Marissa Janine Carter

Diabetic foot ulcers (DFUs) are a devastating complication of diabetes that markedly affects quality of life and generates significant socioeconomic and healthcare burdens. When DFUs fail to respond to standard of care (SOC), advanced therapies including Cellular, Acellular and Matrix‐like Products (CAMPs) are often employed. A novel composite CAMP comprising ovine forestomach matrix and high molecular weight hyaluronic acid, termed ‘OFM‐HA’ has been developed for the treatment of chronic wounds and evaluated in a prospective multi‐centre controlled trial. For this trial, 143 subjects were randomized to receive OFM‐HA plus SOC or SOC alone for the treatment of chronic full thickness wounds of the foot in people with diabetes meeting prespecified eligibility criteria. The primary endpoint was the proportion of wounds healed by 12 weeks. Secondary endpoints included healing time, percentage area reduction, adverse events and changes in pain and quality of life. For the modified intent‐to‐treat population, 46% (31/68) of the OFM‐HA plus SOC group healed by 12 weeks compared to 24% (17/72) in the SOC alone group ( p = 0.008). Kaplan–Meier analysis favoured OFM‐HA plus SOC over 12 weeks (log‐rank p = 0.023). No unexpected safety‐related occurrences were observed. OFM‐HA plus SOC increased 12‐week closure in this selected population. Interpretation is limited by post‐randomization exclusions, differential withdrawal and an adjusted comparison close to the significance threshold ( p = 0.045).

Background: This systematic review aims to determine whether pre- and postoperative hyperbaric oxygen therapy (HBOT) incurs any benefits or harms in soft tissue injuries (STIs) considered for skin flap or graft surgery. Methods: We included adequately powered clinical trials that enrolled patients with STIs serious enough for skin flaps or grafts; evaluated HBOT (≥1.5 ATA) versus control, placebo, or sham procedures; and analyzed survival/healing and complication rates. MEDLINE, Google Scholar, and Embase were searched for relevant literature through June 30, 2024. The Cochrane risk of bias (RoB 2) and the ROBINS-I tools assessed RoB. Meta-analysis and random effects models analyzed randomized controlled trial (RCTs) evaluating flap/graft survival rates within 4 weeks of HBOT (2-2.5 ATA). The GRADE approach determined the evidence recommendations. Results: Among 743 records screened, 45 were assessed; 25 reports from 24 studies (13 RCTs; 11 non-RCTs; 2246 patients) were included. RCT RoB ranged from low RoB (1 trial) to high (2 trials). Nonrandomized trials had moderate RoB (n = 5, 45%), whereas 6 had serious RoB. Four RCTs showed a large, horizontal overall effect size (log odds ratio, 1.045; standard error, 0.3104; z , 3.3.67; P < 0.001; 95% confidence interval, 0.44–1.65). Evidence levels were very low to moderate, with 11 strong and 13 conditional recommendations, including a strong recommendation to use HBOT to heal flaps/grafts in STI/trauma wounds. Conclusions: A strong recommendation for pre- and postoperative HBOT is warranted to mitigate the need for flap/graft surgery and heal flaps and grafts, given the potentially life- and/or limb-threatening harms that could otherwise occur.

