Successful treatment of chronic venous leg ulcers with lyophilized cultured epidermal allografts

The case of a 67-year-old woman with chronic venous leg ulcers and severe gonarthrosis is described. In spite of intensive therapy, the leg ulcers had persisted for 4 years and made the intended orthopaedic operation of the right knee impossible. The patient was treated with lyophilized cultured epidermal allografts and her leg ulcers healed within 40 days. Lyophilized cultured epidermal allografts represent a modern type of active wound dressing that leads to rapid healing of chronic venous leg ulcers and enables patients to undergo surgical intervention.     

Grafting of skin ulcers with cultured autologous epidermal cells

We treated five adult individuals with six full-thickness chronic ulcerations in the skin caused by venous insufficiency, sickle cell anemia, or surgical wounds. Each patient received applications to the ulcerations of sheets of autologous epidermal cells grown in culture. All patients experienced relief of pain after grafting. Four of the six ulcers healed completely in 21 to 35 days, and three of the four remained healed for up to 2 years. One ulceration recurred within 2 months. Our experience suggests that cultured autologous epidermal grafts can provide continuous covering, relief from pain, and rapid healing of chronic debilitating ulcerations of the skin.     

Treatment of leg ulcers with cryopreserved allogeneic cultured epithelium. A multicenter study.

BACKGROUND--In the past few years, several authors have described the usefulness of cultured allogeneic epidermal sheets in promoting wound healing of burns, leg ulcers, and donor sites. This study reports clinical results obtained by different departments in the treatment of chronic leg ulcers by cryopreserved cultured allogeneic epithelium. The freezing procedure and the assessment of viability of the cryopreserved epithelium are also described. A total of 30 ulcers were treated using 138 cryopreserved allografts. OBSERVATIONS--Twenty ulcers (66.6%) healed completely within 12 weeks. Four ulcers showed a 30% to 84.4% reduction in size by 3 weeks but did not heal completely; the remaining six ulcers did not show any improvement. A strong stimulation of granulation tissue formation and of reepithelialization from the wound edge were observed. RESULTS--The results indicate that frozen cultured epidermis, stored in a skin bank, is a valid and generally applicable alternative therapy for the treatment of chronic ulcers.     

Allogeneic cultured keratinocytes in the treatment of leg ulcers. A pilot study.

Forty-two patients (10 males and 32 females) with 52 chronic leg ulcers were treated with sheets of cultured allogeneic keratinocytes. Sixty-five % of the ulcers healed completely and the healing rate differed between various diagnostic groups. The best results were obtained in patients with venous ulcers and wounds with mixed etiology, whereas less improvement was observed with ischaemic ulcers. Rheumatic ulcers also responded well in combination with oral corticosteroids. The overall impression was that the grafting procedure markedly enhanced wound healing.     

Organotypic cultures of autologous hair follicle keratinocytes for the treatment of recurrent leg ulcers

Our purpose was to evaluate, in an open study, the efficacy of epidermal equivalents (EEs), a tissue-engineered epidermis prepared from autologous hair follicle keratinocytes, for the treatment of recurrent leg ulcers (n = 50). To generate EEs, keratinocytes expanded from the outer root sheaths of plucked anagen hair follicles were seeded on cell culture inserts at air-liquid interface. The total culture time was 5 to 6 weeks. Three days after the procedure, 95% of EEs adhered to the wound bed. After 8 weeks, 70% of the total wound surface was re-epithelialized and 32% of the ulcers were healed. After applying the EEs, a major relief of wound pain was noticed by the patients. EEs were applied in ambulatory patients without surgical facilities. Because 92% of the cases included in this study presented a recurrence of their ulcers after a split-thickness skin graft, we consider these ulcers as difficult to treat and propose the EEs as an alternative effective treatment of recurrent leg ulcers.     

Allogeneic cultured epidermal grafts heal chronic ulcers although they do not remain as proved by DNA analysis

To investigate whether allogeneic cultured keratinocytes are rejected or not, and to find out how beneficial their effect on wound healing could be, patients with chronic ulcers were grafted with allogeneic cultured human keratinocytes. In order to examine the epidermal origin of the healed wound, DNA analysis was performed and compared to donor and recipient blood-cell DNA. Healing was observed in 84% of the grafted ulcers by granulation tissue stimulation and would edge effect. In little time 60% of the grafted chronic ulcers healed completely. Although no rejection was observed, DNA analysis revealed that the grafted allogeneic keratinocytes were finally replaced by the patient's own epidermis. This study confirmed that cultured allogeneic keratinocytes that have been grafted on ulcers, play an important role in the wound healing process.     

