Development and evaluation of a simvastatin-loaded biopolymeric scaffold for improved angiogenesis and healing of diabetic wounds

Abstract

In diabetic wounds, lack of angiogenesis limits the supply of oxygen and nutrients at the wound site, resulting in poor healing. A well-known lipid-lowering drug, simvastatin (SIM), exhibited pleiotropic effects in wound healing, including promotion of angiogenesis. However, its clinical application is limited due to its poor physicochemical properties, including low solubility. In this study, a Soluplus and TPGS-based mixed micelle was developed for loading SIM in an in-situ forming chitosan-chondroitin sulfate-based poly-electrolyte complex hydrogel (CH-CS PEC). The hypothesis was that CH-CS PEC would improve overall wound healing due to the favorable viscoelasticity and porosity, whereas SIM would assist neoangiogenesis. SIM-loaded CH-CS PEC exhibited good mechanical stability and viscoelastic properties and demonstrated prolonged release of SIM. The formulation promoted endothelial cell sprouting in an ex-vivo rat aortic ring assay. Applying SIM-loaded CH-CS PEC in a diabetes-induced rat wound model resulted in faster wound closure, increased collagen deposition, and enhanced neovascularization with up-regulation of vascular endothelial growth factor (VEGF) expression. In summary, we have developed a drug-loaded, in-situ forming scaffold that can be directly applied at the wound site and can improve wound healing by promoting angiogenesis and collagen deposition at the wound site. This study demonstrated the combined efficacy of a viscoelastic scaffold and a proangiogenic drug for enhanced wound healing. The easy and simple fabrication method of the drug-loaded scaffold makes it suitable for clinical translation.