A prospective, non comparative, multicenter study to investigate the effect of cadexomer iodine on bioburden load and other wound characteristics in diabetic foot ulcers

Abstract

Few studies regarding wound treatment with topical antimicrobials evaluate change in the bacterial bioburden of the wound with treatment. This study sought out to determine the in vivo effect of cadexomer iodine antibacterial dressing on diabetic foot ulcers (DFUs) that were infected or achieved a critical level of colonisation, looking specifically at wound progression in relation to bioburden. Fifteen patients corresponding to 16 total DFUs met criteria of displaying clinical signs of infection or critical colonisation and were suitable for a topical antibacterial dressing. They underwent weekly treatment for 6 weeks. Cultures were taken at week 0, 3 and 6 as appropriate. At week 6 median log₁₀ bacterial count reduction of 1.0 was observed from baseline (p = 0·025). At week 3‐ a median log₁₀ bacterial count reduction of 0.3 was observed from baseline (p = 0·049). Over the study period there was a 53.6% median reduction of the wound surface area. There were no patients that completely healed their ulcer over the 6 week study period. There was a statistically significant median reduction in the bacterial load over the 6 week period (p = 0·025) as well as 3 weeks (p = 0·049). This was accompanied by a median reduction of 53.6% in ulcer surface area and 50% in ulcer depth from baseline to final.

INTRODUCTION

Diabetes mellitus is increasing in prevalence worldwide, and is estimated to effect 300 million people by 2025 (1). Diabetics have many disease‐related comorbidities including diabetic foot ulcers (DFUs). These patients are prone to foot ulcers due to the combined effects of vascular disease and neuropathy. The lifetime risk of foot ulcers in diabetic patients appears to range from 15% to 25% (1). Individuals with DFUs not only have increased morbidity and mortality but their care represents a significant economic burden 1, 2, 3. In 1994, the cost per hospital admission in Cardiff, UK for an infected DFU cost £1451, which extrapolated to an annual national cost of £17 million (2). Similarly, in 1998 a study in the USA calculated the cost of treating DFU not requiring amputation to be as high as US $17 159 per year (1).

Delayed healing and infection are common problems with DFUs, which place these patients at a higher risk for osteomyelitis, gangrene and eventual limb amputation 4, 5, 6. Other authors note that wounds with >10⁵ microorganisms per gram of tissue may have impaired healing (7). Therefore, it is assumed that if the bacterial load is minimised then wounds will heal quicker and many of the complications of DFUs could be avoided (6). Biofilms may also be responsible for the chronicity of these wounds and for their common infectious complications 8, 9. Therefore, it is considered that suitable antimicrobial therapy is essential to decrease the bacterial load and treat infection (10). At present, identifying the level of bacterial contamination and the density and type of microorganism are crucial in providing appropriate treatment (10).

Wounds have been treated with iodine since the 1840s. Iodine was used extensively during the American Civil War to treat open wounds by bacteriostatic and bacteriocidal mechanisms (9). Iodine denatures proteins and inactivates enzymes, phospholipids and membrane structures (11). Cadexomer iodine is a novel delivery system in which the iodine is contained within a cadexomer starch bead that acts as a carrier and allows the slow, sustained release of iodine into the wound bed, to ensure a steady state of 0·9% iodine concentration at the wound bed 12, 13. The cadexomer starch forms a gel on contact with exudate, and this gel supports autolytic debridement and desloughing of the wound bed (12).

Clinical data on the use of iodine is extensive; however, the majority of these studies focus on chronic venous leg ulcers in patient populations exclusive of diabetics 11, 14, 15, 16. Diabetics display delayed healing and poor white cell function and in general have not been included in prior studies of topical antibacterials. The studies available mainly focus on wound closure rate of non diabetics independent of the bioburden of the wounds (17).

Taken as a whole, the majority of data available in regards to topical antimicrobials is not in vivo. When it is clinical, it is of poor quality with very few studies assessing actual bioburden. Instead, most use wound closure rate as a surrogate marker. One of the only agents that has been appropriately studied for its actual in vivo effect is cadexomer iodine. Iodine has been shown to significantly decrease the bioburden of Staphylococcus aureus in venous stasis ulcers over 6 weeks 18, 19.

