Epidermal Growth Factor Intralesional Delivery in Chronic Wounds: The Pioneer and Standalone Technique for Reversing Wound Chronicity and Promoting Sustainable Healing.

The early expectations about growth factors' (GFs') discovery as an undisputed therapeutic solution for chronic wounds progressively eclipsed when they failed to accelerate acute wound closure and restore the healing trajectory of stagnant ulcers. Critical knowledge about chronic wound biology and GF pharmacology was a conundrum at that time. Diabetes undermines keratinocytes' and fibroblasts' physiology, impairing skin healing abilities. Diabetic ulcers, as other chronic wounds, are characterized by hyperinflammation, unbalanced proteolytic activity, catabolism, and free radical cytotoxicity. This hostile scenario for the chemical stability, integrity, and functionality of GFs led to the conclusion that topical administration may jeopardize GFs' clinical effectiveness. Epidermal growth factor (EGF) has a proximal position in tissues homeostasis by activating survival and mitogenic pathways from embryonic life to adulthood. Seminal experiments disclosed unprecedented pharmacological bounties of parenterally administered EGF. Accordingly, the experience accumulated for more than 20 years of EGF intralesional infiltration of diabetic wound bottoms and edges has translated into sustained healing responses, such as low recurrences and amputation rates. This delivery route, in addition to being safe and tolerated, has shown to restore a variety of circulating biochemical markers ordinarily disturbed in diabetic conditions. EGF infiltration triggers a cascade of local fibroblast reactions, supporting its molecular integrity, prolonged mean residence time, and ultimately eliciting its receptor trafficking and nuclear translocation. The intralesional delivery route seems to warrant that EGF reaches wound fibroblasts' epigenetic core, mitigating the consequences of metabolic memory imprinting.