Low molecular weight heparin improves healing of chronic venous ulcers especially in the elderly

Venous ulcers are common, especially in the elderly, accounting for more than 50% of all lower extremity ulcers with important socioeconomic problems. Improving extracellular matrix functioning, by heparin administration, seems to be a way to support wound healing. A total of 284 patients with venous ulcers were recruited in a 4‐year period. All patients were subjected to the most appropriate treatment after considering their preference (compression therapy followed or not by vein surgery). Patients were randomised into two groups of 142 persons in each (group A and group B as cases and controls, respectively). Patients of group A, in addition to the basic treatment as described earlier, received administration of nadroparin 2850 IU/0.3 ml through subcutaneous injection once a day for 12 months, whereas group B patients received basic treatment alone. Healing was assessed by means of direct ulcer tracing with computerised planimetry. Group A showed a healing rate of 83·80% at 12 months, whereas that of group B was 60·56%. Results by age group surprisingly showed that the group of older patients took the most advantage from long‐term treatment with low molecular weight heparin; this group also had lowest recurrence rate.     

Doxycycline speeds up healing of chronic venous ulcers

Venous ulcers are common, with an overall prevalence of up to 2% in the general population of western countries, and have significant socioeconomic impact. Matrix metalloproteinases (MMPs) are involved in the alteration of extracellular matrix that could lead to venous ulceration. Sixty‐four patients with venous ulcers were recruited in a 22‐month period. All patients were subjected to the most appropriate treatment considering also the patient's wishes (compression therapy followed or not by vein surgery). Patients were randomised into two groups of 32 persons in each (groups A and B). Patients of group A in addition to the basic treatment, described above, received the administration of oral low doses of doxycycline 20 mg b.i.d. for 3 months, whereas patients of group B received basic treatment only. Healing was assessed by means of direct ulcer tracing with computerised planimetry. Group A showed a higher healing rate compared with group B. In group B, the lower healing rate was related to higher levels of MMP‐9; neutrophil gelatinase‐associated lipocalin and vascular endothelial growth factor, documented in plasma; wound fluid and biopsies executed and compared between both groups. Pharmacological treatments, as doxycycline administration, which by means of its immunomodulatory and anti‐inflammatory actions, through the inhibition of MMP, could improve extracellular matrix functioning and represent a possible solution to support wound healing.     

The role of adult tissue‐derived stem cells in chronic leg ulcers: a systematic review focused on tissue regeneration medicine

Wound healing is an articulated process that can be impaired in different steps in chronic wounds. Chronic leg ulcers are a special type of non‐healing wounds that represent an important cause of morbidity and public cost in western countries. Because of their common recurrence after conventional managements and increasing prevalence due to an ageing population, newer approaches are needed. Over the last decade, the research has been focused on innovative treatment strategies, including stem‐cell‐based therapies. After the initial interest in embryonic pluripotent cells, several different types of adult stem cells have been studied because of ethical issues. Specific types of adult stem cells have shown a high potentiality in tissue healing, in both in vitro and in vivo studies. Aim of this review is to clearly report the newest insights on tissue regeneration medicine, with particular regard for chronic leg ulcers.     

The association of wound factors and symptoms of fatigue and pain with wound healing in chronic venous leg ulcers

The purpose of this study was: (1) to characterise the association of wound area, wound exudate C-reactive protein (CRP), broad-spectrum matrix metalloprotease protein (MMPs), and symptoms of fatigue and pain in individuals with chronic venous leg ulcers (CVLUs) over time and (2) to identify factors associated with the wound healing trajectory in CVLUs. Seventy four participants with CVLU who received weekly sharp debridement were recruited from a wound care clinic during the 8-week study period. To examine associations among wound CRP, MMPs, pain, fatigue, and wound healing trajectory over time, we calculated Bayes factors (BF) based on a linear mixed model. The mean age of participants was 71.8 (SD = 9.8) and the mean wound area was 2278 mm² (SD = 7085 mm²) at baseline. Higher fatigue was strongly associated with higher MMPs (BF = 9, 95% HDI: [−.05, .43]), lower CRP (BF = 11, 95% HDI: [−.02, .002]), and large areas of wound (BF = 20, 95% HDI: [−.001, .01]). Higher CRP and MMPs activity in wound exudate and higher fatigue were associated with a larger wound area. To facilitate wound healing, clinicians need to utilise the multifactorial approach, which includes wound treatment and management of symptoms such as pain and fatigue, because of the molecular and psycho-behavioural factors involved in wound healing.     

