Background: Tissue expansion is used for scar reconstruction owing to its excellent clinical outcomes; however, the complications that emerge from tissue expansion hinder repair. Infection is considered a major complication of tissue expansion. This study aimed to analyze the perioperative risk factors for expander infection. Methods: A large, retrospective, single-institution observational study was carried out over a 10-year period. The study enrolled consecutive patients who had undergone tissue expansion for scar reconstruction. Demographics, etiological data, expander-related characteristics and post-operative infection were assessed. Univariate and multivariate logistic regression analysis were performed to identify risk factors for expander infection. In addition, we conducted a sensitivity analysis for treatment failure caused by infection as an outcome. Results: A total of 2374 expanders and 148 cases of expander infection were assessed. Treatment failure caused by infection occurred in 14 expanders. Multivariate logistic regression analysis identified that disease duration of ≤1 year (odds ratio (OR), 2.07; p <0.001), larger volume of expander (200–400 ml vs <200 ml; OR, 1.74; p=0.032; >400 ml vs <200 ml; OR, 1.76; p=0.049), limb location (OR, 2.22; p=0.023) and hematoma evacuation (OR, 2.17; p=0.049) were associated with a high likelihood of expander infection. Disease duration of ≤1 year (OR, 3.88; p=0.015) and hematoma evacuation (OR, 10.35; p=0.001) were so related to high risk of treatment failure. Conclusions: The rate of expander infection in patients undergoing scar reconstruction was 6.2%. Disease duration of <1 year, expander volume of >200 ml, limb location and postoperative hematoma evacuation were independent risk factors for expander infection.

Background: Hypermetabolism, muscle wasting and insulin resistance are challenging yet important rehabilitation targets in the management of burns. In the absence of concrete practice guidelines, however, it remains unclear how these metabolic targets are currently managed. This study aimed to describe the current practice of inpatient rehabilitation across Europe. Methods: An electronic survey was distributed by the European Burn Association to burn centres throughout Europe, comprising generic and profession-specific questions directed at therapists, medical doctors and dieticians. Questions concerned exercise prescription, metabolic management and treatment priorities, motivation and knowledge of burn-induced metabolic sequelae. Odds ratios were computed to analyse associations between data derived from the responses of treatment priorities and knowledge of burn-induced metabolic sequelae. Results: Fifty-nine clinicians with 12.3 ± 9 years of professional experience in burns, representing 18 out of 91 burn centres (response rate, 19.8%) across eight European countries responded. Resistance and aerobic exercises were only provided by 42% and 38% of therapists to intubated patients, 87% and 65% once out-of-bed mobility was possible and 97% and 83% once patients were able to leave their hospital room, respectively. The assessment of resting energy expenditure by indirect calorimetry, muscle wasting and insulin resistance was carried out by only 40.7%, 15.3% and 7.4% respondents, respectively, with large variability in employed frequency and methods. Not all clinicians changed their care in cases of hypermetabolism (59.3%), muscle wasting (70.4%) or insulin resistance (44.4%), and large variations in management strategies were reported. Significant interdisciplinary variation was present in treatment goal importance ratings, motivation and knowledge of burn-induced metabolic sequelae. The prevention of metabolic sequelae was regarded as the least important treatment goal, while the restoration of functional status was rated as the most important. Knowledge of burn-induced metabolic sequelae was linked to higher importance ratings of metabolic sequelae as a therapy goal (odds ratio, 4.63; 95% CI, 1.50–14.25; p < 0.01). Conclusion: This survey reveals considerable non-uniformity around multiple aspects of inpatient rehabilitation across European burn care, including, most notably, a potential neglect of metabolic outcomes. The results contribute to the necessary groundwork to formulate practice guidelines for inpatient burn rehabilitation.

