Physiology and Pathophysiology of Wound Healing in Diabetes

Wound healing is a dynamic process comprising of overlapping phases of hemostasis, inflammation, proliferation, and remodeling that involve multiple cell types. This highly organized and coordinated series of processes result in the restoration of tissue integrity. Deregulation in any of these processes leads to a delayed or nonhealing phenotype as seen in diabetic foot ulcers (DFUs). The functions and cell-to-cell communication between different cell types contributing to wound healing (keratinocytes, fibroblasts, endothelial cells, neutrophils, and macrophages) and their deregulation in chronic nonhealing ulcers are discussed in detail. The balance of signaling factors, including growth factors and gene expression regulators such as microRNA, and their spatiotemporal control is indispensable for successful wound healing, while their dysregulation contributes to pathophysiology of DFUs. Additional factors that contribute to the delayed healing seen in diabetes include macro- and microvascular, neuropathic, immune functions, and microbiome abnormalities. Novel therapeutic approaches including cell therapy, stem cells, and micrografting that provide perspective on how to efficiently treat patients with DFUs are also discussed