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Objective: To compare matrix metalloproteinase (MMP)-9 and the antiproteinase tissue inhibitor of metalloproteinases (TIMP)-1 in wound fluids and sera from patients with chronic non-healing or acute healing wounds. In addition, the functional consequences on MMP-9 activity and general gelatinase activity were assessed., Method: In this observational study, samples were collected from patients with venous leg ulcers (VLUs), patients with type 2 diabetes with neuropathic foot ulcers (DFUs), and from another cohort of VLU patients with sterile split-thickness skin graft donor sites after autologous skin grafting, serving as healing control wounds. MMP-9 and TIMP-1 concentrations were determined by enzyme-linked immunosorbent assays. MMP-9 and gelatinase activities were determined in wound fluids in subsets of the patients., Results: A total of 24 patients took part in the study. No significant differences in MMP-9 wound fluid levels were found among the three groups. TIMP-1 levels were markedly and significantly lower in the two chronic wound groups resulting in a severely unbalanced MMP-9/TIMP-1 ratio, especially notable in the VLU group and possibly in the elevated endogenous MMP-9 activity (p<0.01) compared with the acute wound fluids. At least 20% of the chronic wound fluids displayed atypical patterns on gelatin zymography and showed high general gelatinase activity that was not inhibited by either TIMP-1 or by a gelatinase inhibitor (AG3340). MMP-9 levels were higher in the sera of the patients with type 2 diabetes., Conclusion: We hypothesise that non-MMP proteinases contribute to matrix destruction in a significant number of chronic wounds. Blocking the excessive MMP-9 activity may be insufficient to normalise wound healing. The reasons and effects of the very low TIMP-1 levels in chronic wounds need further clarification.

Objective: Late-stage lymphoedema is characterised by chronic swelling, shape distortion, inflammatory processes and tissue fibrosis. Our aim was to perform a clinical audit of a lymphoedema compression bandaging system (Rosidal Soft foam roll layer and figure-of-eight application of Actico cohesive inelastic bandages) specifically designed for patients with late stage lower limb lymphoedema., Method: The audit explored suitability of the bandaging system, benchmarking limb volume changes with research evidence, and reporting patient and practitioner evaluations., Results: A mean reduction (33%) in excess limb volume was reported for the 11 patients with unilateral lymphoedema who completed a course of bandaging over 12 days. Mean percentage reduction of absolute limb volume after treatment was 8%. Patient and practitioner evaluations indicated the suitability of this bandage system for patients with late stage lymphoedema in terms of comfort and effectiveness., Conclusion: The bandaging system is suitable for patients with late stage chronic swelling. Two parameters for calculating change in limb volume are not interchangeable. Future evaluation of the bandaging system, using validated outcome measures within a comprehensive research study is required., Declaration of Interest: Activa Healthcare provided financial support to the project and supplied the materials.

Objective: The aim of the study was to compare the efficacy of a microorganism-binding (MB) dressing with a silver-containing hydrofiber (SCH) dressing in controlling the bacterial loads of heavily colonised or locally infected chronic venous leg ulcers, before surgical management with homologous skin grafts., Method: A randomised comparative single centre study recruited patients presenting with hard-to-heal critically colonised or locally infected leg ulcers, who could be treated with skin grafting. Inclusion criteria included; ulcers of vascular aetiology, over 18 years old, a wound duration ≥6 months and ankle brachial index (ABPI) >0.6. Patients were randomly assigned to treatment with SCH dressings (Aquacel Ag) or MB dressing (Cutimed Sorbact). Dressings were changed daily over a four-day observation period, after which they were taken for a skin grafting procedure. Swab samples from ulcer beds were taken in order to quantify the bacterial load at inclusion (D0) and at the end of the observation period day 4 (D4). No antibiotics were administered before or during the evaluation period., Results: Both groups (n=20 SCH, n=20 MB) were similar in gender, age, pathophysiology (both had 15 patients with venous leg ulcers and 5 with arterial leg ulcers), ulcer surface, ulcer duration, treatment-related pain and initial bacterial load. Analysing bacterial load variation showed a significant reduction of bacterial burden at D4 in both groups. In the SCH group, we found an average bacterial load reduction of 41.6%, with an average reduction of 73.1% in the MB group (p< 0.00001). No serious adverse events were reported., Conclusion: Our evaluation confirmed that MB and SCH dressings are effective in reducing the bacterial burden in critically colonised or locally infected chronic leg ulcers, without inducing adverse events, with MB dressings significantly more effective., Declaration of Interest: There were no external sources of funding for this study. The authors have no conflicts of interest to declare.

