Reactive Eccrine Syringofibroadenomatosis Associated With Venous Leg Ulcers: A Case Report and Literature Review.

Eccrine syringofibroadenoma (ESFA) is a rare adnexal tumor deriving from the acrosyringeal portion of the eccrine duct. Five subtypes of ESFA were described including a reactive form. Reactive ESFAs are associated with inflammatory and neoplastic dermatoses. In this article, we report the case of a 90-year-old woman presenting with 3 leg ulcers evolving for 2 years surrounded by large verrucous and eczematous lesions. Multiple skin biopsies showed anastomosing epithelial cords connected to the epidermis consistent with ESFA. We identified 8 cases of ESFA associated with chronic leg ulcers in the literature and reviewed their main clinical and histological features.

Deep Venous Stenting Improves Healing of Lower Extremity Venous Ulcers.

BACKGROUND: Long standing, recalcitrant venous ulcers fail to heal despite standard compression therapy and wound care. Stenting of central veins has been reported to assist in venous ulcer healing. This study reports outcomes of deep venous stenting for central venous obstruction in patients with recalcitrant venous ulcers at a single comprehensive wound care center. METHODS: A single center retrospective analysis was conducted of patients with CEAP (Clinical, Etiology, Anatomy, and Pathophysiology) 6 disease that had undergone deep venous stenting in addition to wound care and compression therapy. Intra-operative details, wound healing, and stent patency rates were recorded. Stent patency and intra-operative details were compared between the healed and unhealed groups. RESULTS: Between 2010 and 2019, 15 patients met inclusion criteria (mean age: 63 years old, 12 males). Pre-operative mean wound area was 14.1 cm2 with mean wound duration of 30 months. 93% of patients healed the ulcers at mean healing time of 10.6 months. Wound recurrence rate was 57% with mean recurrence time of 14.8 months. Ten patients presented with an inferior vena cava (IVC) filter, 4 in the healed group and 6 in the unhealed group. The common iliac vein was stented in all patients. Extension into the IVC was required in 4, the common femoral vein in 11, and femoral vein in 2 patients. The average stent length was 190cm. During the follow-up period, primary patency rates in healed patients (mean follow-up time: 19.2 months) was 83% and 59% in the unhealed group (mean follow-up time: 36.6 months); secondary patency rates were 83% and 89%, respectively. CONCLUSIONS: In patients with recalcitrant venous ulcers with central venous obstruction, deep venous stenting resulted in a high rate of healing. However, a prolonged 10 month healing time was observed and despite high stent patency, wound recurrence rate was high.

Extracellular matrix and cellular senescence in venous leg ulcers.

High prevalence of non-healing chronic wounds contributes to a huge healthcare burden across the world. Early treatment interventions for non-healing wounds are vital. It was previously shown that accumulation of 15% or more of senescent cells in a chronic wound edge is an indicator that the wound is unlikely to heal. However, determining the presence of senescent cells would require invasive procedures such as tissue biopsies to be taken. In this study, we found a strong correlation between decreased collagen area and presence of senescent cells in human chronic wounds i.e. venous leg ulcer (VLU), diabetic foot ulcer (DFU) and pressure ulcer (PRU). We also report that the lowest collagen levels were found in VLU patients less than 60 years of age, with a persistent wound of > 24 months. Elevated levels of senescent cells were also found in VLU of males. Second harmonic imaging of collagen at the edge of chronic wounds with a handheld multiphoton device could be used to predict the number of senescent cells, indicating if the wound is on a healing trajectory or not. Our data support the use of collagen imaging in cutaneous wound assessment for a faster and non-invasive method to predict cellular senescence and determining wound trajectory of healing.

Low Intensity Shockwave Treatment Modulates Macrophage Functions Beneficial to Healing Chronic Wounds.

Extracorporeal Shock Wave Therapy (ESWT) is used clinically in various disorders including chronic wounds for its pro-angiogenic, proliferative, and anti-inflammatory effects. However, the underlying cellular and molecular mechanisms driving therapeutic effects are not well characterized. Macrophages play a key role in all aspects of healing and their dysfunction results in failure to resolve chronic wounds. We investigated the role of ESWT on macrophage activity in chronic wound punch biopsies from patients with non-healing venous ulcers prior to, and two weeks post-ESWT, and in macrophage cultures treated with clinical shockwave intensities (150-500 impulses, 5 Hz, 0.1 mJ/mm2). Using wound area measurements and histological/immunohistochemical analysis of wound biopsies, we show ESWT enhanced healing of chronic ulcers associated with improved wound angiogenesis (CD31 staining), significantly decreased CD68-positive macrophages per biopsy area and generally increased macrophage activation. Shockwave treatment of macrophages in culture significantly boosted uptake of apoptotic cells, healing-associated cytokine and growth factor gene expressions and modulated macrophage morphology suggestive of macrophage activation, all of which contribute to wound resolution. Macrophage ERK activity was enhanced, suggesting one mechanotransduction pathway driving events. Collectively, these in vitro and in vivo findings reveal shockwaves as important regulators of macrophage functions linked with wound healing. This immunomodulation represents an underappreciated role of clinically applied shockwaves, which could be exploited for other macrophage-mediated disorders.