Fresh versus cryopreserved cultured allografts for the treatment of chronic skin ulcers

Both fresh and cryopreserved cultured epithelial allografts were used to treat 20 patients with a total of 30 chronic ulcers. A profound stimulation of host epithelialization from the wound edges and epidermal appendages was observed. Our data suggest that allografts, prepared using a simple cryopreservation technique, retain their morphological and functional characteristics, and are as effective as fresh allografts in healing chronic ulceration.     

A portable pulsed electromagnetic field (PEMF) device to enhance healing of recalcitrant venous ulcers: a double-blind, placebo-controlled clinical trial

A prospective, randomized, double-blind, placebo-controlled multicentre study assessed the clinical efficacy and safety of pulsed electromagnetic limb ulcer therapy (PELUT) in the healing of recalcitrant, predominantly venous leg ulcers. The portable device was used at home for 3 h daily during this 8-week clinical trial as an adjunct to a wound dressing. Wound surface area, ulcer depth and pain intensity were assessed at weeks 0, 4 and 8. At week 8 the active group had a 47.7% decrease in wound surface area vs. a 42.3% increase for placebo (P < 0.0002). Investigators' global evaluations indicated that 50% of the ulcers in the active group healed or markedly improved vs. 0% in the placebo group, and 0% of the active group worsened vs. 54% of the placebo group (P < 0.001). Significant decreases in wound depth (P < 0.04) and pain intensity (P < 0.04) favouring the active group were seen. Patients whose ulcers improved significantly after 8 weeks were permitted to continue double-blind therapy for an additional 4 weeks. Eleven active and one placebo patient continued therapy until week 12, with the active treatment group continuing to show improvement. There were no reports of adverse events attributable to this device. We conclude that the PELUT device is a safe and effective adjunct to non-surgical therapy for recalcitrant venous leg ulcers.     

Recombinant human granulocyte-macrophage colony-stimulating factor applied locally in low doses enhances healing and prevents recurrence of chronic venous ulcers

BACKGROUND: Chronic venous leg ulcers have a major medical and economic impact on the elderly worldwide. Healing of the large ulcers (>10 cm2) occurs only in two-thirds of the patients and reulceration of healed ulcers recurs in one-third within 1 year. Because both healing and relapse rate influence greatly a patient's quality of life and the overall cost of treatment, every effort should be made to improve these two parameters. OBJECTIVE: To determine the safety and efficacy of topical low-dose recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF) for the treatment of venous ulcers, and to document any improvement in healing rates. METHODS: Thirty-eight patients (29 women, 9 men; median age, 74 years) with chronic venous insufficiency were treated with topical rhu GM-CSF (5 microg/mL 0.9% sodium chloride solution), followed by application of a compression dressing. All subjects were treated as outpatients. RESULTS: Complete healing was observed in 47 of the 52 ulcers (90.4%). The average healing time was 19 weeks. No systemic or local side-effects from the therapy were observed. Nine chronic ulcers, previously refractory to conventional treatment (pretreatment for more than 46 weeks), showed the same response rate (9/8, or 88.9%) and healing time (mean, 19 weeks). After 40 months, no reulceration of the healed ulcers was observed, but two patients developed new ulcers on the same leg. Healing remained stable, with excellent cosmetic results. CONCLUSIONS: In this first study, topically applied low-dose rhu GM-CSF was a safe treatment for chronic venous leg ulcers. Healing rates were significantly increased and relapse rates were minimal.     

Frequency rhythmic electrical modulation system in the treatment of chronic painful leg ulcers

Electrical current has been recommended for use on chronic wounds; however, the ability of this modality to improve healing of various types of chronic ulcers, arterial, venous, mixed arterial and venous ulcers, diabetic, and pressure ulcers is not well established. The purpose of this study was to examine the effect of frequency rhytmic electrical modulation system (FREMS) on healing of chronic painful leg ulcers.Thirty-five patients with 43 chronic painful leg ulcers participated in the study. The subjects were separated into two random groups, one treated with FREMS and the control group. Our investigation focused on the control of the parameter changes important for ulcer healing: wound surface area, wound appearance (fibrin accumulations, exudation, granulation, and epithelization), ulcer surroundings and associated symptoms. All the parameters were monitored clinically at the beginning, after first, second, and third week, and at the end, after 1 and 2 months of administered therapy, when the scores were determined. Pain intensity was evaluated with visual analog scale (VAS). FREMS therapy was administrated through the device model Aptiva Ballet into sessions and several stages. Comparing the findings of decrease leg ulcer surface, pain, leg ulcer score, score of vicinity (statistically significant at the level P < 0.05) with the controls, it was established that FREMS system accelerated ulcer healing, reduced pain and demonstrated better effects compared to the control group. The results of the study indicate that FREMS therapy accelerates wound closure and depresses the pain of chronic leg ulcers.     

