Wound healing: potential therapeutic options.

This review highlights the range of therapeutic options available to clinicians treating difficult-to-heal wounds. While certain treatments are established in daily clinical practice, most therapeutic interventions lack robust and rigorous data regarding their efficacy, which would help to determine when, and for whom, they should be used. The purpose of this review is to give a broad overview of the available interventions, with a brief summary of the evidence base for each intervention.

Development and validation of a gene expression test to identify hard-to-heal chronic venous leg ulcers.

BACKGROUND: Chronic venous leg ulcers pose a significant burden to healthcare systems, and predicting wound healing is challenging. The aim of this study was to develop a genetic test to evaluate the propensity of a chronic ulcer to heal. METHODS: Sequential refinement and testing of a gene expression signature was conducted using three distinct cohorts of human wound tissue. The expression of candidate genes was screened using a cohort of acute and chronic wound tissue and normal skin with quantitative transcript analysis. Genes showing significant expression differences were combined and examined, using receiver operating characteristic (ROC) curve analysis, in a controlled prospective study of patients with venous leg ulcers. A refined gene signature was evaluated using a prospective, blinded study of consecutive patients with venous ulcers. RESULTS: The initial gene signature, comprising 25 genes, could identify the outcome (healing versus non-healing) of chronic venous leg ulcers (area under the curve (AUC) 0·84, 95 per cent c.i. 0·73 to 0·94). Subsequent refinement resulted in a final 14-gene signature (WD14), which performed equally well (AUC 0·88, 0·80 to 0·97). When examined in a prospective blinded study, the WD14 signature could also identify wounds likely to demonstrate signs of healing (AUC 0·73, 0·62 to 0·84). CONCLUSION: A gene signature can identify people with chronic venous leg ulcers that are unlikely to heal.

The clinical significance and impact of interleukin 15 on keratinocyte cell growth and migration.

Chronic wounds represent a significant burden to health services and are associated with patient morbidity. Novel methods to diagnose and/or treat problematic wounds are needed. Interleukin (IL)-15 is a cytokine involved in a number of biological processes and disease states such as inflammation, healing and cancer progression. The current study explores the expression profile of IL-15 and IL-15 receptor α (IL-15Rα) in chronic wounds and its impact on keratinocytes. IL-15 and IL-15Rα expression were examined in healing and non-healing chronic wounds using qPCR and immunohistochemical analysis. The impact of recombinant IL-15 (rhIL-15) on human adult low calcium temperature (HaCaT) keratinocyte growth and migratory potential was further examined. IL-15 transcript expression was slightly, though non-significantly elevated in healing chronic wounds compared with non-healing chronic wounds. IL-15 protein staining was minimal in both subtypes of chronic wounds. By contrast, IL-15Rα transcript and protein expression were both observed to be enhanced in non-healing chronic wounds compared with healing chronic wounds. The treatment of HaCaT cells with rhIL-15 generally enhanced cell growth and promoted migration. Analysis with small molecule inhibitors suggested that the pro-migratory effect of rhIL-15 may be associated with ERK, AKT, PLCγ and FAK signalling. IL-15 may promote healing traits in keratinocytes and the differential expression of IL-15Rα is observed in chronic wounds. Together, this may imply a complex role for this interleukin in wound healing.

Chronic wound and postamputation claudication pain in a diabetic patient.

Underlying ischaemic disease should be excluded in patients with delayed wound healing. Contrast angiography is a useful imaging method for assessing the specific cause of wound chronicity and may also be helpful in assessing the aetiology of unexplained pain symptoms. Angioplasty provides a practical alternative to more invasive techniques in addressing peripheral ischaemia. Our patient suffered claudication-type pain in his thigh and a non-healing stump wound following below-knee amputation. Magnetic resonance angiography confirmed the presence of arterial stenoses and an angioplasty was successfully performed to improve patency of the profunda femoris vessel. Following the operation, the claudication pain symptoms were significantly reduced and the stump wound went on to heal.

Topical steroids for chronic wounds displaying abnormal inflammation.

