Lower-extremity diabetic ulcers are responsible for 80% of annual worldwide nontraumatic amputations. Epidermal growth factor (EGF) reduction is one of the molecular pillars of diabetic ulcer chronicity, thus EGF administration may be considered a type of replacement therapy. Topical EGF ad­ministration to improve and speed wound healing began in 1989 on burn patients as part of an acute-healing therapy. Further clinical studies based on topically administering EGF to different chronic wounds resulted in disappointing out­comes. An analysis of the literature on unsuccessful clinical trials identified a lack of knowledge concerning: (I) molecular and cellular foundations of wound chronicity and (II) the phar­macodynamic requisites governing EGF interaction with its receptor to promote cell response. Yet, EGF intra- and perile­sional infiltration were shown to circumvent the pharmacody­namic limitations of topical application. Since the first studies, the following decades of basic and clinical research on EGF therapy for problem wounds have shed light on potential uses of growth factors in regenerative medicine. EGF’s molecular and biochemical effects at both local and systemic levels are diverse: (1) downregulation of genes encoding inflammation mediators and increased expression of genes involved in cell proliferation, angiogenesis and matrix secretion; (2) EGF in­tervention positively impacts both mesenchymal and epithelial cells, reducing inflammation and stimulating the recruitment of precursor circulating cells that promote the formation of new blood vessels; (3) at the subcellular level, upregulation of the EGF receptor with subsequent intracellular trafficking, includ­ing mitochondrial allocation along with restored morphology of multiple organelles; and (4) local EGF infiltration resulting in a systemic, organismal repercussion, thus contributing to attenuation of circulating inflammatory and catabolic reac­tants, restored reduction-oxidation balance, and decreased toxic glycation products and soluble apoptogenic effectors. It is likely that EGF treatment may rearrange critical epigenetic drivers of diabetic metabolic memory.

KEYWORDS Epidermal Growth Factor, diabetes, diabetes complications, wound healing, diabetic foot, amputation, ulcer, Cuba