Efficacy and safety of autologous whole blood clot in diabetic foot ulcers: a randomised controlled trial.

OBJECTIVE: Diabetic foot ulcers (DFUs) present a significant global health challenge, resulting in high morbidity and economic costs. Current available treatments often fail to achieve satisfactory healing rates, highlighting the need for novel therapies. This study evaluated the safety and efficacy of a novel autologous whole blood clot (AWBC)-a blood-based, biodegradable provisional matrix-in conjunction with standard of care (SoC) when compared to SoC alone in the treatment of hard-to-heal DFUs. METHOD: A multicentre, prospective, blinded assessor, randomised controlled trial was conducted at 16 sites across the US, South Africa and Turkey. A cohort of patients with hard-to-heal DFUs was enrolled and randomised to either the AWBC group or the control group. The primary endpoint was complete wound closure at 12 weeks, while secondary endpoints included time to heal and percentage area reduction (PAR) at four and eight weeks. Data were analysed using both intention-to-treat (ITT) and per-protocol (PP) populations. RESULTS: The cohort included 119 patients. AWBC treatment resulted in a significantly higher healing rate compared to the control in both ITT (41% versus 15%, respectively; p=0.002) and PP populations (51% versus 18%, respectively; p=0.0075). AWBC treatment also resulted in a shorter mean time to heal and higher durability of wound closure. Safety analysis showed a similar incidence of adverse events (AEs) between groups, with no device-related AEs. CONCLUSION: The AWBC system, by modulating the wound microenvironment and providing a functional extracellular matrix, offered a promising new approach to treating hard-to-heal DFUs, demonstrating superior healing outcomes compared to SoC alone in this study.

Pedal arterial calcification score is associated with the risk of major amputation in chronic limb-threatening ischemia.

OBJECTIVE: The medial arterial calcification (MAC) score is a simple metric that describes the burden of inframalleolar calcification using a plain foot radiograph. We hypothesized that a higher MAC score would be independently associated with the risk of major amputation in patients with chronic limb-threatening ischemia (CLTI). METHODS: We performed a single-institution, retrospective study of 250 patients who had undergone infrainguinal revascularization for CLTI from January 2011 to July 2019 and had foot radiographs available for MAC score calculation. A single blinded reviewer assigned MAC scores of 0 to 5 using two-view minimum plain foot radiographs, with 1 point each for calcification of >2 cm in the dorsalis pedis, plantar, and metatarsal arteries and >1 cm in the hallux and non-hallux digital arteries. RESULTS: The MAC score was 0 in 36%, 1 in 5.2%, 2 in 8.4%, 3 in 14%, 4 in 14%, and 5 in 21%. The MAC score was trichotomized to facilitate analysis and clinical utility (mild, MAC score 0-1; moderate, MAC score 2-4; and severe, MAC score 5). The variables independently associated with a higher MAC score were male sex, diabetes, end-stage renal disease, and the global limb anatomic staging system pedal score. The MAC score was not associated with the Society for Vascular Surgery WIfI (wound, ischemia, foot infection) grade or overall WIfI stage (P = .58). The median follow-up was 759 days (interquartile range, 264-1541 days). A higher MAC score was significantly associated with the risk of major amputation (P < .0001). In a Cox proportional hazards multiple regression model for major amputation that included the trichotomized MAC score, diabetes, end-stage renal disease, and WIfI stage (1-3 vs 4). The MAC score (MAC score 5: hazard ratio [HR], 4.9; 95% confidence interval [CI], 1.9-13.1; P = .001; MAC score 2-4: HR, 3.4; 95% CI, 1.3-8.8; P = .01) and WIfI stage (WIfI stage 4: HR, 2.1; 95% CI, 1.1-3.9; P = .03) were significantly associated with the risk of major amputation. In the subsets of patients with the most advanced WIfI stage of 3 to 4 (191 of 250; 76%) and patients with diabetes (185 of 250; 74%), the MAC score further stratified the risk of major amputation on univariate and multivariate analyses. CONCLUSIONS: The MAC score is a simple, practical tool and a strong independent predictor of major amputation in patients with CLTI. It provides novel clinical data that are currently unmeasured using any validated CLTI staging system. The MAC score is a promising standardized measure of inframalleolar disease burden that can be used in conjunction with the WIfI staging system to help improve outcomes stratification and determine the optimal treatment strategies for patients with CLTI.

Pedal arterial calcification score is associated with hemodynamic change and major amputation after infrainguinal revascularization for chronic limb-threatening ischemia.