ß-acetoxyisovaleryl alkannin (AAN-II) from Alkanna tinctoria promotes the healing of pressure-induced venous ulcers in a rabbit model through the activation of TGF-ß/Smad3 signaling.

Alkannin-based pharmaceutical formulations for improving wound healing have been on the market for several years. However, detailed molecular mechanisms of their action have yet to be elucidated. Here, we investigated the potential roles of AAN-II in improving the healing of pressure-induced venous ulcers using a rabbit model generated by combining deep vein thrombosis with a local skin defect/local skin defect. The extent of healing was evaluated using hematoxylin and eosin (HE) or vimentin staining. Rabbit skin fibroblasts were cultured for AAN-II treatment or TGFB1-sgRNA lentivirus transfection. ELISA was used to evaluate the levels of various cytokines, including IL-1ß, IL-4, IL-6, TNF-α, VEGF, bFGF, TGF-ß and PDGF. The protein levels of TGF-ß sensors, including TGF-ß, Smad7 and phosphor-Smad3, and total Smad3, were assayed via western blotting after TGF-ß knockout or AAN-II treatment. The results show that, for this model, AAN-II facilitates ulcer healing by suppressing the development of inflammation and promoting fibroblast proliferation and secretion of proangiogenic factors. AAN-II enhances the activation of the TGF-ß1-Smad3 signaling pathway during skin ulcer healing. In addition, the results demonstrate that AAN-II and TGF-ß have synergistic effects on ulcer healing. Our findings indicate that AAN-II can promote healing of pressure-induced venous skin ulcers via activation of TGF-ß-Smad3 signaling in fibroblast cells and provide evidence that could be used in the development of more effective treatments.

Compression bandages or stockings versus no compression for treating venous leg ulcers.

BACKGROUND: Leg ulcers are open skin wounds on the lower leg that can last weeks, months or even years. Most leg ulcers are the result of venous diseases. First-line treatment options often include the use of compression bandages or stockings. OBJECTIVES: To assess the effects of using compression bandages or stockings, compared with no compression, on the healing of venous leg ulcers in any setting and population. SEARCH METHODS: In June 2020 we searched the Cochrane Wounds Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE (including In-Process & Other Non-Indexed Citations), Ovid Embase and EBSCO CINAHL Plus. We also searched clinical trials registries for ongoing and unpublished studies, and scanned reference lists of relevant included studies as well as reviews, meta-analyses and health technology reports to identify additional studies. There were no restrictions by language, date of publication or study setting. SELECTION CRITERIA: We included randomised controlled trials that compared any types of compression bandages or stockings with no compression in participants with venous leg ulcers in any setting. DATA COLLECTION AND ANALYSIS: At least two review authors independently assessed studies using predetermined inclusion criteria. We carried out data extraction, and risk-of-bias assessment using the Cochrane risk-of-bias tool. We assessed the certainty of the evidence according to GRADE methodology. MAIN RESULTS: We included 14 studies (1391 participants) in the review. Most studies were small (median study sample size: 51 participants). Participants were recruited from acute-care settings, outpatient settings and community settings, and a large proportion (65.9%; 917/1391) of participants had a confirmed history or clinical evidence of chronic venous disease, a confirmed cause of chronic venous insufficiency, or an ankle pressure/brachial pressure ratio of greater than 0.8 or 0.9. The average age of participants ranged from 58.0 to 76.5 years (median: 70.1 years). The average duration of their leg ulcers ranged from 9.0 weeks to 31.6 months (median: 22.0 months), and a large proportion of participants (64.8%; 901/1391) had ulcers with an area between 5 and 20 cm2. Studies had a median follow-up of 12 weeks. Compression bandages or stockings applied included short-stretch bandage, four-layer compression bandage, and Unna's boot (a type of inelastic gauze bandage impregnated with zinc oxide), and comparator groups used included 'usual care', pharmacological treatment, a variety of dressings, and a variety of treatments where some participants received compression (but it was not the norm). Of the 14 included studies, 10 (71.4%) presented findings which we consider to be at high overall risk of bias. Primary outcomes There is moderate-certainty evidence (downgraded once for risk of bias) (1) that there is probably a shorter time to complete healing of venous leg ulcers in people wearing compression bandages or stockings compared with those not wearing compression (pooled hazard ratio for time-to-complete healing 2.17, 95% confidence interval (CI) 1.52 to 3.10; I2 = 59%; 5 studies, 733 participants); and (2) that people treated using compression bandages or stockings are more likely to experience complete ulcer healing within 12 months compared with people with no compression (10 studies, 1215 participants): risk ratio for complete healing 1.77, 95% CI 1.41 to 2.21; I2 = 65% (8 studies with analysable data, 1120 participants); synthesis without meta-analysis suggests more completely-healed ulcers in compression bandages or stockings than in no compression (2 studies without analysable data, 95 participants). It is uncertain whether there is any difference in rates of adverse events between using compression bandages or stockings and no compression (very low-certainty evidence; 3 studies, 585 participants). Secondary outcomes Moderate-certainty evidence suggests that people using compression bandages or stockings probably have a lower mean pain score than those not using compression (four studies with 859 participants and another study with 69 ulcers): pooled mean difference -1.39, 95% CI -1.79 to -0.98; I2 = 65% (two studies with 426 participants and another study with 69 ulcers having analysable data); synthesis without meta-analysis suggests a reduction in leg ulcer pain in compression bandages or stockings, compared with no compression (two studies without analysable data, 433 participants). Compression bandages or stockings versus no compression may improve disease-specific quality of life, but not all aspects of general health status during the follow-up of 12 weeks to 12 months (four studies with 859 participants; low-certainty evidence). It is uncertain if the use of compression bandages or stockings is more cost-effective than not using them (three studies with 486 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS: If using compression bandages or stockings, people with venous leg ulcers probably experience complete wound healing more quickly, and more people have wounds completely healed. The use of compression bandages or stockings probably reduces pain and may improve disease-specific quality of life. There is uncertainty about adverse effects, and cost effectiveness. Future research should focus on comparing alternative bandages and stockings with the primary endpoint of time to complete wound healing alongside adverse events including pain score, and health-related quality of life, and should incorporate cost-effectiveness analysis where possible. Future studies should adhere to international standards of trial conduct and reporting.

