Effect of total contact cast in non‐healing diabetic foot ulcers in Lebanese patients

The aim of this study was to evaluate the effectiveness of total contact casting (TCC) in treating non‐healing diabetic foot ulcers in Lebanese diabetic patients. Twenty‐three diabetic patients were treated with TCC, and relevant data were collected retrospectively. Sixteen patients were analysed; the average duration of casting was 6 weeks, and 75% of the patients achieved complete ulcer closure without recurrence during one year of follow‐up and without any complications. TCC appears to be an effective treatment of diabetic foot ulcers.     

NPWT促进糖尿病足溃疡创面愈合分子机制的初步研究

目的通过检测与创面愈合进程相关的组织基因表达,探讨采用负压创面治疗(nagetive pressure wound therapy,NPWT),促进糖尿病足溃疡(diabetic foot ulcer, DFU)愈合的作用机制。方法将纳入的50例DFU患者随机分成NPWT组(25例)和对照组(25例)。对照组接受局部湿敷治疗。两组患者治疗前后10 d均取创面肉芽行组织活检,利用RT-PCR检测转移生长因子-β1(transforminggrowth factor beta 1, TGF-β1)、血管内皮生长因子(vascular endothelial growth factor, VEGF)、肿瘤坏死因子-α(tumor necrosis factor-α, TNF-α)、白介素-1β(interleukin-1β, IL-1β)、基质金属蛋白酶-1(matrix metalloproteinase-1, MMP-1)、基质金属蛋白酶-9(matrixmetalloproteinase-9, MMP-9)和基质金属蛋白酶抑制剂-1(tissue inhibitor of metalloproteinase-1, TIMP-1)的mRNA表达,并进行对比分析。结果治疗后10 d,NPWT组患者创面肉芽组织中VEGF、TGF-β1和TIMP-1 mRNA的表达较治疗前显著增加,IL-1β、TNF-α、MMP-1和MMP-9 mRNA的表达显著下降(P<0.05);而对照组上述各项指标的mRNA表达,治疗前后均无显著变化(P>0.05)。结论 NPWT可能通过影响生长因子、炎症细胞因子和基质金属蛋白酶的表达来促进DFU愈合。     

Ulcer‐free survival days and ulcer healing in patients with diabetic foot ulcers: A prospective cohort study

Healing rates may not give a complete indication of the effectiveness and management of diabetic foot ulcers because of high recurrence rates. The most important outcome for patients is remaining ulcer‐free; however, this has hardly been investigated. The aim of our study was to prospectively investigate ulcer‐free survival days and ulcer healing in patients with diabetic foot ulcers. This was a prospective cohort study of all referrals to our diabetic foot expertise centre from December 2014 to April 2017. Outcomes were determined after a minimum follow‐up period of 12 months. Primary outcomes were ulcer‐free survival days and 12‐month healing percentages. Predictors for ulcer‐free survival days and healing were investigated in multivariate analyses. A total of 158 patients were included. Median ulcer‐free survival days in the healed group were 233 days (interquartile range [IQR] 121‐312) and 131 days (IQR 0–298) in the overall population. The healing rate at 12‐month follow up was 67% (106/158), and the recurrence rate was 31% (33/106). Independent predictors of ulcer‐free survival days were duration of diabetes, peripheral artery disease (PAD), cardiovascular disease, end‐stage renal disease (ESRD), and infection. Ulcer‐free survival days are related to PAD and cardiovascular disease, and ulcer‐free survival days should be the main outcome when comparing the effectiveness of management and prevention of the diabetic foot ulcers.     

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

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.     