INTRODUCTION: Chronic, non-healing wounds are often characterised by an excessive, and detrimental, inflammatory response. We review our experience of using a combined topical steroid, antibiotic and antifungal preparation in the treatment of chronic wounds displaying abnormal and excessive inflammation. METHODS: A retrospective review was undertaken of all patients being treated with a topical preparation containing a steroid (clobetasone butyrate 0.05%), antibiotic and antifungal at a tertiary wound healing centre over a ten-year period. Patients were selected as the primary treating physician felt the wounds were displaying excessive inflammation. Healing rates were calculated for before and during this treatment period for each patient. Changes in symptom burden (pain, odour and exudate levels) following topical application were also calculated. RESULTS: Overall, 34 ulcers were identified from 25 individual patients (mean age: 65 years, range: 37-97 years) and 331 clinic visits were analysed, spanning a total time of 14,670 days (7,721 days 'before treatment' time, 6,949 days 'during treatment' time). Following treatment, 24 ulcers demonstrated faster rates of healing, 3 ulcers showed no significant change in healing rates and 7 were healing more slowly (p=0.0006). Treatment generally reduced the burden of pain and exudate, without affecting odour. CONCLUSIONS: In normal wound healing, inflammation represents a transient but essential phase of tissue repair. In selected cases, direct application of a steroid containing agent has been shown to improve healing rates, presumably by curtailing this phase. Further evaluation is required to establish the role of preparations containing topical steroids without antimicrobials in the management of chronic wounds.

Randomised controlled trial of the use of three dressing preparations in the management of chronic ulceration of the foot in diabetes.

OBJECTIVES: To determine the comparative effectiveness and cost-effectiveness of three dressing products, N-A, Inadine and Aquacel, for patients with diabetic foot ulcers, as well as the feasibility and consequences of less frequent dressing changes by health-care professionals. DESIGN: A multicentre, prospective, observer-blinded, parallel group, randomised controlled trial, with three arms. SETTING: Established expert multidisciplinary clinics for the management of diabetic foot ulcers across the UK. PARTICIPANTS: Patients over age 18 with type 1 or type 2 diabetes with a chronic (present for at least 6 weeks) full-thickness foot ulcer (on or below the malleoli) not penetrating to tendon, periosteum or bone, and with a cross-sectional area between 25 and 2500 mm(2). INTERVENTIONS: Participants were randomised 1:1:1 to treatment with one of N-A (a non-adherent, knitted, viscose filament gauze), Inadine (an iodine-impregnated dressing), both traditional dressings, or Aquacel, a newer product. MAIN OUTCOME MEASURES: The primary outcome measure was the number of ulcers healed in each group at week 24. Secondary measures included time to healing, new ulcerations, major and minor amputations, and episodes of secondary infection. RESULTS: A total of 317 patients were randomised. After 88 withdrawals, 229 remained evaluable. A greater proportion of smaller (25-100 mm(2) ulcers healed within the specified time (48.3% versus 37.3%; p = 0.048). There was, however, no difference between the three dressings in terms of percentage healed by 24 weeks, or in the mean time to healing, whether analysed on the basis of intention to treat (Inadine 44.4%, N-A 38.7%, Aquacel 44.7%; not significant) or per protocol (Inadine 55.2%, N-A 59.4%, Aquacel 63.0%; not significant). There was no difference in the quality of healing, as reflected in the incidence of recurrence within 12 weeks. Likewise, there was no difference in the incidence of adverse events, although a greater proportion of those randomised to the non-adherent dressings were withdrawn from the study (34.9% versus 29.1% Aquacel and 19.4% Inadine; p = 0.038). The only statistically significant difference found in the health economic analysis was the cost associated with the provision of dressings (mean cost per patient: N-A 14.85 pounds, Inadine 17.48 pounds, Aquacel 43.60 pounds). The higher cost of Aquacel was not offset by the fewer dressings required. There was no difference in measures of either generic or condition-specific measures of quality of life. However, there was a significant difference in the change in pain associated with dressing changes between the first and second visits, with least pain reported by those receiving non-adherent dressings (p = 0.012). There was no difference in the costs of professional time, and this may relate to the number of dressing changes undertaken by non-professionals. Fifty-one per cent of all participants had at least one dressing change undertaken by themselves or a non-professional carer, although this ranged from 22% to 82% between the different centres. CONCLUSIONS: As there was no difference in effectiveness, there is no reason why the least costly of the three dressings could not be used more widely across the UK National Health Service, thus generating potentially substantial savings. The option of involving patients and non-professional carers in changing dressings needs to be assessed more formally and could be associated with further significant reductions in health-care costs. TRIAL REGISTRATION: Current Controlled Trials ISRCTN78366977.