Glucocorticoid-mediated induction of caveolin-1 disrupts cytoskeletal organization, inhibits cell migration and re-epithelialization of non-healing wounds.

Although impaired keratinocyte migration is a recognized hallmark of chronic wounds, the molecular mechanisms underpinning impaired cell movement are poorly understood. Here, we demonstrate that both diabetic foot ulcers (DFUs) and venous leg ulcers (VLUs) exhibit global deregulation of cytoskeletal organization in genomic comparison to normal skin and acute wounds. Interestingly, we found that DFUs and VLUs exhibited downregulation of ArhGAP35, which serves both as an inactivator of RhoA and as a glucocorticoid repressor. Since chronic wounds exhibit elevated levels of cortisol and caveolin-1 (Cav1), we posited that observed elevation of Cav1 expression may contribute to impaired actin-cytoskeletal signaling, manifesting in aberrant keratinocyte migration. We showed that Cav1 indeed antagonizes ArhGAP35, resulting in increased activation of RhoA and diminished activation of Cdc42, which can be rescued by Cav1 disruption. Furthermore, we demonstrate that both inducible keratinocyte specific Cav1 knockout mice, and MßCD treated diabetic mice, exhibit accelerated wound closure. Taken together, our findings provide a previously unreported mechanism by which Cav1-mediated cytoskeletal organization prevents wound closure in patients with chronic wounds.

Wound cleansing for treating venous leg ulcers.

