nWASP Inhibition Increases Wound Healing via TrKb/PLCγ Signalling.

(1) Background: Chronic wounds represent a major burden to patients and healthcare systems and identifying new therapeutic targets to encourage wound healing is a significant challenge. This study evaluated nWASP as a new therapeutic target in human wound healing and determined how this can be regulated. (2) Methods: Clinical cohorts from patients with chronic wounds were tested for the expression of nWASP and cell models were employed to evaluate the influence of nWASP on cellular functions that are key to the healing process following knockdown and/or the use of nWASP-specific inhibitors. (3) Results: nWASP was significantly elevated at transcript levels in human non-healing chronic wounds versus healing tissues. nWASP inhibitors, wiskostatin and 187-1, along with the knockdown of nWASP, modified both HaCaT and HECV cell behaviour. We then identified two signalling pathways affected by nWASP inhibition: TrkB signalling and downstream PLCγ1 phosphorylation were impaired by nWASP inhibition in HaCaT cells. The healing of wounds in a diabetic murine model was significantly improved with an nWASP inhibitor treatment. (4) Conclusions: This study showed that nWASP activity was related to the non-healing behaviour of chronic wounds and together with the findings in the in vivo models, it strongly suggested nWASP as a therapeutic target in non-healing wounds that are regulated via TrkB and PLCγ1 signalling.

A cross-sector systematic review and synthesis of knowledge on telemedicine interventions in chronic wound management-Implications from a system perspective.

Based on initially identified needs for further telemedicine (TM) and chronic wound management research, the objective of this article is twofold: to conduct a systematic review of existing knowledge on TM interventions in chronic wound management-including barriers and opportunities-across the specialist and primary care sectors, and to incorporate the review findings into a system framework that can be further developed and validated through empirical data. We conclude that there is a pressing need for broader and more comprehensive empirical explorations into quality improvement and integration of TM in chronic wound management, including using system frameworks that can capture cross-sector system perspectives and associated implications. Of practical consideration, we suggest that the design and execution of TM improvement interventions and associated research projects should be conducted in close cooperation with managers and practitioners knowledgeable about barriers and opportunities that can influence the implementation of important interventions within chronic wound management.

Sensitivity of the Wound Edge Gene Signature "WD14" in Responding to Clinical Change: A Longitudinal Cohort Study.

Introduction: WounD14 (WD14) gene signature is a recently developed tool derived from genetic interrogation of wound edge biopsies of chronic venous leg ulcers to identify heard-to-heal wounds and enable clinicians to target aggressive therapies to promote wound healing. This study aimed to evaluate if changes in wound clinical healing status were detected by the WD14 gene signature over time as this is currently poorly understood. Material and methods: WD14 was developed through gene screening and subsequent validation in 3 patient cohorts involving 85 consecutive patients with chronic venous leg ulcers referred to a tertiary wound healing unit. Patients underwent a wound edge biopsy to interrogate for a "healing" or "non-healing" genotype. A smaller cohort (18%) underwent a second biopsy, which comprised this pilot cohort reported herein. Twelve weeks following biopsy, wounds were clinically assessed for healing status based on reduction in size and compared to WD14 genotype. Results: Sequential biopsies and WD14 scores were derived from 16 patients. WD14 signature predicted wound healing status among this cohort at either visit (32 wound edge biopsies) with a positive predictive value (PPV) of 85.2% (95% CI 74.1%-92.0%) and negative predictive value (NPV) of 80.0% (95% CI 34.2%-96.9%). A total of 6 wounds underwent altered clinical status between the 2 visits. In this cohort, WD14 has a PPV of 66.7% (95% CI 47.3%-81.7%) and NPV of 100%. Conclusion: Although the WD14 gene signature did change with wound healing status, larger studies are required to precisely clarify its role and ability to prognosticate wounds of differing clinical status over time.

Modified compression therapy in mixed arterial-venous leg ulcers: An integrative review.