STUDY DESIGN

Therefore, we decided to undertake a prospective, longitudinal cohort study, which examined the in vivo reduction of microbial load within DFUs after debridement and treatment with cadexomer iodine. Reduction of quantitative wound bioburden was our primary assessment. Secondary assessments included change in ulcer surface area, ulcer depth, clinical infectious appearance, varying wound bed tissue types, character of surrounding skin and time to resolution of clinical infection/colonisation. Two forms of cadexomer iodine were employed as the treatment. Study participants were recruited from two tertiary medical centres in the USA.

METHODS

We initiated a hospital sponsored and institutional review board approved clinical protocol. The trial was performed according to the Helsinki Declaration and its revisions. All study participants provided written, informed consent prior to commencing their participation in the study and were allowed to withdraw at their discretion.

Inclusion criteria

Individuals were eligible for the study if they had a DFU with visible signs of a localised clinical infection (which is well defined in the literature as delayed healing, pain/tenderness, increased serous exudate, change in colour of the wound bed, friable, absent or abnormal granulation tissue, pus and odour) 3, 7 or critical colonisation (when the bacterial burden in the wound is intermediate between the categories of colonisation and infection, without exhibiting classic signs of infection) 7, 20. All considered had a DFU grade I or II according to the Meggitt–Wagner scale, had a DFU that was suitable to be dressed with cadexomer iodine, and had at least dopplerable pedal pulses.

Exclusion criteria

Individuals were excluded from the study if they had a known sensitivity to iodine or any of the ingredients of the dressing, had a history of thyroid disorders, had renal impairment (Creatinine clearance of <80 ml/min), were currently taking Lithium, had ≥ Grade III DFU on the Meggitt–Wagner scale, had a wound <2 cm in diameter, had an ulcer that was not exuding, had recent treatment with cadexomer iodine or other topical antibacterials in the last 30 days or recent treatment with antimicrobials.

Any participant that interrupted the treatment regimen for >7 days was withdrawn from the study. Individuals that did not respond to the treatment or who were no longer suitable to receive the therapy were withdrawn from the study only when necessary based on clinical grounds. Those who dropped out, who were withdrawn from the evaluation (except for those withdrawn due to worsening condition of the study ulcer) or who were non evaluable patients were replaced to ensure that 14 evaluable patients completed the study. Participants who dropped out or who were withdrawn were not re‐entered into the evaluation at a later date. All those eligible for inclusion into the study were assigned to the same dressing regime with cadexomer iodine. The duration of therapy was 6 weeks, or until wound closure.

Treatment protocol

Participants were observed for 6 weeks from their study commencement. The initial visit consisted of determination of eligibility, informed consent process, reference ulcer assessment, determination of infection, photographing the DFU, tracing and depth measurement, and punch biopsy. The punch biopsy was performed with a 3 mm punch, to 5 mm in depth at the epithelial margin most representative of the general wound bed. Initial labs investigated for renal impairment and pregnancy status of childbearing aged women. Ulcer assessment, surrounding skin assessment, photographs, wound tracing and depth, dressing application, possible use of and reason to use a secondary dressing were all recorded at interim visits on weeks 1, 2, 3, 4 and 5. At week 3, an interim study biopsy was taken, and at week 6 a final biopsy was taken. These biopsieswere performed immediately adjacent to the previous biopsy sites. All wounds were debrided at each visit prior to placement of the new dressing. A premature biopsy of the DFU was taken at week 4 or 5 if it was thought to possibly heal prior to final study visit on week 6.

Data collection and measures

Data was collected at recruitment and weekly for the DFU in the study. The study was designed to enrol a total of 16 infected DFUs, as an intent to treat analysis.

The primary outcome measure was to quantify the reduction of microbial load within these DFU after debridement and treatment with cadexomer iodine over a 6‐week period. Quantitative cultures were performed using tissue from the above biopsies – a 0·1 g sample of this tissue was placed in a 30 ml polypropylene container and stored at room temperature. Using sterile forceps or a sterile swab, this sample was removed from the container and ground in a sterile pestle, then placed in a clean Petri dish. Care was taken not to expose the tissue to long periods of air contamination. One millilitre of thioglycollate broth was then placed in the tube and the tissue was reground, and then streaked onto the medium. In addition, both the thioglycollate and the chopped meat glucose (CMG) broth were inoculated using the same loop. The plates were then incubated at 35–37°C for 48 hours. Following incubation, the number of colonies that grew for each organism was counted and the cfu/g for that colony was calculated. If no growth was noted at 5 days, the specimen was considered to be sterile.