BACKGROUND: Leg ulcers are open skin wounds that occur below the knee but above the foot. The majority of leg ulcers are venous in origin, occurring as a result of venous insufficiency, where the flow of blood through the veins is impaired; they commonly arise due to blood clots and varicose veins. Compression therapy, using bandages or stockings, is the primary treatment for venous leg ulcers. Wound cleansing can be used to remove surface contaminants, bacteria, dead tissue and excess wound fluid from the wound bed and surrounding skin, however, there is uncertainty regarding the effectiveness of cleansing and the best method or solution to use. OBJECTIVES: To assess the effects of wound cleansing, wound cleansing solutions and wound cleansing techniques for treating venous leg ulcers. SEARCH METHODS: In September 2019 we searched the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE (including In-Process & Other Non-Indexed Citations); Ovid Embase and EBSCO CINAHL Plus. We also searched clinical trials registries for ongoing and unpublished studies, and scanned reference lists of relevant included studies as well as reviews, meta-analyses and health technology reports to identify additional studies. There were no restrictions with respect to language, date of publication or study setting. SELECTION CRITERIA: We considered randomised controlled trials (RCTs) comparing wound cleansing with no wound cleansing, or RCTs comparing different wound cleansing solutions, or different wound cleansing techniques. DATA COLLECTION AND ANALYSIS: We screened studies for their appropriateness for inclusion, assessed their risk of bias using the Cochrane 'Risk of bias' tool, and used GRADE methodology to determine the certainty of evidence. Two review authors undertook these tasks independently, using predetermined criteria. We contacted study authors for missing data where possible. MAIN RESULTS: We included four studies with a total of 254 participants. All studies included comparisons between different types of cleansing solutions, and three of these reported our primary outcomes of complete wound healing or change in ulcer size over time, or both. Two studies reported the secondary outcome, pain. One study (27 participants), which compared polyhexamethylene biguanide (PHMB) solution with saline solution for cleansing venous leg ulcers, did not report any of the review's primary or secondary outcomes. We did not identify any studies that compared cleansing with no cleansing, or that explored comparisons between different cleansing techniques. One study (61 participants) compared aqueous oxygen peroxide with sterile water. We are uncertain whether aqueous oxygen peroxide makes any difference to the number of wounds completely healed after 12 months of follow-up (risk ratio (RR) 1.88, 95% confidence interval (CI) 1.10 to 3.20). Similarly, we are uncertain whether aqueous oxygen peroxide makes any difference to change in ulcer size after eight weeks of follow-up (mean difference (MD) -1.38 cm2, 95% CI -4.35 to 1.59 cm2). Finally, we are uncertain whether aqueous oxygen peroxide makes any difference to pain reduction, assessed after eight weeks of follow-up using a 0 to 100 pain rating, (MD 3.80, 95% CI -10.83 to 18.43). The evidence for these outcomes is of very low certainty (we downgraded for study limitations and imprecision; for the pain outcome we also downgraded for indirectness). Another study (40 participants) compared propyl betaine and polihexanide with a saline solution. The authors did not present the raw data in the study report so we were unable to conduct independent statistical analysis of the data. We are uncertain whether propyl betaine and polihexanide make any difference to the number of wounds completely healed, change in ulcer size over time, or wound pain reduction. The evidence is of very low certainty (we downgraded for study limitations and imprecision). The final study (126 participants) compared octenidine dihydrochloride/phenoxyethanol (OHP) with Ringer's solution. We are uncertain whether OHP makes any difference to the number of wounds healed (RR 0.96, 95% CI 0.53 to 1.72) or to the change in ulcer size over time (we were unable to conduct independent statistical analysis of available data). The evidence is of very low certainty (we downgraded for study limitations and imprecision). None of the studies reported patient preference, ease of use of the method of cleansing, cost or health-related quality of life. In one study comparing propyl betaine and polihexanide with saline solution the authors do not report any adverse events occurring. We are uncertain whether OHP makes any difference to the number of adverse events compared with Ringer's solution (RR 0.58, 95% CI 0.29 to 1.14). The evidence is of very low certainty (we downgraded for study limitations and imprecision). AUTHORS' CONCLUSIONS: There is currently a lack of RCT evidence to guide decision making about the effectiveness of wound cleansing compared with no cleansing and the optimal approaches to cleansing of venous leg ulcers. From the four studies identified, there is insufficient evidence to demonstrate whether the use of PHMB solution compared with saline solution; aqueous oxygen peroxide compared with sterile water; propyl betaine and polihexanide compared with a saline solution; or OHP compared with Ringer's solution makes any difference in the treatment of venous leg ulcers. Evidence from three of the studies is of very low certainty, due to study limitations and imprecision. One study did not present data for the primary or secondary outcomes. Further well-designed studies that address important clinical, quality of life and economic outcomes may be important, based on the clinical and patient priority of this uncertainty.

