Vein surgery with or without skin grafting versus conservative treatment for leg ulcers. A randomized prospective study. The influence of surgical treatment for chronic leg ulcers on the quality dynamics of the patient's life. Rapid healing of venous ulcers and lack of clinical rejection with an allogeneic cultured human skin equivalent. Human Skin Equivalent Investigators Group. An autologous epidermal equivalent tissue-engineered from follicular outer root sheath keratinocytes is as effective as split-thickness skin autograft in recalcitrant vascular leg ulcers. Randomized trial comparing cryopreserved cultured epidermal allografts with hydrocolloid dressings in healing chronic venous ulcers. Pinch skin grafting or porcine dermis in venous ulcers: a randomised clinical trial. Wound stimulation by growth-arrested human keratinocytes and fibroblasts: HP802-247, a new-generation allogeneic tissue engineering product. Treatment of venous leg ulcers with Dermagraft. Cryopreserved and lyophilized cultured epidermal allografts in the treatment of leg ulcers: a pilot study. Tapping into the influence of keratinocyte allografts and biocenosis on healing of chronic leg ulcers: split-ulcer controlled pilot study. Treatment of venous leg ulcers with cryopreserved cultured allogeneic keratinocytes: a prospective open controlled study. Autologous cultured keratinocytes on porcine gelatin microbeads effectively heal chronic venous leg ulcers.
In order for us to evaluate the efficiency of perforator vein surgery and skin grafting in leg ulcer patients, 47 patients were randomized into 3 treatment groups (group A: surgery for incompetent perforators, group B: surgery for incompetent perforators and ulcer excision followed by grafting, group C: control group). All the patients were treated with a compression bandage. When cellulitis was observed, a systemic antibiotic was given; eczema was treated with a steroid ointment. Fourty patients were evaluated regularly during one year after entry. There were no differences between the 3 treatment groups considering base-line characteristics, median ulcer size at entry and after one year. According to a review of the initial phlebograms, the occurrence of post-thrombotic changes in the deep veins were recorded in the majority of the legs. Our results suggest that ligation of incompetent perforators and skin grafting, as used in the present study, may not offer an additional advantage for venous ulcer patients with insufficiency of the deep veins when compared to conservative treatment. However, the removal of insufficient superficial veins was not studied. This study was undertaken to assess the effectiveness of skin grafting and the influence on the quality of the lives of patients who have large chronic venous ulcers.
                We have performed the perspective analysis of the course of the disease and of treatment results after 6 months. Two groups of patients were involved in the study. Group O contains patients who have been treated by performing skin graft surgery, while group C contains patients who have been treated only by conservative means. All patients studied have been treated during the period of 2001-2005 at the Department of Plastic Surgery and Burns and at the Clinic of Skin and Venereal Diseases (CSVD) of Kaunas Medical University Hospital (KMUH). During the visit patients had to complete a questionnaire (enclosed with patient's history of treatment), according to which we evaluated the influence of large chronic venous leg ulcers on the quality of patients' lives. This questionnaire has been developed in accordance with the questionnaire for the evaluation of quality of life prepared by prof. dr. M. E. Hyland.
                At the beginning of the study all patients of O and C groups suffered from pain in the legs. However, at the end of the study, pain decreased only in patients of O group (p < 0.05), while in C group pain practically remained the same. At the beginning of the study, the ulcers deprived many patients from both groups of sleep for most of the night (37-41%). During the repeated questioning it turned out that ulcers only deprived 2.5% of patients in group O of sleep for most of the night, whereas in group C this rose to 19.35%.
                Skin grafting positively influences the quality of patients' lives significantly (p < 0.05). Skin grafting has decreased the limitation of function and improved the dysphoric mood. The coverage of ulcers by autografts of skin thickness, had decreased the leg pain within 6 months, significantly more than by conservative treatment alone (p < 0.05). The amount of patients' personal expenditure on the care and treatment of ulcers, increased within the period of 6 months for 11.2% of patients in whom large CVUL were treated conservatively. The amount of personal expenses decreased to 12.8% of patients in whom skin grafting was applied (p > 0.05). To test the safety, efficacy, and immunological impact of a cultured allogeneic human skin equivalent (HSE) in the treatment of venous ulcers.
                Prospective, randomized study.
                Multicenter study in the outpatient setting.
                Each patient with a venous ulcer received either compression therapy alone or compression therapy and treatment with HSE. The patients were evaluated for HSE safety, complete (100%) ulcer healing, time to wound closure, wound recurrence, and immune response to the HSE.
                The study was completed as planned in 293 randomized patients.
                Treatment with HSE was more effective than compression therapy in the percentage of patients healed by 6 months (63% vs 49%; P=.02, Fisher exact test, 2-tailed) and the median time to complete wound closure (61 days vs 181 days; P=.003, log-rank test). Treatment with HSE was superior to compression therapy in healing larger (> 1000 mm2; P=.02) and deeper ulcers (P=.003) and ulcers of more than 6 months' duration (P=.001). Occurrence of adverse events was similar in both groups. No symptoms or signs of rejection occurred in response to treatment with HSE, and no HSE-specific immune responses were detected in vitro to bovine collagen or to alloantigens expressed on keratinocytes or fibroblasts.
