Wound-healing trajectories as outcome measures of venous stasis ulcer treatment

Outcome measures of venous ulcer healing are not uniformly accepted. Stringent criteria of 100% closure fail to provide information of healing over the entire span of repair. Wound-healing trajectories (plot of percentage of wound closure versus time of wound treatment) were constructed for 232 patients treated in eight clinical trials at two independent wound care/research centres. Trajectories were constructed for ulcers that totally healed (100% closure) and those that did not (<100% closure) over a 20-week period. Kaplan-Meier survival plots determined the percentage of patients achieving total healing versus time of treatment. The wound-healing trajectories were almost identical for patients achieving complete ulcer healing, as were the trajectories for patients with less than 100% closure. The trajectories for the ulcers healing completely were significantly different from those with <100% closure. Only 60% of all patients achieved 100% closure by 20 weeks. Using linear regression, it was predicted that it would take 31 weeks for all patients to achieve total healing. Total healing is an inadequate outcome measure for healing of venous stasis ulcers. Clinical trials using this measure would require excessive time periods. As wound-healing trajectories for patients treated at two centres mimic one another, shifting the wound-healing trajectory from one of impaired healing to one of a more ideal healing course may be considered a better outcome measure for determining healing of venous stasis ulcers.     

Evaluation of the use of prognostic information for the care of individuals with venous leg ulcers or diabetic neuropathic foot ulcers

This is a randomized factorial design clinical trial that investigates the efficacy and feasibility of providing prognostic information on wound healing. Prognostic information was provided based on baseline or 4-week wound characteristics. Healing rates were then determined at 24 weeks for venous leg ulcers and 20 weeks for diabetic neuropathic foot ulcers. Centers that had access to baseline information for venous leg ulcer prognosis had an odds ratio (OR) of healing of 1.42 (95% confidence interval [CI]: 1.03, 1.95) while centers that had access to information at 4 weeks had an OR of healing of 1.43 (95% CI: 1.05, 1.95) compared with controls. Diabetic neuropathic foot ulcer patients treated in centers that had been randomized to receive only 4-week prognostic information were more likely to heal than individuals seen in centers randomized to receive no intervention (OR 1.50, 95% CI: 1.05, 2.14). Our study found that it is feasible and efficacious to provide prognostic information on venous leg ulcers and diabetic neuropathic foot ulcers in a wound care setting using an existing administrative database. This intervention was easy to administer and likely had low associated costs. This method of dispersing prognostic information to healthcare providers should be expanded to include recently published treatment algorithms.     

Healing rates and cost efficacy of outpatient compression treatment for leg ulcers associated with venous insufficiency.

OBJECTIVE: Although newer techniques to promote the healing of leg ulcers associated with chronic venous insufficiency are promising, improved healing rates and cost effectiveness are unproven. We prospectively followed a series of patients who underwent treatment with outpatient compression for venous stasis ulcers without adjuvant techniques to determine healing rates and costs of treatment. METHODS: Two hundred fifty-two patients with clinical or duplex scan evidence of chronic venous insufficiency and active leg ulcers underwent treatment with ambulatory compression techniques. The patients were prospectively followed with wound measurements at 1-week to 2-week intervals, and the factors that were associated with delayed healing were determined. RESULTS: Of all the ulcers, 57% were healed at 10 weeks of treatment and 75% were healed at 16 weeks. Ultimately, 96% of the ulcers healed, and only 1 major amputation was necessitated (0.4%). Initial ulcer size and moderate arterial insufficiency (ankle brachial index, 0.5 to 0.8; n = 34) were factors that were independently associated with delayed healing (P <.01). Patient age, ulcer duration before treatment, and morbid obesity did not significantly affect healing times. The cost of 10 weeks of outpatient treatment with compression techniques ranged from $1444 to $2711. CONCLUSION: The treatment of venous stasis ulcers with compression techniques results in reliable, cost-effective healing in most patients. Current adjuvant techniques may prove to be useful but are likely to be cost effective only in a minority of cases, particularly in patients with large initial ulcer size or arterial insufficiency.     

