The importance of inflammation control for the treatment of chronic diabetic wounds

Diabetic chronic wounds cause massive levels of patient suffering and economic problems worldwide. The state of chronic inflammation arises in response to a complex combination of diabetes mellitus-related pathophysiologies. Advanced treatment options are available; however, many wounds still fail to heal, exacerbating morbidity and mortality. This review describes the chronic inflammation pathophysiologies in diabetic ulcers and treatment options that may help address this dysfunction either directly or indirectly. We suggest that treatments to reduce inflammation within these complex wounds may help trigger healing.     

The outcome of sutured wounds compared with tissue adhesive for paediatric wound closure: A meta-analysis

A meta-analysis investigation was executed to measure the outcome of sutured wounds (SWs) compared with tissue adhesive (TA) for paediatric wound closure (PWC). A comprehensive literature inspection till February 2023 was applied and 2018 interrelated investigations were reviewed. The 18 chosen investigations enclosed 1697 children with PWC in the chosen investigations' starting point, 977 of them were utilising SWs, and 906 were utilising TA. Odds ratio (OR) in addition to 95% confidence intervals (CIs) were used to compute the value of the effect of SWs compared with TA for PWC by the dichotomous approaches and a fixed or random model. SWs had significantly higher wound cosmetic (WC) scores (mean deviation [MD], 1.70; 95% CI, 0.57–2.84, P = .003), lower wound dehiscence (WD) (OR 0.60; 95% CI, 0.06–0.43, P < .001), and lower cost (MD, −10.22; 95% CI, −10.94 to −9.50, P < .001) compared with those with TA in PWC. No significant difference was found between children utilising SWs and TA in wound infection (WI) (OR, 0.45; 95% CI, 0.15–1.30, P = .14) with no heterogeneity (I² = 0%) in PWC. SWs had significantly higher WC scores, lower WD, and lower cost, yet, no significant difference was found in WI compared with those with TA in PWC. However, care must be exercised when dealing with its values because of the low sample size of some of the nominated investigations and the low number of selected investigations for the meta-analysis.     

Effect of platelet-rich plasma vs standard management for the treatment of diabetic foot ulcer wounds: A meta-analysis

We performed a meta-analysis to evaluate the effect of platelet-rich plasma vs standard management for the treatment of diabetic foot ulcer wounds. A systematic literature search up to March 2022 was performed and 1435 subjects with diabetic foot ulcer wounds at the baseline of the studies; 723 of them were treated with platelet-rich plasma, and 712 used control. Odds ratio (OR) with 95% confidence intervals (CIs) was calculated to assess the effect of platelet-rich plasma vs standard management for the treatment of diabetic foot ulcer wounds using the dichotomous method with a random or fixed-effect model. The use of autologous platelet-rich plasma resulted in significantly higher complete-healed diabetic foot ulcer wounds compared with control (OR, 1.95; 95% CI, 1.49-2.56, P < 0.001). The use of allogeneic platelet-rich plasma resulted in significantly higher complete-healed diabetic foot ulcer wounds compared with control (OR, 6.19; 95% CI, 2.32-16.56, P < 0.001). The use of autologous and allogeneic platelet-rich plasma resulted in significantly higher complete-healed diabetic foot ulcer wounds compared with control. Though, the analysis of outcomes should be with caution because of the low number of studies in certain comparisons, for example, allogeneic platelet-rich plasma compared with control.     

The efficacy of low-frequency ultrasound as an added treatment for chronic wounds: A meta-analysis

