Lower extremity ulceration is one of the serious and long-term diabetic complications rendering a significant social burden in terms of amputation and quality-of-life reduction. Diabetic patients experience a substantial wound-healing deficit. These lesions are featured by an exaggerated and prolonged inflammatory reaction with a significant impairment in local bacterial invasion control. Experimental and clinical evidences document the deleterious consequences of the wound's pro-inflammatory phenotype for the repair process. From a biochemical standpoint, hyperinflammation favours wound matrix degradation, thus, amplifying a pre-existing granulation tissue productive cells' invasiveness and recruitment deficit. Tumour necrosis factor perpetuates homing of inflammatory cells, triggers pro-apoptotic genes and impairs reepithelialisation. Advanced glycation end-products act in concert with inflammatory mediators and commit fibroblasts and vascular cells to apoptosis, contributing to granulation tissue demise. Therapeutic approaches aimed to downregulate hyperinflammation and/or attenuate glucolipotoxicity may assist in diabetic wound healing by dismantling downstream effectors. These medical interventions are demanded to reduce amputations in an expanding diabetic population.

A multicenter, double-blind, placebo-controlled trial was carried out to evaluate the intra-lesional infiltration of recombinant epidermal growth factor (EGF) in Wagner's grade 3 or 4 diabetic foot ulcers (DFUs). Subjects (149) were randomised to receive EGF (75 or 25 microg) or placebo, three times per week for 8 weeks and standard good wound care. The main endpoint was granulation tissue covering > or = 50% of the ulcer at 2 weeks. It was achieved by 19/48 controls versus 44/53 in the 75 microg group [odds ratio (OR): 7.5; 95% confidence interval (CI): 2.9-18.9] and 34/48 in the 25 microg group (OR: 3.7; 1.6-8.7). Secondary outcome variables such as end-of-treatment complete granulation response (28/48 controls, 46/53 with 75 microg and 34/48 with 25 microg EGF), time-to-complete response (controls: 5 weeks; both EGF dose groups: 3 weeks), and wound closure after follow-up (25/48 controls, 40/53 with 75 microg and 25/48 with 25 microg EGF) were also treatment dependent. Multivariate analyses yielded that they were significantly enhanced by 75 microg EGF treatment and neuropathic versus ischemic ulcers. Most adverse events were mild and no drug-related severe adverse reactions were reported. It was concluded that recombinant human EGF (rhEGF) local injections offer a favourable risk-benefit balance in patients with advanced DFU.

This study examined if a series of epidermal growth factor (EGF) local infiltrations can enhance the healing process of complicated diabetic wounds. Twenty-nine in-hospital patients with diabetic neuropathic or ischaemic lesions with high risk of amputation were treated in a non controlled pilot study conducted at the National Institute of Angiology, Havana. Lesions, classified as Wagner's grade 3 or 4, included ulcers > or = 20 cm2 for > or = 25 days or amputation residual bases > or = 30 cm2 for > or = 15 days, healing refractory despite comprehensive wound care. EGF (25 microg) intralesional infiltrations (approximately 250 microl of a 25 microg/ml solution/injection point) were performed thrice weekly up to the eighth week. Wound closure was monitored during the treatment and recurrence examined for a year following discharge from hospital. Eighty-six per cent of the patients treated showed a productive granulation at infiltration session 8. Histological examination at this point indicated a substantial wound matrix transformation, granulation tissue cell repopulation and angiogenesis. Of the 29 patients treated, amputation was prevented in 17 (58.6%) of them who completed 24 infiltration sessions. They averaged 71.1 +/- 18.3% of reepithelisation during a mean in-hospital period of 66.5 +/- 4.9 days. Wound recurrence after 1 year of follow-up appeared in only one patient. Preliminary evidences suggest that EGF intralesional infiltrations may be effective in reducing diabetic lower limb amputation.

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