Objective: This post hoc analysis determined the correlation between wound bed preparation (WBP), defined as complete debridement of nonviable tissue and complete granulation tissue coverage, and wound closure, using data from a published, Consolidated Standards of Reporting Trials (CONSORT)-compliant randomized controlled trial that evaluated bromelain-based enzymatic debridement (BBD) compared with a placebo gel vehicle (GV) or nonsurgical standard of care (NSSOC) in patients with chronic venous leg ulcers (VLUs). Approach: Patients with chronic VLUs were randomized (3:3:2 ratio) to daily treatment with BBD, GV, or NSSOC for up to 2 weeks and followed up weekly with NSSOC for 12 weeks. Wound closure incidence was compared between those who did and did not achieve WBP by 14 days or anytime during the study. Results: Data were analyzed from 119 VLUs. Among 80 wounds that achieved WBP anytime during the study, 42% healed; among 39 wounds without WBP, only 10.3% healed (relative risk [RR] = 4.1, p = 0.0004, negative predictive value [NPV] = 90%). Among 37 wounds that achieved WBP by 14 days, 54% healed; among 78 wounds that did not achieve WBP by 14 days, only 22% healed (NPV = 78%). Wounds were 2.4 times more likely to achieve closure anytime during the study, if they achieved WBP by 14 days (RR = 2.4, p = 0.0005). Innovation: This landmark analysis confirms that WBP status is an early predictive variable of wound closure. Conclusion: WBP of chronic VLUs significantly increased the likelihood of wound closure and is a critical, though not sufficient, condition for healing.

BACKGROUND: People with chronic limb-threatening ischemia lack Food and Drug Administration-approved therapies for wound healing, creating an unmet need for novel approaches. Prior studies of biologics in chronic limb-threatening ischemia have largely targeted end-stage patients with amputation-free survival as the primary outcome. This trial evaluated the efficacy of intramuscular administration of AMG0001, a plasmid encoding human HGF (hepatocyte growth factor), to promote ulcer healing in patients with chronic limb-threatening ischemia and neuroischemic ulcers. METHODS: LEGenD-1 was a double-blind, randomized, placebo-controlled phase II trial conducted at 22 US sites. Seventy-five participants with neuroischemic ulcers and toe pressure or transcutaneous oxygen pressure between 30 and 59 mm Hg were randomized to receive AMG0001 at 4 mg, 8 mg, or placebo. Injections were administered intramuscularly along an angiographically guided target artery path on days 0, 28, 56, and 84. The 2 coprimary end points were time to complete healing and the proportion of subjects with ulcers healed by 6 months in a pooled AMG0001 analysis. Secondary end points included healing by 12 months, ulcer recurrence, and hemodynamic changes. RESULTS: Baseline characteristics were comparable across groups (mean age 62.6 years; 80.0% male; 70.7% with diabetes). Mean toe pressure was 46.1 mm Hg, and transcutaneous oxygen pressure was 49.8 mm Hg. Median time to healing was significantly shorter with AMG0001 versus placebo (84 versus 280 days; P =0.007); 4 mg: 98 days ( P =0.017); 8 mg: 84 days ( P =0.022). By 6 months, 63.3% of AMG0001-treated participants healed versus 38.5% of placebo ( P =0.053). By 12 months, healing rates were 77.6% versus 46.2% ( P =0.010). Adverse events were similar across groups. CONCLUSIONS: Anatomically targeted intramuscular delivery of AMG0001 significantly accelerated healing in patients with moderate chronic limb-threatening ischemia and neuroischemic ulcers and may represent a promising nonsurgical therapeutic strategy. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04267640.

Objective: To identify how cellular and/or tissue-based products (CTPs) relate to value in terms of cost per quality-adjusted life years (QALYs) in wound care in comparison with treatments in other medical fields. Approach: This is a cross-sectional study and a cost-effectiveness analysis. Payment limits for each CTP were obtained via the Healthcare Common Procedure Coding System Q codes and formulated as cost inputs into a cost-utility model published for treatment of Wagner 1 diabetic foot ulcers using dehydrated human amnion and chorion allograft versus standard of care (SOC). Additional changes to cap the number of CTP applications and adjustments for recent inflation were made. The literature was searched for other cost-utility models in other diabetes-related diseases as a comparison. Results: When the payment limit was ≤$140 per square centimeter, interventions were dominant (less costly, better outcomes) compared with SOC. When the limit exceeded $430 per square centimeter, the cost-effectiveness threshold of $100,000/QALY was exceeded. Newer Q codes are generally much more expensive and likely to not be cost-effective, similar to the results for many other chronic diabetes-related diseases . Innovation: This study presents decision makers with tools, by which they can determine as to whether a given CTP is likely to be cost-effective for patients. Conclusion: Over a third of all CTPs will very likely result in noncost-effective interventions. This number is likely to be higher when wounds are larger or used in other wound types where they are less efficacious. The recent trend in much higher costs for CTPs is worrisome.

