Our purpose was to compare healing characteristics of diabetic foot ulcers treated with dehydrated human amniotic membrane allografts (EpiFix®, MiMedx, Kennesaw, GA) versus standard of care. An IRB-approved, prospective, randomised, single-centre clinical trial was performed. Included were patients with a diabetic foot ulcer of at least 4-week duration without infection having adequate arterial perfusion. Patients were randomised to receive standard care alone or standard care with the addition of EpiFix. Wound size reduction and rates of complete healing after 4 and 6 weeks were evaluated. In the standard care group (n = 12) and the EpiFix group (n = 13) wounds reduced in size by a mean of 32·0% ± 47·3% versus 97·1% ± 7·0% (P < 0·001) after 4 weeks, whereas at 6 weeks wounds were reduced by −1·8% ± 70·3% versus 98·4% ± 5·8% (P < 0·001), standard care versus EpiFix, respectively. After 4 and 6 weeks of treatment the overall healing rate with application of EpiFix was shown to be 77% and 92%, respectively, whereas standard care healed 0% and 8% of the wounds (P < 0·001), respectively. Patients treated with EpiFix achieved superior healing rates over standard treatment alone. These results show that using EpiFix in addition to standard care is efficacious for wound healing.

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Objective: High bacterial load contributes to chronicity of wounds and is diagnosed based on assessment of clinical signs and symptoms (CSS) of infection, but these characteristics are poor predictors of bacterial burden. Point-of-care fluorescence imaging (FL) MolecuLight i:X can improve identification of wounds with high bacterial burden (>10 4 colony-forming unit [CFU]/g). FL detects bacteria, whether planktonic or in biofilm, but does not distinguish between the two. In this study, diagnostic accuracy of FL was compared to CSS during routine wound assessment. Postassessment, clinicians were surveyed to assess impact of FL on treatment plan. Approach: A prospective multicenter controlled study was conducted by 20 study clinicians from 14 outpatient advanced wound care centers across the United States. Wounds underwent assessment for CSS followed by FL. Biopsies were collected to confirm total bacterial load. Three hundred fifty patients completed the study (138 diabetic foot ulcers, 106 venous leg ulcers, 60 surgical sites, 22 pressure ulcers, and 24 others). Results: Around 287/350 wounds (82%) had bacterial loads >10 4 CFU/g, and CSS missed detection of 85% of these wounds. FL significantly increased detection of bacteria (>10 4 CFU/g) by fourfold, and this was consistent across wound types ( p < 0.001). Specificity of CSS+FL remained comparably high to CSS ( p = 1.0). FL information modified treatment plans (69% of wounds), influenced wound bed preparation (85%), and improved overall patient care (90%) as reported by study clinicians. Innovation: This novel noncontact, handheld FL device provides immediate, objective information on presence, location, and load of bacteria at point of care. Conclusion: Use of FL facilitates adherence to clinical guidelines recommending prompt detection and removal of bacterial burden to reduce wound infection and facilitate healing.