Dystrophic calcification as a cause for non healing leg ulcers

Despite advances in molecular biology and a repertoire of other therapeutic options, chronic venous leg ulcers remain a significant problem within our society. There are various reasons, both local and systemic, which contribute to the non healing nature of such wounds. Among them, dystrophic calcification (DC) or calcified deposits within the ulcer bed, although rare, is an overlooked and a seldom reported cause. In the presence of DC, wound healing cannot proceed through a timely and orderly manner resulting in a non healing ulcer. In this article, we discuss the aetiology, pathophysiology and the management options of this rarely reported condition. We also report their clinical prognosis using a series of patients with venous ulcers complicated by DC leading to difficulties in healing.     

Hyperhomocysteinaemia and chronic venous ulcers

Chronic venous ulceration (CVU) is the major cause of chronic wounds of lower extremities, and is a part of the complex of chronic venous disease. Previous studies have hypothesised that several thrombophilic factors, such as hyperhomocysteinaemia (HHcy), may be associated with chronic venous ulcers. In this study, we evaluated the prevalence of HHcy in patients with venous leg ulcers and the effect of folic acid therapy on wound healing. Eighty‐seven patients with venous leg ulcers were enrolled in this study to calculate the prevalence of HHcy in this population. All patients underwent basic treatment for venous ulcer (compression therapy ± surgical procedures). Patients with HHcy (group A) received basic treatment and administered folic acid (1·2 mg/day for 12 months) and patients without HHcy (group B) received only basic treatment. Healing was assessed by means of computerised planimetry analysis. The prevalence of HHcy among patients with chronic venous ulcer enrolled in this study was 62·06%. Healing rate was significantly higher (P < 0·05) in group A patients (78·75%) compared with group B patients (63·33%). This study suggests a close association, statistically significant, between HHcy and CVU. Homocysteine‐lowering therapy with folic acid seems to expedite wound healing. Despite these aspects, the exact molecular mechanisms between homocysteine and CVU have not been clearly defined and further studies are needed.     

Efficacy and cost‐effectiveness of octenidine wound gel in the treatment of chronic venous leg ulcers in comparison to modern wound dressings

The aim of this study was to determine the efficacy, safety and cost‐effectiveness of an octenidine‐based wound gel in the treatment of chronic venous leg ulcers. For this purpose, 49 wounds were treated with either modern wound‐phase‐adapted dressings alone (treatment arm 1; n = 17), octenidine wound gel plus modern wound‐phase‐adapted dressings (treatment arm 2; n = 17) or octenidine wound gel alone (treatment arm 3; n = 15). During the study period of 42 days with dressing changes every 3–5 days, wound healing characteristics and treatment costs of different dressings were analysed. Wound size reduction was significantly better (P = 0·028) in both octenidine wound gel treatment arms compared to modern dressings alone with total reductions of 14·6%, 64·1% and 96·2% in treatment arms 1–3. Early wound healing was merely observed under octenidine wound gel treatment (n = 9), whereby lowest treatment costs were generated by octenidine wound gel alone (€20·34/dressing change). As a result, the octenidine wound gel is cost‐effective and well suitable for the treatment of chronic venous leg ulcers, considering both safety and promotion of wound healing.     

The impact of a new intervention for venous leg ulcers: A within-patient controlled trial

A major obstacle to the development of new treatments for venous leg ulcers is the difficulty in generating evidence for their effectiveness. Randomised controlled trials using complete healing as the endpoint are seldom powered to be successful, owing to the heterogeneity of cohorts. A novel approach to the evaluation of treatments is presented, using a self-controlled trial model and two metrics of short-term healing rate as alternate endpoints: rate of wound margin advance, and percentage area reduction over 4 weeks. Two different treatment regimens are compared: multi-layer compression alone, versus multi-layer compression combined with activation of the venous leg pump by neuromuscular stimulation. With 60 patients, adding neuromuscular stimulation to multilayer compression resulted in a significant two-fold increase in the rate of wound healing over a 4-week period, both in terms of wound margin advance and in terms of percentage area reduction. The use of these short-term intermediate endpoint metrics together with a self-controlled study design offers potential for distinguishing between the relative efficacies of interventions more rapidly, with greater sensitivity, and with fewer subjects than a conventional RCT cohort model.     