Use of homologous platelet factors in achieving total healing of recalcitrant skin ulcers

We used homologous platelet-derived wound healing factors (HPDWHF) to achieve complete healing of recalcitrant ulcers of diverse cause. Twenty-three patients with 27 skin ulcers who had been receiving conventional wound care with no evidence of healing for an average period of 25 weeks (range, 12 to 156 weeks) were studied. The patients were first subjected to controlled wound care for 3 months, with saline solution and silver sulfadiazine dressings used in all cases. At the end of this period, persistent nonhealing ulcers were treated by topical use of HPDWHF and silver sulfadiazine. Ulcer parameters were recorded on the first day and every week during therapy until complete epithelization was achieved in either group. Each ulcer acted as its own control. In the controlled wound care group, only three ulcers in three patients achieved complete healing; the remaining 24 ulcers in 20 patients failed to achieve even 50% healing in the stipulated 3-month period. However, when subjected to HPDWHF applications, these ulcers healed completely, 100% healing occurring in 9.67 +/- 4.9 weeks (range, 3 to 19 weeks), which is highly significant (p less than 0.01). The healing response to HPDWHF applications was of uniform progression over the weeks. Only the basic cause of the ulcer determined the healing rates in this group. The shortest and the longest time to achieve 100% healing occurred in patients with diabetes (6.88 +/- 2.97 weeks) and in the venous stasis group (14.00 +/- 7.07 weeks). Age, sex, location of ulcer, ulcer duration, and ulcer measurements had no influence on the HPDWHF-stimulated healing rates. This is the earliest report of HPDWHF-stimulated repair in chronic nonhealing skin ulcers.     

Frozen Allogeneic Human Epidermal Cultured Sheets for the Cure of Complicated Leg Ulcers

BACKGROUND: Skin ulcers due to venous stasis or diabetes are common among the elderly and are difficult to treat. Repeated applications of cell-based products have been reported to result in cure or improvement of leg ulcers of small size in a fraction of patients. OBJECTIVE: To examine the effects of frozen human allogeneic epidermal cultures for the treatment of acute and chronic ulcers. METHODS: We treated a series of 10 consecutive patients with leg ulcers of different etiology and duration with frozen human allogeneic epidermal cultures stored frozen and thawed for 5-10 minutes at room temperature before application. Three patients had ulcers with exposed Achilles or extensor tendon. The ulcers treated were as large as 160 cm2 in area and of up to 20-years' duration. After preliminary preparation of the wounds by debridement to remove necrotic tissue and application of silver sulfadiazine to control infection, thawed cultures were applied biweekly from 2 to 15 times depending on the size and complexity of the ulcer. RESULTS: All ulcers healed, including those with tendon exposure. After the first few applications, granulation tissue formed in the ulcer bed and on exposed tendons, and epidermal healing took place through proliferation and migration of cells from the margins of the wound. The time required for complete healing ranged from 1 to 31 weeks after the first application. CONCLUSION: The use of frozen human allogeneic epidermal cultures is a safe and effective treatment for venous or diabetic ulcers, even those with tendon exposure. It seems possible that any leg ulcer will be amenable to successful treatment by this method.     

Allogeneic keratinocyte for intractable chronic diabetic foot ulcers: A prospective observational study

Chronic diabetic foot ulcers (DFUs) are a common problem in patients with diabetes and are often difficult to treat. The application of newly developed dressing material in patients with chronic DFUs has been reported to be effective. The purpose of this study was to evaluate the usefulness of allogeneic keratinocyte treatment for chronic DFUs. We performed weekly allogeneic keratinocyte treatment for up to 12 weeks in 71 patients with intractable DFUs. We investigated healing rate, wound‐healing velocity, and time to 50% wound size reduction and analysed factors affecting ulcer healing. Fifty‐six patients (78.8%) had complete wound healing. Forty‐six patients (64.7%) showed complete healing within an average of 6.1 weeks, and 10 patients (14.1%) showed partial healing with an average 35.5% reduction vs initial size at the end of follow up. The 10 patients who showed partial healing continued to receive treatment after the 12‐week study period. The mean time to complete wound healing was 7.8 weeks. Fifteen patients (21.1%) experienced treatment failure because of infection, local necrosis, no change in ulcer size, or osteomyelitis during the follow‐up period. No adverse events were observed. Allogeneic keratinocyte treatment is effective for chronic, difficult‐to‐treat DFUs.     