OBJECTIVE: Pedal medial arterial calcification (pMAC) is associated with major amputation in patients with chronic limb-threatening ischemia (CLTI). We hypothesize that this association would be related to unresolved distal ischemia. We investigated relationships across pMAC score, hemodynamic change, and major amputation after infrainguinal revascularization for CLTI. METHODS: This is a single-institution, retrospective study of 306 patients who underwent technically successful infrainguinal revascularization for CLTI (2011-2020) and had foot x-rays for blinded pMAC scoring (0-5). A total of 136 (44%) patients had toe pressure measurements performed within 90 days before and 60 days after revascularization. Ischemia grade (0-3) was assigned using the Society for Vascular Surgery Wound, Ischemia, foot Infection (WIfI) system. RESULTS: The revascularization approach was open bypass in 118 (38%) and endovascular in 188 (62%) patients. pMAC scores were trichotomized (0-1 [125; 41%], 2-4 [116; 38%], 5 [65; 21%]). Post-revascularization WIfI ischemia grade was improved in 78 of 136 (57%) and unchanged/worsened in 58 of 136 (43%). A lower pMAC score was associated with hemodynamic improvement (P = .004). Failure to improve the ischemia grade was associated with major amputation (P = .0002). In the endovascular subgroup, WIfI ischemia grade was improved in 43 of 90 (48%) with available measurements, and 37 of 188 (20%) underwent major amputation. In a multivariate logistic model, pMAC 5 was the only factor independently associated with unimproved ischemia grade after endovascular treatment (odds ratio: 4.0 [1.1-16.6], P = .04). In a Cox proportional hazards model, factors independently associated with major amputation after endoluminal revascularization were WIfI stage 4 (hazard ratio [HR]: 2.7 [1.3-5.7], P = .007) and pMAC score (pMAC: 2-4: HR: 10.6 [1.4-80.7], P = .02; pMAC: 5: HR: 15.5 [2.0-119], P = .008). In the bypass subgroup, WIfI ischemia grade was improved in 35 of 46 (76%) with available measurements but was not associated with pMAC score (P = .88) or any other baseline patient or limb characteristics. A total of 19 of 118 (16%) patients underwent major amputation. In a Cox proportional hazards model including bypass conduit, WIfI stage, and pMAC score, the only factor independently associated with major amputation after bypass was use of nonautologous conduit (HR: 5.6 [1.8-17.6], P = .003). CONCLUSIONS: The pMAC score is independently associated with persistent distal ischemia and major amputation after technically successful revascularization for CLTI. These data suggest that pMAC may be a marker for hemodynamic response to revascularization and risk of limb loss, and it may have a stronger influence on the outcome of endoluminal interventions.

The influence of adequate debridement and placental-derived allografts on diabetic foot ulcers.

OBJECTIVE: To determine the role of debridement when patients are using placental-derived allografts (PDAs), data from two prospective, multicentre, randomised controlled trials (RCTs) were evaluated for the quality or adequacy of debridement on diabetic foot ulcers (DFUs) treated with PDAs. Results were compared with real-world findings via a retrospective analysis of 2015-2019 Medicare claims for DFUs. METHOD: Debridement adequacy in the prospective RCTs was adjudicated by three blinded wound care specialists. Treatments included two PDAs, dehydrated human amnion/chorion membrane (DHACM, n=54) or dehydrated human umbilical cord (DHUC, n=101), compared with standard of care (SOC, n=110). The key outcome was the influence of adequate debridement on rates of complete closure within 12 weeks. Additionally, a retrospective analysis of 2015-2019 Medicare claims for DFUs that received routine debridement at intervals ranging from every 1-7 days (18,900 total episodes), 8-14 days (35,728 total episodes), and every 15 days or greater (34,330 total episodes) was performed. RESULTS: Within the RCTs, adequate debridement occurred in 202/265 (76%) of patients, 90/110 (82%) SOC ulcers, 45/54 (83%) of DHACM-treated ulcers, and in 67/101 (66%) of DHUC-treated ulcers. Complete closure occurred in 150/202 (74%) of adequately debrided ulcers, and in only 13/63 (21%) of ulcers without adequate debridement, p<0.0001. Debridement was the most significant factor for closure even when controlling for other clinical characteristics. Within the Medicare claims data 21% (18,900/88,958) of episodes treated with SOC only had debridement intervals of ≤7 days. Short debridement intervals in combination with the use of DHACM demonstrated statistically significant better outcomes than SOC including: 65% fewer major amputations (p<0.0001), higher DFU resolution rates (p=0.0125), 42% fewer emergency room visits (p<0.0001) and reduced usage of other hospital resources (admissions and readmissions). CONCLUSION: Prospectively collected data examining the quality of debridement and retrospectively analysed data examining the frequency of debridement supports routine adequate wound debridement, particularly at intervals of seven days, as an essential component of wound care. Optimal use of placental-derived allografts improves outcomes and lowers the use of healthcare resources.