Objective: Exercise has the potential to offer a range of health benefits in addition to improving healing outcomes for people with venous leg ulcers (VLUs). However, despite evidence-based recommendations, most of these individuals do not engage in regular exercise. The aim of this study was to gain an understanding of the perspectives of adults with VLUs, in relation to exercise., Method: This was a qualitative design using semi-structured interviews and discussions. Ten participants with venous leg ulceration volunteered to participate. Recruitment was through a specialist wound clinic. Verbatim data were collected by an experienced moderator using a semi-structured guide. Data saturation was reached after three group discussions and two interviews. A random selection of transcripts was sent back to the participants for verification. Thematic content analysis was used to determine major themes and categories. Two transcripts were independently analysed, categories and themes independently developed, cross checked and found comparable. Remaining transcripts were analysed using the developed categories and codes., Results: Regardless of their current exercise routine, participants reported exercising before venous leg ulceration and expressed an interest in either becoming active or maintaining an active lifestyle. Overall, four themes emerged from the findings: i) participant understanding of the relationship between chronic venous insufficiency and exercise patterns; ii) fear of harm impacts upon positive beliefs and attitudes to exercise; iii) perceived factors limit exercise; and iv) structured management facilitates exercise., Conclusion: The value of exercise in improving outcomes in VLUs lies in its capacity to promote venous return and reduce the risk of secondary conditions in this population. Despite motivation and interest in being exercise active, people with VLUs report many obstacles. Further exploration of mechanisms that assist this patient population and promote understanding about management of barriers, coupled with promotion of enabling factors, is vital for improving their exercise participation.

To achieve good patient outcomes, clinicians must ensure that clinical decision making is informed by valid and reliable evidence. This review examines the evidence on the clinical efficacy and reproducibility of compression applied by the KTwo bandage system. Its aim is to describe the evidence, not critique it. However, it clearly shows there is a body of evidence, from simple comparative evaluations to a randomised controlled trial, demonstrating the effectiveness of this system

Objective: To determine the effect of topically applied amelogenin extracellular matrix protein(AEMP) in patients with non-healing venous leg ulcers combined with atrophie blanche., Method: This retrospective case series of patients with non-healing venous leg ulcers with atrophie blanche of the distal proportion of their lower legs, where non-healing was defined as no progress toward healing for 3 months previously, under standard therapy. Patient records were reviewed for associated diseases, wound diagnoses, distal blood pressure, previous treatments and changes in wound area. Patients were treated with AEMP once a week, for a period of 12 weeks, or until full healing., Results: Eleven patient records were reviewed retrospectively. The median age of the patients was 81 years (range 40-95 years), with a mean wound size of 4.7 ± 3.Scm2 and median wound duration of 6 months (range 3-444 months).AII patients had venous or combined arterial/venous insufficiency. After 12 weeks' treatment with AEMP, complete healing, defined as I 00% re-epithelialisation, was documented in four patients (36%), marked improvement(> SO% epithelialisation) in three patients (54%, 55% and 83% wound closure, respectively), slight improvement in one patient (9.4% wound closure), no change for two patients and worsening in one.AEMP was well tolerated, and no patients reported side effects., Conclusion: The results of this retrospective study suggest that AEMP improves healing in chronic venous leg ulcers combined with atrophie blanche.

