Efficacy of Human Recombinant Epidermal Growth Factors vs Conventional Therapy for the Treatment of Chronic Venous Ulcers

A Retrospective Case Series

Maria Teresa Cacua Sanchez, PhD; Luis Fernando Giraldo, APRN; Jhon Alejandro Díaz, EPA


Wounds. 2021;33(2):41-49. 

In This Article

Abstract and Introduction


Introduction: Venous ulcers are the terminal phase of chronic venous insufficiency, the result of induced skin disorders and maintained by persistent venous hypertension. Affecting a large part of the adult population, they drain economic resources and greatly impact patient quality of life.

Objective: The objective of this descriptive, retrospective case series was to determine the efficacy of recombinant human epidermal growth factor (rhEGF) plus compression therapy vs standard of care in 48 patients with active ulcers resulting from chronic venous insufficiency.

Materials and Methods: In this descriptive, retrospective case series, 24 patients (mean age, 62.4 years) received rhEGF by intralesional and perilesional infiltration with compression therapy, and 24 patients (mean age, 69.4 years) received treatment with topical hydrocolloid gels and compression therapy. In 62.5% of patients, the ulcers were located in the internal malleoli. Ulcer progression time, ulcer size, Wollina score index, number of conventional cures, rhEGF vials used, and time to epithelialization were documented.

Results: Epithelialization of the active ulcer was reached in 100% of intervened patients. In the 24 patients receiving rhEGF, 71% achieved wound closure in 8 weeks or less, and the remaining percentage achieved closure within 9 and 12 weeks. In the conventional therapy group, patients achieved closure in an average of 29.5 weeks, with a minimum of 13 weeks and a maximum of 46 weeks.

Conclusions: Although conventional therapy with the use of hydrocolloids and compression achieved adequate epithelialization of venous ulcers, the use of rhEGF significantly decreased healing time and could be a beneficial therapy to these patients who have few therapeutic options.


Vascular ulcers are a challenge for health care professionals. Venous etiologies are most common, ranging from 80% to 90% of all ulcers;[1,2] chronic venous insufficiency may originate from thrombosis, an alteration in the valve system, or a failure in the muscular pump, resulting in venous hypertension in the lower limbs.[3] The prevalence of venous ulcers ranges between 0.10% and 0.30%, and 3 to 5 new cases are reported per 1000 people per year.[4] These figures are doubled in population segments over 65 years of age.

Venous ulcers are also the most common type of chronic leg wound. Once they are triggered, like all chronic ulcers, they tend to have an insidious progress, are difficult to heal, and involve large areas of the surrounding skin.[5] A review of the literature finds that 40% to 50% will remain active for 6 to 12 months, and 10% will reach progress for up to 5 years.[6] According to some studies, venous ulcer care constitutes 50% of the total nursing time in primary care, thus having a high socioeconomic impact.[7]

Treatment of venous ulcers entails an arduous task for health care personnel, being frequently prolonged and, in many cases, proving difficult to appreciate progress. Also, the required treatment of the background pathology has an annual US estimated cost of $1.5 billion to $3.5 billion.[8]

For some authors, such as Borges,[9] there is still doubt about the best treatment for venous ulcers. However, the management objectives must include the following pillars: promote healing, improve quality of life, and reduce adverse effects[10] since active ulcers can become infected, causing an additional delay in the healing process.

The literature shows that compression therapy (3 or 4 layers of bandage) is the gold standard for healing ulcers of venous etiologies (type A recommendation).[11] However, 30% fail to heal after 1 year of treatment, becoming a complex and long-lasting pathology.[12]

Therefore, it should be taken into account that the initial response to treatment is a predictive factor of healing. It has been established that a decrease of approximately 15% of the surface of the wound after 1 or 2 weeks of treatment justifies continuing the established treatment.[13] If this does not occur, the patient should be reassessed. It has been pointed out that to reduce the long-term impact in the patient's healing process, as well as to contain costs, the use of adjuvant and advanced therapies should be considered since small-scale studies have demonstrated that initiating advanced therapy more quickly achieves better results than seen with traditional treatments. With a primary objective of reducing healing time, accelerating and modulating the healing process will minimize the risk of complications, reduce physical and emotional limitations in the patient, and decrease consumption of socio-health resources associated with significant labor costs.

Much progress has been made in the knowledge of biology in wound healing. The healing process has been found to be driven by a variety of soluble factors derived from cells, including the production of proinflammatory cytokines and proteolytic enzymes (metalloproteases, elastase, and plasmin) that destroy the extracellular matrix and inactivate growth factor.[14] Moreover, understanding which of these molecules are overexpressed and which are in deficit and with low bioavailability, as is the case with the growth factor, it has been possible to develop medications, such as the recombinant human epidermal growth factor (rhEGF) nepidermin to repair, regenerate, and enhance new tissues in vascular wounds.

Nepidermin is a healing and stimulating agent that facilitates circumventing the biofilm barrier and is more efficient and safe for application in chronic ulcers.[15] The rhEGF is typically administered perilesionally and intralesionally at a dose of 75 μg diluted in sterile water for injection, 3 times per week; the administrations are maintained until complete granulation of the lesion is achieved or up to 8 weeks.[16]

Among the experiences of nepidermin application in venous ulcers, a case series published in 2019 concluded that use of this drug reduced the healing time of chronic venous ulcers. In such cases, the time and number of vials that a patient would need for the treatment was determined; the average time of treatment was 5.6 weeks with 15.7 vials per patient.[17] In another case report of a patient with a venous ulcer, 75 μg of nepidermin was applied 3 times per week for 8 weeks, achieving 95% granulation and 90% epithelialization at the end of therapy.[18] It has been concluded that local intralesional administration of rhEGF promotes wound healing by correcting the expression of biological factors, which are altered in patients with ulcers, thereby reducing the release of reactive oxygen species and increasing serum levels of antioxidative capacity to improve the biochemical environment of the ulcer. Compared with the current standard of care for managing chronic venous ulcers, rhEGF is more effective, shows a shorter time to achieve complete healing of the lesion, and is well tolerated with an excellent safety profile.[18]

Consequently, this study was proposed to determine whether granulation and epithelialization of a chronic venous ulcer could be achieved more quickly by using intralesional nepidermin plus compression therapy vs topical hydrocolloid therapies plus compression therapy, thereby improving the patient's health status in a shorter time.

The authors sought to determine the observed efficacy of rhEGF in a case series of patients with chronic venous insufficiency (Clinical-Etiology-Anatomy-Pathophysiology [CEAP] classification C6) plus compression therapy compared with conventional treatment with hydrocolloid gels plus compression therapy, measured in treatment time and progress of ulcer granulation. Other objectives included evaluating the number of cures and vials needed to fulfill the therapeutic goal, which was the closure of the venous ulcer.