Multi-centre prospective randomised controlled clinical trial to evaluate a bioactive split thickness skin allograft vs standard of care in the treatment of diabetic foot ulcers.

Diabetic foot ulcers (DFUs) pose a significant risk for infection and limb loss. Advanced wound therapies including human skin allografts have shown promise in resolving these challenging wounds. The primary objective of this randomised, prospective study was to compare the response of 100 subjects with non-healing DFUs of which 50 were treated with a cryopreserved bioactive split thickness skin allograft (BSA) (TheraSkin; Misonix,Inc., Farmingdale, NY) compared with 50 subjects treated with standard of care (SOC, collagen alginate dressing) at 12 weeks. Both groups received standardised care that included glucose monitoring, weekly debridement's as appropriate, and an offloading device. The primary endpoint was proportion of full-thickness wounds healed at 12 weeks, with secondary endpoints including differences in percent area reduction (PAR) at 12 weeks, changes in Semmes-Weinstein monofilament score, VAS pain, and w-QoL. The result illustrated in the intent-to-treat analysis at 12 weeks showed that 76% (38/50) of the BSA-treated DFUs healed compared with 36% (18/50) treated with SOC alone (adjusted P = .00056). Mean PAR at 12 weeks was 77.8% in the BSA group compared with 49.6% in the SOC group (adjusted P = .0019). In conclusion, adding BSA to SOC appeared to significantly improve wound healing with a lower incidence of adverse events related to treatment compared with SOC alone.

Fetal bovine acellular dermal matrix for the closure of diabetic foot ulcers: a prospective randomised controlled trial.

AIM: The purpose of this clinical trial was to evaluate the safety and efficacy of a fetal bovine acellular dermal matrix (FBADM) plus standard of care (SOC) for treating hard-to-heal diabetic foot ulcers (DFUs). METHOD: A prospective, multi-centre, randomised controlled trial was carried out. The study included a 2-week run-in period, a 12-week treatment phase and a 4-week follow-up phase. The primary endpoint was complete wound closure at 12 weeks. RESULTS: Twenty-one US sites enrolled and randomised 226 patients with hard-to-heal DFUs. The study was terminated early due to the COVID-19 pandemic, which led to a modified intent-to-treat (mITT) population of 207 patients, with 103 in the FBADM group and 104 in the SOC group. Of these participants, 161 completed the study per protocol (mPP population), with 79 receiving FBADM, and 82 without. At the first analysis point, patients treated with FBADM were found to be significantly more likely to achieve complete wound closure compared with SOC alone (mITT: 45.6% versus 27.9% p=0.008; mPP: 59.5% versus 35.6% p=0.002). The difference in outcome yielded an odds ratio of 2.2 (95% confidence interval (CI): 1.2, 3.9; p=0.008). Median time to closure within 12 weeks was 43 days for the FBADM group compared to 57 days for the SOC group (p=0.36). The median number of applications of FBADM to achieve closure was one. Adverse events were similar between groups and no product-related serious adverse events occurred. CONCLUSIONS: These results indicate that in many cases a single application of FBADM in conjunction with SOC offers a safe, faster and more effective treatment of DFUs than SOC alone.

Increased Reintervention After Infrainguinal Revascularization for Chronic Limb-Threatening Ischemia in Women.

