Physiology and Pathophysiology of Wound Healing in Diabetes
Irena Pastar, Nathan C. Balukoff, Andrew P. Sawaya, Nicole M. Vecin, Marjana Tomic‐Canic
Abstract
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 and barrier integrity. Deregulation in any of these processes leads to a delayed or a 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 here in detail. The balance of signaling factors, including growth factors cytokines and chemokines, and gene expression regulators, along with 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 deregulated immune response, macro- and microvascular complications, neuropathy, and microbial dysbiosis. Discussion of therapeutics including cell therapy, stem cells, and stem cell-derived extracellular vesicles provide approaches for potentially effective treatments of patients with DFUs is also included.