Background: The current study aimed to evaluate the value of immune cell counts and neutrophil-to-lymphocyte ratio (NLR) when attempting to predict 28-day mortality. Methods: We conducted an observational retrospective study that included consecutive septic patients. Severity scores on the first day and peripheral circulating immune cell counts (at day 1, day 3, day 5 and day 7 of admission) were collected during each patient’s emergency intensive care unit stay. We assessed the associations of peripheral circulating immune cell counts and NLR with the severity of illness. The relationships between 28-day mortality and peripheral circulating immune cell counts and NLR with were evaluated using Cox proportional cause-specific hazards models. Results: A total of 216 patients diagnosed with sepsis caused by IAI were enrolled. The lymphocyte counts (days 1, 3, 5 and 7) and monocyte counts (days 3, 5 and 7) were significantly lower in non-survivors (n = 72) than survivors (n = 144). The NLR values at each time point were significantly higher in non-survivors. The day 1 lymphocyte counts, as well as the monocyte counts, were significantly lower in the highest-scoring group, when stratified by the Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores, than in the other groups (p < 0.05). The day 1 NLR was significantly higher in the highest-scoring group than in the other groups (p < 0.05). The day 5 and day 7 lymphocyte counts, day 3 and day 7 monocyte counts and day 7 NLR were significant predictors of 28-day mortality in the Cox proportional hazards models (day 5 lymphocyte count: hazard ratio, 0.123 (95% CI, 0.055–0.279), p < 0.001; day 7 lymphocyte count: hazard ratio, 0.115 (95% CI, 0.052–0.254), p < 0.001; day 3 monocyte count: hazard ratio, 0.067 (95% CI, 0.005–0.861), p = 0.038; day 7 monocyte count: hazard ratio, 0.015 (95% CI, 0.001–0.158), p < 0.001; day 7 NLR: hazard ratio, 0.773 (95% CI, 0.659–0.905), p = 0.001). Conclusions: The results showed that circulating lymphocytes and monocytes were dramatically decreased within 7 days in non-survivors following sepsis from an IAI. Lymphocyte counts, monocyte counts and NLR appeared to be associated with the severity of illness, and they may serve as independent predictors of 28-day mortality in septic patients with IAIs.

Background: Gut ischemia and hypoxia post severe burn leads to breakdown of intestinal epithelial barrier and enteric bacterial translocation (EBT), resulting in serious complications, such as systemic inflammatory response syndrome, sepsis and multiple organ failure. Cystic fibrosis transmembrane conductance regulator (CFTR) is known to be downregulated by hypoxia and modulate junctional complexes, which are crucial structures maintaining the intestinal barrier. This study aimed to investigate whether CFTR plays a role in both regulating the intestinal barrier and mediating EBT post severe burn, as well as the signaling pathways involved in these processes. Methods: An in vitroCaco-2 cell model subjected to hypoxic injury and an in vivomouse model with a 30% total body surface area full-thickness dermal burn were established. DF 508 mice (mice with F508del CFTR gene mutation) were used as an in vivo model to further demonstrate the role of CFTR in maintaining normal intestinal barrier function. QRT-PCR, western blot, ELISA, TER assay and immunofluorescence staining were used to detect the expression and localization of CFTR and tight junction proteins, as well as the function of tight junctions. Results: Our data indicated that, in Caco-2 cells, the hypoxia condition significantly reduced CFTR expression; activated extracellular signal-regulated kinase and nuclear factor-κB signaling; elevated secretion of inflammatory factors (tumor necrosis factor-α, interleukin-1βand interleukin-8); downregulated zonula occludens-1, occludin and E-cadherin expression; decreased transep-ithelial electrical resistance values; and led to a cellular mislocation of ZO-1. More importantly, knockdown of CFTR caused similar alterations. The upregulation of inflammatory factors and downregulation of tight junction proteins (ZO-1 and occludin) induced by knockdown of CFTR could be reversed by specific extracellular signal-regulated kinase or nuclear factor-κB inhibition. In support of the in vitrodata, exuberant secretion of pro-inflammatory mediators and EBT was observed in the intestine of severely burnt mice in vivo. EBT occurred in DF508 mice (mice with the F508del CFTR gene mutation), accompanied by augmented tumor necrosis factor-α, interleukin-1βand interleukin-8 levels in the ileum compared to wildtype mice. In addition, vitamin D3 was shown to protect the intestinal epithelial barrier from hypoxic injury. Conclusions: Collectively, the present study illustrated that CFTR and downstream signaling were critical in modulating the intestinal epithelial junction and EBT post severe burn.