Classification and treatment of chronic nonhealing wounds. Successful treatment with autologous platelet-derived wound healing factors (PDWHF)

Previous animal data showed that platelets contain growth factors that stimulate capillary endothelial migration (angiogenesis), fibroblast proliferation and migration, and collagen synthesis. This study utilized autologous platelet-derived wound healing factors (PDWHF) to treat 49 patients with chronic nonhealing cutaneous ulcers. Patients were classified on the basis of 20 clinical and wound status parameters to generate a wound severity index. Forty-nine patients--58% diabetic (20% with renal transplants); 16% with trauma, vasculitis, etc.; 14% with decubitus ulcers; and 6% each with venous stasis or arterial insufficiency--with a total of 95 wounds had received conventional wound care for an average of 198 weeks (range: 1-1820 weeks). After informed consent was obtained, patients received autologous PDWHF. Mean 100% healing time for all patients was 10.6 weeks. There was no abnormal tissue formation, keloid, or hypertrophic scarring. A multivariant analysis showed a direct correlation to 100% healing with initial wound size and the initiation of PDWHF therapy. This is the first clinical demonstration that locally acting growth factors promote healing of chronic cutaneous ulcers.     

Clinical efficacy of a silver‐releasing foam dressing in venous leg ulcer healing: a randomised controlled trial

Biatain and Biatain‐Ag are two identical wound dressings except the fact that Biatain‐Ag releases silver. In the present multinational double‐blinded randomised controlled trial the effect of the two dressings were compared for treatment of venous leg ulcers. A total of 181 patients were treated for 6 weeks with either Biatain or Biatain‐Ag followed by 4 weeks treatment with Biatain. Biatain‐Ag showed superior performance in relative wound area reduction after 6 weeks treatment and the estimated treatment difference increased after 10 weeks indicating that the effect of silver continues at least for 4 weeks after treatment. A subgroup of the patients differed significantly from the others with respect to parameters associated with a poor healing prognosis; patients were older, had significant history of venous thrombosis, larger ulcers with longer duration and more often recurrent. For this subgroup of patients Biatain‐Ag showed significant (P < 0·05) better performance in terms of relative ulcer area reduction and healing rate. In conclusion, this study suggests the superior performance of Biatain‐Ag compared with the non silver‐releasing dressing Biatain in particular for patients having ulcers associated with a poor healing prognosis.     

Off-loading of hindfoot and midfoot neuropathic ulcers using a fiberglass cast with a metal stirrup

BACKGROUND: This study was designed to assess the effectiveness of a method of off-loading large neuropathic ulcers of the hindfoot and midfoot. The device used is composed of a fiberglass cast with a metal stirrup and a window around the ulcer. METHODS: A retrospective study of 14 diabetic and nondiabetic patients was performed. All had chronic plantar hindfoot or midfoot neuropathic ulcers that failed to heal with conventional treatment methods. A fiberglass total contact cast with a metal stirrup was applied. A window was made over the ulcer to allow daily ulcer care. RESULTS: The average duration of ulcer before application of the metal stirrup was 26 + 13.2 (range 7 to 52) months. The ulcer completely healed in 12 of the 14 patients treated. The mean time for healing was 10.8 weeks for midfoot ulcers and 12.3 weeks for heel ulcers. Complications developed in four patients: three developed superficial wounds and one developed a full-thickness wound. In three of these four patients, local wound care was initiated, and the stirrup cast was continued to complete healing of the primary ulcer. CONCLUSIONS: A fiberglass cast with a metal stirrup is an effective off-loading device for midfoot and hindfoot ulcers. It is not removable and does not depend on patient compliance. The window around the ulcer allows for daily wound care, drainage of the ulcer and the use of vacuum-assisted closure (VAC) treatment. The complication rate is comparable to that of total contact casting.     