BACKGROUND: The objective of this study was to determine if there are gender-based differences in major adverse limb events after revascularization for chronic limb-threatening ischemia (CLTI) and to identify potential associated factors. METHODS: This was a single-center retrospective analysis of 151 patients who underwent infrainguinal revascularization for CLTI between April 2013 and December 2015. Only the first revascularized limb was included in patients with bilateral CLTI. Demographic data and clinical outcomes were collected using electronic medical records. RESULTS: The mean age was 68.1 ± 12.1 years, and 55 of 151 (36%) were women. Women were less likely to carry a diagnosis of hyperlipidemia (60% vs. 83%; P = 0.003), less likely to be on a statin medication (58% vs. 81%; P = 0.004), and less likely to undergo an infrapopliteal revascularization (60% vs. 77%; P = 0.04) compared with men. There were no differences between genders with regard to the Society for Vascular Surgery Wound Ischemia and Foot Infection stage at presentation or utilization of open versus endovascular intervention. During the median follow-up time of 678 days (interquartile range, 167-1277 days), 48 of 151 patients (32%) underwent reintervention on the threatened limb and 23 of 151 patients (15%) underwent major amputation. Women were more likely than men to need reintervention (P = 0.02). There was no difference between genders for major amputation (P = 0.48) or overall survival (P = 0.65). In a multivariable Cox proportional hazards model for reintervention that included gender, preoperative body mass index, hyperlipidemia, preoperative anticoagulation, and ischemia score ≥2 (all P < 0.20 in univariate analysis), female gender (hazard ratio [HR], 1.96 [1.10-3.54]; P = 0.02) and hyperlipidemia (HR, 2.32 [1.07-5.03]; P = 0.03) were significantly associated with increased rates of reintervention. CONCLUSIONS: Women undergoing lower extremity revascularization for CLTI were more likely to require reintervention compared with men but had similar rates of limb preservation. Further study is required to understand potential causative factors to improve treatment outcomes in women.

A confirmatory study on the efficacy of dehydrated human amnion/chorion membrane dHACM allograft in the management of diabetic foot ulcers: A prospective, multicentre, randomised, controlled study of 110 patients from 14 wound clinics.

A randomised, controlled multicentre clinical trial was conducted at 14 wound care centres in the United States to confirm the efficacy of dehydrated human amnion/chorion membrane allograft (dHACM) for the treatment of chronic lower extremity ulcers in persons with diabetes. Patients with a lower extremity ulcer of at least 4 weeks duration were entered into a 2-week study run-in phase and treated with alginate wound dressings and appropriate offloading. Those with less than or equal to 25% wound closure after run-in were randomly assigned to receive weekly dHACM application in addition to offloading or standard of care with alginate wound dressings, for 12 weeks. A total of 110 patients were included in the intent-to-treat (ITT) analysis, with n = 54 in the dHACM group and n = 56 in the no-dHACM group. Of the participants, 98 completed the study per protocol, with 47 receiving dHACM and 51 not receiving dHACM. The primary study outcome was percentage of study ulcers completely healed in 12 weeks, with both ITT and per-protocol participants receiving weekly dHACM significantly more likely to completely heal than those not receiving dHACM (ITT-70% versus 50%, P = 0.0338, per-protocol-81% versus 55%, P = 0.0093). A Kaplan-Meier analysis was performed to compare the time-to-healing performance with/without dHACM, showing a significantly improved time to healing with the use of allograft, log-rank P < 0.0187. Cox regression analysis showed that dHACM-treated subjects were more than twice as likely to heal completely within 12 weeks than no-dHACM subjects (HR: 2.15, 95% confidence interval 1.30-3.57, P = 0.003). At the final follow up at 16 weeks, 95% of dHACM-healed ulcers and 86% of healed ulcers in the no-dHACM group remained closed. These results confirm that dHACM is an efficacious treatment for lower extremity ulcers in a heterogeneous patient population.

Continuous Temperature-Monitoring Socks for Home Use in Patients With Diabetes: Observational Study.

BACKGROUND: Over 30 million people in the United States (over 9%) have been diagnosed with diabetes. About 25% of people with diabetes will experience a diabetic foot ulcer (DFU) in their lifetime. Unresolved DFUs may lead to sepsis and are the leading cause of lower-limb amputations. DFU rates can be reduced by screening patients with diabetes to enable risk-based interventions. Skin temperature assessment has been shown to reduce the risk of foot ulceration. While several tools have been developed to measure plantar temperatures, they only measure temperature once a day or are designed for clinic use only. In this report, wireless sensor-embedded socks designed for daily wear are introduced, which perform continuous temperature monitoring of the feet of persons with diabetes in the home environment. Combined with a mobile app, this wearable device informs the wearer about temperature increases in one foot relative to the other, to facilitate early detection of ulcers and timely intervention. OBJECTIVE: A pilot study was conducted to assess the accuracy of sensors used in daily wear socks, obtain user feedback on how comfortable sensor-embedded socks were for home use, and examine whether observed temperatures correlated with clinical observations. METHODS: Temperature accuracy of sensors was assessed both prior to incorporation in the socks, as well as in the completed design. The measured temperatures were compared to the reference standard, a high-precision thermostatic water bath in the range 20°C-40°C. A total of 35 patients, 18 years of age and older, with diabetic peripheral neuropathy were enrolled in a single-site study conducted under an Institutional Review Board-approved protocol. This study evaluated the usability of the sensor-embedded socks and correlated the observed temperatures with clinical findings. RESULTS: The temperatures measured by the stand-alone sensors were within 0.2°C of the reference standard. In the sensor-embedded socks, across multiple measurements for each of the six sensors, a high agreement (R2=1) between temperatures measured and the reference standard was observed. Patients reported that the socks were easy to use and comfortable, ranking them at a median score of 9 or 10 for comfort and ease of use on a 10-point scale. Case studies are presented showing that the temperature differences observed between the feet were consistent with clinical observations. CONCLUSIONS: We report the first use of wireless continuous temperature monitoring for daily wear and home use in patients with diabetes and neuropathy. The wearers found the socks to be no different from standard socks. The temperature studies conducted show that the sensors used in the socks are reliable and accurate at detecting temperature and the findings matched clinical observations. Continuous temperature monitoring is a promising approach as an early warning system for foot ulcers, Charcot foot, and reulceration.