Secondary outcomes evaluated were change in ulcer surface area, depth, varying wound bed tissue types, character of surrounding skin and time to resolution of clinical infection/colonisation over the 6‐week treatment period. Clinical infection or critical colonisation was defined as the presence of malodor, localised ulcer pain between dressing changes, local oedema, local erythema, presence of purulent exudate, presence of friable granulation tissue, increased temperature or delayed healing (21). These were graded by the principal investigator and were not blinded in any fashion.

The ulcer surface area and depth was recorded by study personnel using Visitrak® (Smith & Nephew, Hull, UK) grids and Visitrak® depth, respectively. The investigator at each site commented on the wound bed tissue types, character of the surrounding skin, and whether the DFU appeared to be clinically infected; using well‐known criteria including presence of necrotic debris, friable granulation tissue, wound breakdown, foul odour and oedema with serous exudate 9, 22.

Treatment protocol

Participants were observed for 6 weeks from their study commencement. The initial visit consisted of determination of eligibility, informed consent process, reference ulcer assessment, determination of infection, photographing the DFU, tracing and depth measurement, and punch biopsy. The punch biopsy was performed with a 3 mm punch, to 5 mm in depth at the epithelial margin most representative of the general wound bed. Initial labs investigated for renal impairment and pregnancy status of childbearing aged women. Ulcer assessment, surrounding skin assessment, photographs, wound tracing and depth, dressing application, possible use of and reason to use a secondary dressing were all recorded at interim visits on weeks 1, 2, 3, 4 and 5. At week 3, an interim study biopsy was taken, and at week 6 a final biopsy was taken. These biopsies were performed immediately adjacent to the previous biopsy sites. All wounds were debrided at each visit prior to placement of the new dressing. A premature biopsy of the DFU was taken at week 4 or 5 if it was thought to possibly heal prior to final study visit on week 6.

Statistics

The following six analysis sets were used in this study; full analysis set – all patients (intent to treat) with a baseline assessment that had an application of cadexomer iodine. The safety analysis set was the same as the full analysis set. The primary analysis set (for week 3) consisted of all patients that had an application of cadexomer iodine and had biopsies taken at weeks 0 and 3 and if the biopsy was missing at week 3, this was due to either healing of the ulcer or due to the patient withdrawing from the study due to the ulcer condition worsening. If patients were missing for other reasons, they were not included in the analysis. The primary analysis set (for week 6) was similar to the primary analysis set for week 3 but for biopsies taken as week 0 and 6. Finally (for week 3), all patients that had an application of cadexomer iodine and had a biopsy recorded at week 3 were used for a sensitivity analysis of the reduction in log₁₀ bacterial count at week 3 (i.e. only patients that have biopsy data at weeks 0 and 3). A similar application was used for week 6 data. The full and safety analysis sets contained 15 patients with 16 wounds, the primary analysis set at week 3 had 13 patients with 14 wounds, the primary analysis set at week 6 also had 13 patients with 14 wounds, the sensitivity analysis set at week 3 had had 12 patients with 13 wounds and the sensitivity analysis set at week 6 had 10 patients with 11 wounds.

A McNemars χ ² test was used to evaluate the primary and secondary endpoints longitudinally across the duration of the study. Wilcoxon signed‐rank test with Hodges–Lehmann estimates were used to determine significance of reduction in bioburden from baseline, as well as the secondary endpoint changes; at both 3 and 6 weeks. Sensitivity analysis was carried out as noted above. All statistical analysis was carried out using SAS software package 9.1 (Cary, NC).

RESULTS

The trial consisted of 15 participants representing 16 wounds. Three patients were withdrawn early from the study, they all had non wound associated serious adverse events (respiratory failure after a traumatic fall, urosepsis and a calcaneal fracture). Therefore, a total of 12 participants representing 13 ulcers successfully completed the study. There were no substitutions of patients.

The study population (n = 15) of individuals recruited had a gender distribution of 11 (68·8%) males and 5 (31·1%) females. The mean age was 56 years (range 41–72 years). There were 5 ulcers (31%) classified as Wagner grade I, and 11 ulcers (69%) classified as Wagner grade II. The overall median duration of the patients' ulcer being treated was 39 weeks (SD = 75 weeks). The median surface area of the wounds was 2·7 cm²(SD = 6·9 cm). One patient had diabetes type I (6·3%) and 15 patients had diabetes type II (93·8%). The location and characteristics of the DFU are listed in Table 1. The mean duration of diabetes was 18·2 years. All participants with diabetes were being treated, 11 (68·8%) used insulin, 8 (50%) used oral treatment and 1 (6·3%) was diet controlled.