The effect of 22.5 kHz low‐frequency contact ultrasound debridement (LFCUD) on lower extremity wound healing for a vascular surgery population: A randomised controlled trial

The aim of this study was to compare changes in wound size and appearance and health complication rates in patients with vasculopathy and lower‐extremity wounds treated with or without low‐frequency contact ultrasound debridement (LFCUD) This study was a randomised controlled trial. The study was conducted in a vascular surgery service, including outpatient wound clinic and inpatient ward, in a tertiary care academic centre. In total, 70 patients with vasculopathy and lower‐extremity wounds of mixed aetiology were enrolled in the trial; 68 completed the study. Patients were randomised to receive LFCUD plus usual care (n = 33) or usual care (n = 37) at 4 weekly visits, and were followed thereafter for up to 12 wk. The main outcome measures included closed wounds, change in wound surface area (WSA), and wound appearance by the revised Photographic Wound Assessment Tool (revPWAT). After 4 weekly LFCUD treatments, patients in the LFCUD group had significantly better wound appearance (total revPWAT score) compared with the control group treated only with usual care (P = <0.05). LFCUD‐treated wounds also had a significant reduction in WSA over 4 wk that was not found in the UC group. LFCUD treatment was also associated with a greater number of healed wounds, odds ratio 5.00 (95% CI 1.24‐20.25), and fewer instances of wound deterioration. Weekly LFCUD applications to patients with significant vasculopathy resulted in superior healing outcomes when compared with current usual wound care practice.     

The efficacy of low‐frequency ultrasound as an added treatment for chronic wounds: A meta‐analysis

We performed a meta‐analysis to evaluate the effect of low‐frequency ultrasound as an added treatment for chronic wounds. A systematic literature search up to May 2022 was performed and 838 subjects with chronic wounds at the baseline of the studies; 412 of them were using the low‐frequency ultrasound (225 low‐frequency high‐intensity contact ultrasound for diabetic foot wound ulcers, and 187 low‐frequency low‐intensity non‐contact ultrasound for a venous leg wound ulcers), and 426 were using standard care (233 sharp debridements for diabetic foot wound ulcers and 193 sham treatments for venous leg wound ulcers). Odds ratio (OR), and mean difference (MD) with 95% confidence intervals (CIs) were calculated to assess the effect of low‐frequency ultrasound as an added treatment for chronic wounds using the dichotomous, and contentious methods with a random or fixed‐effect model. The low‐frequency high‐intensity contact ultrasound for diabetic foot wound ulcers had significantly lower non‐healed diabetic foot wound ulcers at ≥3 months (OR, 0.37; 95% CI, 0.24‐0.56, P < .001), a higher percentage of diabetic foot wound ulcers area reduction (MD, 17.18; 95% CI, 6.62‐27.85, P = .002) compared with sharp debridement for diabetic foot wound ulcers. The low‐frequency low‐intensity non‐contact ultrasound for a venous leg wound ulcers had a significantly lower non‐healed venous leg wound ulcers at ≥3 months (OR, 0.31; 95% CI, 0.15‐0.62, P = .001), and higher percentage venous leg wound ulcers area reduction (MD, 18.96; 95% CI, 2.36‐35.57, P = .03) compared with sham treatments for a venous leg wound ulcers. The low‐frequency ultrasound as an added treatment for diabetic foot wound ulcers and venous leg wound ulcers had significantly lower non‐healed chronic wound ulcers at ≥3 months, a higher percentage of chronic wound ulcers area reduction compared with standard care. The analysis of outcomes should be with caution because of the low sample size of all the 17 studies in the meta‐analysis and a low number of studies in certain comparisons.     

Efficacy and safety of recombinant human epidermal growth factor for diabetic foot ulcers: A systematic review and meta‐analysis of randomised controlled trials

To evaluate the efficacy and safety of recombinant human epidermal growth factor (rhEGF) in treating diabetic foot ulcers (DFUs), we conducted both database searches (PubMed, MEDLINE, EMBASE, CENTRAL, and Web of Science) and reference searches for randomised controlled trials from the inception of databases to 30 January 2020. Two reviewers independently scrutinised the trials, extracted data, and assessed the quality of trials. The primary outcome was the proportion of complete healing. The secondary outcomes were mean time to complete healing and adverse events. A subgroup analysis was performed by different administration routes. Statistical analyses were performed in RevMan 5.3. The time to complete healing Kaplan‐Meier curves was pooled in the R software. Of the 156 citations, 9 trials (720 participants) met eligibility criteria and were included. The rhEGF achieved a higher complete healing rate than placebo (OR: 2.79, [95% CI: 1.99, 3.99]). The rhEGF also significantly shorten complete healing time (MD: −14.10 days, [95% CI: −18.03, −10.16]). Subgroup analysis showed that topical application was superior to intralesional injection, but that may be because of different ulcer severity they included. No significant difference was shown in adverse events. Results were coherent with sensitivity analyses. Therefore, rhEGF is an effective and safe treatment for DFUs.     