We performed a meta-analysis to evaluate the effect of low-frequency ultrasound as an added treatment for chronic wounds. A systematic literature search up to May 2022 was performed and 838 subjects with chronic wounds at the baseline of the studies; 412 of them were using the low-frequency ultrasound (225 low-frequency high-intensity contact ultrasound for diabetic foot wound ulcers, and 187 low-frequency low-intensity non-contact ultrasound for a venous leg wound ulcers), and 426 were using standard care (233 sharp debridements for diabetic foot wound ulcers and 193 sham treatments for venous leg wound ulcers). Odds ratio (OR), and mean difference (MD) with 95% confidence intervals (CIs) were calculated to assess the effect of low-frequency ultrasound as an added treatment for chronic wounds using the dichotomous, and contentious methods with a random or fixed-effect model. The low-frequency high-intensity contact ultrasound for diabetic foot wound ulcers had significantly lower non-healed diabetic foot wound ulcers at ≥3 months (OR, 0.37; 95% CI, 0.24-0.56, P < .001), a higher percentage of diabetic foot wound ulcers area reduction (MD, 17.18; 95% CI, 6.62-27.85, P = .002) compared with sharp debridement for diabetic foot wound ulcers. The low-frequency low-intensity non-contact ultrasound for a venous leg wound ulcers had a significantly lower non-healed venous leg wound ulcers at ≥3 months (OR, 0.31; 95% CI, 0.15-0.62, P = .001), and higher percentage venous leg wound ulcers area reduction (MD, 18.96; 95% CI, 2.36-35.57, P = .03) compared with sham treatments for a venous leg wound ulcers. The low-frequency ultrasound as an added treatment for diabetic foot wound ulcers and venous leg wound ulcers had significantly lower non-healed chronic wound ulcers at ≥3 months, a higher percentage of chronic wound ulcers area reduction compared with standard care. The analysis of outcomes should be with caution because of the low sample size of all the 17 studies in the meta-analysis and a low number of studies in certain comparisons.     

Knowledge mapping of extracellular vesicles in wound healing: A bibliometric analysis (2002-2022)

Extracellular vesicles in wound healing have become an active research field with substantial value and potential. Nevertheless, there are few bibliometric studies in this field. We aimed to visualise the research hot spots and trends of extracellular vesicles in wound healing using a bibliometric analysis to help understand the future development of basic and clinical research. The articles and reviews regarding extracellular vesicles in the wound healing were selected from the Web of Science Core Collection. VOSviewers, CiteSpace and R package “bibliometric” were used to conduct this bibliometric analysis. A total of 1225 articles from 56 countries led by China and the United States were included. The number of publications related to extracellular vesicles increased year by year. Shanghai Jiaotong University, Huazhong University of Science and Technology, Sun Yat-sen University and Central South University are the main research institutions. International Journal of Molecular Sciences is the most popular journal in this field, while Stem Cell Research & Therapy is the most frequently cited journal. These papers come from 7546 authors, among which Zhang Wei has published the most papers and Zhang Bin has the most cocited papers. The research on the treatment strategy of extracellular vesicles in the process of wound healing is the main topic in this field. “exosomes”, “miRNA”, “angiogenesis”, “regenerative medicine”, “inflammation” and “diabetic wound” are the main key words of emerging research hotspots. This is the first bibliometric study, which comprehensively summarises the research trend and development of extracellular vesicles and exocrine bodies in wound healing. These informations determine the latest research frontiers and hot directions, and provide reference for the study of extracellular vesicles and exosomes.     

Use of wound edge inversion (epibole) to generate recalcitrant and inflamed diabetic wounds

Robust and predictive pre-clinical models of recalcitrant diabetic wounds are critical for advancing research efforts toward improving healing. Murine models have logistic and genetic benefits versus larger animals; however, native murine healing inadequately represents clinically recalcitrant wounds in humans. Furthermore, current humanization techniques employing devices, deleterious mutations or chemical agents each carry model-specific limitations. To better replicate human wounds in a mouse, we developed a novel wound-edge inversion (WEI) technique that mimics the architecture of epibole and mitigates contracture, epithelialization, and consequently wound closure. In this study, we evaluated the reliability and durability of the WEI model in wild-type and obese diabetic mice and compared to healing after (i) punch biopsy, (ii) mechanical/silicone stenting or (iii) exogenous oxidative stressors. In wild-type mice, WEI demonstrated favourable closure characteristics compared to both control and stented wounds, however, wounds progressed to closure by 4 weeks. In contrast, diabetic WEI wounds persisted for 6–10 weeks with reduced contracture and epithelialization. In both diabetic and wild-type mice, WEI sites demonstrated persistence of inflammatory populations, absence of epithelialization, and histologic presence of alpha-SMA positive granulation tissue when compared to controls. We conclude that the WEI technique is particularly valuable for modelling recalcitrant diabetic wounds with sustained inflammation and dysfunctional healing.     