Effective use of negative pressure wound therapy provides quick wound-bed preparation and complete graft take in the management of chronic venous ulcers

Venous ulcers are characterised by longstanding and recurrent loss of skin integrity. Once occurred, healing is slow and recurrence is high because of inappropriate conditions of the wound bed. This study involves 20 patients with chronic venous ulcers at least 6 weeks of duration treated with negative pressure wound therapy (NPWT). Patients underwent a radical debridement of all devitalised tissues in the first operation. After adequate haemostasis, silver-impregnated polyurethane foam was applied. Once the wounds were determined to be clean and adequate granulation tissue formation was achieved, split-thickness skin grafts were applied. Black polyurethane foam was applied over them. All wounds completely healed without the need for further debridement or regrafting. The mean number of silver-impregnated foam dressing changes prior to grafting was 2·9 (one to eight changes). The mean number of NPWT foam changes was 2·6 after skin grafting (two to five changes). Two patients who did not use conservative treatments for chronic venous insufficiency (CVI) after discharge from the hospital had recurrence of venous ulcers in the follow-up period. Application of NPWT provides quick wound-bed preparation and complete graft take in venous ulcer treatment.     

Relationship between edema and the healing rate of stasis ulcers of the leg

Leg volumes and ulcer size were measured in patients who underwent four consecutive different treatment regimens for stasis ulcers. Most ulcers enlarged on simple wound care. Any regimen which included external support led to healing, but there was no correlation between the healing rate and the amount of swelling in the leg. Our evidence suggests that both the ulcer and the edema are due to the same cause, probably venous stasis, and any therapy which does not improve venous drainage is probably doomed to failure.     

Two-step autologous grafting using HYAFF scaffolds in treating difficult diabetic foot ulcers: results of a multicenter, randomized controlled clinical trial with long-term follow-up

This study evaluated the efficacy and tolerability of an autologous tissue-engineered graft--a 2-step HYAFF autograft--in the treatment of diabetic foot ulcers compared with standard care. In all, 180 patients with dorsal or plantar diabetic foot ulcers (unhealed for ≥1 month) were randomized to receive Hyalograft-3D autograft first and then Laserskin autograft after 2 weeks (n = 90; treatment group) or nonadherent paraffin gauze (n = 90; control group). Efficacy and adverse events were assessed weekly for 12 weeks, at 20 weeks, and at 18 months. The primary efficacy outcome was complete ulcer healing at 12 weeks. Wound debridement, adequate pressure relief, and infection control were provided to both groups. At 12 weeks, complete ulcer healing was similar in both groups (24% of treated vs 21% controls). A 50% reduction in ulcer area was achieved significantly faster in the treatment group (mean 40 vs 50 days; P = .018). Weekly percentage ulcer reduction was consistently higher in the treatment group. At 20 weeks, ulcer healing was achieved in 50% of the treated group as compared with 43% of controls. Dorsal ulcers had a 2.17-fold better chance of wound healing per unit time following autograft treatment (P = .047). In a subgroup with hard-to-heal ulcers, there was a 3.65-fold better chance of wound healing following autograft treatment of dorsal ulcers (P = .035). Adverse events were similar in both groups. The study results demonstrated the potential of this bioengineered substitutes to manage hard-to-heal dorsal foot ulcers.     