Human placental membrane as a wound cover for chronic diabetic foot ulcers: a prospective, postmarket, CLOSURE study.

OBJECTIVE: To evaluate the safety and efficacy of a chorioamniotic allograft, used as a wound cover for chronic foot ulcers, in patients with diabetes. METHODS: A multicentre, prospective, postmarket study where eligible patients received up to 11 weekly wound cover applications. Computerised planimetry was used to calculate the diabetic foot ulcer (DFU) area each week. The primary endpoint of the study was wound closure assessment. Secondary endpoints included DFU recurrence and morbidity. RESULTS: A total of 63 patients with 64 ulcers were enrolled, after successful completion of a two-week run-in period. Patients were predominantly male and had risk factors for delayed healing. Mean baseline DFU area was 3.8cm2 (standard deviation (SD): 4.8). After 12 weeks, a total of 19 (40%) DFUs had closed. Results varied by size category, 'small' (≤2.0cm2), 'medium' (>2.0-4.0 cm2), and 'large' (>4.0-25.0 cm2), with higher percentage closure in the 'small' DFU group, compared with the 'medium' and 'large' DFUs (57%, 33%, and 10%, respectively). Of those DFUs that closed, the average closure time was 6.5 weeks. There were no unanticipated adverse events. CONCLUSION: Known risk factors for healing, including DFU size, location and duration, affected the outcomes. However, the results are in line with the literature and support the use of the chorioamniotic allograft in chronic and complex cases.

A multicentre randomised controlled trial evaluating the efficacy of dehydrated human amnion/chorion membrane (EpiFix® ) allograft for the treatment of venous leg ulcers.

A randomised, controlled, multicentre clinical trial was conducted to evaluate the efficacy of dehydrated human amnion/chorion membrane (EpiFix) allograft as an adjunct to multilayer compression therapy for the treatment of non-healing full-thickness venous leg ulcers. We randomly assigned 109 subjects to receive EpiFix and multilayer compression (n = 52) or dressings and multilayer compression therapy alone (n = 57). Patients were recruited from 15 centres around the USA and were followed up for 16 weeks. The primary end point of the study was defined as time to complete ulcer healing. Participants receiving weekly application of EpiFix and compression were significantly more likely to experience complete wound healing than those receiving standard wound care and compression (60% versus 35% at 12 weeks, P = 0·0128, and 71% versus 44% at 16 weeks, P = 0·0065). A Kaplan-Meier analysis was performed to compare the time-to-healing performance with or without EpiFix, showing a significantly improved time to healing using the allograft (log-rank P = 0·0110). Cox regression analysis showed that subjects treated with EpiFix had a significantly higher probability of complete healing within 12 weeks (HR: 2·26, 95% confidence interval 1·25-4·10, P = 0·01) versus without EpiFix. These results confirm the advantage of EpiFix allograft as an adjunct to multilayer compression therapy for the treatment of non-healing, full-thickness venous leg ulcers.

Determinants of midterm functional outcomes, wound healing, and resources used in a hospital-based limb preservation program.