Table 1.

Diabetic foot ulcers (DFU) characteristics

Location of reference ulcer
Metatarsal head	8 (50%)
Midfoot	4 (25%)
Heel	2 (12·5%)
Dorsal	1 (6·3%)
Great toe	1 (6·3%)
Wagner Grade of reference ulcer
Grade 1	5 (31·3%)
Grade 2	11 (68·8%)
Duration of current ulcer (weeks)
Median	39
Size of ulcer
Median ulcer area (cm2)	2·7
Median ulcer depth (cm)	0·4

Dressings were changed on an average of 8 times/week (range 5–16 times/week). All 15 patients (100%) attended at baseline and assessment 1. Fifteen participants with DFUs (93·8%) were assessed at study visits 2 and 4, with only 14 patients (87·5%) evaluated at visit 3 and 5. Thirteen patients with DFU (81·3%) were evaluated at assessment 6.

Wound microflora

There were a total of 16 biopsies taken at initial study visit. Thirteen different aerobes were isolated at baseline. The most common initial wound microflora was Methicillin‐resistant S. aureus (29·4%) followed by Pseudomonas aeruginosa (11·8%). Additional microflora was present less frequently in the remaining DFUs included in the study (Figure 1).

Figure 1.

Additional microflora was present in a smaller amount of diabetic foot ulcers (DFU). Each wound had multiple microflorae present.

Primary assessment

At initial screening, the mean log₁₀ total bacterial count was 5·2 cfu/g (3·8–5·9 cfu/g). At 6 weeks, a median log₁₀ bacterial count reduction of 1·0 was observed from baseline and was found to be statistically significant (P = 0·025). A log₁₀ bacterial count reduction of 0·3 was observed from baseline to 3 weeks, which was also statistically significant (P = 0·049). One patient was lost to follow‐up but ulcer area had decreased from 2·64cm² to 1·79 cm² at the final visit. Another participant had a biopsy at baseline and week 1 but discontinued following an unrelated adverse event.

Secondary assessments

Reduction in ulcer surface area

The mean ulcer area at baseline was 5·9 cm² (median = 2·7 cm²). There was a median ulcer area reduction of 2 cm² observed over all patients corresponding to a 53·6% reduction in surface area from baseline to final assessment. DFU that were ≤2·7 cm² at baseline decreased in size by a median of 81·7%, whereas those that were >2·7 cm² decreased by a median of 27·3% (Figure 2). There was a median ulcer surface area reduction of 58·8% in ulcers that were deemed ‘clinically’ infected at baseline and a median of 43·1% in ulcers that were not deemed critically colonised at baseline (P = 0·918). There was a median reduction in wound surface area from baseline to 6 weeks of 45·5% for patients with a log₁₀ count at baseline ≤ median (= 5·5 cfu/g) and a median of 64·5% for patients with a log₁₀ count at baseline > median (= 5·5 cfu/g). There was a notable reduction in ulcer surface areas of 78·6% for patients who had their reference ulcer for ≤ median duration (= 39 weeks old) compared to a median reduction of 45·8% in patients who had the DFU for > median duration (P = 1). No ulcers completely healed by the end of the 6‐week study period.

Figure 2.

Reduction in the diabetic foot ulcers (DFU) surface area. (A) Initial study visit patient A, (B) 6‐week study visit patient A, (C) Initial study visit patient B and (D) 5‐week study visit patient B.

Reduction in ulcer depth

There was a median ulcer depth reduction of 0·2 cm observed over all patients, corresponding to a decrease in depth of 50% from baseline to final. DFU that were ≤0·4 cm (= median ulcer depth at baseline) reduced by 33·3%, whereas ulcers that were >0·4 cm reduced by 60% (Figure 3). There was a median ulcer depth reduction of 50% in ulcers that were ‘clinically’ infected at baseline and a median of 25% in ulcers that were not ‘clinically’ infected at baseline (P = 0·119). There was a median reduction in ulcer depth from baseline to 6 weeks of 39·3% for patients with a log₁₀ count at baseline ≤ median (= 5·5 cfu/g) and a median of 50% for patients with a log₁₀ count at baseline > median (= 5·5 cfu/g). There was a reduction in ulcer depth of 55% for patients who had their reference ulcer for ≤ median duration (= 39 weeks old) compared to a median reduction of 41·7% in patients who had ulcers for > median duration (P = 0·442).