Diabetic foot complications that lead to lower extremity amputations pose a significant challenge to the entire global health system. In this multicentre clinical trial, 26 patients with chronic Wagner one diabetic foot ulcers (DFUs) were treated with a unique human keratin matrix graft applied either weekly or bi‐weekly, in addition to standard of care. The hypothesis was that bi‐weekly application would be similar to weekly application. The primary endpoint was complete wound closure by 12 weeks, and secondary endpoints included healing time, percent area reduction and weekly changes in peripheral neuropathy, pain and quality of life. In the intent‐to‐treat population, 77% (10/13) of DFUs treated with bi‐weekly application healed compared with 69% (9/13) treated with weekly application. The mean time to heal within 12 weeks in the bi‐weekly group was 61 days and in the weekly group was 54 days. The mean percent area reduction at 12 weeks was 94.7% in the bi‐weekly group compared with 84.8% in the weekly group. The number of grafts used in the bi‐weekly group was 3.9 compared with 6.2 in the weekly group. The results of this trial confirm our hypothesis that whether bi‐weekly or weekly application of the unique keratin matrix graft is used to treat nonhealing indolent DFUs, there is a high rate of complete healing. Based on these results, future studies should be conducted that further investigate the use of this novel human keratin matrix graft for the treatment of chronic DFUs.

As the incidence of diabetic foot ulcers (DFU) increases, better treatments that improve healing should reduce complications of these ulcers including infections and amputations. We conducted a randomized controlled trial comparing outcomes between a novel purified reconstituted bilayer membrane (PRBM) to the standard of care (SOC) in the treatment of non‐healing DFUs. This study included 105 patients who were randomized to either of two treatment groups (n = 54 PRBM; n = 51 SOC) in the intent to treat (ITT) group and 80 who completed the study per protocol (PP) (n = 47 PRBM; n = 33 SOC). The primary endpoint was the percentage of wounds closed after 12 weeks. Secondary outcomes included percent area reduction, time to healing, quality of life, and cost to closure. The DFUs that had been treated with PRBM healed at a higher rate than those treated with SOC (ITT: 83% vs. 45%, p = 0.00004, PP: 92% vs. 67%, p = 0.005). Wounds treated with PRBM also healed significantly faster than those treated with SOC with a mean of 42 versus 62 days for SOC (p = 0.00074) and achieved a mean wound area reduction within 12 weeks of 94% versus 51% for SOC (p = 0.0023). There were no adverse events or serious adverse events that were related to either the PRBM or the SOC. In comparison to the SOC, DFUs healed faster when treated with PRBM. Thus, the use of this PRBM is an effective option for the treatment of chronic DFUs.

In 2022, the Alliance of Wound Care Stakeholders convened the 2-day Wound Care Evidence Summit™. The Summit brought together a multidisciplinary group of stakeholders that included payers, government agency policymakers, prominent researchers, wound care medical specialty societies, patient and clinical associations, wound care clinics, and manufacturers to discuss wound care evidence and coverage issues. The Summit focused on a wide variety of wound care topics, with an emphasis on the processes payers use to create their coverage policies and the type, quantity, and characteristics of clinical evidence payers require. The most valuable outcome of the Summit was the frank and open discourse among stakeholders, with unprecedented participation from payers and the U.S. Food and Drug Administration (FDA) on the subjects of trial design, product-approval pathways, and coverage policy determination. Stakeholders provided actionable ideas for ways to improve clinical trial research and design that will yield better evidence and ultimately better wound care. This article examines the quality, adequacy, and relevance of the existing chronic wound care research base and discusses the gaps, associated problems, and implications for clinical trial design and execution as identified by Summit participants.