OBJECTIVE: The objective of this study was to assess midterm functional status, wound healing, and in-hospital resource use among a prospective cohort of patients treated in a tertiary hospital, multidisciplinary Center for Limb Preservation. METHODS: Data were prospectively gathered on all consecutive admissions to the Center for Limb Preservation from July 2013 to October 2014 with follow-up data collection through January 2016. Limbs were staged using the Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) threatened limb classification scheme at the time of hospital admission. Patients with nonatherosclerotic vascular disorders, acute limb ischemia, and trauma were excluded. RESULTS: The cohort included 128 patients with 157 threatened limbs; 8 limbs with unstageable disease were excluded. Mean age (±standard deviation [SD]) was 66 (±13) years, and median follow-up duration (interquartile range) was 395 (80-635) days. Fifty percent (n = 64/128) of patients were readmitted at least once, with a readmission rate of 20% within 30 days of the index admission. Mean total number of admissions per patient (±SD) was 1.9 ± 1.2, with mean (±SD) cumulative length of stay (cLOS) of 17.1 (±17.9) days. During follow-up, 25% of limbs required a vascular reintervention, and 45% developed recurrent wounds. There was no difference in the rate of readmission, vascular reintervention, or wound recurrence by initial WIfI stage (P > .05). At the end of the study period, 23 (26%) were alive and nonambulatory; in 20%, functional status was missing. On both univariate and multivariate analysis, end-stage renal disease and prior functional status predicted ability to ambulate independently (P < .05). WIfI stage was associated with major amputation (P = .01) and cLOS (P = .002) but not with time to wound healing. Direct hospital (inpatient) cost per limb saved was significantly higher in stage 4 patients (P < .05 for all time periods). WIfI stage was associated with cumulative in-hospital costs at 1 year and for the overall follow-up period. CONCLUSIONS: Among a population of patients admitted to a tertiary hospital limb preservation service, WIfI stage was predictive of midterm freedom from amputation, cLOS, and hospital costs but not of ambulatory functional status, time to wound healing, or wound recurrence. Patients presenting with limb-threatening conditions require significant inpatient care, have a high frequency of repeated hospitalizations, and are at significant risk for recurrent wounds and leg symptoms at later times. Stage 4 patients require the most intensive care and have the highest initial and aggregate hospital costs per limb saved. However, limb salvage can be achieved in these patients with a dedicated multidisciplinary team approach.

A clinical trial of Integra Template for diabetic foot ulcer treatment.

Individuals with diabetes mellitus are at an increased risk of developing a diabetic foot ulcer (DFU). This study evaluated the safety and efficacy of Integra Dermal Regeneration Template (IDRT) for the treatment of nonhealing DFUs. The Foot Ulcer New Dermal Replacement Study was a multicenter, randomized, controlled, parallel group clinical trial conducted under an Investigational Device Exemption. Thirty-two sites enrolled and randomized 307 subjects with at least one DFU. Consented patients were entered into the 14-day run-in phase where they were treated with the standard of care (0.9% sodium chloride gel) plus a secondary dressing and an offloading/protective device. Patients with less than 30% reepithelialization of the study ulcer after the run-in phase were randomized into the treatment phase. The subjects were randomized to the control treatment group (0.9% sodium chloride gel; n = 153) or the active treatment group (IDRT, n = 154). The treatment phase was 16 weeks or until confirmation of complete wound closure (100% reepithelialization of the wound surface), whichever occurred first. Following the treatment phase, all subjects were followed for 12 weeks. Complete DFU closure during the treatment phase was significantly greater with IDRT treatment (51%) than control treatment (32%; p = 0.001) at sixteen weeks. The median time to complete DFU closure was 43 days for IDRT subjects and 78 days for control subjects in wounds that healed. The rate of wound size reduction was 7.2% per week for IDRT subjects vs. 4.8% per week for control subjects (p = 0.012). For the treatment of chronic DFUs, IDRT treatment decreased the time to complete wound closure, increased the rate of wound closure, improved components of quality of life and had less adverse events compared with the standard of care treatment. IDRT could greatly enhance the treatment of nonhealing DFUs.

Effectiveness of a Continuous Remote Temperature Monitoring Program to Reduce Foot Ulcers and Amputations: Multicenter Postmarket Registry Study.

