Targeting diabetic foot ulcer pathophysiology: altered signaling pathways and 3D scaffold as an emerging treatment strategy.

Abstract

Diabetic wound healing, especially in the context of diabetic foot ulcers, remains a major clinical challenge due to the complex interplay of metabolic, vascular, and cellular dysfunctions caused by chronic hyperglycemia. Impaired healing is driven by weakened inflammatory response, decreased blood vessel formation, reduced collagen production, and impaired fibroblast function. Hyperglycemia activates multiple damaging pathways, including the polyol, protein kinase C, hexosamine, and advanced glycation end-product pathways, which collectively induce oxidative stress and chronic inflammation. In addition, diabetic wounds exhibit impaired responses to hypoxia, marked by reduced expression of hypoxia-inducible factors (HIF-1 and HIF-1α), and elevated phenyl pyruvate, which activate macrophage-driven inflammation through CD36-PPT1-NLRP3 axis. Excessive matrix metalloproteinase (MMP) activity and poor collagen deposition disrupt extracellular matrix remodeling, further compromising tissue repair. Key signaling pathways such as PI3K/Akt, MAPK, TGF-β/SMAD, Notch, NfκB, VEGF, Wnt/β-catenin, and Nrf2 are dysregulated in diabetic wounds, undesirably affecting cell survival, inflammation resolution, and angiogenesis. To overcome these challenges, 3D scaffolds have emerged as an innovative therapeutic approach. Mimicking native ECM, it promotes cell adhesion, proliferation, and differentiation, and also enables controlled delivery of bioactive materials like stem cells, antimicrobials, and growth factors. Fabrication uses advanced materials like hydrogels, nanofibers, and smart polymers; these scaffolds are promising in restoring normal healing dynamics. This review explores the pathophysiology, major dysregulated pathways in DFU, and the evolving role of 3D scaffolds in diabetic wound treatment with supportive evidence of preclinical and clinical studies to improve clinical outcomes and patient's quality of life.