P24 Repurposing drugs to find new medicines to promote wound healing

Abstract Introduction and aims It is estimated that chronic wounds cost the NHS £6.6 billion a year, which will rise due to an ageing population. Despite improvements in their management, there have been limited advances in identifying an intervention that can promote wound healing. Myofibroblasts are a key cell in the wound healing process; however, in chronic wounds, these cells are not activated, resulting in the wound failing to close. Our previous research identified 26 drugs that could induce myofibroblast activation in dermal fibroblasts. Therefore, we hypothesized that these drugs could be repurposed as novel therapeutics for chronic wounds of the skin. Methods Primary dermal fibroblasts were isolated from abdominal skin of patients undergoing breast reconstruction surgery. Concentration–response curves for the 26 drugs were constructed at varying concentrations (0.03–100 µmol L−1), and then stained for α-smooth muscle actin (SMA) expression. The drugs that maintained 100% α-SMA expression or increased expression [compared with the transforming growth factor (TGF)-β1 only control] were then taken forward for further testing in secondary functional assays [total extracellular matrix (ECM) production and keratinocyte epithelial–mesenchymal transition (EMT)]. Results Of the 26 drugs, only 8 maintained ≥ 100% α-SMA expression at all concentrations up to 10–30 µmol L−1. Of these drugs, olmesartan showed the most promise, with an average 25% increase in α-SMA expression at 0.03–10 µmol L−1. When tested in an ECM production assay, the eight drugs could maintain or increase total ECM production at concentrations up to 30 µmol L−1, compared with the TGF-β1 only control. A similar pattern was seen in the keratinocyte EMT assay, where increased expression of vimentin and fibronectin was seen across the eight drugs. Conclusions This work has identified eight drugs that can increase cellular markers associated with key phenotypes of wound healing. These drugs could be repurposed for use in chronic wounds, with studies in organoid models of chronic wound as potential next steps.