Recombinant human platelet-derived growth factor-BB (becaplermin) for healing chronic lower extremity diabetic ulcers: an open-label clinical evaluation of efficacy

Topically applied recombinant human platelet-derived growth factor-BB (becaplermin) is a new pharmacologically active therapy for chronic, neuropathic, lower extremity diabetic ulcers. In previous studies, becaplermin gel was administered once daily but dressings were changed twice daily. In the present study of 134 patients with diabetes mellitus and full thickness lower extremity ulcers, dressings were changed only once per day, simplifying the treatment regimen. Efficacy criteria included the percentage of patients achieving complete healing within the 20-week treatment period, the time to achieve complete healing, the rate of ulcer recurrence during the 6-month period following healing, and treatment compliance. Complete healing of ulcers was achieved in 57. 5% of patients, with a mean time to closure of 63 days and a recurrence rate of 21% at 6 months. Of the potential factors affecting ulcer healing, only drug compliance (p < 0.001), dressing compliance (p < 0.01), the presence of infection (p < 0.01), baseline ulcer area (p < 0.05), and baseline total wound evaluation score (p < 0.05) were significantly associated with healing. Results of this study further confirm the efficacy and safety of becaplermin gel for the treatment of lower extremity diabetic ulcers.     

Early healing rates and wound area measurements are reliable predictors of later complete wound closure

This study was undertaken to determine if healing rates are reliable early predictors of ultimate complete wound closure in venous leg ulcers and diabetic foot wounds. We conducted a retrospective analysis of 306 venous leg ulcers and 241 diabetic foot ulcers enrolled in two large controlled, prospective, randomized pivotal trials to compare topical wound treatments, to determine whether certain early markers of healing could be correlated with later total wound closure. Two-sided tests at 95% confidence demonstrated that wound margin advance, initial healing rate, percent wound surface area reduction, and wound healing trajectories (all p <0.001) were powerful predictors of complete wound healing at 12 weeks. Wounds with poor healing progress by these criteria at 4 weeks were highly likely to remain unhealed after 8 additional weeks of treatment. Analysis of the diabetic foot ulcers and venous leg ulcers subgroups separately demonstrated consistent statistical test results with high significance; similarly, the results remained valid independent of the topical treatment used. The early prediction of eventual wound healing or nonhealing using early healing rates may enable more efficient triage of patients to advanced healing technologies. We believe that these surrogate markers are robust predictors of healing regardless of wound etiology and that they merit wider use in clinical trials and routine patient care.     

Autologous fibroblasts to treat deep and complicated leg ulcers in diabetic patients

Large complicated leg ulcers, not responsive to standard therapy, after surgical debridement and under parenteral specific antibiosis, must be occlusively covered to improve wound healing. In 10 diabetic patients with deep (Wagner degree 3), large, and Staphylococcus aureus (n=7) or Pseudomonas aeruginosa (n=5)-infected leg (n=1), or foot (n=9) ulcers, we have applied, as a coverage, meshes of in vitro expanded autologous fibroblasts. Complete ulcer healing was observed in seven patients after 8, 12, 12, 14, 16, 18, and 20 weeks from the first graft application (Figures 2 and 3). Two patients had >70% wound healing at 20 and 28 weeks after the first treatment. One patient, previously submitted to a bypass vascular procedure, died of acute myocardial infarction 16 weeks after the first fibroblast autograft application and with a healing wound evenly filled with granulation tissue. In our opinion, the application of autologous in vitro expanded fibroblasts is a satisfactory therapeutic option to treat large leg ulcers and is particularly indicated in patients with chronic diseases such as diabetes or autoimmune diseases on steroid treatment.     

Differentiating diabetic foot ulcers that are unlikely to heal by 12 weeks following achieving 50% percent area reduction at 4 weeks