ANTECEDENTES: Las úlceras de la pierna son heridas cutáneas abiertas que se producen por debajo de la rodilla, pero por encima del pie. La mayoría de las úlceras de la pierna son de origen venoso, y se producen como resultado de la insuficiencia venosa, en la que el flujo de sangre a través de las venas se ve afectado; suelen surgir debido a coágulos de sangre y venas varicosas. El tratamiento de compresión (vendas o medias) es el tratamiento principal para las úlceras venosas de la pierna. La limpieza de la herida se puede utilizar para eliminar los contaminantes superficiales, las bacterias, el tejido muerto y el exceso de líquido de la base de la úlcera y de la piel circundante; sin embargo, no se sabe con certeza cuál es la efectividad de la limpieza ni cuál es el mejor método o solución a utilizar. OBJETIVOS: Evaluar los efectos de la limpieza de heridas, las soluciones de limpieza de heridas y las técnicas de limpieza de heridas para el tratamiento de las úlceras venosas de la pierna. MÉTODOS DE BÚSQUEDA: En septiembre de 2019 se hicieron búsquedas en el Registro especializado del Grupo Cochrane de Heridas (Cochrane Wounds Group), en el Registro Cochrane central de ensayos controlados (CENTRAL); Ovid MEDLINE (incluido In­Process & Other Non­Indexed Citations); Ovid Embase y EBSCO CINAHL Plus. También se buscaron estudios en curso y no publicados en los registros de ensayos clínicos, y se examinaron las listas de referencias de los estudios incluidos pertinentes, así como de las revisiones, los metanálisis y los informes de tecnología sanitaria para identificar estudios adicionales. No hubo restricciones en cuanto al idioma, la fecha de publicación ni el contexto de los estudios. CRITERIOS DE SELECCIÓN: Se consideraron los ensayos controlados aleatorizados (ECA) que compararon la limpieza de heridas con ninguna limpieza de heridas, o ECA que compararon diferentes soluciones de limpieza de heridas o diferentes técnicas de limpieza de heridas. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Se examinaron los estudios para determinar si eran adecuados para inclusión, el riesgo de sesgo se evaluó mediante la herramienta Cochrane "Risk of bias" y se utilizó el método GRADE para determinar la certeza de la evidencia. Dos autores de la revisión realizaron estas tareas de forma independiente, utilizando criterios predeterminados. Cuando fue posible, se estableció contacto con los autores de los estudios para obtener los datos faltantes. RESULTADOS PRINCIPALES: Se incluyeron cuatro estudios con un total de 254 participantes. Todos los estudios incluyeron comparaciones entre diferentes tipos de soluciones de limpieza, y tres de ellos informaron sobre los desenlaces principales de esta revisión, cicatrización completa de la herida o cambio en el tamaño de la úlcera con el tiempo, o ambos. Dos estudios informaron sobre el desenlace secundario de dolor. Un estudio (27 participantes), que comparó la solución de polihexametileno biguanida (PHMB) con el suero fisiológico para la limpieza de las úlceras venosas de la pierna, no informó sobre ninguno de los desenlaces principales ni secundarios de la revisión. No se identificaron estudios que compararan la limpieza con ninguna limpieza, o que explorara comparaciones entre diferentes técnicas de limpieza. Un estudio (61 participantes) comparó el peróxido de oxígeno acuoso con el agua estéril. No hay certeza de que el peróxido de oxígeno acuoso suponga alguna diferencia en el número de heridas completamente cicatrizadas tras 12 meses de seguimiento (razón de riesgos [RR] 1,88; intervalo de confianza [IC] del 95%: 1,10 a 3,20). Del mismo modo, no hay certeza de que el peróxido de oxígeno acuoso suponga alguna diferencia en el cambio del tamaño de la úlcera tras ocho semanas de seguimiento (diferencia de medias [DM] ­1,38 cm2; IC del 95%: ­4,35 a 1,59 cm2). Por último, no hay certeza de que el peróxido de oxígeno acuoso suponga alguna diferencia en la reducción del dolor, evaluada tras ocho semanas de seguimiento mediante una calificación del dolor de 0 a 100 (DM 3,80; IC del 95%: ­10,83 a 18,43). La evidencia para estos desenlaces es de certeza muy baja (se disminuyó la calificación por las limitaciones del estudio y la imprecisión; para el desenlace dolor también se disminuyó la calificación por medidas indirectas). Otro estudio (40 participantes) comparó la propil betaína y la polihexanida con una solución salina. Los autores no presentaron los datos brutos en el informe del estudio, por lo que no fue posible realizar un análisis estadístico independiente de los datos. No se sabe si la propil betaína y la polihexanida suponen alguna diferencia en el número de heridas completamente cicatrizadas, en el cambio del tamaño de la úlcera con el tiempo o en la reducción del dolor de la herida. La evidencia es de certeza muy baja (se disminuyó por las limitaciones del estudio y la imprecisión). El último estudio (126 participantes) comparó el dihidrocloruro de octenidina/fenoxietanol (OHP) con la solución de Ringer. No hay certeza de que el OHP suponga alguna diferencia en el número de heridas cicatrizadas (RR 0,96; IC del 95%: 0,53 a 1,72) ni en el cambio del tamaño de la úlcera con el tiempo (no fue posible realizar un análisis estadístico independiente de los datos disponibles). La evidencia es de certeza muy baja (se disminuyó por las limitaciones del estudio y la imprecisión). Ninguno de los estudios informó sobre la preferencia de los pacientes, la facilidad de uso del método de limpieza, el coste o la calidad de vida relacionada con la salud. En un estudio en el que se compara la propil betaína y la polihexanida con la solución salina, los autores no informaron la aparición de eventos adversos. No hay certeza de que el OHP suponga alguna diferencia en el número de eventos adversos en comparación con la solución de Ringer (RR 0,58; IC del 95%: 0,29 a 1,14). La evidencia es de certeza muy baja (se disminuyó por las limitaciones del estudio y la imprecisión). CONCLUSIONES DE LOS AUTORES: En la actualidad se carece de evidencia de ECA para guiar la toma de decisiones sobre la efectividad de la limpieza de heridas en comparación con ninguna limpieza y los enfoques óptimos para la limpieza de las úlceras venosas de la pierna. A partir de los cuatro estudios identificados, no hay evidencia suficiente para demostrar si el uso de la solución PHMB en comparación con el suero fisiológico; el peróxido de oxígeno acuoso en comparación con el agua estéril; la betaína propil y la polihexanida en comparación con un suero fisiológico; o el OHP en comparación con la solución de Ringer supone alguna diferencia en el tratamiento de las úlceras venosas de la pierna. La evidencia de tres de los estudios es de certeza muy baja, debido a las limitaciones de los estudios y a la imprecisión. Un estudio no presentó datos para los desenlaces principales ni secundarios. Podría ser importante realizar más estudios bien diseñados que aborden desenlaces clínicos, de calidad de vida y económicos importantes, sobre la base de la prioridad clínica y para el paciente de esta falta de certeza.

