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 polymicrobial 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 neuroischemic 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. Brief reflections on diabetes and the wound healing failure Since the seminal contribution of Banting and Best diabetes treatment was revolutionized. Hereafter, insulin therapy eliminated ketoacidosis as a principal cause of death among diabetics who enjoyed a longer lifespan. However, traditional insulin therapy combined with emerging novel approaches did not translate into a significant reduction of major complications that nowadays lead to morbidity and mortality [1]. Type 2 Diabetes Mellitus (T2-DM) is a heterogeneous and complex process comprising multiple pathogenic factors [2] and multi-organs complications’ that remain as a challenge for scientists and clinicians. T2-DM has progressively expanded as a pandemic condition accounting for 90% to 95% of all the diabetic population [3,4]. Diabetic foot ulceration (DFU) is one of the most frightened diabetic complications, leading to amputation-disability, social exclusion and early mortality [5]. The lifetime incidence of foot ulcers has been estimated to reach up to 34% of subjects with diabetes whereas diabetes-related lower extremity complications affect about 159 million people worldwide [6,7]. Accordingly, diabetic population still contributes to 80% of all non-traumatic lower extremities amputations around the world [8]. An illuminating review by Armstrong and coworkers prompted for the first time to distinguish the ulcer healing process not as the mere route for limb salvage, but as the foremost alternative to prevent early mortality. The 5-year relative mortality rate after limb amputation in diabetics rises to 68% only preceded by lung cancer [9]. *Correspondence to: Jorge Berlanga-Acosta, Center for Genetic Engineering and Biotechnology, Havana, Cuba, E-mail: jorge.berlanga@cigb.edu.cu