This retrospective analysis included intent-to-treat control patient data from two published, randomised, diabetic foot ulcer (DFU) trials in an effort to differentiate ulcers that are unlikely to heal by 12 weeks despite early healing progress [≥50% percent area reduction (PAR) at 4 weeks]. Predicted and actual wound area trajectories in DFUs that achieved early healing progress were analysed from weeks 5 to 12 and compared for ulcers that did and did not heal at 12 weeks. In 120 patients who achieved ≥50% PAR by week 4, 62 (52%) failed to heal by 12 weeks. Deviations from the predicted healing course were evident by 6 weeks for non healing ulcers. A 2-week delay in healing significantly lowered healing rates (P = 0·001). For DFUs with ≥50% PAR at 4 weeks, those achieving ≥90% versus <90% PAR at 8 weeks had a 2·7-fold higher healing rate at 12 weeks (P = 0·001). A PAR of <90% at 8 weeks provided a negative predictive value for DFU healing at 12 weeks of 82%. For ulcers that fail to progress or worsen from weeks 4 to 6, and those that fail to achieve 90% PAR at 8 weeks, reevaluation of the wound and its treatment is recommended.     

Long-term outcomes of flap transfer for treatment of intractable venous stasis ulcers in the lower extremity

There is little information about long-term outcomes of flap transfer for treatment of venous stasis ulcers in the lower extremity. Eleven patients who underwent free and pedicled flap transfer for treatment of intractable venous stasis ulcers were evaluated retrospectively. The operative procedures consisted of removal of the ulcer and surrounding lipodermatosclerotic tissue, venous stripping, and flap transfer. No ulcer recurrences in the territory of the transferred flap were identified for a mean of 11 years during the follow-up period. However, four patients developed new ulcers in the same leg after the flap transfer at 18, 24, 52, and 81 months. This was probably the result of incomplete excision of surrounding lipodermatosclerotic tissue. Three of four recurrent ulcers were healed with additional procedures. The results of this study indicated that flap transfer combined with venous stripping could lead to long-term healing of venous stasis ulcers. However, incomplete excision of surrounding lipodermatosclerotic tissue caused new ulceration around the transferred flap.     

A randomized,controlled trial of Promogran (a collagen/oxidized regenerated cellulose dressing) vs standard treatment in the management of diabetic foot ulcers

HYPOTHESIS: Promogran, a wound dressing consisting of collagen and oxidized regenerated cellulose, is more effective that standard care in treating chronic diabetic plantar ulcers. DESIGN: Randomized, prospective, controlled multicenter trial. SETTING: University teaching hospitals and primary care centers. PATIENTS: A total of 276 patients from 11 centers were enrolled in the study. The mean age of the patients was 58.3 years (range, 23-85 years). All patients had at least 1 diabetic foot ulcer. INTERVENTIONS: Patients were randomized to receive Promogran (n = 138) or moistened gauze (control group; n = 138) and a secondary dressing. Dressings were changed when clinically required. The maximum follow-up for each patient was 12 weeks. MAIN OUTCOME MEASURE: Complete healing of the study ulcer (wound). RESULTS: After 12 weeks of treatment, 51 (37.0%) Promogran-treated patients had complete wound closure compared with 39 (28.3%) control patientss, but this difference was not statistically significant (P =.12). The difference in healing between treatment groups achieved borderline significance in the subgroup of patients with wounds of less than 6 months' duration. In patients with ulcers of less than 6 months' duration, 43 (45%) of 95 Promogran-treated patients healed compared with 29 (33%) of 89 controls (P =.056). In the group with wounds of at least 6 months' duration, similar numbers of patients healed in the control (10/49 [20%]) and the Promogran (8/43 [19%]; P =.83) groups. No differences were seen in the safety measurements between groups. Patients and investigators expressed a strong preference for Promogran compared with moistened gauze. CONCLUSIONS: Promogran was comparable to moistened gauze in promoting wound healing in diabetic foot ulcers. It showed an additional efficacy for ulcers of less than 6 months' duration that was of marginal statistical significance. Furthermore, Promogran had a safety profile that was similar to that of moistened gauze, with greater user satisfaction. Therefore, Promogran may be a useful adjunct in the management of diabetic foot ulceration, especially in ulcers of less than 6 months' duration.     

