Type 2 diabetes mellitus is a metabolic noncommunicable disease with an expanding pandemic magnitude. Diabetes predisposes to lower extremities ulceration and impairs the healing process leading to wound chronification. Diabetes also dismantles innate immunity favoring wound infection. Amputation is therefore acknowledged as one of the disease's complications. Hyperglycemia is the proximal detonator of systemic and local toxic effectors including proinflammation, acute-phase proteins elevation, and spillover of reactive oxygen and nitrogen species. Insulin axis deficiency weakens wounds' anabolism and predisposes to inflammation. The systemic accumulation of advanced glycation end-products irreversibly impairs the entire physiology from cells-to-organs. These factors in concert hamper fibroblasts and endothelial cells proliferation, migration, homing, secretion, and organization of a productive granulation tissue. Diabetic wound bed may turn chronically inflammed, procatabolic, and an additional source of circulating pro-inflammatory cytokines, establishing a self-perpetuating loop. Diabetic fibroblasts and endothelial cells may bear mitochondrial damages becoming prone to apoptosis, which impairs granulation tissue cellularity and perfusion. Endothelial progenitor cells recruitment and tubulogenesis are also impaired. Failure of wound reepithelialization remains a clinical challenge while it appears to be biologically multifactorial. Ulcer prevention by primary care surveillance, education, and attention programs is of outmost importance to reduce worldwide amputation figures.

Chemotaxis, mitogenesis, motogenesis and cytoprotection are common cellular events involved in both tumourigenesis and tissue repair, which appear amplified upon growth factors exposure. Epidermal growth factor (EGF) promotes these events in epithelial and mesenchymal cells through the binding to a specific tyrosine kinase receptor. In experimental oncology settings, EGF does not initiate malignant transformation but exhibits 'tumour promotion'. These observations have raised doubts on the clinical use of EGF despite solid demonstrations of efficacy in experimental conditions and clinical trials. The results of a Pubmed and Bioline investigation on EGF clinical uses and preclinical safety data are presented here. EGF topical administration has been used since 1989 to enhance the healing process of a variety of peripheral tissues wounds (16 clinical reports), as well as its intravenous, oral and rectal administration for gastrointestinal damages (11 clinical reports). EGF therapeutic efficacy and excellent tolerability seem demonstrated. Lack of long-term adverse effects is highlighted in those studies with 6, 12 and 24 months of patients follow-up. Although post-treatment follow-up may fall short for malignant growth, there are no reports on evidences linking EGF clinical use with cancer. A multicentre, nationwide survey in Cuba, 15 years after randomly using silver sulphadiazine with EGF or not in burn victims yielded that cancer incidence was comparable between EGF-treated and control subjects and that such incidence rate does not differ from the age-matched national incidence for those 15-year period. All the animal species subjected to long-term EGF systemic administration exhibit dose-dependent and reversible epithelial organs hyperplasia with no changes in cells phenotypic differentiation. Histotypic pre-malignant markers were not identified. The results emerged from co-carcinogenesis studies and from transgenic mice over-expressing EGF are conflicting and indicate that EGF overexposure, either innate or postnatal, may not be sufficient to transform cells. The ability of EGF to heal injured tissues in life-threatening scenarios or to assist in preventing physical and social disability advocates for its clinical use under a rational medical risk/benefit balance.

Diabetes is constantly increasing at a rate that outpaces genetic variation and approaches to pandemic magnitude. Skin cells physiology and the cutaneous healing response are progressively undermined in diabetes which predisposes to lower limb ulceration, recidivism, and subsequent lower extremities amputation as a frightened complication. The molecular operators whereby diabetes reduces tissues resilience and hampers the repair mechanisms remain elusive. We have accrued the notion that diabetic environment embraces preconditioning factors that definitively propel premature cellular senescence, and that ulcer cells senescence impair the healing response. Hyperglycemia/oxidative stress/mitochondrial and DNA damage may act as major drivers sculpturing the senescent phenotype. We review here historical and recent evidences that substantiate the hypothesis that diabetic foot ulcers healing trajectory, is definitively impinged by a self-expanding and self-perpetuative senescent cells society that drives wound chronicity. This society may be fostered by a diabetic archetypal secretome that induces replicative senescence in dermal fibroblasts, endothelial cells, and keratinocytes. Mesenchymal stem cells are also susceptible to major diabetic senescence drivers, which accounts for the inability of these cells to appropriately assist in diabetics wound healing. Thus, the use of autologous stem cells has not translated in significant clinical outcomes. Novel and multifaceted therapeutic approaches are required to pharmacologically mitigate the diabetic cellular senescence operators and reduce the secondary multi-organs complications. The senescent cells society and its adjunctive secretome could be an ideal local target to manipulate diabetic ulcers and prevent wound chronification and acute recidivism. This futuristic goal demands harnessing the diabetic wound chronicity epigenomic signature.

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