Objective: To use in vitro biofilm models of wound bacterial isolates and compare the biofilms produced for different combinations of wound bacterial species., Method: In vitro biofilms, generated by Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus oralis and Micrococcus luteus in microtitre plates and a constant depth film fermentor (CDFF), were studied. The tested isolates all originated from chronic venous leg ulcers. Biofilms of individual and dual combinations of these species were generated in microtitre plate wells at 37°C for 24-96 hours and also in the CDFF for 7 days. The extent of biofilm formation from these systems was then measured using crystal violet staining and/or total viable counts., Results: All the chronic wound bacteria formed biofilms (both individually and in mixed culture) in these models. In mixed species microtitre plate biofilms, both P. aeruginosa and S. aureus appeared to antagonise biofilm formation by S. oralis and M. luteus, with P. aeruginosa completely inhibiting the growth of these organisms. Similar effects were evident in the CDFF model, when all four bacterial species were added simultaneously, with M. luteus being 'out-competed' by the other organisms present and occurring at numbers at the limits of detection; however, there was an apparent increase in the numbers of S. oralis compared with its single culture equivalent., Conclusion: The study highlighted differences in biofilm formation ability for the tested species in both closed and open model systems. Using dual species biofilms, distinct species antagonism was observed with apparent antagonism of pathogenic species over 'commensal' ones. Such a finding provides insight into possible bacterial interactions during development of 'non-healing' wound biofilms.

Objective: To assess whether a difference in venous reflux pattern, ulcer size or duration, regular medications or the daily use of walking aids can predict the healing of a chronic venous leg ulcer (VLU)., Method: In this prospective, randomised, single-centre study, 110 consecutive patients with chronic leg ulcers were assessed. Ninety-nine patients met the inclusion criteria and a controlled, conservative 3-month treatment period was initiated, in which 90 patients were managed with standardised local treatment combined with compression therapy. In this group, 62 VLUs healed within 12 weeks and 28 were still open after 12 weeks. The study group consisted of 22 patients with non-healed ulcers and a control group (n=28), which was selected randomly from the healers. In both groups, venous reflux profiles were assessed using colour-flow duplex imaging., Results: The study and control groups did not differ in smoking habits, age, gender or daily oral medications. On average, the healing wounds were 5cm² before starting controlled treatment (range 1-80cm²) and had been open for 7 months (range 2-48 months); the non-healing wounds were on average 11.2cm² (range 1-31cm²) and had been open for 26 months (range 8-106 months). Venous disease severity scores were similar for both groups (12.6 vs. 13.4). Five patients (18%) with healed ulcers regularly used walking aids, the use of which was more frequent (36%) among non-healers (p<0.001). Venous reflux profiles differed significantly between the groups, with isolated superficial reflux noted in 64% of healers, compared with 36% of non-healers. In addition, isolated deep reflux was found in 14% of the healers, compared with 41% of non-healers (p=0.0002). The rate of popliteal reflux was significantly higher in non-healers (59% versus 21%; p=0.0004)., Conclusion: Long duration of a chronic venous ulcer may predict a poor outcome. The presence of deep venous reflux, especially in the popliteal vein, is typically found in those legs with non-healed ulcers. .

Objective: To compare the effect on the microcirculation in venous leg ulcers (VLUs) of two treatment regimens that promote a moist wound environment versus paraffin gauze. The hypothesis is that moist wound dressings are more likely to stimulate the microcirculation and therefore angiogenesis., Method: Patients with non-healing VLUs were randomised to receive either a foam dressing (Suprasorb P), a collagen dressing (Suprasorb C) plus the foam dressing, or paraffin gauze (control). All patients wore short-stretch high compression bandages. Parameters used to measure the effects of the treatments on the microcirculation were: TcPO2 measurements, video laser Doppler measurements and the number of capillaries in the wound bed. The progression towards healing was measured by the reduction in ulcer area and formation of granulation tissue. The treatment period was four weeks., Results: Significant increases in TcPO2 values were reported between baseline and week 4 for patients receiving the foam dressing only or the collagen plus foam dressing combination (p<0.008 versus p<0.003 respectively). There was also a significant increase in the number of capillaries for the collagen plus foam treatment only (p<0.002)., Conclusion: This pilot study suggests that a moist wound environment stimulates perfusion of blood and oxygen to the wound tissue, thereby promoting angiogenesis. The collagen and foam dressing combination demonstrated superior results to the control and the foam dressing only. Monitoring the microcirculation may help to assess the effect of dressings on VLU healing, although more research is needed., Declaration of Interest: This pilot study was supported by a limited grant from Lohmann & Rauscher GmbH, Germany.