The efficacy and safety of cold atmospheric plasma as a novel therapy for diabetic wound in vitro and in vivo

Cold atmospheric plasma (CAP) is a group of various chemical active species, such as ozone and nitric oxide, generated by working gas. CAP was demonstrated to have an effect on tissue regeneration and wound healing. We conducted this study to evaluate the efficacy and safety of CAP as a novel therapy for diabetic wounds in vitro and in vivo. The plasma consists of ionised helium gas that is produced by a high‐voltage and high‐frequency power supply. Eight‐week‐old male db/db mice and C57BL mice were treated with helium gas (control group), 90s' CAP (low‐dose group), and 180s' CAP (high‐dose group). Mice were treated and observed for 2 weeks. Skin samples from around the wound and blood samples were collected. Our in vitro analysis included scratch wound‐healing assays by using human HaCaT immortalised human epidermal cells. After 14 days of treatment, CAP could obviously promote diabetic wound healing. Wound closure rates were significantly higher in the low‐dose group and high‐dose groups compared with the control group. Meanwhile, compared with the control group, the protein expression of IL‐6, tumour necrosis factor‐α, inducible nitric oxide synthase, and superoxide dismutase in two CAP groups significantly decreased, while the protein expression of vascular endothelial growth factor and transforming growth factor‐β in two CAP groups significantly increased (all P < .05); these data show good agreement with the change in mRNA level (all P < .05). In vitro, scratch wound‐healing assays showed that plasma treatment could effectively ensure healing within 3 minutes of exposure (all P < .05). In addition, no difference was found in histological observations of normal skin and the level of serum alanine transaminase, aspartate aminotransferase, blood urea nitrogen, creatinine, and white blood cells among the CAP groups and control group. CAP treatment for 3 minutes every day improves wound healing in diabetic mice by suppressing inflammation, reducing oxidative stress, and enhancing angiogenesis, involving several proteins signalling, and it is safe for the liver and kidney.     

Development of a model to predict closure of chronic wounds in Germany: Claims data analysis

Patients with chronic leg ulcer, pressure ulcer, or diabetic foot ulcer suffer from significant disease burden. With a view to improving healthcare provision sustainably, a predictive model of time to closure (time-to-event analysis) based on claims data was developed. To identify potential predictors of wound closure, clinical information absent from statutory health insurance (SHI) data was modelled. In patients with leg ulcers, age of the patient (hazard ratios [HR] 0.99), increasing number of comorbidities (HR 0.94), inpatient stays (HR 0.74), and treatment by a specialised wound care professional (HR 1.18) were significant predictors of time to closure (adjusted model). In almost all models, the number of inpatient stays and of comorbidities predicted a lower probability of healing. In addition, the age and the sex of the patient were found to be significant predictors in some models (leg ulcer: HR 0.99; pressure ulcer: HR 0.99). Increasing number of comorbidities and inpatient stays were predictors for closure time in all models. Since these predictors may give an indication of wound severity, further clinical information should be considered in future models, as also indicated by the moderate values of the c-statistics. This requires future data linkage between SHI and primary studies (eg, registers).     

The usefulness of platelet-rich plasma to manage skin wounds: A meta-analysis

A meta-analysis investigation to measure the usefulness of platelet-rich plasma (PRP) to manage skin wounds (SWs). A comprehensive literature inspection till February 2023 was applied and 1349 interrelated investigations were reviewed. The 22 chosen investigations enclosed animals' SWs were in the chosen investigations' starting point, 3348 of them were treated with PRP, and 2259 were control. Odds ratio (OR) in addition to 95% confidence intervals (CIs) were used to compute the value of the usefulness of PRP to manage SWs by the dichotomous and continuous approaches and a fixed or random model. PRP significantly higher percent of decreases in open wound area (OWA) (MD, 10.07; 95% CI, 6.55-13.59, P < 0.001), and lower healing time (HT) (MD, −6.31; 95% CI, −10.69 to −1.93, P = 0.005) compared to control in animals' SWs. PRP had a significantly higher percent of decreases in OWA and lower HT compared to control in animals' SWs. However, caused of the small sample sizes of several chosen investigations for this meta-analysis, care must be exercised when dealing with its values.     