Pain reduction by dehydrated human amnion/chorion membrane allograft in nondiabetic leg ulcers might be an early indicator of good response: A case series

Dehydrated human amnion/chorion membrane allograft (dHACM) derived from placenta is increasingly used for skin and soft tissue repair in several medical specialties. Promising effects of dHACM were also reported in chronic venous and diabetic leg ulcers. However, dHACM is cost‐intensive and its effect on chronic leg ulcers of other etiologies and pain reduction is unknown. Clinical predictors of a favorable response to dHACM during the early treatment period could help to limit unnecessary costs. In our case series with six patients suffering from chronic lower leg ulcers of various etiology, the effect of dHACM once per week on reduction of pain and wound size during a 5‐week period was examined. dHACM resulted in effective pain reduction and improved wound healing in three patients with chronic leg ulcers due to calciphylaxis, chronic venous disease and reactive angioendotheliomatosis. Pain reduction after 1 to 2 applications of dHACM predicted a favorable healing response. Hence, our observation indicates that assessment of pain 3 weeks after initiation of dHACM may be a clinical predictor to justify dis‐/continuation of dHACM and thereby may help to limit costs.     

Autologous suction blister grafting for chronic leg ulcers

Background Non‐healing leg ulcers represent a treatment problem. Objective Investigate grafting of autologous suction blister roofs as treatment. Methods Twenty‐nine chronic, non‐healing leg ulcers of various aetiologies in 18 inpatients were treated by autologous epidermal grafting using the roofs of suction blisters. Results 55% of ulcers completely healed 2 to 6 weeks after grafting. A 50–90% reduction in size was documented in 34% and no change was observed in 11% of ulcers. Twelve weeks after grafting, 89% of ulcers were healed completely. In most ulcers, we observed a stimulation of reepithelialization from the wound edge (‘edge effect’) and an accelerated formation of healthy granulation tissue. During a follow‐up period of 12 months, 90% of the ulcers remained healed. Conclusion Grafting of autologous suction blister roofs is an effective treatment option for non‐healing leg ulcers. The advantages of the method are its lack of pain, low costs and immediate availability.     

Unterschiedliche Abheilungsdauer und Häufigkeit der Hospitalisation bei Ulcus cruris verschiedener Ursachen

Background

Leg ulcers are a symptom of a heterogeneous group of diseases. Their treatment causes substantial costs due to the long healing times and extensive wound care measures. There is a paucity of information about healing times and the necessity of hospital treatment for leg ulcers of different etiologies.

Materials and methods

In this retrospective study, healing times and the frequency of in-hospital treatment of 355 patients with leg ulcers attending a wound care clinic of a university hospital were examined.

Results

The proportion of healed ulcers was 32.0?% after 3 months and 54.3?% after 6 months with an average treatment duration of 6.1 months for all ulcers. This proportion of healed ulcers was higher for venous ulcers with 45.5?% after 3 months and 63.0?% after 6 months, whereas only 30.0?% of mixed arterial-venous ulcers and 35.0?% of hypertensive ischemic leg ulcers (HYTILU) were healed after 6 months. Of the latter group, 71?% of patients were hospitalized at least once during the observation period as compared to 47?% of patients with a venous ulcer. The duration of the hospital stay was longer for mixed ulcers and HYTILU with an average of 30 days vs. 23 days for venous ulcers.

Conclusions

These data indicate that the healing times of ulcers of different etiologies differ substantially and that especially ulcers with arteriosclerosis as a causative factor have longer healing times. The fact that they require in-hospital treatment more frequently and for longer periods has significant socio-economic consequences.     

Management of leg ulcers with hydrocolloid occlusive dressing

Twenty-two patients with 31 leg ulcers of various causes received local wound management consisting of the application of an adhesive hydrocolloid (HC) occlusive dressing (DuoDerm). Group 1 comprised 15 patients (11 outpatients) with 19 ulcers. Approximately two thirds (12/19) of the ulcers healed when treated solely with the HC dressing; mean treatment time was 57 days. Group 2 comprised seven hospitalized patients with at least two leg ulcers of similar size and distribution. The 20 ulcers in the seven patients were treated with either mild topical antimicrobial wet dressings (Sweitzer's 1:32 solution) or HC dressings, with each patient serving as his own "control." All 20 ulcers healed; the average time to healing was 44 days with HC dressing and 42 days with wet dressing management. Most of the patients reported convenience in management and substantial relief of pain with the use of HC dressings.     