The anatomical elements of the lower limb work together to optimise venous return. This review examines the mechanisms involved, and the devices available to measure movement, giving opportunities for new preventive interventions.

This article, the first of a series of four on venous leg ulceration, discusses theories relating to the pathophysiology underlying the condition, and the range of diagnostic procedures undertaken to establish that ulceration is of venous origin.

Objective: The tissue contraction phenomenon associated with wound healing is of prime importance for wound closure. Contractile properties of human fibroblasts from chronic venous leg ulcers were compared with those of normal fibroblasts using in vitro models., Method: Biopsies were taken from the uninvolved skin of the thigh, the epithelialised ulcer edge and the non-epithelialised ulcer centre in four patients (average age: 78 years). Fibroblasts were obtained by an explant technique and expanded in vitro in Dulbecco's Modified Eagle's Medium supplemented with 10% foetal calf serum and used for the assays at their fourth passage. Intracellular alpha-smooth muscle actin expression (alphaSM-actin) was studied by immunofluorescence labelling of cells cultured in monolayer. Contractile properties were evaluated using three-dimensional collagen lattices., Results: Fibroblasts from the ulcer centre were the richest cells in actin filaments. Both populations of venous ulcer fibroblasts contracted more rapidly and to a greater extent than normal fibroblasts. The peak contractile forces developed by fibroblasts from the ulcer centre and the ulcer edge were 30% and 18% greater than normal fibroblasts respectively., Conclusion: Some functions of fibroblasts, in particular the generation of contractile forces and the formation of cytoplasmic actin filaments, seem not to be affected in chronic venous ulcers., Declaration of Interest: This study was supported by the Fondation Coloplast pour la Qualite de la Vie of France.

Objective: This study set out to compare healing rates, handling properties and patient comfort of a four-layer bandage system (Profore) and Unna's Boot in the treatment of venous leg ulcers., Method: This was a prospective randomised parallel-group trial. Patients with venous leg ulcers from four centres in Italy were randomised to receive treatment with either Unna's Boot or Profore. Time to healing was recorded for a maximum of 24 weeks. Pain was assessed using a visual analogue scale. Staff assessed ease of application, while patients rated comfort., Results: Data were available for 68 patients with 68 wounds. At 24 weeks complete healing was seen in 74% of the Profore group compared with 66% of the Unna's Boot group. The median time spent in the study was 50 days (range: 7-175 days), corresponding to 51 days (range: 7-175 days) for Profore patients and 49 days (range: 7-168 days) for Unna's Boot patients. There was no difference (p = 0.13) between the groups in time to closure. Overall, more Profore than Unna's Boot applications were rated as excellent. There was a significant difference, in favour of Profore, in ease of application at the final application (p = 0.013). At the initial application, there was a significant difference in bandage appearance (p = 0.04), again favouring Profore, but this was not sustained at the final application (p = 0.18)., Conclusion: Profore is as effective as Unna's Boot in the treatment of venous leg ulcers.

Objective: This study aimed to compare the accuracy and inter-observer reproducibility of leg ulcer measurements made using digital images and conventional contact tracing., Method: The accuracy of measurements made with these two methods by four observers of 11 shapes with a known area was assessed. The time taken to do this was also measured. Following this, the accuracy and inter-observer reproducibility of the two methods was measured for patients with leg ulcers presenting to the vascular clinic, with contact tracing as the reference., Results: For the reference shapes, both methods had a mean error of less than 5%. Contact tracing significantly underestimated the area by 3.9% (p < 0.05), while digital tracing showed no significant error. Digital tracing was quicker than contact tracing, especially for larger shapes (p < 0.05). For leg ulcers, there was no significant difference between area measurements made by the two methods. Inter-observer variation of digital tracing was greater for the ulcers than the reference shapes. This was due to differences in subjective interpretation and technical problems in recording some images., Conclusion: Measurement of leg ulcer area using computer-aided tracing of digital camera images is more accurate and quicker than contact tracing provided that appropriate care is taken when taking the pictures. Digital images offer considerable advantages in the shared hospital-community care of patients with leg ulcers.