Effect of stem cell treatment on burn wounds: A systemic review and a meta-analysis

A meta-analysis was performed to evaluate the effect of stem cells treatment in managing burn wounds. A systematic literature search up to March 2022 incorporated 24 studies reported between 2013 and 2021 including 400 animals with burn wounds at the beginning of the study; 211 were using stem cells treatment, and 189 controlled. Statistical tools like the contentious method were used within a random or fixed-influence model to establish the mean difference (MD) with 95% confidence intervals (CIs) to evaluate the influence of stem cells treatment in managing burn wounds. Stem cells treatment had a significantly higher burn wound healing rate (MD, 15.18; 95% CI, 11.29-19.07, P < .001), higher blood vessel number (MD, 12.28; 95% CI, 10.06-14.51, P < .001), higher vascular endothelial growth factor (MD, 10.24; 95% CI, 7.19-13.29, P < .001), lower interleukin-1 level (MD, −98.48; 95% CI, −155.33 to −41.63, P < .001), and lower tumour necrosis factor α level (MD, −28.71; 95% CI, −46.65 to −10.76, P < .002) compared with control in animals' models with burn wounds. Stem cells treatment had a significantly higher burn wound healing rate, higher blood vessel number, higher vascular endothelial growth factor, lower interleukin-1 level, and lower tumour necrosis factor α level compared with control in animals' models with burn wounds. Further studies are required to validate these findings.     

Effect of honey dressing in the management of diabetic foot ulcers: A meta-analysis

A meta-analysis study to assess the effect of honey dressing (HD) in the management of diabetic foot ulcer (DFU). A comprehensive literature examination till January 2023 was implemented and 1794 linked studies were appraised. The picked studies contained 882 subjects with DFUs were in the picked studies' baseline, 424 of them were using HD, and 458 were using a control. Odds ratio (OR) in addition to 95% confidence intervals (CIs) were used to calculate the consequence of HD in the management of DFUs after DFU by the dichotomous and continuous styles and a fixed or random model. The HD applied to DFUs caused a significantly higher wound healing rate (OR, 2.06; 95% CI, 1.45-2.93, P < .001) and lower wound healing time (MD, −10.42; 95% CI, −16.27- −4.58, P < .001) compared with the control. The HD applied to DFUs caused a significantly higher wound healing rate and lower wound healing time compared with the control. Although precautions should be taken when commerce with the consequences since most of the picked studies for this meta-analysis was with low sample sizes.     

Effect of ultrasound-supported wound debridement in subjects with diabetic foot ulcers: A meta-analysis

A meta-analysis study to assess the effect of ultrasound-supported wound debridement (USSD) in subjects with diabetic foot ulcer (DFU). A comprehensive literature examination till January 2023 was implemented and 1873 linked studies were appraised. The picked studies contained 577 subjects with DFUs in the studies' baseline, 282 of them were using USSD, 204 were using standard care, and 91 were using a placebo. Odds ratio (OR) in addition to 95% confidence intervals (CIs) were used to calculate the consequence of USSD in subjects with DFUs by the dichotomous styles and a fixed or random effect model. The USSD applied to DFU caused a significantly higher wound healing rate compared with the standard care (OR, 3.08; 95% CI, 1.94–4.88, P < .001) with no heterogeneity (I² = 0%) and the placebo (OR, 7.61; 95% CI, 3.11–18.63, P = .02) with no heterogeneity (I² = 0%). The USSD applied to DFUs caused a significantly higher wound healing rate compared with the standard care and the placebo. Though precautions should be taken when commerce with the consequences as all of the picked studies for this meta-analysis was with low sample sizes.     