                Treatment with HSE healed venous ulcers more rapidly and in more patients than compression therapy alone. There was no clinical or laboratory evidence of rejection or sensitization in response to HSE application. These data suggest that HSE represents a significant advance in the treatment of venous ulcers, particularly those that are difficult to heal. The outer root sheath of hair follicles plays an important role in epidermal regeneration in vivo. Keratinocytes isolated by explantation of outer root sheath tissue have extensive proliferative capacity irrespective of donor age, which probably depends on pluripotent epithelial stem cells residing in the outer root sheath. These keratinocytes can be organotypically grown to epidermal equivalents in vitro. We report here that in a multicenter, randomized phase II study, EpiDex trade mark, a tissue-engineered, fully differentiated autologous epidermal equivalent derived from keratinocytes of the outer root sheath of plucked anagen hair follicles, is as effective as split-thickness skin autografting in the promotion of healing and complete closure of recalcitrant vascular leg ulcers. Cultured epidermal allografts have been successfully used to treat a variety of wounds. Their postulated mechanism of action is through release of cytokines that stimulate epithelialization. On the basis of previous experience we expected ulcers treated with cryopreserved cultured allografts (CCAs) to be healed by 6 weeks. Hydrocolloid dressings (HCDs) have also been reported to be effective in the treatment of venous ulcers.
                Our purpose was to compare the effectiveness of CCAs with HCDs in healing chronic venous ulcers.
                Forty-three patients with 47 ulcers were enrolled in a randomized controlled trial. Ulcers not healed by 6 weeks were changed to the other treatment.
                No difference in the number of healed ulcers between the two groups was observed at 6 weeks. Healing rate, percent reduction of initial ulcer size, and radial progression toward wound closure were significantly greater for CCAs than for HCDs. Pain relief was not significantly different.
                CCAs achieve more rapid healing and greater reduction in ulcer size than HCDs. Chronic venous ulcers are common, and even with effective compression or elevation large ulcers may take months to heal. Pinch skin grafting may allow healing from epithelial islands throughout the surface area of the ulcer, and a prospective randomised trial was therefore conducted comparing this treatment with porcine dermis dressings. Most patients were treated as outpatients, 25 ulcers being randomised to treatment with pinch skin grafts and 28 to treatment with porcine dermis. Though the groups were well matched, the mean healing rate in the first week was 15 cm2 for pinch skin grafts compared with 3.5 cm2 with porcine dermis (p less than 0.02). By life table analysis 64% of ulcers treated by pinch grafts were healed at six weeks and 74% by 12 weeks compared with 29% and 46% of ulcers, respectively, treated with porcine dermis dressings (chi2 = 4.1; p less than 0.05). All ulcers that failed to heal within 12 weeks included an area posterior to the medial malleolus, where local compression may have been inadequate. Pinch skin grafting improves the rate of healing in large venous ulcers and is a simple technique that may be performed as an outpatient procedure under local anaesthesia. HP802-247 is a new-generation, allogeneic tissue engineering product consisting of growth-arrested, human keratinocytes (K) and fibroblasts (F) delivered in a fibrin matrix by a spray device.
                To identify the preferred dose of HP802-247 based on cell concentration and K/F ratio.
                A multicenter, randomized, double-blind, placebo-controlled, explorative phase II study of 6 different doses of HP802-247 administered once per week for 12 consecutive weeks in chronic venous leg ulcers.
                HP802-247 was safe and well tolerated and showed increasing efficacy dependent on cell concentration and K/F ratio, in line with in vitro growth factor release data. The mean complete closure rate at week 12 for all patients treated with HP802-247 was 40%, and for placebo it was 33%. In contrast to placebo, all HP802-247 dose groups improved from week 12 to 24.
                As an integral part of a rational tissue engineering product development, this explorative trial identified the preferred dose of HP802-247 for further clinical studies. A number of different treatment approaches have been recommended for the treatment of venous ulceration, including local ulcer treatment, compression and drug therapy. Recent advances in tissue engineering have resulted in living tissues being developed for cutaneous wound repair and skin replacement. The aim of this pilot study was to compare the rate of healing of venous ulcers in patients treated with Dermagraft (a human fibroblast-derived dermal replacement) and compression therapy or compression therapy alone.
                A total of 18 patients with venous ulceration of the leg were recruited into the pilot study. Ten patients were treated with Dermagraft and compression therapy, and eight patients were treated with compression therapy alone. Healing was assessed by ulcer tracing and computerised planimetry. Skin perfusion was measured by laser Doppler.
                Five (50%) of the patients treated with Dermagraft and one (12.5%) control patient had healed by the end of the 12-week study period (NS). The total ulcer area rate of healing and linear rate of healing was significantly improved in patients treated with Dermagraft (P=0.001 and P=0.006, respectively, Mann-Whitney U-test). The number of capillaries increased in both the treatment and control group. Peri-ulcer skin perfusion increased by 20% in patients treated with Dermagraft, compared with 4.9% in the control group.