Evaluation of the Effect of Plasma from Patients with Trophic Ulcers on the Function of Dermal Fibroblasts, Mesenchymal Stem Cells, and Endothelial Cells.

We studied the effect of platelet lysate and platelet-poor plasma from patients with trophic ulcers with and without type 2 diabetes mellitus on proliferation, migration, and apoptosis of human dermal fibroblast, mesenchymal stem cells, and endothelial cells. It is shown that plasma obtained from patients with type 2 diabetes mellitus produced inhibitory effects.

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.

Autotransplantation of the Adipose Tissue-Derived Mesenchymal Stromal Cells in Therapy of Venous Stasis Ulcers.

Adipose tissue is a reliable source of mesenchymal stromal cells (MSC) for use in regenerative medicine. The aim of this pilot study was to describe the method, and assess the safety and the potential efficacy of transplantation of autologous adipose tissue-derived MSC for the treatment of chronic venous stasis ulcers. Study group consisted of 11 patients (mean age: 66.6 ± 9.5 years) with chronic venous stasis ulcers. Adipose tissue was harvested by tumescent-aspiration method. Stromal cells were separated using a dedicated closed system in a real-time bedside manner. The phenotype of cells was determined immediately after separation. Cell concentrate was implanted subcutaneously around the wound and the wound bed. All ulcers were assessed planimetrically before autotransplantation and every two weeks during the six-month follow-up. During the study all patients received standard local and general treatment. The preparation contained an average of 5.6 × 106 ± 4 × 106 cells per milliliter. The phenotype of 65-82% of transplanted cells expressed MSC markers: CD73+ CD90+ and CD34+. An improvement was observed in 75% of ulcers. The data showed highly significant negative correlation (p < 0.0001) between wound size and wound closure degree. There was no correlation of ulcer healing with other parameters evaluated, including age of the patients. No serious side effects were observed. Autotransplantation of adipose tissue stromal cells may be a safe and promising treatment method for chronic venous ulcers.

Ultrasound- and fluoroscopy-guided foam sclerotherapy for lower extremity venous ulcers.

OBJECTIVE: In foam sclerotherapy for varicose veins, ultrasound can track the spread of foam in only one direction. We hypothesized that using fluoroscopy in combination with ultrasound can reveal the spread of foam to deep veins through perforator veins and to other varicose veins in different directions. In this study, we examined the safety and effectiveness of ultrasound- and fluoroscopy-guided foam sclerotherapy for lower extremity venous ulcers. METHODS: This retrospective study included all patients receiving ultrasound- and fluoroscopy-guided foam sclerotherapy for varicose ulcers (Clinical, Etiology, Anatomy, and Pathophysiology class 6) of the lower extremities at the Fourth Affiliated Hospital of Jiangsu University (Zhenjiang, China) between May 1, 2016, and April 30, 2018. Polidocanol foam sclerosant was injected through indwelling needles (placed every 20 cm for saphenous veins and every 5-10 cm for others) into the varicose veins. When the contrast medium in the target vessels was replaced by the hypointense foam sclerosant or on signs of foam entry into the perforator veins under fluoroscopy, the injection was stopped and the site was manually pressed. All patients received postprocedure compression with elastic bandages until ulcer healing and compression stockings (30-40 mm Hg) thereafter. RESULTS: A total of 35 patients (42 limbs) were included. The maximal ulcer diameter was 3.6 ± 1.4 cm (range, 1.1-5.8 cm). The number of injection sites ranged from 3 to 10; total foam amount ranged from 4.5 to 35 mL. All 35 patients completed 12-month follow-up. Ulcer healing rate was 100%, and 1-year recurrence rate was 2.9%. The Venous Clinical Severity Score was 12.98 ± 3.91 before treatment, decreasing to 3.02 ± 2.39 at 12 months (P < .01). Superficial thrombophlebitis developed in 21 (50%) limbs. No deep venous thrombosis or pulmonary embolism was observed during follow-up. Among the 33 limbs (27 patients) with ultrasound examination at 12 months, 28 (84.8%) limbs had complete occlusion and the remaining 5 (15.2%) had recanalization. CONCLUSIONS: Ultrasound- and fluoroscopy-guided foam sclerotherapy is safe and effective for the treatment of venous ulcers of the lower extremities.