Synergistic effect of low‐intensity pulsed ultrasound on growth factor stimulation of nucleus pulposus cells

Low‐intensity pulsed ultrasound (LIPUS) has been reported to stimulate the activity of various cells. We have reported that the capacity of human intervertebral nucleus pulposus cell line to synthesize proteoglycan (PG) was increased by exposure to LIPUS, and postulated that one of the mechanisms underlying this response was an increase in expression of the transforming growth factor‐β type I receptor gene (TGFβR1). Therefore, the present study was conducted to assess the synergistic effect of LIPUS and TGF‐β on nucleus pulposus cells harvested from canines. The cells were cultured under four different sets of conditions: control group (Group A), LIPUS group (Group B), TGF‐β1 group (Group C), and LIPUS + TGF‐β1 group (Group D). They were evaluated by measuring cell proliferation, PG synthesis, PG content, gene expression of TGFβR1, and TGF‐β1 concentration. There were no significant differences in proliferation during culture. However, PG synthesis and endogenous TGF‐β1 production increased and demonstrated a synergistic effect between LIPUS and TGF‐β. Because LIPUS is safe and noninvasive, the results of the present study suggest that it would be a promising new therapy for prevention of intervertebral disc degeneration, which is said to be one of the primary causes of low back pain. © 2007 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 25:1574–1581, 2007     

Effects of non contact low‐frequency ultrasound on healing of suspected deep tissue injury: a retrospective analysis

The purpose of this study was to assess the effectiveness of non contact low‐frequency ultrasound on the healing of suspected deep tissue injury (SDTI). Participants were adults ranging in age from 28 to 93 years old, with multiple diagnoses including anaemia, diabetes mellitus and hypertension. Data were examined retrospectively on 85 patients (intervention group = 43 and non intervention group = 42) with 127 SDTI (intervention group = 64 and non intervention group = 63). Participants in both groups received standard of care for treating pressure ulcers. A severity score was used to assess SDTI severity before treatment and healing/progression after treatment. This scale measures surface area, wound colour/tissue assessment, and skin integrity with potential scores of 3 to 18 (higher scores indicate greater severity). A significant difference in changes in wound severity was found (t = 5·67, P < 0.000). Difference in mean change scores was 2·52 on the 3–18 severity scale. The decrease in wound severity for the intervention group was 1·45. Severity in the non intervention group increased by 1·06. This exploratory study of the effect of the non contact low‐frequency ultrasound provides initial findings that support its use with SDTI.     

A single arm prospective feasibility study evaluating wound closure with a unique wearable device that provides intermittent plantar compression and offloading in the treatment of non‐healing diabetic foot ulcers

The incidence and economic burden of diabetic foot ulcers continues to rise throughout the world. In this prospective study, a unique device designed to offload the wound, enhance circulation and monitor patient compliance was evaluated for safety and efficacy. The device provides offloading and intermittent plantar compression to improve the pedal flow of oxygenated blood and support wound healing while recording patient use. Ten patients with non‐healing diabetic foot ulcers UTgrade 1A/Wagner grade 1 were treated weekly for up to 12 weeks. The primary endpoint was complete wound closure at 12 weeks, and secondary endpoints included healing time, percent area reduction and changes in pain using the visual analogue pain scale. Eight out of ten wounds healed within 12 weeks(80%), and the mean healing time was 41 days(95% CI:24.3–58.3). The percent area reduction was 75(SD:53.9). The baseline visual analogue pain scale was 4.5(2.9) as compared with 3.3(3.4) at end of study. No device‐related or serious adverse events were reported. This unique intermediate plantar compression and offloading device may be considered as an alternative for safe and effective for treatment of non‐healing diabetic foot ulcers. During treatment, wound healing was significantly accelerated, and pain was improved. Larger randomised controlled trials are underway to validate these early findings.     