Leg ulcers remain an increased burden to healthcare cost and morbidity in modern society. While most leg ulcers are venous in origin, recognition and prompt identification of concomitant arterial occlusive disease is critical to determine underlying aetiology and subsequent management. This integrative review presents the current evidence to establish the role of modified compression therapy (MCT) in treatment of mixed arterial venous leg ulcers (MAVLU). A literature search was conducted using the electronic databases CINAHL, MEDLINE, PUBMED, and Embase. Ten studies met the eligibility criteria and were subsequently analysed. Our review concludes that MCT, with compression pressures between 20 and 30 mmHg, can promote healing in MAVLU with moderate arterial insufficiency (0.5 ≤ ABPI ≤0.8). If ABPI is <0.5, MCT can be considered once restoration of acceptable ABPI is achieved. Intolerance, lack of response or further deterioration of disease within 3 months should prompt further arterial imaging and intervention. MCT is generally well tolerated with no adverse outcomes reported. A holistic yet individualised approach is vital in order to account for all factors influencing this patient-led decision-making process, ultimately ensuring effective treatment, which improves patient's quality of life and reduces socioeconomic burden of the disease.

Microcirculatory Flux and Pulsatility in Arterial Leg Ulcers is Increased by Intermittent Neuromuscular Electrostimulation of the Common Peroneal Nerve.

BACKGROUND: Neuromuscular electrical stimulator (NMES) devices increase blood flow to the lower limb by a process of intermittent muscular contraction initiated by a transdermal stimulus to the common peroneal nerve. However, its effects on localized microvascular blood supply to lower limb wounds are unknown. This study is a single-center open label study measuring the effect of neuromuscular stimulation of the common peroneal nerve on the microvascular blood flow within the wound bed of arterial leg ulcers. METHODS: Eights patients with ischemic lower limb wounds had an NMES (geko™) applied to the common peroneal nerve. Baseline and intervention analysis of blood flow to the wound bed and edge was performed using Laser Speckle Contrast Imaging. Mean flow (flux) and pulse amplitude (pulsatility) were measured. RESULTS: Stimulation of the common peroneal nerve with the NMES resulted in a significantly increased flux and pulsatility in both the wound bed and the wound edge in all 8 patients. CONCLUSIONS: Neuromuscular electrical stimulation immediately increases microcirculatory blood flow to the wound bed and edge in patients with ischemic lower limb wounds. These data may provide mechanistic insight into the clinical efficacy of NMES in healing wounds. www.clinicaltrials.gov NCT03186560.

A pilot multi-centre prospective randomised controlled trial of RECELL for the treatment of venous leg ulcers.

Venous leg ulcers (VLUs) have a significant impact on approximately 3% of the adult population worldwide, with a mean NHS wound care cost of £7600 per VLU over 12 months. The standard care for VLUs is compression therapy, with a significant number of ulcers failing to heal with this treatment, especially with wound size being a risk factor for non-healing. This multicentre, prospective, randomised trial evaluated the safety and effectiveness of autologous skin cell suspension (ASCS) combined with compression therapy compared with standard compression alone (Control) for the treatment of VLUs. Incidence of complete wound closure at 14 weeks, donor site closure, pain, Health-Related Quality of Life (HRQoL), satisfaction, and safety were assessed in 52 patients. At Week 14, VLUs treated with ASCS + compression had a statistically greater decrease in ulcer area compared with the Control (8.94 cm2 versus 1.23 cm2 , P = .0143). This finding was largely driven by ulcers >10 to 80 cm2 in size, as these ulcers had a higher mean percentage of reepithelialization at 14 weeks (ASCS + compression: 69.97% and Control: 11.07%, P = .0480). Additionally, subjects treated with ASCS + compression experienced a decrease in pain and an increase in HRQoL compared with the Control. This study indicates that application of ASCS + compression accelerates healing in large venous ulcers.

Humidified Warmed CO2 Treatment Therapy Strategies Can Save Lives With Mitigation and Suppression of SARS-CoV-2 Infection: An Evidence Review.

The coronavirus disease (COVID-19) outbreak has presented enormous challenges for healthcare, societal, and economic systems worldwide. There is an urgent global need for a universal vaccine to cover all SARS-CoV-2 mutant strains to stop the current COVID-19 pandemic and the threat of an inevitable second wave of coronavirus. Carbon dioxide is safe and superior antimicrobial, which suggests it should be effective against coronaviruses and mutants thereof. Depending on the therapeutic regime, CO2 could also ameliorate other COVID-19 symptoms as it has also been reported to have antioxidant, anti-inflammation, anti-cytokine effects, and to stimulate the human immune system. Moreover, CO2 has beneficial effects on respiratory physiology, cardiovascular health, and human nervous systems. This article reviews the rationale of early treatment by inhaling safe doses of warmed humidified CO2 gas, either alone or as a carrier gas to deliver other inhaled drugs may help save lives by suppressing SARS-CoV-2 infections and excessive inflammatory responses. We suggest testing this somewhat counter-intuitive, but low tech and safe intervention for its suitability as a preventive measure and treatment against COVID-19. Overall, development and evaluation of this therapy now may provide a safe and economical tool for use not only during the current pandemic but also for any future outbreaks of respiratory diseases and related conditions.