Feasibility of an electrostimulation system treatment for wound healing: a case series of patients with chronic ulcers in Barbados

Major advances have been made in the development of new therapies for chronic wounds. Fenzian?, an electrostimulation system (ES), has been clinically used for a variety of conditions. The ES was recently tested in the Barbadian population for tolerability and acceptability by asthma patients, with encouraging results. Barbados has an estimated 170 people with diabetes having some form of lower‐extremity amputation annually. Here, we describe a case series of 21 chronic ulcer patients with diabetes recruited as inpatients (n = 10) and outpatients (n = 11) in a pilot study to evaluate the feasibility and acceptability of ES in the Barbadian population. Results showed statistically significant improvement among those in the inpatient‐ versus outpatient‐recruited group for wound perimeter (P = 0·04), wound surface area (P = 0·03) and wound volume (P = 0·08). We also demonstrate that the improvement continued after cessation of ES treatment. Participants reported increased levels of pain at the end of treatment, and there was no statistically significant change in the reported quality of life. Our results showed greater improvements in reduction of ulcer size for participants from the inpatient‐ versus outpatient‐recruited group.     

Identifying relationships between symptom clusters and quality of life in adults with chronic mixed venous and arterial leg ulcers

The objective of this study was to identify symptom clusters and their effect on quality of life (QOL) of adults with chronic leg ulcers of mixed venous and arterial aetiology. A secondary analysis of data from four existing prospective longitudinal studies conducted by a wound healing research group in Australia was undertaken. A total of 110 patients who met the inclusion criteria were selected for this study. Exploratory factor analysis (EFA) was used to identify symptom clusters and correlational analyses to examine relationships between the identified symptom clusters and QOL. The EFA identified two distinct symptom clusters: a ‘systemic symptom cluster’ consisting of pain, fatigue and depressive symptoms; and a ‘localised‐leg symptom cluster’ including pain, fatigue, oedema, lower limb inflammation and exudate. Physical QOL correlated significantly with the systemic symptom cluster (r = ?0·055, P < 0·0001) and the localised‐leg symptom cluster (r = ?0·054, P < 0·0001), whereas mental QOL was associated only with the systemic symptom cluster (r = ?0·038, P = 0·01). The results suggest that appropriate intervention strategies targeting specific symptom clusters should be developed. Targeting patients with symptom clusters is particularly important because they are at high risk and the most vulnerable for reduced QOL.     

Growth factors for treating chronic venous leg ulcers: A systematic review and meta-analysis

Chronic venous leg ulcers (VLU) are wounds that commonly occur due to venous insufficiency. Many growth factors have been introduced over the past two decades to treat VLU. This systematic review and meta-analysis evaluates the impact of growth factor treatments of VLU in comparison to control for complete wound healing, percent reduction in wound area, time to wound healing, and adverse events. A systematic review and meta-analysis of randomised trials was conducted. MEDLINE and EMBASE were searched up to December 2020. Studies were included if they compared a growth factor versus placebo or standard care in patients with VLU. From 1645 articles, 13 trials were included (n = 991). There was a significant difference between any growth factor and placebo in complete wound healing (P = 0.04). Any growth factor compared to placebo significantly increased the likelihood of percent wound reduction by 48.80% (P = <0.00001). There was no difference in overall adverse event rate. Most comparisons have low certainty of evidence according to Grading of Recommendations, Assessment, Development, and Evaluation. This meta-analysis suggests that growth factors have a beneficial effect in complete wound healing of VLU. Growth factors may also increase percent reduction in wound area. The suggestion of benefit for growth factors identified in this review is not a strong one based on the low quality of evidence.     

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.     

Effect of oxidised regenerated cellulose/collagen matrix on proteases in wound exudate of patients with chronic venous ulceration

Oxidised regenerated cellulose/collagen matrix (ORC/collagen matrix) modifies wound microenvironments by binding and inactivating excess levels of proteases such as elastase, plasmin and gelatinases in wound exudates. To compare levels of the gelatinases matrix metalloproteinase 2 (MMP-2), elastase and plasmin in wound exudates collected from chronic venous insufficiency patients with venous leg ulcers treated with either an ORC/collagen matrix or a standard control therapy. During a 12-week treatment period, wound exudate samples were obtained from a control group of 10 patients treated with a hydrocolloid dressing and a treatment group of 17 patients treated with a combination of ORC/collagen matrix and hydrocolloid dressing. On admission and days 5, 14 and every subsequent 14th day, ulcers were photographed to determine healing rate and changes in ulcer appearance, and MMP-2 concentration and the gelatinase, elastase and plasmin activities were analysed from wound exudates. The patients treated with ORC/collagen matrix showed a significant decrease in elastase, plasmin and gelastinase activity as compared with the control group, with no significant difference in the MMP-2 concentrations between the two groups. The results show a significant and immediate reduction in protease activity in wound exudates from venous leg ulcers treated with ORC/collagen.     