Figure 3.

Reduction in the diabetic foot ulcers (DFU) depth. (A) Initial study visit, (B) 6‐week study visit.

Presence of infection

Seven patients (43·8%) that originally had a ‘clinically’ infected ulcer at baseline no longer had a ‘clinical’ infection at the end of the study (Figure 4). There were two patients (12·5%) that appeared to remain ‘clinically’ infected at the study completion. Seven patients (43·8%) remained non infected from a clinical standpoint for the entire study period. There were no patients that transitioned from a non infected ulcer to an infected ulcer at the end of the study. A McNemars test provided significant evidence of a reduction in the signs of ‘clinical’ infection from baseline to final assessment (P = 0·008).

Figure 4.

Reduction in appearance of clinical infection. (A) Initial study visit, (B) 6‐week study visit.

Additional secondary assessments

The ulcers' appearance notably changed throughout the treatment period with cadexomer iodine. The percentage of beefy red tissue increased from a median of 55% to a median of 85% at the conclusion of the trial. There was a median of 60% healthy tissue (a combination of the % pink epithelial and % beefy red granulation tissue) noted at baseline and this increased to 90% at final assessment, P = 0·052, which represents a marginally statistically significant increase in healthy tissue from baseline to the final assessment. The percentage of dull red tissue decreased from baseline, and there was no longer any friable granulation tissue at the completion of the study. The level of exudate decreased in five patients, remained unchanged in ten patients and increased in one patient. Patients' pain level associated with their DFU was recorded at baseline for 10 of the 15 participants. Those 10 participants had their pain tracked throughout the study. Five patients had decreased pain with treatment, four patients experienced no change and one patient had a mild to moderate increase in pain. The other five patients, corresponding to six DFUs, did not have pain at the start or completion of the study. Cadexomer iodine dressing was found to be easy to apply and change without contributing to much pain.

DISCUSSION

Our primary objective was to assess the in vivo effect of cadexomer iodine treatment on bioburden in DFUs that were infected, expressed clinical signs of infection or displayed critical colonisation. Secondary assessments included evaluating the effect that cadexomer iodine has on DFU surface area, depth, clinical infection, wound bed appearance, level of exudate, ease of dressing application and patients' associated DFU pain level.

Our data reveals that cadexomer iodine was able to achieve a statistically significant reduction in DFU bioburden from baseline to study completion, which supports the use of cadexomer iodine as a treatment to reduce the bacterial counts in DFU. The reduction in bioburden from ulcer baseline was also found to be statistically significant at the 3‐week study period, although not as striking as after 6 weeks of treatment. Placed in other terms, the median bacterial reduction was 89·2% from baseline to week 6 and 46·2% from baseline to week 3. This is the first study that we know of that has evaluated the actual in vivo effect of cadexomer iodine on the bioburden of a DFU. We presume that if the bioburden is minimal the DFU will have more favourable healing progression, and the other DFU variables examined should improve relative to the decreased level of bioburden.

Secondary assessments

Reduction in ulcer surface area, depth and infection

All of the participants' DFUs reduced in surface area and depth by the completion of the 6‐week study period (or the final study visit). The smaller ulcers at baseline appeared to have more success with wound contraction than the larger ulcers. However, since we were measuring the surface area reduction in terms of percentage, it makes sense that the smaller ulcers would have a higher percentage of surface area reduction as the same size decrease in surface area would proportionally calculate to a much larger percentage when evaluating the smaller DFU. Wounds that appeared ‘clinically’ infected at baseline had a slightly better reduction in surface area and depth than those that were not infected. This may be due to more infected appearing wounds having a greater proportion of the healing inhibited by bacterial burden than less infected appearing wounds. Therefore, the ‘clinically’ infected wounds were in more need of bioburden control. In support of this theory, the DFUs with a greater than median log₁₀ bacterial count at baseline had more success in reducing the surface area and depth than those below the median log₁₀ bacterial count at baseline 7, 20. This again highlights the relationship between bioburden on wound closure.