Background: Burn injury in elderly patients can result in poor outcomes. Prognostic nutritional index (PNI) can predict the perioperative nutritional status and postoperative outcomes. We aim to evaluate the risk factors, including PNI, for one-year mortality after burn surgery in elderly patients. Methods: Burn patients aged ≥65 years were retrospectively included. PNI was calculated using the following equation: 10 × serum albumin level (g/dL) + 0.005 × total lymphocyte count (per mm³). Cox regression, receiver operating characteristic curve and Kaplan–Meier survival analyses were performed to evaluate the risk factors for postoperative one-year mortality. Results: Postoperative one-year mortality occurred in 71 (37.6%) of the 189 elderly burn patients. Risk factors for one-year mortality were PNI on postoperative day one (hazard ratio (HR) = 0.872; 95% CI = 0.812–0.936; p < 0.001), Sequential Organ Failure Assessment score (HR = 1.112; 95% CI = 1.005–1.230; p = 0.040), American Society of Anesthesiologists physical status (HR = 2.064; 95% CI = 1.211–3.517; p = 0.008), total body surface area burned (HR = 1.017; 95% CI = 1.003–1.032; p = 0.015) and preoperative serum creatinine level (HR = 1.386; 95% CI = 1.058–1.816; p = 0.018). The area under the curve of PNI for predicting one-year mortality after burn surgery was 0.774 (optimal cut-off value = 25.5). Patients with PNI ≤25.5 had a significantly lower one-year survival rate than those with PNI >25.5 (32.1% vs 75.9%, p < 0.001). Conclusions: PNI on postoperative day one was associated with postoperative one-year mortality in elderly burn patients. The postoperative one-year survival rate was lower in patients with PNI ≤25.5 than in those with PNI >25.5. These findings indicate the importance of identifying elderly burn patients with low PNI, thereby reducing the mortality after burn surgery.

Background: Patients with burn injuries are considered to have an increased risk of venous thromboembolism (VTE). While untreated VTEs can be fatal, no studies have examined chemoprophylaxis effectiveness. This study aimed to quantify the variation in prevalence of VTE prophylaxis use in patients in Australian and New Zealand burns units and whether prophylaxis use is associated with in-hospital outcomes following burn injury. Methods: Admission data for adult burns patients (aged ≥16 years) admitted between 1 July 2016 and 31 December 2018 were extracted from the Burns Registry of Australia and New Zealand. Mixed effects logistic regression modelling investigated whether VTE prophylaxis use was associated with the primary outcome of in-hospital mortality. Results: There were 5066 admissions over the study period. Of these patients, 81% (n = 3799) with a valid response to the VTE prophylaxis data field received some form of VTE prophylaxis. Use of VTE prophylaxis ranged from 48.6% to 94.8% of patients between units. In-hospital death was recorded in <1% of patients (n = 33). After adjusting for confounders, receiving VTE prophylaxis was associated with a decrease in the adjusted odds of in-hospital mortality (adjusted odds ratio = 0.21; 95% CI, 0.07–0.63; p = 0.006). Conclusions: Variation in the use of VTE prophylaxis was observed between the units, and prophylaxis use was associated with a decrease in the odds of mortality. These findings provide an opportunity to engage with units to further explore differences in prophylaxis use and develop future best practice guidelines.

