Delivery of apoptotic neutrophils to improve angiogenesis during wound healing

PROJECT SUMMARY/ABSTRACT Every year, millions of patients suffer from impaired wound healing due to injuries, surgeries, and diseases, creating a significant public health and economic burden. The process of skin wound healing involves clotting, inflammation, cell proliferation and migration, re-vascularization, and remodeling, and often results in scarring. In diabetic patients or large wounds, insufficient angiogenesis slows healing and worsens scarring. Attempts to deliver growth and angiogenic factors or cells fall short of providing complete relief, and there is a critical need for new strategies to promote angiogenesis and tissue repair during wound healing. The proposed project aims to develop a novel therapeutic approach for improved angiogenesis during wound healing by leveraging natural interactions of immune cells. We propose to deliver apoptotic neutrophils (AN) within a degradable hydrogel scaffold that will induce efferocytosis and phagocytosis, respectively, in local macrophages (Mφs), promoting their angiogenic signaling and tissue repair without causing inflammation. In preliminary work, AN delivery in a gelatin methacrylate (GelMA)-based hydrogel significantly enhanced angiogenesis in a murine skin wound model, both in wild type and in diabetic mice. Furthermore, addition of AN and/or GelMA to macrophages in culture stimulated their secretion of angiogenic growth factors. We propose here to investigate the effects of GelMA-AN on Mφ uptake and growth factor secretion (Aim 1), and on angiogenesis and wound healing of a full-thickness skin wound (Aim 2). This project will establish a new method to enhance Mφ angiogenesis signaling, providing a platform for further investigation, and developing a therapeutic intervention for improved wound healing. This proposed approach leverages the role of immune cells and angiogenesis in wound healing, with modulation of Mφs phenotype conversion for successful wound healing and tissue repair.