Epidermal Growth Factor Therapy Impact on Scar Tissue Resilience of Diabetic Lower Limbs Ulcers-An Enlightening Hypothesis

Abstract

Diabetes patients experience an accelerated aging process that increases their predisposition to multiorgan complications and earlier death. Lower extremity ulceration and wound chronification are among the devastating complications of diabetes. Likewise, ulcer recurrence is a frequent and challenging event whose cellular and molecular driving forces have remained elusive. Thus far educative prevention and interventions on predisposing factors are the only tools to prolong ulcer remission. Cellular senescence plays a critical role in diabetics healing impairment. Hyperglycemia-associated glucooxidative stress and other biochemical derangements can foster this premature senescence. Since diabetic microenvironment is permissive to senescence, we have hypothesized that the increasing thresholds of scar's senescent fibroblasts may contribute to wound recurrence. Diabetic wounds healing therapies have not accounted for a consistent reduction in recurrences rates. Reviewing 18 clinical trials of representative therapeutic alternatives for the healing of diabetic lower extremity wounds; indicated that epidermal growth factor therapy-either topical or by infiltrative delivery, proved to be the only intervention associated to the lowest recurrences rates. According to literature evidences, we propose that epidermal growth factor exerts a local rejuvenating effect by replacing senescent cells, or by dismounting/reversing the fibroblasts' epigenetic senescence program. This growth factor may potentially act as a senolytic agent for diabetic wounds, promoting the neodermal resilience and tolerance to physical and mechanical stress.