Does localized iron loss in venous disease lead to systemic iron deficiency? A descriptive pilot study.

Haemosiderin deposition in the legs of patients with venous leg ulcers is well established, and several theories suggest this stored iron has a role in disease pathophysiology. In this novel pilot study of patients with chronic venous leg ulcers, we aimed to establish the relationship between wound fluid iron levels, serum iron parameters and healing. Fifteen patients with venous ulcers were included in the study. Blood samples were taken for full blood count and iron studies, while simultaneously wound fluid was obtained from the wound surface using filter paper. Wound areas were measured at initial and 4 week (+/- 2 day) follow-up visits. We found a positive correlation between wound fluid and serum iron (correlation co-efficient 0.27) and those with the lowest wound fluid iron level were also anemic. No association was found between initial wound area and wound fluid iron level but the largest wound areas were found in patients with anemia. Only 38% of patients demonstrated a reduction in wound area during the 4 week study, and 80% of those were not anemic or iron deficient. Conversely in those patients whose wounds did not reduce in size 88% were anemic or iron deficient. These findings demonstrate a previously unrecognized phenomenon of systemic iron store depletion secondary to leaching out of the body in wound exudate. In addition, these results suggest a high prevalence of anemia in patients with chronic venous ulcers, though whether this is cause or effect requires further research. Our findings also suggest that patients with venous ulcers have a high prevalence of iron deficiency and anemia, which appears to be often undiagnosed, and that diagnostic criteria for iron deficiency in patients with chronic wounds need to be revised to reflect the effect of chronic inflammation on iron metabolism.

An overview of the relationship between anaemia, iron, and venous leg ulcers.

The factors preventing healing in venous leg ulcers are still not fully understood. Iron-mediated tissue damage has been hypothesised, yet anecdotally anaemia is also thought to have a negative effect on wound healing. This article summarises the current evidence for these theories and their likely effects in the context of venous ulceration. A comprehensive search of the literature was conducted. Studies suggest that a number of forms of iron including haemosiderin and ferritin are implicated in progression of venous disease, ulcer formation, and impaired healing, which is thought to be primarily free radical mediated. There is a paucity of evidence for the role of iron deficiency and anaemia on ulcer healing; however, there is likely to be a highly complex interplay between the damaging effects of iron on local tissues and the negative effects of anaemia-mediated tissue hypoxia. Studies looking at options to increase local oxygen delivery such as topical haemoglobin suggest that this may have an impact on some aspects of healing, but findings are generally inconclusive. There is growing evidence that locally elevated iron levels may have a detrimental effect on ulcer healing and formation; however, more robust research is needed.

A prospective pilot study of thigh-administered intermittent pneumatic compression in the management of hard-to-heal lower limb venous and mixed aetiology ulcers.

This was a prospective observational pilot study of a unique intermittent pneumatic compression (IPC) device designed to be applied in the thigh region of the affected limb in patients with lower limb ulceration of both venous and mixed (venous and arterial) aetiologies. This compression system consists of a circumferential three-chamber thigh garment and an electronic pneumatic compression pump operating over a repeated 4-minute cycle. Patients were recruited from outpatient wound clinics. Those recruited were treated with standard therapy in addition to IPC, which was applied for 2 hours per day, and followed up for a total of 8 weeks. The primary objective of the study was to examine the effects of IPC on wound healing over an 8-week period. The other objectives were to assess patients' experiences of pain and the acceptability of IPC device. Twenty-one patients were recruited, and wounds progressed towards healing in 95.24% (20/21) of the patients. Pain scores decreased in 83.33% (15/18) of the patients. Most patients felt that the thigh-applied IPC device was comfortable and easy to apply and remove. The thigh-administered IPC device can be recommended for use in routine clinical practice, especially when other treatment options are limited.