MicroRNA-34 Family Enhances Wound Inflammation by Targeting LGR4.

Venous ulcers are the most common type of human chronic nonhealing wounds and are stalled in a constant and excessive inflammatory state. The molecular mechanisms underlying the chronic wound inflammation remain elusive. Moreover, little is known about the role of regulatory RNAs, such as microRNAs, in the pathogenesis of venous ulcers. We found that both microRNA (miR)-34a and miR-34c were upregulated in the wound-edge epidermal keratinocytes of venous ulcers compared with normal wounds or the skin. In keratinocytes, miR-34a and miR-34c promoted inflammatory chemokine and cytokine production. In wounds of wild-type mice, miR-34a-mimic treatment enhanced inflammation and delayed healing. To further explore how miR-34 functions, LGR4 was identified as a direct target mediating the proinflammatory function of miR-34a and miR-34c. Interestingly, impaired wound closure with enhanced inflammation was also observed in Lgr4 knockout mice. Mechanistically, the miR-34-LGR4 axis regulated GSK-3ß-induced p65 serine 468 phosphorylation, changing the activity of the NF-κB signaling pathway. Collectively, the miR-34-LGR4 axis was shown to regulate keratinocyte inflammatory response, the deregulation of which may play a pathological role in venous ulcers.

Associations between patient, treatment, or wound-level factors and venous leg ulcer healing: Wound characteristics are the key factors in determining healing outcomes.

Chronic venous leg ulcers are challenging to heal and often recur. This has a significant impact on older individual health and is a financial burden on health care resources. This study aimed to identify factors associated with the healing of venous leg ulcers via secondary examination of data from a previously published prospective randomized controlled trial of elastic and inelastic compression systems. The data from the 45 patients who finished the trial was reanalyzed for a hypothesis generating study. Larger ulcers, higher exudate levels, larger calf circumferences, and longer ulcer duration at baseline were associated with lack of healing at 12 weeks. There was some evidence that NSAID use was associated with an increased likelihood of nonhealing (unadjusted OR for healing, 0.13, 95% CI (0.02, 0.70)). There was no evidence that other variables, including gender and BMI, were associated with healing. The key risk factors for wound healing are largely wound based or inherent to wound development, as these were found to be the factors with the strongest associations in the analysis. Future research should address how and why these factors are associated with wound healing over a longer time frame and explore how NSAIDs may affect wound healing outcomes.

Efficacy and Safety of 4% Hibiscus rosa-sinensis Leaf Extract Ointment as an Adjunct Treatment to Compression Stockings on the Closure of Venous Leg Ulcers: A Pilot Study.

INTRODUCTION: Venous leg ulcers (VLUs), the most common leg ulceration worldwide, are caused by venous hypertension due to venous reflux, the failure of the calf muscle to pump, and venous flow obstruction. They are associated with a reduced quality of life, particularly in relation to pain and physical function. Hibiscus rosa-sinensis is commonly employed because of its many medicinal properties, and studies have shown Hibiscus contains phytochemicals that have antimicrobial, antioxidant, and anti-inflammatory properties that promote wound healing. OBJECTIVE: The authors evaluate the efficacy and safety of 4% gumamela leaf extract ointment in the closure of VLUs among patients seen in a dermatology outpatient department in the Philippines. MATERIALS AND METHODS: The study included male or female patients with leg ulcers confirmed by duplex scan to be venous in origin and willing to have elastic compression therapy. Patients were instructed to clean the wound with normal saline solution and to apply the extract twice daily. The study was conducted for 12 weeks or until wound closure. Wounds were evaluated and photographed at baseline and every subsequent 2 weeks. Efficacy of therapy was evaluated based on ulcer area size using planimetry method at each visit. Safety was assessed using a 4-point grading system to monitor possible adverse reactions, namely pruritus, rash, burning, and urticaria. RESULTS: Twelve patients were included in the study; 5 patients had an initial ulcer area of ⟩ 10 cm2 and 7 had an initial ulcer area of ≤ 10 cm2. By the end of the study, 10 patients (83.3%) achieved complete ulcer closure in ⟨ 12 weeks, 1 patient (8.3%) had a decrease in ulcer area ⟩ 50% by week 12, and 1 patient (8.3%) had ⟨ 50% decrease in ulcer area at the end of the study. CONCLUSIONS: Data showed compression stockings with 4% gumamela leaf extract ointment application could close VLUs in ⟨ 12 weeks. Applied with compression stockings, the ointment shows potential use in VLU management.