Safety and performance evaluation of a next‐generation antimicrobial dressing in patients with chronic venous leg ulcers

The objective of this study was to investigate the safety and performance of AQUACEL? Ag+ dressing, a wound dressing containing a combination of anti‐biofilm and antimicrobial agents, in the management of chronic wounds. Patients (n = 42) with venous leg ulcers exhibiting signs of clinical infection were treated for 4 weeks with AQUACEL? Ag+ dressing, followed by management with AQUACEL? wound dressings for 4 weeks. Wound progression, wound size, ulcer pain and clinical evolution of the wound were assessed for up to 8 weeks. Adverse events were recorded throughout the study. AQUACEL? Ag+ dressing had an acceptable safety profile, with only one patient discontinuing from the study, because of a non‐treatment‐related adverse event. After 8 weeks, substantial wound improvements were observed: 5 patients (11·9%) had healed ulcers and 32 patients (76·2%) showed improvement in ulcer condition. The mean ulcer size had reduced by 54·5%. Patients reported less pain as the study progressed. Notable improvements were observed in patients with ulcers that were considered to require treatment with systemic antibiotics or topical antimicrobials at baseline (n = 10), with a mean 70·2% reduction in wound area. These data indicate that AQUACEL? Ag+ dressing has an acceptable safety profile in the management of venous leg ulcers that may be impeded by biofilm.     

Role of matrix metalloproteinases in non‐healing venous ulcers

Chronic venous ulceration (CVU) of the lower limbs is a common condition affecting 1% of the adult population in Western countries, which is burdened with a high complication rate and a marked reduction in the quality of life often due to prolonged healing time. Several metalloproteinases (MMPs) such as MMP‐9 together with neutrophil gelatinase‐associated lipocalin (NGAL) appear to be involved in the onset and healing phases of venous ulcer, but it is still unclear how many biochemical components are responsible for prolonged healing time in those ulcers. In this study, we evaluate the role of MMP‐1 and MMP‐8 in long lasting and refractory venous ulcers. In a 2‐year period we enroled 45 patients (28 female and 17 male, median age 65) with CVU. The enroled population was divided into two groups: group I were patients with non‐healing ulcers (ulcers that had failed to heal for more than 2 months despite appropriate treatments) and group II were patients with healing ulcers (ulcers in healing phases). MMP‐1 and MMP‐8 were measured in fluids and tissues of healing and non‐healing ulcers by means of enzyme‐linked immunosorbent assay (ELISA) and Western blot analysis, respectively. In particular the patterns of the collagenases MMP‐1 and MMP‐8 in healing wounds were distinct, with MMP‐8 appearing in significantly greater amounts especially in the non‐healing group. Our findings suggest that MMP‐1, and MMP‐8 are overexpressed in long lasting CVU. Therefore, this dysregulation may represent the main cause of the pathogenesis of non‐healing CVU.     

Induction of MMP-1, MMP-3 and TIMP-1 in normal dermal fibroblasts by chronic venous leg ulcer wound fluid*

In the wound bed of chronic venous leg ulcers, an imbalance of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) may cause excessive proteolysis and impair wound granulation. Soluble mediators in the wound environment may be responsible for this imbalance. The in vitro effect of wound fluid from venous leg ulcers on dermal fibroblast production of MMP-1, MMP-3 and TIMP-1 was compared with the effect of acute wound fluid from two different sources: fluid from post-mastectomy axillary drains and fluid from skin graft donor sites. Significantly higher MMP-1 and MMP-3 levels were induced by chronic venous leg ulcer wound fluid compared with both types of acute wound fluid (P < 0.005). Chronic venous ulcer wound fluid reduced TIMP-1 protein levels significantly more than acute graft fluid (P < 0.05). Venous ulcer wound fluid significantly increased MMP-1 and MMP-3 production in dermal fibroblasts and reduced TIMP-1 production, confirming that mediators in the leg ulcer microenvironment can potentially induce excessive proteolysis in the ulcer dermis by altering the balance between MMPs and TIMPs. Inflammatory mediators including interleukin-1beta and tumour necrosis factor-alpha can induce these MMPs. Further work is required to confirm the factors responsible for the induction of a high MMP and low TIMP profile in fibroblasts by venous ulcer wound fluid.     

