Epidermal Growth Factor (EGF) intralesional infiltrations: From the bench to the diabetic ulcers cells

Abstract

Diabetes mellitus remains with an ever-increasing prevalence, indefectibly associated to progressive and irreversible complications. Diabetic lower extremities ulcerations contribute to amputations, disability, and mortality. Ulcers result from a wound healing failure characterized by proliferative arrest, apoptosis, and senescence of granulation tissue-producing cells. Diabetic wounds are also distinguished by an inflamed, toxic, and degradative environment, acting as deterrents for local growth factors availability and receptors’ physiology. The emergence of growth factors caused expectation as biological modifiers for wounds repair arrest. The clinical introduction of growth factors was precocious when critical pieces of chronicity pathophysiology and growth factors pharmacology remained elusive. Mounting observations indicated that topical administration of these agents failed by the effect of local proteolysis, narrow bioavailability window, inadequate local kinetics/ diffusion, and a regenerating poly-microbial biofilm. As an alternative to circumvent these pharmacodynamics obstacles as to preserve EGF biological capabilities, we developed a series of experiments which provided the rationale and fundamentals for an intra-ulcer infiltrative delivery route. The clinical development program has included from a proof-of-concept to post-marketing studies in poor-prognosis ischemic, neuropathic and neuro-ischemic wounds. Along 18 years of clinical progress more than 259 000 patients were treated. As demonstrated by pharmacovigilance studies, aside from the success in the primary healing, the infiltrated EGF accounted for a reduction of amputation risks, negligible rates of annual recurrence, and prolonging survival of the healed patients. This pharmacological intervention is added to conventional treatments and surgical procedures. Infiltrated EGF has proved to reverse wound cells arrest being efficacious and safe for long terms of follow up.