Management of sacrococcygeal pilonidal sinus disease.

The ideal treatment for patients who suffer from pilonidal sinus disease should lead to a cure with a rapid recovery period allowing a return to normal daily activities, with a low level of associated morbidity. A variety of different surgical techniques have been described for the primary treatment of pilonidal sinus disease and current practice remains variable and contentious. Whilst some management options have improved outcomes for some patients, the complications of surgery, particularly related to wound healing, often remain worse than the primary disease. This clinical review aims to provide an update on the management options to guide clinicians involved in the care of patients who suffer from sacrococcygeal pilonidal sinus disease.

Neuromuscular electrostimulation on lower limb wounds.

The geko™ is a disposable neuromuscular electrostimulation (NMES) device intended to increase blood circulation and promote wound healing in a range of lower limb conditions. The purpose of this case series was to evaluate the therapeutic effect of the geko device on wound healing outcomes over an 8-week period. Thirty patients with non-healing wounds (≥ 12-week duration) of either venous leg ulceration (VLU), mixed leg ulceration (MLU) or diabetic foot ulceration aetiology were recruited from a local outpatient wound clinic in the South Wales area. Over the 8 weeks 2 participants (8%) achieved complete re-epithelialisation between baseline and endpoint. Mean wound surface area decreased (7.6 cm2) and there was an increase of 21% in the mean percentage of granulation tissue in the wound bed. Pain levels reduced in 52% of patients who completed the study, but the extent of oedema reduction was difficult to establish given that 76% of the cohort were treated with a form of compression as part of standard care. The findings support the use of the therapy in patients with painful VLUs and MLUs, but further research needs to be conducted to establish the generalisability of the findings to the wider population of patients living with chronic wounds of differing aetiology in the lower limb.

Impact of pigment epithelium-derived factor on colorectal cancer in vitro and in vivo.

Pigment epithelial derived factor (PEDF) is a secreted glycoprotein that is a non-inhibitory member of the serine protease inhibitor (serpin) family. PEDF exhibits multiple biological properties including neuroprotective, anti-angiogenic, and immune-modulating. Interestingly, PEDF exerts the inhibitory effects in cancers derived from certain tissues, including prostatic, ovarian, and pancreatic carcinomas. The current study aimed to elucidate its role in colorectal cancer development. PEDF expression in human colorectal cancer tissue was assessed using quantitative polymerase chain reaction (qPCR) and immunohistochemical staining (IHC). The effect of treatment with recombinant PEDF on cellular function was examined using in vitro functional assays. PEDF expression was downregulated in colorectal cancer cell tissue. Treatment with recombinant PEDF resulted in significant decreases in the rate of colorectal cancer cell migration and invasion and an increase in cellular adhesion in colorectal cancer cell lines examined. These results indicate that upregulation of PEDF expression may serve as a new strategy for further investigation of therapeutic relevance to the prevention of the metastatic spread of colorectal cancer.

An unusual presentation of a common condition: Allergic contact dermatitis.

Allergic contact dermatitis commonly affects patients with chronic venous leg ulcers and can contribute to impaired wound healing. Many allergens have been identified, and despite the use of advanced dressings, the incidence of allergy has remained high. We discuss an unusual presentation of allergic contact dermatitis in a patient with a chronic wound. The patient's history was consistent with a recurrent venous leg ulcer, but on this occasion, the wound continued to deteriorate despite optimal treatment. This prompted further investigation, which included patch testing. Although the clinical features were not suggestive of allergy, the patch test was positive for several allergens, including Atrauman® dressings, which the patient was using at the time. This case highlights the importance of regular reassessment and accurate diagnosis for the management of chronic wounds. It also demonstrates that allergic contact dermatitis can contribute to delayed wound healing without causing the classical clinical features of inflammation of the surrounding skin, and even hypoallergenic, non-adherent dressings can be sensitising.

In vitro significance of SOCS-3 and SOCS-4 and potential mechanistic links to wound healing.

