Mechanobiology of Fibroblast Activation in Skin Grafting

Abstract

AbstractSurgical 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 long-term activation and transition of low-contractile fibroblasts to hyper-contractile myofibroblast cells. To test whether there is a relationship between graft preparation and long-term 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 skin grafts with a wide range of clinically relevant meshing configurations, and evaluated the responses of human dermal fibroblasts to these strain levels within skin tissue constructs. We found a previously unknown role of the extracellular collagen matrix in the development of mechanical memory in fibroblasts and their long-term activation level. Using an integrated experimental and theoretical approach, we showed that time- and strain-dependent behavior of the extracellular collagen matrix determines the stress level that cells experience during skin tissue stretching and subsequently the cell activation level after tissue unloading.