Effect of diabetic foot ulcers and other risk factors on the prevalence of lower extremity amputation: A meta-analysis

A meta-analysis study was conducted to measure the consequence of diabetic foot ulcers (DFUs) and other risk factors (RFs) on the prevalence of lower extremity amputation (LEA). A comprehensive literature inspection till February 2023 was applied and 2765 interrelated studies were reviewed. Of the 32 chosen studies enclosed, 9934 subjects were in the chosen studies' starting point, and 2906 of them were with LEA. Odds ratio (OR) in addition to 95% confidence intervals (CIs) were used to compute the value of the effect of DFUs and other RFs on the prevalence of LEA by the continuous and dichotomous approaches and a fixed or random effect model. Male gender (OR, 1.30; 95% CI, 1.17–1.44, P < .001), smoking (OR, 1.24; 95% CI, 1.01–1.53, P = .04), previous foot ulcer (OR, 2.69; 95% CI, 1.93–3.74, P < .001), osteomyelitis (OR, 3.87; 95% CI, 2.28–6.57, P < .001), gangrene (OR, 14.45; 95% CI, 7.03–29.72, P < .001), hypertension (OR, 1.17; 95% CI, 1.03–1.33, P = .01), and white blood cells count (WBCC) (MD, 2.05; 95% CI, 1.37–2.74, P < .001) were significantly shown to be an RF in LEA in subjects with DFUs. Age (MD, 0.81; 95% CI, −0.75 to 2.37, P = .31), body mass index (MD, −0.55; 95% CI, −1.15 to 0.05, P = .07), diabetes mellitus type (OR, 0.99; 95% CI, 0.63–1.56, P = .96), and glycated haemoglobin (MD, 0.33; 95% CI, −0.15 to 0.81, P = .17) were not shown to be an RF in LEA in subjects with DFUs. Male gender, smoking, previous foot ulcer, osteomyelitis, gangrene, hypertension, and WBCC were significantly shown to be an RF in LEA in subjects with DFUs. However, age and diabetes mellitus type were not shown to be RF in LEA in subjects with DFUs. However, caused of the small sample sizes of several chosen studies for this meta-analysis, care must be exercised when dealing with its values.     

The majority of US combat casualty soft-tissue wounds are not infected or colonized upon arrival or during treatment at a continental US military medical facility

Background

The microbiology of war wounds has changed as medicine and warfare have evolved. This study was designed to determine the microbial flora and bacterial quantification of present-day war wounds in US troops from Iraq and Afghanistan upon arrival at the National Naval Medical Center (NNMC).

Methods

Patients with extremity combat wounds treated with a vacuum-assisted wound closure device were enrolled in study. Wounds were biopsied every 48 to 72 hours with quantitative microbiology performed on all biopsies.

Results

Two hundred forty-two wound biopsies from 34 patients; 167 (69%) showed no growth, and 75 (31%) showed positive growth. The incidence of any bacterial isolation from biopsies weekly from the time of injury was 28% (first), 31% (second), and 37% (≥third). Acinetobacter baumannii was the most prevalent isolate.

Conclusions

Most soft-tissue wounds from Iraq and Afghanistan do not have significant bacterial burden upon arrival to and during initial treatment at NNMC. Improved evaluation of combat wound microbiology at all levels of care is warranted to determine shifts in microbiology and to impact care practices.     

