Mechanobiological aspects of (dysregulated) wound healing and the foreign body response

Mechanosensing describes the response of cells to mechanical stimuli. The wound healing cells (fibroblasts) in our body react strongly to mechanical stimuli, but for many years, almost all experiments have been performed on polystyrene, a kind of plastic with a stiffness that is far beyond the physiological range. It is known from the literature that stiffness exerts a direct effect on a variety of cells. The studies described in this dissertation examined the effect of stiffness on (impaired) wound healing and the foreign body reaction, with focus on fibroblasts, macrophages and foreign body giant cells. To this end, an in vitro culture system has been developed with variable stiffness within the (patho)physiological range. Macrophage polarization towards the inflammatory (M1) or wound healing (M2) phenotype was not directly regulated by stiffness. In contrast, macrophage fusion, as observed during the foreign body response, was regulated by stiffness.
In addition, the effect of stiffness on spectrins, proteins that are involved in migration and cell integrity, was considered. Spectrin knockdown did not appear to exert a direct influence on fibroblast function: migration, wound healing and response to a specific growth factor involved in wound healing were all similar when comparing knockdown cells with control samples. Finally, the effect of vitamin C on fibroblast function was studied. In addition to a (known) effect on collagen biosynthesis, a novel effect of vitamin C was observed which greatly enhanced stress fibre formation as seen in myofibroblasts in dysregulated wound healing.