A systematic review of Calendula officinalis extract for wound healing.

Use of complementary and alternative medicine for wound healing is influencing mainstream medical practice. This systematic review evaluates the role of Calendula officinalis flower extract as monotherapy compared to control for wound healing in vivo. Searches were conducted in PubMed, EMBASE, Cochrane Central Register of Controlled Trials, CINAHL, and Scopus (up to April 2018) with 14 studies meeting the inclusion criteria, comprising 7 animal experiments and 7 clinical trials. Findings from the review on acute wound healing showed faster resolution of the inflammation phase with increased production of granulation tissue in the test groups treated with extract. These findings were consistent in five animal studies and one randomized clinical trial. Chronic wound healing studies were varied. Two clinical control studies on venous ulcers demonstrated decreased ulcer surface area compared to controls. Another randomized clinical trial demonstrated no improvement for the calendula group in diabetic leg ulcer healing. Burn healing similarly showed mixed results. Two animal studies demonstrated a prophylactic effect for the administration of calendula extract prior to burn injury. A randomized clinical trial of patients suffering from partial to full thickness burns demonstrated no benefit for topical application of calendula extract compared to controls. Two randomized clinical trials assessed the potential for extract to prevent acute post radiation dermatitis, with one study showing improvements compared to trolamine, while the other found no improvement compared to aqua gel cream. Animal studies provide moderate evidence for improved recovery from the inflammation phase and increased production of granulation tissue in calendula extract treatment groups. This review identified some evidence for the beneficial effects of C. officinalis extract for wound healing, consistent with its role in traditional medicine. There is a need for larger, well-designed randomized control trials to assess the effect of calendula on wound healing including complications.

Antibiogram in the biopsy of chronic venous ulcers related to sudden changes in the pain profile.

INTRODUCTION: Chronic venous insufficiency (CVI) has an important impact on the public health system in particular due to the occurrence of chronic venous ulcers (UCV) and infections. OBJECTIVE: To evaluate cultures of biopsies of chronic venous ulcers of patients who suffered an acute change in the intensity of pain of the lesion. METHOD: Antibiograms of the cultures of chronic venous ulcer biopsies of patients who suffered an acute change in the lesion with significant pain for 24 hours were evaluated. All patients were treated between 2011 and 2015 in the Vascular Surgery Outpatient Clinic of the Medical School in São José do Rio Preto. Other causes of pain such as chronic arterial insufficiency and problems with the dressings were ruled out. RESULTS: Positive cultures were detected in 34 of the 35 patients whose pain was resolved by antibiotic therapy. CONCLUSION: Acute changes in the intensity of pain associated with chronic venous ulcers seem to be related to local infectious disease.

Evaluation of wound fluid biomarkers to determine healing in adults with venous leg ulcers: A prospective study.

Clinical practice guidelines recommend using repeated wound surface area measurements to determine if a chronic ulcer is healing. This results in delays in determining the healing status. This study aimed to evaluate whether any of a panel of biomarkers can determine the healing status of chronic venous leg ulcers. Forty-two patients with chronic venous leg ulcers had their wound measured and wound fluid collected at weekly time points for 13 weeks. Wound fluid was analyzed using multiplex enzyme-linked immunosorbent assay to determine the concentration of biomarkers in the wound fluid at each weekly time point. Healing status was determined by examining the change in wound size at the previous and subsequent weeks. Predictive accuracy with 95% confidence intervals (CI) is reported. Of 42 patients, 105 evaluable weekly time points were obtained, with 32 classified as healing, 27 as nonhealing, and 46 as indeterminate. Thirteen biomarkers significantly differed between healing and nonhealing wounds (p < 0.1) and were included in a multivariate logistic regression model. Granulocyte macrophage-colony stimulating factor (p < 0.001) and matrix metalloprotease-13 (p = 0.004) were the best predictors of wound healing. Receiver operating characteristic curves indicated 92% accuracy (95% CI: 85%,100%) for granulocyte macrophage-colony stimulating factor, and 78% accuracy (95% CI: 65%,90%) for matrix metalloprotease-13 in discriminating between healing and nonhealing wounds. This study found that two biomarkers from wound fluid can predict healing status in chronic venous leg ulcers. These findings may lead to the ability to determine the future trajectory of a wound and the ability to modify treatment accordingly.