Randomized trial and local biological effect of autologous platelets used as adjuvant therapy for chronic venous leg ulcers

OBJECTIVES: Platelet products have been proposed as adjuvant therapy for wound healing. We undertook this study to determine the healing effect of topically applied frozen autologous platelets (FAP) on chronic venous ulcers, compared with effect of placebo, and whether use of topical FAP modifies local expression of vascular endothelial growth factor (VEGF), keratinocyte growth factor (KGF), interleukin 8 (IL-8), and tissue inhibitor of metalloproteinase-1 (TIMP-1) in wound fluid. METHODS: This randomized, placebo-controlled, double-blind trial was carried out in institutional practice, with ambulatory patients with proved chronic venous leg ulcers. In all patients, whole venous blood was drawn for preparation of FAP. FAP or normal saline solution was applied three times per week for up to 12 weeks, together with hydrocolloids and standardized compression bandages. Leg ulcer surface was assessed with numerical pictures. IL-8, VEGF, KGF, and TIMP-1 levels were determined (enzyme-linked immunosorbent assay) in wound fluid after each 4 weeks of treatment. RESULTS: Fifteen patients were randomized into two groups with comparable leg ulcer characteristics. Mean percent reduction in ulcer area was 26.2% in the FAP group versus 15.2% in the placebo group (P =.94). One ulcer in each group was completely healed at study end. Levels of TIMP-1 increased significantly during FAP treatment. IL-8 concentration was significantly lower in wound fluid of healing ulcers than in the fluid of nonhealing ulcers, in both FAP and placebo groups. Growth factor levels were not modified with FAP treatment. CONCLUSION: Topical autologous platelets have no significant adjuvant effect on healing of chronic venous leg ulcers and increased wound fluid TIMP-1 concentration. Ulcer healing is associated with a decrease in wound fluid IL-8.     

The impact of differential expression of extracellular matrix metalloproteinase inducer, matrix metalloproteinase-2, tissue inhibitor of matrix metalloproteinase-2 and PDGF-AA on the chronicity of venous leg ulcers.

INTRODUCTION: Alteration in the expression of extracellular matrix metalloproteinase inducer (EMMPRIN), matrix metalloproteinase-2 (MMP-2), tissue inhibitors of matrix metalloproteinases (TIMP-2) and platelet derived growth factor (PDGF-AA) may contribute to poor healing in venous leg ulcers. AIM: The aim of this study is to determine the expression of EMMPRIN, MMP-2, TIMP-2 and PDGF-AA in the ulcer exudates and perivascular tissue of healing and non-healing chronic venous ulcers. PATIENTS, MATERIALS AND METHODS: Forty patients with chronic venous ulcers were included in this study, with a mean age of 60 years. Eleven patients were males and 29 were females. All patients had normal ankle brachial index and a venous ulcer of at least 8 weeks duration. Immuno-histochemistry using monoclonal antibodies to PDGF-AA, MMP-2, TIMP-2 and EMMPRIN was carried out on paraffin embedded punch biopsy skin specimens from the ulcer edge. Enzyme linked immunosorbent assay for PDGF, MMP-2 and TIMP-2 were carried out on wound fluids collected from patients. The ulcer size and character at the initial assessment and after 8 weeks were assessed to determine the status of ulcer healing. RESULTS: No significant difference was seen in the expression of TIMP-2, MMP-2 and EMMPRIN between the two groups. However, in the non-healing group high levels of MMP-2 and low levels of TIMP-2 in the wound fluid suggest a strong correlation of these two markers in the state of healing. Analysis of wound fluid by ELISA demonstrated high PDGF-AA in the healing group (p = 0.021). Significantly increased levels of PDGF-AA (p<0001) was noted in the perivascular area on immuno-histochemistry of healing ulcers. These data suggest that PDGF-AA plays an important role in healing of venous ulcers. CONCLUSION: Non-healing venous ulcers are associated with greater activity MMP-2 activity. The ratio of MMPs to their inhibitors TIMPs, dictate the rate of healing of the ulcers. PDGF-AA activity is associated with ulcer healing, though the mechanism is unclear. EMMPRIN expression in chronic venous ulcers probably parallels the chronicity of the condition rather than propagate it. However, further studies with larger samples are needed.