BACKGROUND: Neuropathic foot ulcers are the leading cause of nontraumatic foot amputations, particularly among patients with diabetes. Traditional methods of monitoring and managing these patients are periodic in-person clinic visits, which are passive and may be insufficient for preventing neuropathic foot ulcers and amputations. Continuous remote temperature monitoring has the potential to capture the critical period before the foot ulcers develop and to improve outcomes by providing real-time data and early interventions. For the first time, the effectiveness of such a strategy to prevent neuropathic foot ulcers and related complications among high-risk patients in a real-world commercial setting is reported. OBJECTIVE: This study aims to evaluate the effectiveness of a real-world continuous remote temperature monitoring program in preventing neuropathic foot ulcers and amputations in patients with diabetes. METHODS: In this retrospective analysis of a real-world continuous remote temperature monitoring program, 115 high-risk patients identified by clinical providers from 15 geographically diverse private podiatry offices were analyzed. Patients received continuous remote monitoring socks as part of the program. The enrollment was based on medical necessity as decided by their managing physician. We evaluated data from up to 2 years before enrollment and up to 3 years during the program. The primary outcome was the rate of wound development. Secondary outcomes included amputation rate, the severity of the foot ulcers, and the number of visits to an outpatient podiatry clinic after enrolling in the program. RESULTS: We observed significantly lower rates of foot ulceration (relative risk reduction [RRR] 0.68; 95% CI 0.52-0.79; number needed to treat [NNT] 5.0; P<.001), less moderate to severe ulcers (RRR 0.86; 95% CI 0.70-0.93; NNT 16.2; P<.001), less amputations (RRR 0.83; 95% CI 0.39-0.95; NNT 41.7; P=.006), and less hospitalizations (RRR 0.63; 95% CI 0.33-0.80; NNT 5.7; P<.002). We found a decrease in outpatient podiatry office visits during the program (RRR 0.31; 95% CI 0.24-0.37; NNT 0.46; P<.001). CONCLUSIONS: Our findings suggested that a real-world continuous remote temperature monitoring program was an effective strategy to prevent foot ulcer development and nontraumatic foot amputation among high-risk patients.

Comparative effectiveness of mechanically and electrically powered negative pressure wound therapy devices: a multicenter randomized controlled trial.

This study was designed to compare the ultraportable mechanically powered Smart Negative Pressure (SNaP) Wound Care System (Spiracur, Sunnyvale, CA) with the electrically powered Vacuum-Assisted Closure (VAC) Therapy System (Kinetic Concepts, Inc. [KCI], San Antonio, TX) in a multicenter, comparative efficacy, noninferiority-powered, randomized controlled trial. We enrolled 132 people with noninfected, nonischemic, nonplantar lower extremity diabetic and venous wounds. Each subject was randomly assigned (1:1) to treatment with either system in conjunction with appropriate off-loading and compression therapy. The trial evaluated treatment for up to 16 weeks or complete wound closure (defined as complete reepithelialization without drainage). Primary end point analysis of wound size reduction found that SNaP-treated subjects demonstrated noninferiority to the VAC-treated subjects at 4, 8, 12, and 16 weeks (p = 0.0030, 0.0130, 0.0051, and 0.0044, respectively). Kaplan-Meier analysis showed no significant difference in complete wound closure between SNaP- and VAC-treated subjects at all time points. Device related adverse events and complications such as infection were also similar between treatment groups. These data support similar wound healing outcomes between the SNaP system and the VAC system in the population studied.

NorLeu3-A(1-7) stimulation of diabetic foot ulcer healing: results of a randomized, parallel-group, double-blind, placebo-controlled phase 2 clinical trial.

This randomized, double-blind, placebo-controlled Phase 2 clinical trial explored NorLeu(3)-A(1-7) (DSC127) safety and healing efficacy in diabetic foot ulcers. Patients with chronic, noninfected, neuropathic, or neuroischemic plantar Wagner Grade 1 or 2 foot ulcers (n = 172) were screened for nonhealing. Subjects were randomized to receive 4 weeks' once-daily topical treatment with 0.03% DSC127 (n = 26), 0.01% DSC127 (n = 27), or Placebo (n = 24), followed by 20 weeks' standard of care. DSC127 was assessed for safety (including laboratory values and adverse events), primary efficacy (% ulcers completely epithelialized at Week 12), and durability of effect. Baseline, demography, and safety parameters were compared between intent-to-treat groups and were comparable. Dose-response curves for DSC127 effect on % area reduction from baseline at Week 12 (40% placebo; 67% 0.01% DSC127; 80% 0.03% DSC127) and 24 (23% placebo; 53% 0.01% DSC127; 95% 0.03% DSC127) followed a log-linear pattern for both intent-to-treat and per-protocol populations. Covariate analysis compared reduction in ulcer area, depth, and volume from baseline; reductions in the 0.03% DSC127 group were greater at Weeks 12 and 24. Placebo-treated ulcers healed in a median 22 weeks vs. 8.5 weeks for 0.03%DSC127 (p = 0.04). This study provides preliminary evidence that DSC127 is safe and effective in accelerating the healing of diabetic foot ulcers.

Initial clinical assessment of a novel multifunctional topical ointment for difficult-to-heal wounds: a case series.