Investigation of standing balance in patients with diabetic neuropathy at different stages of foot complications.

BACKGROUND: Diabetic peripheral neuropathy is known to cause postural instability. This study investigated standing balance in patients with diabetic neuropathy with secondary foot complications: foot ulceration, partial foot amputation and trans-tibial amputation, which are expected to pose further challenge to balance control. METHODS: In this cross-sectional study, 23 patients with diabetic neuropathy alone (controls) were compared with 23 patients with diabetic foot ulceration, 16 patients with partial foot amputation and 22 patients with trans-tibial amputation. Posturography was used to determine the centre of pressure excursion during quiet standing. Differences between the 4 groups were tested using ANOVA and post-hoc comparisons. FINDINGS: The 4 groups varied in neuropathy score (P=0.001) and demonstrated significant decline in balance from neuropathy alone to foot ulceration, to partial foot amputation and trans-tibial amputation based on total excursion of centre of pressure (P<0.001) and centre of pressure excursion in antero-posterior direction (P<0.001). The excursion of centre of pressure in medio-lateral direction varied between 4 groups (P<0.05) however, there was no significant trend. The distance between ankles increased significantly from neuropathy to trans-tibial amputee group (P=0.001). Post-hoc comparison with controls revealed that each of three study groups demonstrated decreased balance (diabetic neuropathy vs. foot ulceration, P=0.001, diabetic neuropathy vs. partial foot amputation, P=0.002 and diabetic neuropathy vs. trans-tibial amputation, P=0.009). INTERPRETATION: Balance deterioration among patient groups from diabetic neuropathy alone to trans-tibial amputation appears to result from bio-mechanical impairment caused by progression of foot complications in addition to postural instability caused by diabetic neuropathy.

The influence of exercise on foot perfusion in diabetes.

AIMS: Diabetic foot disease is associated with both macro- and microvascular disease. Exercise has both positive and negative effects on the perfusion of lower limbs with peripheral arterial occlusive disease (PAOD). We aimed to measure changes in foot perfusion following a brief period of lower-limb exercise in individuals with and without Type 2 diabetes and non-critical PAOD. METHODS: Subjects were allocated to groups according to the presence or absence of diabetes, PAOD on colour duplex imaging and clinically detectable peripheral neuropaIthy. Transcutaneous oxygen tension (TcPO(2)), transcutaneous carbon dioxide tension (TcPCO(2)), ankle-brachial pressure indices, toe pressures and toe-brachial pressure indices (TBI) were measured. RESULTS: One hundred and sixteen limbs were studied in 61 subjects. Post-exercise, toe pressure and TBI increased in the non-diabetic group with arterial disease, but not in the groups with diabetes. Foot TcPO(2) values increased in groups with diabetes and TcPCO(2) decreased in all groups with arterial disease. Increased chest TcPO(2) and decreased TcPCO(2) were demonstrated in the groups with diabetes. CONCLUSIONS: Elevations in foot TcPO(2) and reductions in TcPCO(2) indicate improved cutaneous perfusion response to local heating post-exercise. Elevated toe pressures in the non-diabetes group suggest that improved perfusion may be associated with enhanced lower limb macrovascular haemodynamics. However, improvements in TcPO(2) and TcPCO(2) at foot and chest sites in diabetes imply a global change in cutaneous perfusion. The results suggest that brief exercise results in an improvement in cutaneous perfusion in non-critical PAOD, particularly in individuals with diabetes.

Environmental analysis of plastic production processes: comparing petroleum-based polypropylene and polyethylene with biologically-based poly-beta-hydroxybutyric acid using life cycle analysis.

