Human Epidermal Growth Factor Enhances Healing of Diabetic Foot Ulcers

Abstract

OBJECTIVE -To study the healing effect of recombinant human epidermal growth factor (hEGF) on diabetic foot ulcers. RESEARCH DESIGN AND METHODS-A total of 127 consecutive patients were screened and 61 diabetic subjects were recruited into this double-blind randomized controlled study. Predetermined criteria were used for diagnosis and classification of the diabetic wound. The patients were randomized into three groups. All patients attended our Diabetes Ambulatory Care Center every other week for joint consultation with the diabetologist and the podiatrist. Group 1 (control) was treated with Actovegin 5% cream (Actovegin), group 2 with Actovegin plus 0.02% (wt/wt) hEGF, and group 3 with Actovegin plus 0.04% (wt/wt) hEGF. The study end point was the complete closure of the wound. Failure to heal was arbitrarily defined as incomplete healing after 12 weeks.RESULTS -Final data were obtained from 61 patients randomly assigned into three groups. The mean ages of the patients, wound sizes, wound duration, metabolic measurements, and comorbidities were comparable within groups, except that group 3 had more female patients. Mean follow-up for the patients was 24 weeks. Data were cutoff at 12 weeks, and results were analyzed by intention to treat. After 12 weeks, in group 1 (control) eight patients had complete healing, two patients underwent toe amputation, and nine had nonhealing ulcers. In group 2 (0.02% [wt/wt] hEGF) 12 patients experienced wound healing, 2 had toe amputations, and 7 had nonhealing ulcers. Some 20 of 21 patients in group 3 (0.04% [wt/wt] hEGF) showed complete wound healing. Healing rates were 42.10, 57.14, and 95% for the control, 0.02% (wt/wt) hEGF, and 0.04% (wt/wt) hEGF groups, respectively. Kaplan-Meier survival analysis suggested that application of cream with 0.04% (wt/wt) hEGF caused more ulcers to heal by 12 weeks and increased the rate of healing compared with the other treatments (log-rank test, P ϭ 0.0003).CONCLUSIONS -Our data support the contention that application of hEGF-containing cream, in addition to good foot care from a multidisciplinary team, significantly enhances diabetic foot ulcer wound healing and reduces the healing time. Diabetes Care 26:1856 -1861, 2003D iabetic foot ulcer is a major complication of diabetes. People with diabetes show a 5-to 50-fold higher risk of nontraumatic amputation compared with individuals who do not suffer from diabetes (1). Between 1996 and 1998, diabetic patients accounted for 47% of all the lower-limb amputations performed in our hospital (M.W.T., K.-M.L., G.K., unpublished data), comparable to published data (2). The major risk factor leading to diabetic foot ulcer is poor diabetes control, which results in neuropathic and vascular changes. In general, diabetic foot ulcers are difficult to heal and frequently lead to amputation if complicated by infection and gangrene. Several new treatment modalities, such as exposure to an oxygen chamber, the use of platelet-derived growth factor (PDGF), and the application of various local dressings, have p...

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“…Presumably, quality authentic rEGF was employed in these studies; the success rate of complete healing of DFU increased from less than 50% found in placebo controls, wherein only debridement was administered [26], to as high as 95% observed in patients treated with both debridement and rEGF [26]. This facile and effective treatment protocol [26], although it is not yet officially approved for medical applications, has been employed successfully to treat thousands of DFU (unpublished data). Intriguingly and obviously, the protocol is very safe as there has not been a single incident of side effect observed in individuals treated by the topical method described.…”

“…The rEGF products available from various expression activities were analyzed for their efficacies in promoting treatments of skin diseases, including hard-to-heal wounds such as diabetic foot ulcers [25][26][27][28], bedsores [29], scalds [30] and Stevens-Johnson syndrome [31], of which the last disorder results usually from a severe allergic reaction to a medication [32][33]. Despite the positive outcomes shown in these studies, the efficacies of EGF as an active ingredient in skin care or medical applications have been controversial, in particular in studies conducted in earlier times [34].…”

“…Given the demonstration that authentic rEGF is effective in treating a variety of human wounds through topical administration [6,26,[30][31], and that the protocol employed is simple and safe [6,26], if a license is sought for rEGF to be applied as a drug in a country, a lengthy and expensive process, which includes: a. Successful attainment of the national patent concerned [44], b. Accomplishment of rEGF production under current Good Manufacturing Practice Regulations and lastly, c. Fulfilment of FDA clinical trial requirements, is necessary [45].…”

“…The application of rEGF in enhancing treatment of DFU employing simply a topical approach has been well documented in many separate and independent studies [26,29]. Presumably, quality authentic rEGF was employed in these studies; the success rate of complete healing of DFU increased from less than 50% found in placebo controls, wherein only debridement was administered [26], to as high as 95% observed in patients treated with both debridement and rEGF [26].…”

“…Years of devoted research have resulted in cost-effective protocols for authentic rEGF production, and substantial evidence to support the effectiveness of the simple and safe topical protocol in enhancing treatments of DFU [26]. Paradoxically then, the long durations taken for patent application and FDA clearance and approval processes, which are meant to benefit the inventors/ investors and patients, respectively, deprive the opportunities of millions of DFU patients from enjoying the prompt healing effect of rEGF simply through topical treatment, and more importantly, from avoiding amputation, which will result in devastating consequences.…”