Chronic wounds are characterized by prolonged inflammation, bacterial bioburden, and ischemia. These factors represent the barriers to wound healing that need to be addressed in order to achieve wound closure. The authors performed the initial clinical testing of WinVivo Wound Ointment ("WinVivo"), a novel topical ointment containing several botanicals that have been previously shown to promote favorable wound environment and advance wound healing. In this series of 13 patients with difficult-to-heal lower-extremity wounds, WinVivo was well tolerated and demonstrated the ability to simultaneously support granulation tissue formation; decrease the amount of exudate, edema, and malodor; and reduce pain. The ulcers included in this study have been present for a minimum of 3 weeks and a maximum of 5 years prior to the start of treatment with WinVivo. Eight of 13 wounds have previously been treated with at least 1 type of advanced wound healing modality, such as dermal substitutes or negative-pressure wound therapy. Treatment with WinVivo lasted for 3 to 12 weeks and resulted in a mean 88% wound closure, with 4 wounds healing completely. In addition to significant reduction in wound size, all patients have exhibited other clinical benefits, suggesting overall improvement in wound conditions. Future studies in a larger population, as well as case-control studies comparing WinVivo with a standard of care, are therefore warranted to further evaluate the efficacy of this new treatment.

Utilization of a Smart Sock for the Remote Monitoring of Patients With Peripheral Neuropathy: Cross-sectional Study of a Real-world Registry.

BACKGROUND: Remote patient monitoring (RPM) devices are increasingly being used in caring for patients to reduce risks of complications. Temperature monitoring specifically has been shown in previous studies to provide a useful signal of inflammation that may help prevent foot ulcers. OBJECTIVE: In this cross-sectional study, we evaluated utilization data for patients who were prescribed smart socks as remote temperature monitoring devices. METHODS: This study evaluated data from a patient registry from January to July 2021. The utilization data, which were collected starting from the first full month since patients were prescribed the smart socks, were evaluated along with retention over time, the average time that the socks were worn, and the number of days that the socks were worn per month and per week. RESULTS: A total of 160 patients wore the smart sock RPM device for 22 to 25 days per month on average. The retention rate was 91.9% (147/160) at the end of the 7-month period; a total of 13 patients were lost to follow-up during this period. The average number of days that the socks were worn per week was 5.8. The percentage of patients with a utilization rate of >15 days ranged from 79.7% (106/133) to 91.9% (125/136) each month. CONCLUSIONS: This study shows a high level of utilization for a smart sock RPM device and a high compliance rate. A future prospective study on the clinical outcomes after the use of the smart socks may further solidify the idea of conducting temperature monitoring for foot ulcer prevention.

An Evaluation of Real-world Smart Sock-Based Temperature Monitoring Data as a Physiological Indicator of Early Diabetic Foot Injury: Case-Control Study.

BACKGROUND: Lower extremity complications of diabetes represent major health care complications both in terms of cost and impact to quality of life for patients with diabetic peripheral neuropathy. Temperature monitoring has been shown in previous studies to provide a useful signal of inflammation that may indicate the early presence of a foot injury. OBJECTIVE: In this study, we evaluated the temperature data for patients that presented with a diabetic foot injury while using a sock-based remote temperature monitoring device. METHODS: The study abstracted data from patients who were enrolled in a remote temperature monitoring program (2020-2021) using a smart sock (Siren Care). In the study cohort, a total of 5 participants with a diabetes-related lower extremity injury during the study period were identified. In the second comparison cohort, a total of 26 patients met the criteria for monitoring by the same methods but did not present with a diabetes-related podiatric lower extremity injury during the same period. The 15-day temperature differential between 6 defined locations on each foot was the primary outcome measure among subjects who presented with a diagnosed foot injury. Paired t tests were used to compare the differences between the two groups. RESULTS: A significant difference in temperature differential (temperature measured in °F) was observed in the group that presented with a podiatric injury over the course of evaluation versus the comparator group that did not present with a podiatric injury. The average difference from all 6 measured points was 1.4 °F between the injury group (mean 3.6, SD 3.0) and the comparator group (mean 2.2, SD 2.5, t=-71.4, df=39; P<.001). CONCLUSIONS: The results of this study suggest temperature monitoring in a sock form factor could be used to predict a developing foot injury. The continuous temperature monitoring system employed has implications for further algorithm development to enable early detection. The study was limited by a nonrandomized, observational design with limited injuries present in the study period. We look forward to further studies that will refine the predictive potential and confirm or refute the current promising data.