Abstract
Chronic non-healing wounds, most notably diabetic foot ulcers (DFUs), remain a leading source of disability, amputation, and mortality among the more than 537 million adults living with diabetes worldwide. The molecular pathology of diabetic wounds is characterized by persistent inflammation, deficient angiogenesis, oxidative stress, neuropathy, microbial dysbiosis, and an extracellular matrix (ECM) in which growth factors are sequestered, prematurely degraded, or biologically inactive. Recombinant growth factor therapy was once viewed as a transformative solution, yet four decades of clinical experience have revealed that the unmodified molecules are limited by extremely short half-lives, susceptibility to proteases and advanced glycation end-products (AGEs), supraphysiologic dosing requirements, off-target effects, and prohibitive manufacturing costs. Growth factor engineering a convergence of protein engineering, biomaterials science, gene and cell therapy, and synthetic biology has emerged as a powerful strategy to overcome these limitations by reshaping the spatiotemporal presentation of molecular cues in the wound bed. This review provides a state-of-the-art synthesis of the biology of growth factors in diabetic wound repair, surveys the principal engineering modalities (structural mutagenesis, fusion proteins, ECM-mimetic tethers, controlled-release vehicles, gene- and cell-based delivery, exosomes, and stimuli-responsive smart materials), and critically appraises preclinical and clinical evidence for each. Emphasis is placed on the four cardinal families—platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), fibroblast growth factors (FGFs), and epidermal growth factor (EGF) and emerging targets such as stromal cell-derived factor-1 (SDF-1), hepatocyte growth factor (HGF), and insulin-like growth factor-1 (IGF-1). The review concludes with regulatory, manufacturing, and ethical considerations and outlines a forward-looking agenda incorporating artificial intelligence-guided protein design, multi-cue release, immune reprogramming, and personalized medicine