Chronic venous leg ulcers are becoming more prevalent, but the standard treatment heals only approximately half of lesions (1). What to do when the small vessels are damaged and the tissue inflammation is hard to stop? American scientists believe in the cell therapy. Their long-standing research resulted in the study (2) of spray-applied human allogeneic fibroblasts and keratinocytes. The paper was published in the August issue of the Lancet. The researchers avoided expensive tissue engineering and still achieved therapeutic success. Soon the greater circle of patients might benefit from this new method.
Heavy legs, evening hour
Chronic venous insufficiency (CVI) is characterized by the symptoms of venous stasis due to the retrograde flow of the blood in veins, their stricture and obstruction. The disease is connected with varicose veins and insufficiency of vein valves. Patients of advanced age, women (especially pregnant), the obese and working in the sitting position are prone to CVI. First symptoms include the feeling of heaviness of the lower extremities, exacerbating usually in the evening and alleviating after the rest and lifting of the legs. Doctors observe teleangiectasia, dilated and winding varicose veins as well as edema. In serious cases venous ulcerations are formed, typically on the skin of 1/3 of the shin, on the medial malleus side. It can lead to thrombosis or infection and usually causes a great deal of pain.
Cell therapy principles
Standard treatment of venous ulcers include infection control, management of the wound with regular changing of the dressings and according to some authors – compression. Sometimes major surgical intervention is required. There are several types of dressings available, those which take part in the process of healing are called “active dressings” (3). The most complex ones, based on genetic engineering, mimic the epidermis or even the whole dermis. In order to manage skin defects with cultured cells, two main approaches are known (4). First suggests complete replacement of lost tissue by permanent grafting of proliferative autologous cells. The second promotes regeneration by stimulation of the cells left in the wound using timely applied non-proliferating allogeneic or xenogeneic cells.
Modern dressings imitate the skin
Among active dressings we distinguish acellular skin substitutes, which are usually made of just collagen fibres, and one-layer or two-layer skin substitutes made of various types of cells. The application of one-layer autologous epidermal graft, consistent with the first mentioned-above approach, requires the creation of donor site wound, which seems to be a major disadvantage. Until now the most advanced variation in the second group is a two-layer allogeneic skin equivalent. It is made of neonatal fibroblasts cultured within a bovine matrix and neonatal keratinocytes placed on top of this layer. In one trial 63% of venous leg ulcers healed within 24 weeks of skin-equivalent treatment in comparison to 49% treated with compression therapy alone (5).
The young heal the old
The discussed study, performed by American scientists, enrolled 205 participants with chronic venous leg ulcers which were divided into 4 treatment groups and one control. The former received cell therapy in 2 different concentrations once in 7 days or every 14 days and all four-layer compression bandages. The latter were treated with compression and just neutral vehicle (human fibrogen and thrombin solution). HP802-247, the main interest of this study, is a name for the spray-applied cell therapy, which contains growth-arrested allogeneic neonatal keratinocytes and fibroblasts. It fulfills the second approach to cell therapy. The cells had been cultured in a laboratory, but were originally derived from newborn foreskin samples removed during circumcision. Researchers made sure that the release of growth factors was high, which might be the cause of trial’s success.
Meet the future
The significance of this clinical trial is great as this is surely a major study, designed as a multicentre, double-blind, randomized, placebo-controlled. As a phase 2 trial it was aimed to check the treatment’s efficacy and safety, as well as establish the suitable dose. The aims of the study were achieved. The greatest beneficial effect was gained at a dose of 0,5 ×10⁶ cells/mL every 2 weeks. At 14 weeks 70% of the wounds were healed, compared with 46% in the control group. Adverse events were as frequent in the active group than in the control. As the results were positive, the trial can be followed by larger phase 3 trails. It seems that the product may have a chance to appear on a market one day and also be applicable in other chronic wounds such as ischaemic or diabetic foot ulcers.
1) O’Meara S, Cullum NA, Nelson EA. Compression for venous leg ulcers. Cochrane Database Syst Rev 2009; 1: CD000265.
2) Kirsner RS, Marston WA, Snyder RJ et al. Spray-applied cell therapy with human allogeneic fi broblasts and
keratinocytes for the treatment of chronic venous leg ulcers: a phase 2, multicentre, double-blind, randomised, placebo-controlled trial. Lancet 2012; published online Aug 3. http://dx.doi.org/10.1016/S0140-6736(12)60644-8.
3) Maria Żmudzińska, Magdalena Czarnecka-Operacz. Management of venous leg ulcers – modern wound dressings. Post Dermatol Alergol 2006; XXIII, 3: 143–148
4) Goedkoop R, Juliet R, You PH, et al. Wound stimulation by growth-arrested human keratinocytes and fi broblasts: HP802-247, a new-generation allogeneic tissue engineering product. Dermatology 2010; 220: 114–20.
5) Falanga V, Margolis D, Alvarez O, et al. Rapid healing of venous ulcers and lack of clinical rejection with an allogeneic cultured human skin equivalent. Human Skin Equivalent Investigators Group. Arch Dermatol 1998; 134: 293–300.
Would You like to know more? Watch on MEDtube.net: Skin – Ulcer – Amputation Stump.