Advanced therapies such as bioengineered skin substitutes (BSS) and dehydrated human amnion/chorion membrane (dHACM) have been shown to promote healing of chronic diabetic ulcers. An interim analysis of data from 60 patients enrolled in a prospective, randomised, controlled, parallel group, multi-centre clinical trial showed that dHACM (EpiFix ® , MiMedx Group Inc., Marietta, GA) is superior to standard wound care (SWC) and BSS (Apligraf ® , Organogenesis, Inc., Canton, MA) in achieving complete wound closure within 4-6 weeks. Rates and time to closure at a longer time interval and factors influencing outcomes remained unassessed; therefore, the study was continued in order to achieve at least 100 patients. With the larger cohort, we compare clinical outcomes at 12 weeks in 100 patients with chronic lower extremity diabetic ulcers treated with weekly applications of Apligraf (n = 33), EpiFix (n = 32) or SWC (n = 35) with collagen-alginate dressing as controls. A Cox regression was performed to analyse the time to heal within 12 weeks, adjusting for all significant covariates. A Kaplan-Meier analysis was conducted to compare timeto-heal within 12 weeks for the three treatment groups. Clinical characteristics were well matched across study groups. The proportion of wounds achieving complete closure within the 12-week study period were 73% (24/33), 97% (31/32), and 51% (18/35) for Apligraf, EpiFix and SWC, respectively (adjusted P = 0⋅00019). Subjects treated with EpiFix had a very significant higher probability of their wounds healing [hazard ratio (HR: 5⋅66; adjusted P: 1⋅3 x 10−7 ] compared to SWC alone. No difference in probability of healing was observed for the Apligraf and SWC groups. Patients treated with Apligraf were less likely to heal than those treated with EpiFix [HR: 0⋅30; 95% confidence interval (CI): 0⋅17-0⋅54; unadjusted P: 5⋅8 x 10−5 ]. Increased wound size and presence of hypertension were significant factors that influenced healing. Mean time-to-heal within 12 weeks was 47⋅9 days (95% CI: 38⋅2-57⋅7) with Apligraf, 23⋅6 days (95% CI: 17⋅0-30⋅2) with EpiFix group and 57⋅4 days (95%CI: 48⋅2-66⋅6) with the SWC alone group (adjusted P = 3⋅2 x 10 −7 ). Median number of grafts used per healed wound were six (range 1-13) and 2⋅5 (range 1-12) for the Apligraf and EpiFix groups, respectively. Median graft cost was $8918 (range $1,486-19,323) per healed wound for the Apligraf group and $1,517 (range $434-25,710) per healed wound in the EpiFix group (P < 0⋅0001). These results provide further evidence of the clinical and resource utilisation superiority of EpiFix compared to Apligraf for the treatment of lower extremity diabetic wounds. 272

A prospective, randomised, controlled, multi-centre comparative effectiveness study of healing using dehydrated human amnion/chorion membrane allograft, bioengineered skin substitute or standard of care for treatment of chronic lower extremity diabetic ulcers Zelen CM, Gould L, Serena TE, Carter MJ, Keller J, Li WW. A prospective, randomised, controlled, multi-centre comparative effectiveness study of healing using dehydrated human amnion/chorion membrane allograft, bioengineered skin substitute or standard of care for treatment of chronic lower extremity diabetic ulcers. Int Wound J 2015; 12:724-732 AbstractA prospective, randomised, controlled, parallel group, multi-centre clinical trial was conducted at three sites to compare the healing effectiveness of treatment of chronic lower extremity diabetic ulcers with either weekly applications of Apligraf ® (Organogenesis, Inc., Canton, MA), EpiFix ® (MiMedx Group, Inc., Marietta, GA), or standard wound care with collagen-alginate dressing. The primary study outcome was the percent change in complete wound healing after 4 and 6 weeks of treatment. Secondary outcomes included percent change in wound area per week, velocity of wound closure and a calculation of the amount and cost of Apligraf or EpiFix used. A total of 65 subjects entered the 2-week run-in period and 60 were randomised (20 per group). The proportion of patients in the EpiFix group achieving complete wound closure within 4 and 6 weeks was 85% and 95%, significantly higher (all adjusted P-values ≤ 0⋅003) than for patients receiving Apligraf (35% and 45%), or standard care (30% and 35%). After 1 week, wounds treated with EpiFix had reduced in area by 83⋅5% compared with 53⋅1% for wounds treated with Apligraf. Median time to healing was significantly faster (all adjusted P-values ≤0⋅001) with EpiFix (13 days) compared to Apligraf (49 days) or standard care (49 days). The mean number of grafts used and the graft cost per patient were lower in the EpiFix group campared to the Apligraf group, at 2⋅15 grafts at a cost of $1669 versus 6⋅2 grafts at a cost of $9216, respectively. The results of this study demonstrate the clinical and resource utilisation superiority of EpiFix compared to Apligraf or standard of care, for the treatment of diabetic ulcers of the lower extremities. IntroductionDiabetes and its associated morbidities are a growing problem, negatively impacting populations throughout the world and imposing severe financial burdens on healthcare resources.Worldwide, 285 million people or approximately 6⋅4% of the world's population is estimated to have diabetes and these numbers are expected to increase to 7⋅7% and 439 million adults by 2030 (1). In 2012, more than 22⋅3 million people in 724