Polymers based on olefins have wide commercial applicability. However, they are made from non-renewable resources and are characterised by difficulty in disposal where recycle and re-use is not feasible. Poly-beta-hydroxybutyric acid (PHB) provides one example of a polymer made from renewable resources. Before motivating its widespread use, the advantages of a renewable polymer must be weighed against the environmental aspects of its production. Previous studies relating the environmental impacts of petroleum-based and bio-plastics have centred on the impact categories of global warming and fossil fuel depletion. Cradle-to-grave studies report equivalent or reduced global warming impacts, in comparison to equivalent polyolefin processes. This stems from a perceived CO(2) neutral status of the renewable resource. Indeed, no previous work has reported the results of a life cycle assessment (LCA) giving the environmental impacts in all major categories. This study investigates a cradle-to-gate LCA of PHB production taking into account net CO(2) generation and all major impact categories. It compares the findings with similar studies of polypropylene (PP) and polyethylene (PE). It is found that, in all of the life cycle categories, PHB is superior to PP. Energy requirements are slightly lower than previously observed and significantly lower than those for polyolefin production. PE impacts are lower than PHB values in acidification and eutrophication.

A pilot study on the effect of topical negative pressure on quality of life.

OBJECTIVE: To discover the impact of topical negative pressure (TNP) on quality of life. METHOD: An exploratory prospective cohort study was conducted on 26 patients undergoing TNP. The Cardiff Wound Impact Schedule (CWIS), a wound-specific tool, was used to investigate quality-of-life scores before therapy and four weeks after therapy or at wound closure. Wound dimensions were measured at both assessments, and the values for the CWIS domains (physical symptoms, social functioning, well-being and overall quality of life) were investigated using parametric and non-parametric tests. RESULTS: The mean duration of TNP therapy was 3.3 +/- 1.7 weeks. Topical negative pressure therapy helped to achieve complete wound closure in 14 patients (54%), and there was a mean reduction in wound surface area from 52.2 cm2 (range 4-150) to 26.8 cm2 (0-120). While there was no significant change in quality of life in patients whose wounds healed (1 +/- 11.9), the physical-functioning domain improved in obese patients (20 +/- 21, p < 0.05) and worsened in ambulatory patients (-3 +/- 13, p < 0.05). The portableTNP system had no significant impact on quality of life (-3 +/- 16), while the global quality-of-life score worsened with surgical intervention (-0.5 +/- 2, p < 0.05). CONCLUSION: Although TNP aids wound closure in patients with complex wounds, in selected cases their quality of life can worsen. This is the first exploratory cohort study of its kind, and has identified an urgent need to validate the use of patient-based outcome measures in TNP therapy. Such data can be useful in allocating resources and justifying funding in wound care.

Use of a hydrocapillary dressing in the management of highly exuding ulcers: a comparative study.

OBJECTIVE: To evaluate the safety and performance of Alione Hydrocapillary dressing (Coloplast A/S) in the management of highly exuding chronic venous leg ulcers and compare it with two hydropolymer dressings,Tielle and Tielle Plus (Johnson & Johnson). METHOD: A comparative clinical trial was conducted on 97 patients with an ankle brachial pressure index > or = 0.8 and a highly exuding leg ulcer. Ulcer duration was at least four weeks. Treatment continued until healing or for a maximum of 12 months. RESULTS: There was no statistically significant difference in healing time or wound area reduction between the two treatment protocols. The test dressing (Alione Hydrocapillary) had better absorption capacity and was more comfortable for the patients than the comparator dressings (Tielle/Tielle Plus) and adhered less to the wound bed.Also, more patients preferred the test dressing to their previous treatment. Although severe leakage and maceration were observed more frequently in the comparator group compared with the test group, this was not statistically significant. CONCLUSION: Both treatment protocols were safe and effective in treating highly exuding chronic venous leg ulcers. The test dressing performed as well as or better than the comparator dressings for all study parameters and more patients preferred the test dressing to their previous dressing compared with the comparator dressings.

Sustained silver-releasing dressing in the treatment of diabetic foot ulcers.