Cadexomer iodine was also successful in clearing up ‘clinically’ infected ulcers. This too is likely related to the decreased bioburden evident at the 3 and 6‐week study periods. Seven patients (43·8%) that had ‘clinically’ infected ulcers at baseline no longer had a ‘clinical’ infection at the conclusion of the study. Two patients (12·5%) continued to have ‘clinically’ infected ulcers throughout the study, but no patients went from being non infected to ‘clinically’ infected.

Additional secondary assessments

Cadexomer iodine improved the appearance of the wound bed throughout the study period. Dull red tissue and friable granulation tissue are obstacles to wound healing. It is well known that wounds must have a well‐vascularised wound bed, must be free of infection, fibrinous material, scarring and excess exudate in order to progress towards healing and resolution (7). From a visual standpoint it would appear that cadexomer iodine effectively prepared the wound bed in the majority of cases. In addition, while we did not assess the contents of the wound fluid in this study, it has been noted that DFU wound fluid is high in proteases and it is thought that these fluid inhibit wound closure (7), the cadexomer iodine had variable effects on the level of exudate that the DFU expressed. Finally, ulcer pain, which is thought to be a surrogate marker in the diabetic for bacterial invasion, was down regulated or at minimum maintained in all patients.

Cadexomer iodine product

The participants were treated with two different forms of cadexomer iodine in this study. IODOSORB™ (Smith & Nephew) is a gel application of cadexomer iodine, while IODOFLEX™ (Smith & Nephew) is an absorbable pad that is capable of removing exudate while providing cadexomer iodine to the wound bed. Gel treatment was applied at 70 assessments overall (77·8%) and absorbable cadexomer iodine impregnated pad treatment was applied at 20 assessments (22·2%). There was no statistical difference noted between participants that were treated with the different preparations of cadexomer iodine across all of our data points, and therefore we have not differentiated between the results in this study.

Of note, this dressing is indicated to be replaced every 72 hours or as needed, however, the participants in our study had more frequent dressing changes. Many of the patients enrolled resided in nursing home facilities or were seen at home by visiting nurses that were accustomed to doing daily dressing changes and continued to do so throughout the study. We do not believe that the study patients necessarily needed daily dressing changes, but received them due to independent nursing practices.

Safety

There were two adverse events across 15 patients, and 1 patient was lost to follow‐up prior to study completion. The two adverse events were not related to the study material. Both patients were admitted to the hospital for treatment, and the conditions resolved.

STUDY LIMITATIONS

A main disadvantage of this study is the small sample size, and its lack of a control arm. Ideally, a larger study with two statistically powered arms to show a 20% difference in bacterial kill could be designed. However, funding for such a trial may be hard to secure. In addition, monitoring the patients for a longer time interval would be beneficial. However, most patients dropped below the critical 10⁵ bacterial level, which would indicate that they should proceed to an adjunctive wound closure arm. None of the participants with DFUs enrolled achieved complete wound closure by the end of the 6‐week study period. It would be interesting to see if the wounds progressed to closure with treatment or if they hit a plateau.

In addition, we did not interrogate the biofilm status of the DFU. This could be another potential barrier to wound resolution, and needs to be evaluated further (8). However, to date there have been no such in human studies done. While iodine has been compared to other wound treatments in the past, it has never been analysed and compared for success of decreasing wound bioburden and biofilm in DFU.

STUDY RECOMMENDATIONS AND CONCLUSIONS

Too many studies of antimicrobial dressings do not assess the bacterial effect in vivo. This study provides the first evaluation of the effect of cadexomer iodine on bioburden reduction of DFUs.

After obtaining and analysing our data, we propose an algorithm designed to decrease the bioburden and ultimately heal difficult to treat DFU. Initial treatment is pressure off‐loading and mechanical (sharp) debridement to remove necrotic debris and decrease the bioburden (and potential biofilm) of the wound. After sharp debridement follows application of daily or every other day topical antibacterial to the DFU. The ideal properties of the topical preparation are proven antibacterial efficacy (ideally against biofilms as well), wound fluid absorption, maintenance debridement and balancing of wound environment.

ACKNOWLEDGEMENTS

We acknowledge the financial support of Smith & Nephew (Hull, UK). This material is the result of work supported with resources and the use of facilities at the Bay Pines VA Healthcare System. The contents of this paper do not represent the views of the Department of Veterans Affairs or the United States Government.