Diabetic Foot Ulcers and Epidermal Growth Factor: Revisiting the Local Delivery Route for a Successful Outcome

Figure 1

Impact of high glucose burden in multiple organs and tissues complications. Cells exposure to high glucose concentrations is harmful. Hyperglycemia triggers the activation of transcription factors that impose a proinflammatory phenotype which may also increase circulating levels of proinflammatory cytokines. This inflammatory/reactive condition further amplifies insulin resistance and raises the accumulation of more inflammatory cells within the wound. By its side, insulin resistance hinders the proanabolic function of insulin. Inflammation perpetuation and anabolism breakdown contribute to imposing a poorly synthetic, prodegradative environment in the wound. In fact, some of the inflammation-activating transcription factors are also involved in matrix proteases transcription activation. The role of epigenetics is increasingly filling gaps and has explained the molecular bases of the metabolic memory. Oxidative stress by an excessive and uncontrolled generation of free radicals is a sine qua non condition of diabetes. Pivotal roles are primarily played by free radicals in damaging mitochondrial structures which further ensures more radical toxicity. The damage spectrum includes reticular stress and apoptosis, autophagy, growth factors receptors signaling disruption, orchestration of a precocious senescence program, and proliferative arrest. All these factors disrupt the healing cascade and contribute to wound chronification. Similar toxicity is generated by the accumulation of the advanced glycation or glycoxidation-end products (AGEs). AGEs contribute to wound chronification by multiple roads that include deterioration of the innate immune mechanism with the ensued infection and perpetuation of procatabolic and proinflammatory conditions, so as to induce fibroblasts and endothelial cells apoptosis.