Treatment of chronic diabetic lower extremity ulcers with advanced therapies: a prospective,randomised, controlled,multi‐centre comparative study examining clinical efficacy and cost

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 time‐to‐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.     

An exploratory clinical study on the safety and efficacy of an autologous fibroblast‐seeded artificial skin cultured with animal product‐free medium in patients with diabetic foot ulcers

Cultured dermal substitutes have been used for the treatment of chronic skin ulcers; however, the biological risks of animal‐derived materials in the culture process such as foetal bovine serum (FBS) have been reported. In this study, we prepared an autologous fibroblast‐seeded artificial dermis (AFD) using animal‐product‐free medium supplemented with 2% patient autologous serum and without any animal‐derived materials such as trypsin in the culturing process. We applied the AFD in five patients with diabetic ulcers and investigated its safety and efficacy. As the primary endpoint, we defined ‘wound bed improvement' according to the percentage of granulation area to the whole wound area on day 21, and 60% or higher was regarded as improved. The mean age of the patients was 60·6 years and the mean duration of the ulcer was 22·6 months. In the evaluation of the primary endpoint, the ‘wound bed’ was improved in all patients [proportion of improvement: 100%, 95% confidence interval (CI): 48% to 100%]. Three patients had complete wound healing within 12 weeks after application and two patients had >80% wound healing at 12 weeks. Side effects were not serious. Our AFD may be a safe and effective treatment of diabetic ulcers.     

Human amniotic membrane allograft,a novel treatment for chronic diabetic foot ulcers: A systematic review and meta‐analysis of randomised controlled trials

To evaluate the efficacy and safety of human amniotic membrane (HAM) allograft in treating chronic diabetic foot ulcers (DFUs), a comprehensive search of randomised controlled trials in MEDLINE, EMBASE, PubMed, CENTRAL and Web of Science was conducted to December 7, 2019. Two reviewers independently screened the studies, extracted data, and evaluated the quality of studies. The primary outcome was the proportion of complete healing. The secondary outcomes were mean time to complete healing and adverse events. Statistical analyses were performed using RevMan 5.3. We identified 257 articles, of which 7 articles (465 participants) were included in the meta‐analysis. The proportion of complete wound healing in HAM plus standard of care (SOC) group was 3.88 times as high as that in SOC alone (RR: 3.88 [95% CI: 2.34, 6.44]) at 6 weeks, and 2.01 times at 12 weeks (RR: 2.01 [95%CI: 1.45, 2.77]). The intervention group had a significantly shorter time to complete healing (MD: −30.33 days, [95% CI: −37.95, −22.72]). The number needed to treat within 6 weeks was 2.3 ([95% CI: 1.8, 3.1]). No significant difference was shown in adverse events. Results were consistent in a sensitivity analysis. Hence, HAM plus SOC is effective and safe in treating chronic DFUs.     

Nano‐hydrogel embedded with quercetin and oleic acid as a new formulation in the treatment of diabetic foot ulcer: A pilot study

Wound healing, especially diabetic ones, is a relevant clinical problem, so it is not surprising that surgical procedures are often needed. To overcome invasive procedures, several strategies with drugs or natural compound are used. Recently, in an experimental study, we described an increase in keratinocyte proliferation after their exposition to quercetin plus oleic acid. In the present clinical study, we evaluated both the clinical efficacy and the safety of nano‐hydrogel embedded with quercetin and oleic acid in the treatment of lower limb skin wound in patients with diabetes mellitus (DM). Fifty‐six DM patients (28 men and 28 women, mean age 61.7 ± 9.2 years) unsuccessfully treated with mechanical compression were enrolled and randomised to receive an add on treatment with hyaluronic acid (0.2%) or nano‐hydrogel embedded with quercetin and oleic acid. The treatment with nano‐hydrogel embedded with quercetin and oleic acid significantly (P < .01) reduced the wound healing time, in comparison to hyaluronic acid (0.2%) without developing of adverse drug reactions, suggesting that this formulation could be used in the management of wound healing even if other clinical trials must be performed in order to validate this observation.