Wound healing and the management of chronic wounds represent a significant burden on the NHS. Members of the suppressor of cytokine signalling (SOCS) family have been implicated in the regulation of a range of cellular processes. The current study aims to explore the importance of SOCS-3 and SOCS-4 in regulating cellular traits associated with wound healing. SOCS-3 over-expression and SOCS-4 knockdown mutant lines were generated and verified using q-PCR and western blotting in human keratinocytes (HaCaT) and endothelial cells (HECV). Over-expression of SOCS-3 resulted in a significantly reduced proliferative rate in HaCaT keratinocytes and also enhanced the tubule formation capacity of HECV cells. SOCS-4 knockdown significantly reduced HaCaT migration and HECV cell tubule formation. Suppression of SOCS-4 influenced the responsiveness of HaCaT and HECV cells to EGF and TGFß and resulted in a dysregulation of phospho-protein expression in HaCaT cells. SOCS-3 and SOCS-4 appear to play regulatory roles in a number of keratinocyte and endothelial cellular traits associated with the wound healing process and may also be able to regulate the responsiveness of these cells to EGF and TGFß. This implies a potential regulatory role in the wound healing process and, thus highlights their potential as novel therapies.

Expression of the SOCS family in human chronic wound tissues: Potential implications for SOCS in chronic wound healing.

Cytokines play important roles in the wound healing process through various signalling pathways. The JAK-STAT pathway is utilised by most cytokines for signal transduction and is regulated by a variety of molecules, including suppressor of cytokine signalling (SOCS) proteins. SOCS are associated with inflammatory diseases and have an impact on cytokines, growth factors and key cell types involved in the wound­healing process. SOCS, a negative regulator of cytokine signalling, may hold the potential to regulate cytokine­induced signalling in the chronic wound­healing process. Wound edge tissues were collected from chronic venous leg ulcer patients and classified as non-healing and healing wounds. The expression pattern of seven SOCSs members, at the transcript and protein level, were examined in these tissues using qPCR and immunohistochemistry. Significantly higher levels of SOCS3 (P=0.0284) and SOCS4 (P=0.0376) in non-healing chronic wounds compared to the healing/healed chronic wounds were observed at the transcript level. Relocalisation of SOCS3 protein in the non-healing wound environment was evident in the investigated chronic biopsies. Thus, the results show that the expression of SOCS transcript indicated that SOCS members may act as a prognostic biomarker of chronic wounds.

Wound bed preparation: TIME for an update.

While the overwhelming majority of wounds heal rapidly, a significant proportion fail to progress through the wound-healing process. These resultant chronic wounds cause considerable morbidity and are costly to treat. Wound bed preparation, summarised by the TIME (Tissue, Inflammation/infection, Moisture imbalance, Epithelial edge advancement) concept, is a systematic approach for assessing chronic wounds. Each of these components needs to be addressed and optimised to improve the chances of successful wound closure. We present an up-to-date literature review of the most important recent aspects of wound bed preparation. While there are many novel therapies that are available to the treating clinician, often, there are limited data on which to assess their clinical value, and a lack of appreciation for adequate wound bed preparation needed before expensive therapy is used to heal a wound.

New Surfactant-based Dressing Product to Improve Wound Closure Rates of Nonhealing Wounds: A European Multicenter Study Including 1036 Patients.

OBJECTIVE: A new surfactant-based biomaterial containing the antimicrobial 1% silver sulfadiazine (SSD) was developed at the University of Virginia (Charlottesville, VA) to improve outcomes for nonhealing wounds. This study's objective was to clinically test the wound care outcomes of the new surfactant-based antimicrobial wound dressing (SAWD) in a multicenter trial. METHODS AND MATERIALS: This cohort study enrolled 1036 patients with any nonhealing wound of > 3 months duration not responding to standard-of-care treatments from 10 wound care centers in 7 European countries. The SAWD was used for all wound types at all stages of complexity, healing, and severity. Data collection ranged from 6 months to 2 years and measured the percentage of patients achieving wound closure and time to complete closure. RESULTS: Of the 1036 patients, 70% achieved wound closure, 24.6% were still in treatment at data collection, and 5.4% had a therapy change. The majority (56%) of these non-healing wounds achieved wound closure within 11 weeks. Patients were treated with the SAWD for 3 weeks to more than 1 year with no complications or adverse effects from long-term SSD antimicrobial use. CONCLUSION: Ten centers concluded that the new SAWD provided positive results (improved wound closure rates, reduction of inflammation, pain, and odor), improvements in clinical application (faster and easier dressing change), and improved patient compliance.