                The data from this small pilot study suggests that Dermagraft is associated with improved healing of venous ulceration. Following this pilot study, further clinical studies are needed to confirm the validity of these results in 'hard to heal' venous leg ulcers. In the conservative therapy of venous leg ulcers modern types of dressings are used most frequently. In the past 20 years 'active wound dressings' - cultured epidermal keratinocytes as autografts and allografts - were also introduced in the management of leg ulcers.
                The aim of our study was to compare the effect of cryopreserved and lyophilized cultured epidermal allografts in the treatment of venous leg ulcers. Evaluation of the therapy was documented as photodocumentation, planimetry, healing time and evaluation of pain relief over a 3-month period after application. Fifty patients with venous leg ulcers were selected. Twenty-five patients (group I) were treated with cryopreserved keratinocytes and 25 (group II) with lyophilized keratinocytes.
                The final evaluation 3 months after the application of allografts showed 84% of healed ulcers in group I and 80% in group II. The number of healed ulcers and the healing rate both showed no statistically significant differences. The size of the ulcer was reduced by half during the first week in both groups. The size differences during the first week are statistically significant in both groups and they are comparable (P < 0.001). The intensity of the pain was statistically significantly reduced during the first week after application in both groups (P < 0.001).
                The cryopreserved and lyophilized cultured allografts are comparable in healing rate, course of healing and relief of pain, and also in planimetric changes during the healing of venous leg ulcers. Lyophilized allografts are more convenient for routine use than cryopreserved allografts as they can be stored at room temperature. These results could give rise to the more frequent use of lyophilized allografts in slow-healing venous leg ulcers. Cultured keratinocytes may represent an alternative therapy aiming at boosting leg ulcer healing. There is no evidence-based study comparing objectively the healing rate of split-ulcer portions covered or not covered by cultured keratinocytes.
                To assess the effect of cultured keratinocytes on the healing rate of leg ulcers.
                Five applications of fresh (cela, XCELLentis, Ghent, Belgium) or frozen (CryoCeal, XCELLentis) cultured allogeneic keratinocytes were performed at weekly intervals to treat large leg ulcers (mean diameter > 5 cm) in four patients. A split-ulcer study was designed to secure a control area covered only by petrolatum gauze. Clinical, planimetric, bacteriologic, and immunohistologic assessments of the keratinocyte-treated and control parts of the ulcers were performed.
                Compared with controls, planimetry revealed a beneficial effect afforded by cryopreserved cultured keratinocytes on the ulcer healing rate of two of four ulcers (+12 and 81%). The healing effect was obtained on the ulcers associated with the lowest bacterial load. Cultured keratinocytes did not qualitatively and quantitatively modify the ulcer biocenosis. They did not affect the number of any type of inflammatory cells present in the granulation tissue (type I dermal dendrocytes, macrophages, T lymphocytes, granulocytes). No specific side effect of cultured keratinocytes was evidenced.
                In this small case series, it appears that cultured allogeneic keratinocytes may be helpful in the healing process of venous leg ulcers. However, a clean wound with reduced bacterial load seems to be the prerequisite condition for obtaining a beneficial effect. Twenty-seven patients with chronic venous leg ulcers were assigned to two treatment groups. Fifteen were treated with cryopreserved cultured allogeneic keratinocyte sheets and compression bandages and 12 with compression only. The observation time was 8 weeks and the keratinocyte grafting procedure was performed once weekly. The mean reduction of the initial wound area was 35% in the treatment group and 14% in the control group. This difference was not significant. The poor effect on wound healing given by the cryopreserved allogeneic keratinocyte sheets contrasts with our earlier experience using fresh keratinocyte sheets. We believe that this is due to a weakened condition of the cryostored cells, as we have shown a loss in protein synthesis capacity of at least 50%. We have established a specific bioreactor microcarrier cell culture system using porcine gelatin microbeads as carriers to produce autologous keratinocytes on a large scale. Moreover, we have shown that autologous keratinocytes can be cultured on porcine collagen pads, thereby forming a single cell layer. The objective of this study was to compare efficacy and safety of autologous cultured keratinocytes on microbeads and collagen pads in the treatment of chronic wounds. Fifteen patients with recalcitrant venous leg ulcers were assigned to three groups in a single-center, prospective, uncontrolled study: five underwent a single treatment with keratinocyte monolayers on collagen pads (group 1); another five received a single grafting with keratinocyte-microbeads (group 2); and the last five received multiple, consecutive applications of keratinocyte-microbeads 3 days apart (group 3). All patients were followed for up to 12 weeks. By 12 weeks, there was a mean reduction in the initial wound area of 50, 83, and 97 percent in the three groups, respectively. The changes in wound size were statistically significant between the first and third groups (p= 0.0003). Keratinocyte-microbeads proved to be more effective than keratinocyte monolayers on collagen pads when the former were applied every 3 days. Rapid availability within 10-13 days after skin biopsy and easy handling represent particular advantages.
Bilayer artificial skin, used in conjunction with compression bandaging, increases venous ulcer healing compared with a simple dressing plus compression. Further research is needed to assess whether other forms of skin grafts increase ulcer healing.