Diabetic Foot Ulcer Wound Healing and Tissue Regeneration: Signaling Pathways and Mechanisms

Abstract

This chapter digs into the complexities of diabetic foot ulcer (DFU) wound healing, encompassing cellular responses from fibroblasts, keratinocytes, and macrophages, as well as humoral responses involving the release of growth factors and cytokines. The normal wound healing process is hindered in diabetics by factors like infections, venous insufficiency, impaired oxygenation, age-related changes, immune dysfunction, and a dry environment, contributing to delayed and challenging wound healing. The discussion then focuses on the intricate interplay of signaling cascades, including PI3K/Akt, MAPK/ERK, and Wnt/β-catenin, in the pathology of DFUs. Diabetes induces disruptions in the PI3K/Akt pathway, impeding cell migration and angiogenesis due to compromised insulin signaling and increased oxidative stress. Abnormalities in the MAPK pathway, essential for inflammation and tissue remodeling, further impact wound closure in DFUs. Additionally, downregulation of the Wnt/β-catenin pathway, crucial for tissue regeneration, contributes to immune dysfunction, delaying healing in diabetic wounds. Finally, the chapter explores multifaceted factors contributing to the pathogenesis of DFUs, including epigenetic modifications, oxidative stress, advanced glycation end products (AGEs), the polyol pathway, diacylglycerol-protein kinase C (DAG-PKC) activation, and the nitric oxide (NO) pathway. Persistent hyperglycemia in diabetes hinders wound healing, causing chronic ulcers and complications. Addressing these mechanisms is crucial for revolutionizing management.