Prognostic indicators in venous ulcers

BACKGROUND: Venous ulcers can be difficult to heal, and prognostic factors for healing have not been fully elucidated. OBJECTIVE: The objective of this study was to analyze the results of a large multicenter venous ulcer trial to retrospectively establish prognostic factors for venous ulcer healing. METHODS: This study examined data from a previously published prospective randomized placebo-controlled trial of an oral medication versus placebo treatment for venous ulcers. Local leg ulcer care involved the use of a moisture-retentive dressing and sustained graduated compression with a paste bandage and a self-adherent wrap. The oral medication or placebo was administered on a daily basis with the same dressings and bandage system in both groups for 12 weeks. A total of 165 patients completed the full 12-week treatment period; 83 received ifetroban, 82 received placebo. RESULTS: There was no statistically significant difference in outcome between the two groups. The study showed that consistent local ulcer treatment with a clearly defined system of care was associated with an unexpectedly high percentage (55%) of long-standing large venous ulcers (mean duration, 27 months; mean area, 15.9 cm(2)) being healed in both groups. Baseline ulcer area and duration of leg ulcer were found to be important in predicting outcome. Ulcers of short duration were found to be most likely to heal. Percent healing and ulcer area at week 3 were good predictors of 100% healing. Ulcers that had at least 40% healing by week 3 predicted more than 70% of the outcomes correctly. CONCLUSION: From this large study it was determined that baseline ulcer area and ulcer duration are significant predictors of 100% healing and time to heal. Percent healing and ulcer area at week 3 are good predictors of complete ulcer healing. Ulcers that are large, long-standing, and slow to heal after 3 weeks of optimal therapy are unlikely to heal rapidly, and might benefit from alternative therapies.     

Prostaglandin E1 treatment of leg ulcers caused by venous or arterial incompetence

An open and a double-blind study were undertaken on patients with leg ulcers caused mainly by venous (VI) or arterial incompetence (AI). They were treated with intravenous infusions or injections of prostaglandin E1 (PGE1). Eight of 10 patients in the open study experienced relief of pain and a complete or almost complete healing of their ulcers. In the double-blind study (20 patients) 4 out of 5 patients with a history of leg ulcers due to VI for more than 5 year responded to the PGE1 treatment, compared with one of 5 treated with saline. In the saline group 3 more patients with VI of shorter duration improved. In 3 of 5 patients of PGE1 with ulcers due to AI the original ulcer area was reduced by 78--65% after 70 days, while in the 2 remaining cases healing occurred later on. No effect was noted in the 2 patients with ulcers due to AI who received saline infusions. The results indicate the beneficial effect of PGE1 on pain and healing in leg ulcers caused by peripheral vascular disease.     

Treatment of venous leg ulcers with cryopreserved cultured allogeneic keratinocytes: a prospective open controlled study

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%.     

Pinch grafting of chronic leg ulcers in primary care: fourteen years' experience

Pinch grafting for treatment of chronic leg ulcers has been evaluated mainly in hospitalized and immobilized patients. This study describes the results of 199 pinch graft operations of 126 chronic leg and foot ulcers in 85 patients in primary care between 1987 and 2001. The aetiology of the ulcers was venous insufficiency in 43% and multi-factorial in 25% (77% with venous insufficiency as the main determinant). The mean ulcer size was 13.5 cm2 and the mean ulcer duration was 15.9 months. The overall healing rate within 3 months was 33%, ranging from 19% for multi-factorial or combined venous and arterial ulcers to 48% for venous ulcers. Within 12 months the overall healing rate was 60%, with 67% healed venous ulcers. The results from our study suggest that pinch grafting is suitable for treating chronic leg ulcers, especially venous ulcers, in primary care.     

Role of sulphydryl-containing agents in the management of venous (varicose) ulceration. A new approach

This randomized double-blind controlled study examined whether sulphydryl-containing agents influence the healing of venous ulceration occurring for the first time on the medial side of the leg. Graduated compression bandaging, which exerted a mean ankle pressure of 40.6 +/- 0.4 mmHg, and a mean below-knee pressure of 17.1 +/- 0.2 mmHg, healed 70% of ulcers within 12 weeks (n = 46). The addition of the sulphydryl-containing agents DL-cysteine (n = 46) or DL-methionine-methyl sulphonium chloride (n = 45) to the compression bandaging (daily application of the powder for 7 days, followed by once weekly applications until the end of the study 3 months later) significantly (P < 0.01) stimulated healing of venous ulceration relative to control values when studied 4, 8 and 12 weeks after commencing treatment. After 3 months of treatment, both sulphydryl-containing compounds healed 93% of the ulcers. The results show that sulphydryls stimulate healing of venous ulceration.     

Grafting of venous leg ulcers. An intraindividual comparison between cultured skin equivalents and full-thickness skin punch grafts

Skin equivalents that consisted of a noncontracted collagen gel populated with allogeneic fibroblasts and covered with autologous cultured keratinocytes were used for grafting venous leg ulcers. The results were compared in the same patient with those obtained with a routinely used standard method of grafting with autologous full-thickness punch grafts. The skin equivalents and the punch grafts were grafted successfully in four of five patients. The median healing time of ulcers grafted with skin equivalents was 18 days whereas that of ulcers covered with punch grafts was 15 days. The cosmetic appearance of the skin equivalent-grafted ulcers was better than that of the punch-grafted ulcers.