骨髓间充质干细胞在糖尿病模型创面中向表皮细胞分化的初步研究

目的：探讨糖尿病皮肤创面微环境中的骨髓间充质干细胞分化为表皮细胞的可能性。方法：从大鼠骨髓中分离纯化骨髓间充质干细胞。选取第3—4代细胞,应用5-溴脱氧尿嘧啶（5-BrdU）标记技术进行细胞标记;同时采用一次性腹腔内注射链脲佐菌素制作糖尿病大鼠模型。2周后,在大鼠背部人工造成圆形创面,将已标记的骨髓间充质干细胞以注射方式回植入糖尿病大鼠创面组织周围,分别于注射后2、3周取材,常规石蜡包埋、连续切片,行BrdU和角蛋白免疫组织化学染色。结果：BrdU阳性细胞出现在表皮、真皮及皮下组织各层,连续切片表皮层中部分阳性细胞同时也表达角蛋白。结论：在糖尿病渍疡愈合过程中,骨髓间充质干细胞具有向表皮细胞分化的潜能。     

The relationship between vitamin D deficiency and diabetic foot ulcer: A meta-analysis

A meta-analysis investigation to measure the relationship between vitamin D deficiency (VDD) and diabetic foot ulcer (DFU). A comprehensive literature inspection till February 2023 was applied and 1765 interrelated investigations were reviewed. The 15 chosen investigations enclosed 2648 individuals with diabetes mellitus in the chosen investigations' starting point, 1413 of them were with DFUs, and 1235 were without DFUs. Odds ratio (OR) in addition to 95% confidence intervals (CIs) were used to compute the value of the relationship between VDD and DFU by the dichotomous and continuous approaches and a fixed or random model. Individuals with DFUs had significantly lower vitamin D levels (VDL) (MD, −7.14; 95% CI, −8.83 to −5.44, P < 0.001) compared to those without DFU individuals. Individuals with DFUs had a significantly higher number of VDD individuals (OR, 2.27; 95% CI, 1.63-3.16, P < 0.001) compared to those without DFU individuals. Individuals with DFU had significantly lower VDL and a significantly higher number of VDD individuals compared to those without DFU individuals. However, caused of the small sample sizes of several chosen investigations for this meta-analysis, care must be exercised when dealing with its values.     

Fibronectin in hyperglycaemia and its potential use in the treatment of diabetic foot ulcers: A review

Metabolism of fibronectin, the protein that plays a key role in the healing of wounds, is changed in the patients with diabetes mellitus. Fibronectin can interact with other proteins and proteoglycans and organise them to form the extracellular matrix, the basis of the granulation tissue in healing wounds. However, diabetic foot ulcers (DFUs) suffer from inadequate deposition of this protein. Degradation prevails over fibronectin synthesis in the proteolytic inflammatory environment in the ulcers. Because of the lack of fibronectin in the wound bed, the assembly of the extracellular matrix and the deposition of the granulation tissue cannot be started. A number of methods have been designed that prevents fibronectin degradation, replace lacking fibronectin or support its formation in non-healing wounds in animal models of diabetes. The aim of this article is to review the metabolism of fibronectin in DFUs and to emphasise that it would be useful to pay more attention to fibronectin matrix assembly in the ulcers when laboratory methods are translated to clinical practice.     

Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and susceptibility to diabetic nephropathy in Chinese type 2 diabetic patients: a meta-analysis

Abstract

The association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and diabetic nephropathy (DN) or diabetes mellitus (DM) risk has been widely reported, but the results are still debatable. To investigate the role of MTHFR C677T polymorphism on DM or DN, 13 separate studies in the Chinese population on the relation between MTHFR C677T polymorphism and DM or DN were analyzed by a meta-analysis. Five genetic models were used to estimate the association between MTHFR C677T polymorphism and the risk of DM or DN. Overall, our meta-analysis for DN versus healthy controls produced significant results for all genetic contrasts except for the co-dominant model (allele contrast: OR?=?2.24, 95%CI: 1.88–2.65, p?<?0.00001, P_{heterogeneity}?=?0.49). However, the meta-analysis for DM versus healthy controls produced non-significant results for all contrasts (allele contrast: OR?=?1.12, 95%CI: 0.92–1.35, p?=?0.25, P_{heterogeneity}?=?0.07). In addition, the meta-analysis for DM versus DN produced significant results for all contrasts (allele contrast: OR?=?1.88, 95%CI: 1.65–2.15, p?<?0.00001, P_{heterogeneity}?=?0.83). The current meta-analysis suggested that MTHFR C677T polymorphism might influence DN risk, but not for DM in the Chinese population.