Mobility range,level of pain and sleep quality of patients with venous leg ulcers

This study aimed to compare mobility range, level of pain and sleep quality in patients with venous leg ulcers to age- and gender-matched controls without ulcers. Twenty patients with venous leg ulceration and 20 matched controls each answered a questionnaire, completed the short-physical performance battery, filled in a subject diary and wore a smartwatch for 1 week. The median daily step counts of the ulcer group (3622 steps/day) and the control group (5133 steps/day) were significantly different (P = .017). Significant correlations between total step count and age, duration of physical outdoor activities and scores in the short-physical performance battery were observed in the ulcer group. The scores in the short-physical performance battery were significantly different in both groups (P = .005), indicating weaker physical performance in the ulcer group. The greatest difference in the self-reported level of pain between the two groups was stated during movement. On average, the ulcer group slept shorter by 1 h 38 min (P = .002) and had 0.7 wake phases per night (P = .019) more than the control group. Assessing mobility in patients with venous leg ulcers can be used to develop preventive and interventional concepts to improve and individualise physical therapies.     

PredyCLU: a prediction system for chronic leg ulcers based on fuzzy logic; part I – exploring the venous side

Chronic leg ulcers (CLUs) are a common occurrence in the western population and are associated with a negative impact on the quality of life of patients. They also cause a substantial burden on the health budget. The pathogenesis of leg ulceration is quite heterogeneous, and chronic venous ulceration (CVU) is the most common manifestation representing the main complication of chronic venous disease (CVD). Prevention strategies and early identification of the risk represent the best form of management. Fuzzy logic is a flexible mathematical system that has proved to be a powerful tool for decision‐making systems and pattern classification systems in medicine. In this study, we have elaborated a computerised prediction system for chronic leg ulcers (PredyCLU) based on fuzzy logic, which was retrospectively applied on a multicentre population of 77 patients with CVD. This evaluation system produced reliable risk score patterns and served effectively as a stratification risk tool in patients with CVD who were at the risk of developing CVUs.     

A meta-review of the impact of compression therapy on venous leg ulcer healing

This meta-review aimed to appraise and synthesise findings from existing systematic reviews that measured the impact of compression therapy on venous leg ulcers healing. We searched five databases to identify potential papers; three authors extracted data, and a fourth author adjudicated the findings. The AMSTAR-2 tool was used for quality appraisal and the certainty of the evidence was appraised using GRADEpro. Data analysis was undertaken using RevMan. We identified 12 systematic reviews published between 1997 and 2021. AMSTAR-2 assessment identified three as high quality, five as moderate quality, and four as low quality. Seven comparisons were reported, with a meta-analysis undertaken for five of these comparisons: compression vs no compression (risk ratio [RR]: 1.55; 95% confidence interval [CI] 1.34-1.78; P < .00001; moderate-certainty evidence); elastic compression vs inelastic compression (RR: 1.02; 95% CI: 0.96-1.08; P < .61 moderate-certainty evidence); four layer vs <four-layer bandage systems (RR: 1.07; 95% CI: 0.82-1.40; P < .63; moderate-certainty evidence); comparison between different four-layer bandage systems (RR: 1.08; 95% CI: 0.93-1.25; P = .34; moderate-certainty evidence); compression bandage vs compression stocking (RR 0.95; 95% CI 0.87-1.03; P = .18; moderate-certainty evidence). The main conclusion from this review is that there is a statistically significant difference in healing rates when compression is used compared with no compression, with moderate-certainty evidence. Otherwise, there is no statistically different difference in healing rates using elastic compression vs inelastic compression, four layer vs <four-layer bandage systems, different four-layer bandage systems, or compression bandages vs compression stockings.     

下肢慢性静脉溃疡的综合治疗

目的探讨下肢慢性静脉溃疡的综合治疗方法。方法回顾性分析2012年7月~2013年1月我科收治的10例下肢慢性静脉溃疡患者（10条患肢）的临床资料,均采用大隐静脉高位结扎加抽剥并联合应用透光曲张静脉刨吸术、泡沫硬化剂注射、腔镜深筋膜下交通静脉结扎术等方法处理小腿病灶。分别在术前及术后3个月对临床症状的改善情况采集数据,按临床严重程度评分（VCSS）方法进行评估。结果患者均成功实施联合手术治疗方案,在术后的VCSS评分项目中得到改善[（12.3±2.06）v s （9.6±1.71）]。随访（6.70±1.45）个月,疼痛较前均有缓解,未发现患肢有曲张浅静脉残余或复发,8例溃疡基本愈合,仅有2例还有残余溃疡,但都控制在2 cm内,已愈合的溃疡未见复发。结论下肢慢性静脉溃疡经正确选择联合治疗方案进行处理后的效果是理想且安全的,而且其短期效果稳定。