An advisory panel of academicians, private practice physicians, podiatrists, nurse clinicians, research nurses, industrial scientists, and an epidemiologist was chosen to develop guidelines for the treatment of venous ulcers of the lower extremity. METHODSPrevious guidelines, meta-analyses, PubMed, MEDLINE, EMBASE, The Cochrane Database of Systematic Reviews, recent review articles of venous ulcer treatment, and the Medicare/CMS consensus of usual treatment of chronic wounds were all reviewed for evidence. Guidelines were formulated, the underlying principle(s) enumerated, and evidence references listed and coded. The code abbreviations for the evidence citations were as follows: There were major differences between our approach to evidence citations and past approaches to evidence-based guidelines. Most past approaches relied only on publications regarding clinical human studies. Laboratory or animal studies were not cited. We have used wellcontrolled animal studies that present proof of principle, especially when a clinical series corroborated the laboratory results. It was also clear that principles that have been validated for other chronic wound types often are applicable to venous ulcers. Therefore, evidence was sometimes cited that was not specific for venous ulcers.

BackgroundVenous leg ulcers can be very hard to heal and represent a significant medical need with no effective therapeutic treatment currently available.Principal FindingsIn wound edge biopsies from human venous leg ulcers we found a striking upregulation of dermal N-cadherin, Zonula Occludens-1 and the gap junction protein Connexin43 (Cx43) compared to intact skin, and in stark contrast to the down-regulation of Cx43 expression seen in acute, healing wounds. We targeted the expression of these proteins in 3T3 fibroblasts to evaluate their role in venous leg ulcers healing. Knockdown of Cx43 and N-cadherin, but not Zonula Occludens-1, accelerated cell migration in a scratch wound-healing assay. Reducing Cx43 increased Golgi reorientation, whilst decreasing cell adhesion and proliferation. Furthermore, Connexin43 and N-cadherin knockdown led to profound effects on fibroblast cytoskeletal dynamics after scratch-wounding. The cells exhibited longer lamelipodial protrusions lacking the F-actin belt seen at the leading edge in wounded control cells. This phenotype was accompanied by augmented activation of Rac-1 and RhoA GTPases, as revealed by Förster Resonance Energy Transfer and pull down experiments.ConclusionsCx43 and N-cadherin are potential therapeutic targets in the promotion of healing of venous leg ulcers, by acting at least in part through distinct contributions of cell adhesion, migration, proliferation and cytoskeletal dynamics.

This cross‐sectional international survey assessed patients’ perceptions of their wound pain. A total of 2018 patients (57% female) from 15 different countries with a mean age of 68·6 years (SD = 15·4) participated. The wounds were categorised into ten different types with a mean wound duration of 19·6 months (SD = 51·8). For 2018 patients, 3361 dressings/compression systems were being used, with antimicrobials being reported most frequently (n= 605). Frequency of wound‐related pain was reported as 32·2%, ‘never’ or ‘rarely’, 31·1%, ‘quite often’ and 36·6%, ‘most’ or ‘all of the time’, with venous and arterial ulcers associated with more frequent pain (P= 0·002). All patients reported that ‘the wound itself’ was the most painful location (n= 1840). When asked if they experienced dressing‐related pain, 286 (14·7%) replied ‘most of the time’ and 334 (17·2%) reported pain ‘all of the time’; venous, mixed and arterial ulcers were associated with more frequent pain at dressing change (P < 0·001). Eight hundred and twelve (40·2%) patients reported that it took <1 hour for the pain to subside after a dressing change, for 449 (22·2%) it took 1–2 hours, for 192 (9·5%) it took 3–5 hours and for 154 (7·6%) patients it took more than 5 hours. Pain intensity was measured using a visual analogue scale (VAS) (0–100) giving a mean score of 44·5 (SD = 30·5, n= 1981). Of the 1141 who reported that they generally took pain relief, 21% indicated that they did not feel it was effective. Patients were asked to rate six symptoms associated with living with a chronic wound; ‘pain’ was given the highest mean score of 3·1 (n= 1898). In terms of different types of daily activities, ‘overdoing things’ was associated with the highest mean score (mean = 2·6, n= 1916). During the stages of the dressing change procedure; ‘touching/handling the wound’ was given the highest mean score of 2·9, followed by cleansing and dressing removal (n= 1944). One thousand four hundred and eighty‐five (80·15%) patients responded that they liked to be actively involved in their dressing changes, 1141 (58·15%) responded that they were concerned about the long‐term side‐effects of medication, 790 (40·3%) of patient indicated that the pain at dressing change was the worst part of living with a wound. This study adds substantially to our knowledge of how patients experience wound pain and gives us the opportunity to explore cultural differences in more detail.