology of Fibroblast Activation in Skin Grafting

Surgical repair of chronic wounds often requires split-thickness skin grafts in which epidermis and a thin part of the dermis from one site are harvested, cut into a meshwork, and stretched to cover a larger wound area. The main drawback of split-thickness skin grafting is excessive contracture of the skin graft in the wound site which is caused by the activation and transition of low-contractile fibroblasts to hyper-contractile myofibroblast cells. While a low amount of cellular contractile forces is required for wound healing, excessive contractile forces generated by hyperactivated cells can cause tightening of the skin graft, pain, scarring, and even graft failure. To test whether is a relationship between graft preparation and graft contracture, we hypothesized that the strain field that cells experience within a meshed graft regulates the activation of fibroblasts, and that the strain field and therefore cell activation level can be tailored by adjusting the meshing configurations to control the graft contracture. To test the hypothesis, we estimated strain fields of grafts with a wide range of clinically relevant meshing configurations, and evaluated the responses of human dermal fibroblasts to these strain levels within tissue constructs. We first showed that the choice of meshing configuration can induce a significant change in the graft strain level ranging from less than 5% to more than 30%. We then found that cells within tissue constructs statically stretched to 30% had significantly lower contractile force than cells within tissue constructs stretched to 5%. Data were used to fit a model of fibroblast activation, with activation peaking at a critical strain before decreasing due to cytoskeletal fluidization. The model was applied to predict conditions of meshing that tune graft contracture to desired levels. Results suggest a potential pathway for harnessing the memory of mechanical loading in fibroblasts to define and predict outcomes of skin graft surgeries.