This study investigated the clinical performance and safety of a sustained silver-releasing foam dressing, Contreet Foam, in the treatment of diabetic foot ulcers. Twenty-seven patients with diabetic foot ulcers of grade I or II (Wagner's classification) were followed for six weeks: one week run-in using Biatain dressings, four weeks' treatment with Contreet dressings. Four ulcers healed during the four-week treatment with Contreet 56% in average. Contreet Foam showed good exudate management properties and was considered easy to use. Only two infections occurred showed that all six of the non-study ulcers developed an infection during the study. All ulcers (study ulcers as well as non-study ulcers) were treated according to good practice of diabetic wound care. There were no directions for the treatment of secondary wounds. No device-related adverse events were observed. This study demonstrated that Contreet Foam is safe and easy to use and effectively supports healing and good wound progress of diabetic foot ulcers.

Wound-related osteomyelitis: a case of containment not cure.

Community nurses need to be aware that some patients with osteomyelitis are treated with antibiotics alone. Such patients often have co-morbidities and quality of life issues that directly impact on the decision to treat osteomyelitis surgically. However, adopting a conservative approach to osteomyelitis management is associated with an increased risk of osteomyelitis recurrence. The rationale for managing chronic wound-related osteomyelitis with antibiotics is discussed. Community nurses caring for patients that have received antibiotics alone to treat osteomyelitis need to be aware of the potential for osteomyelitis recurrence and how to make the diagnosis.

Diagnosing foot infection in diabetes.

Infection represents the presence of an inflammatory response and tissue injury due to the interaction of the host with multiplying bacteria. The disease spectrum is a consequence of the variability in these interactions. Diabetes, because of its effects on the vascular, neurological, and immune systems, can compromise the local and systemic response to infection, potentially masking the typical clinical features and hindering diagnosis. The early recognition of infection, particularly osteomyelitis, is paramount in the management of diabetic foot disease. Careful clinical appraisal remains the cornerstone of the assessment. Hematologic, biochemical, and radiological investigations are important aids in assessing the severity of infection. Microbiological assessment, particularly in more severe infection, requires good-quality samples, combined with rapid transport in an appropriate medium and effective communication with the laboratory. A focused, systematic approach to the accurate diagnosis and treatment of infection, combined with careful monitoring, ensures the maintenance of optimal management.

Wound dressings in diabetic foot disease.

Wound dressings represent a part of the management of diabetic foot ulceration. Ideally, dressings should alleviate symptoms, provide wound protection, and encourage healing. No single dressing fulfills all the requirements of a diabetic patient with an infected foot ulcer. Dressings research in this area is generally poor. However, each category of dressings has particular characteristics that aid selection. Nonadhesive dressings are simple, inexpensive, and well tolerated. Foam and alginate dressings are highly absorbent and effective for heavily exuding wounds. Hydrogels facilitate autolysis and may be beneficial in managing ulcers containing necrotic tissue. Dressings containing inidine and silver may aid in managing wound infection. Occlusive dressings should be avoided for infected wounds. All dressings require frequent change for wound inspection. Heavily exudating ulcers require frequent change to reduce maceration of surrounding skin. Dressing choice should be guided by the characteristics of the ulcer, the requirements of the patient, and costs.

Measurement of the skin microcirculation through intact bandages using laser Doppler flowmetry.

The microcirculation under compression bandages has been assessed by numerous methods; however, the measurement techniques can disrupt the bandage-skin interface, affecting the measurement. In this study, a non-invasive method for measuring cutaneous blood flow using laser Doppler flowmetry (LDF) is presented. Ten volunteers had their microcirculation assessed by a laser Doppler probe being placed on their upper forearm with and without a light-transmissive gel and with a compression bandage plus light-transmissive gel. A circulatory challenge to the bandaged forearm in two of the volunteers was also undertaken. The median (95% confidence interval) perfusion (p.u.) for the skin surface was 24 (15-33) perfusion units (p.u.), and the skin plus light-transmissive gel demonstrated a higher perfusion: 66 (50-82) p.u., (p < 0.012). The addition of the compression bandage, with additional gel allowed to permeate through to the underlying skin, decreased the perfusion to 27 (20-34) p.u. (p < 0.007). In both volunteers, the microcirculatory flow responded to the vascular challenge, resulting in flow changes related to the cuff pressure (45-27 and 14-8 p.u.). This method demonstrated that it may be possible to assess the microcirculation through intact bandages, without the need to place any sensors at the skin-bandage interface.