Significance: Quality of life (QoL) is important to patients with chronic wounds and is rarely formally evaluated. Understanding what comorbidities most affect the individual versus their wounds could be a key metric. Recent Advances: The last 20 years have seen substantial advances in QoL instruments and conversion of patient data to a single value known as the health utilities index (HUI). We review these advances, along with wound-related QoL, and analyze real-world comorbidities challenging wound care. Critical Issues: To understand the impact of underlying comorbidities in a real-world patient population, we examined a convenience sample of 382 patients seen at a hospital-based outpatient wound center. This quality reporting study falls outside the regulations that govern human subject research. Comorbid conditions were used to calculate HUIs using a variety of literature-reported approaches, while Wound-Quality-of-Life (W-QoL) questionnaire data were collected from patients during their first visit. The mean number of conditions per patient was 8; 229 patients (59.9%) had utility values for comorbidities/conditions, which were worse/lower than their wounds' values. Sixty-three (16.5%) patients had depression and/or anxiety, 64 (16.8%) had morbid obesity, and 204 (53.4%) had gait and mobility disorders, all of which could have affected W-QoL scoring. The mean minimum utility value (0.5) was within 0.05 units of an average of 13 studies reporting health utilities from wound care populations using the EuroQol 5 Dimension instrument. Future Directions: The comorbidity associated with the lowest utility value is what might most influence the QoL of patients with chronic wounds. This finding needs further investigation.

Purpose: Small observational studies suggest subclinical disease occurrence in the normal-appearing scalp zones of several primary cicatricial alopecias. To aid patient management, we began routinely evaluating the entire scalp of patients with acne keloidalis nuchae (AKN), including trichoscopy-guided biopsies. Patients and Methods: This retrospective study evaluated 41 patients sequentially presenting with AKN at a single clinic between June and December 2022. Primary lesions and normal-appearing scalp in the superior parietal scalp at least 5 cm away from AKN-affected zones were clinically evaluated, and areas showing perifollicular erythema or scales/casts on trichoscopy were biopsied and histologically analyzed. Results: Forty-one men with AKN, including 20 men of African descent, 17 Hispanic, and 4 European-descended Whites, were evaluated. All patients, including 22% with associated folliculitis decalvans, showed scalp-wide trichoscopy signs of perifollicular erythema or scaling in normal-appearing scalp areas. All patients showed histologic evidence of perifollicular infundibulo-isthmic lymphocytoplasmic infiltrates and fibrosis (PIILIF), with 96% showing Vellus or miniaturized hair absence. PIILIF was often clinically mistaken for seborrheic dermatitis (44– 51%). All White patients had mild papular acne keloidalis nuchae lesions mistaken for seborrheic dermatitis. Conclusion: PIILIF may be a precursor to a wide spectrum of primary cicatricial alopecias, including AKN and folliculitis decalvans. This finding carries implications for the early diagnosis and management of AKN and other primary cicatricial alopecias. Plain Language Summary: Acne keloidalis nuchae (AKN) is a type of hair loss and scalp condition marked by scarring and inflammation. This condition falls under a group of chronic hair and scalp issues known as primary cicatricial alopecia (PCA). Current treatments for AKN and similar PCAs often do not work well, and the condition tends to return. We have found a hidden scalp condition that could be causing AKN and other PCAs. It’s a subtle disease that affects the entire scalp, even though it might not show noticeable symptoms. We have observed this condition in all 41 AKN patients in our study, and it’s characterized by certain changes in the hair and scalp’s structure and immune system response. Other studies have linked this condition to various other PCAs. We believe this hidden condition could be causing AKN and making it come back after treatment. This study suggests that treating AKN might require a broader approach beyond just treating the visible symptoms. Since this hidden condition exists in other PCAs, it might be a common cause.