Abnormally high levels of some proteases are associated with pathological changes in the wound bed of venous leg ulcers. This study involved two experiments which measured proteases in wound fluid harvested from leg ulcers in order to predict healing. In the first experiment, neutrophil elastase, a protease, was harvested from wound fluid extracted from the bandages of seven patients with leg ulcers. This was undertaken once a week over a period of up to six weeks. The amount of elastase recovered from the bandages showed wide variation between patients and there was no consistent correlation between the activity of elastase and healing of the ulcers, as determined nine months after sampling for the enzyme. The second experiment determined the stability of neutrophil elastase that was added to bandages for one week. The stability was found to vary from approximately 50% to 100%, depending on the type of bandage used. In addition to the possibility of using protease measurements to predict healing, the procedure was found to be simple, non-invasive and relatively inexpensive, and could be performed routinely in the clinic.

A systematic review of randomised controlled trials (RCTs) was conducted to establish the effectiveness of low-level laser therapy as a treatment for venous leg ulcers. Wound-care journals, conference proceedings and electronic databases (including Medline and Cinahl) were searched up to October 1997 for RCTs comparing low-level laser therapy with sham laser, no laser, or non-coherent light of other wavelengths. In addition, companies who manufacture or distribute therapeutic lasers were contacted for any unpublished or ongoing studies. Results from searches were scrutinised by one reviewer to identify possible RCTs and full reports of these were obtained. Details of eligible studies were extracted and summarised using a data extraction sheet. Data extraction was checked by a second reviewer. Meta-analysis was used to combine the results of trials where the interventions and outcome measures were sufficiently similar. A total of four eligible RCTs were identified. Two compared treatment with laser therapy to sham or placebo laser treatment. One study compared laser therapy with ultraviolet therapy. The fourth was a three-armed study which compared the effects of laser therapy alone, laser therapy plus infrared light, and non-coherent unpolarised red light. The comparisons of laser therapy with placebo, and laser therapy with ultraviolet therapy, showed no significant difference between treatments with regard to ulcer healing rates. The comparison of laser with red light showed a significant increase in complete healing at nine months for the combination of laser and infrared light compared to non-coherent unpolarised red light. We have not found any evidence of the benefit of low-level laser therapy per se on venous leg ulcer healing. It appears that a combination of HeNe laser and infrared light may promote the healing of venous ulcers, however more research is needed.

This study examines how the microenvironment created by fluid in chronic wounds influences the growth of dermal fibroblasts. Newborn fibroblasts, which are known to grow rapidly, were used as a model system to explore how chronic wound fluid affects the growth of regenerative fibroblasts. Wound fluid was collected from patients with chronic venous leg ulcers (duration longer than two months). The biological properties of this fluid were then further characterised to elucidate its molecular effects on cell growth. Results indicate that chronic wound fluid dramatically inhibited the growth of newborn dermal fibroblasts. This growth inhibitory effect was variable among donors, reversible and heat-sensitive. The inhibitory effect was due not to cytotoxicity or impaired plating efficiency of these cells, but to specific interference with the cell cycle. Chronic wound fluid arrested newborn fibroblast growth by preventing entry into the S-phase, or DNA synthesis-phase, of the cell cycle. In contrast to its effects on newborn fibroblasts, chronic wound fluid either stimulated or had a minimal effect on fibroblasts which had been cultured from the edge of chronic venous leg ulcers and healthy tissue on the upper thigh in the same patient. This may partially account for the impaired healing seen in chronic venous leg ulcers.

For many years it was believed that disease within the deep venous system, such as a deep vein thrombosis or post-phlebitic limb, was the main cause of venous ulceration. There is, however, increasing awareness of the impact of both deep and superficial venous valvular incompetence and reflux on the aetiology and healing of venous ulceration. It is now widely accepted that superficial venous disease alone can result in increased venous pressure at the ankle and subsequent skin damage and ulceration.