Background: Delayed wound healing is one of the major complications of diabetes mellitus and is characterized by prolonged inflammation, delayed re-epithelialization and consistent oxidative stress, although the detailed mechanism remains unknown. In this study, we aimed to investigate the potential role and effect of pterostilbene (PTE) and hematopoietic stem cells (HSCs) on diabetic wound healing. Methods: Diabetic rats were used to measure the epigenetic changes in both HSCs and peripheral blood mononuclear cells (PBMCs). A cutaneous burn injury was induced in the rats and PTE-treated diabetic HSCs were transplanted for evaluation of wound healing. In addition, several biomedical parameters, including gene expression, oxidative stress, mitochondrial function and inflammation in macrophages, were also measured. Results: Our data showed that PTE had a much stronger effect than resveratrol on accelerating diabetic wound healing, likely because PTE can ameliorate diabetes-induced epigenetic changes to estrogen receptor β promoter in HSCs, while resveratrol cannot. Further investigation showed that bone marrow transplantation of PTE-treated diabetic HSCs restores diabetes-induced suppression of estrogen receptor β and its target genes, including nuclear respiratory factor-1 and superoxide dismutase 2, and protects against diabetes-induced oxidative stress, mitochondrial dysfunction and elevated pro-inflammatory cytokines in both PBMCs and macrophages, subsequently accelerating cutaneous wound healing. Conclusions: HSC may play an important role in wound healing through transferring epigenetic modifications to subsequent PBMCs and macrophages by differentiation, while PTE accelerates diabetic wound healing by modulating diabetes-induced epigenetic changes in HSCs. Thus, PTE may be a novel therapeutic strategy for diabetic wound healing.

Wound healing is a complex process involving four overlapping phases: haemostasis, inflammation, cell recruitment and matrix remodeling. In mouse models, surgical, pharmacological and genetic approaches targeting androgen actions in skin have shown that androgens increase interleukin-6 and tumor necrosis factor-α production and reduce wound re-epithelization and matrix deposition, retarding cutaneous wound healing. Similarly, clinical studies have shown that cutaneous wound healing is slower in men compared to women. However, in major burn injury, which triggers not only local wound-healing processes but also systemic hypermetabolism, the role of androgens is poorly understood. Recent studies have claimed that a synthetic androgen, oxandrolone, increases protein synthesis, improves lean body mass and shortens length of hospital stay. However, the possible mechanisms by which oxandrolone regulates major burn injury have not been reported. In this review, we summarize the current findings on the roles of androgens in cutaneous and major burn wound healing, as well as androgens as a potential therapeutic treatment option for patients with major burn injuries.

Burn is an under-appreciated trauma that is associated with unacceptably high morbidity and mortality. Although the survival rate after devastating burn injuries has continued to increase in previous decades due to medical advances in burn wound care, nutritional and fluid resuscitation and improved infection control practices, there are still large numbers of patients at a high risk of death. One of the most common complications of burn is sepsis, which is defined as “severe organ dysfunction attributed to host’s disordered response to infection” and is the primary cause of death in burn patients. Indeed, burn injuries are accompanied by a series of events that lead to sepsis and multiple organ dysfunction syndrome, such as a hypovolaemic state, immune and inflammatory responses and metabolic changes. Therefore, clear diagnostic criteria and predictive biomarkers are especially important in the prevention and treatment of sepsis and septic shock. In this review, we focus on the pathogenesis of burn wound infection and the post-burn events leading to sepsis. Moreover, the clinical and promising biomarkers of burn sepsis will also be summarized.

Biological markers that evaluate physical healing as well as psychological impact of a burn are essential for effective treatment of paediatric burns. The objective of this review is to summarize the evidence supporting the use of biomarkers in children with burns. An extensive review of the literature was performed using PubMed. A total of 59 biomarkers were identified relating to burn presence, specifically relating to processes involved in inflammation, wound healing, growth and metabolism. In addition, biomarkers involved in the stress response cascade following a burn trauma were also identified. Although many biomarkers have been identified that are potentially associated with burn-related physical and psychological trauma, an understanding of burn biology is still lacking in children. We propose that future research in the field of children’s burns should be conducted using broad screening methods for identifying potential biomarkers, examine the biological interactions of different biomarkers, utilize child-appropriate biological fluids such as urine or saliva, and include a range of different severity burns. Through further research, the biological response to burn injury may be fully realized and clinically relevant diagnostic tests and treatment therapies utilizing these biomarkers could be developed, for the improvement of healing outcomes in paediatric burn patients.

Background: Traumatic brain edema (TBE) is caused by a specific water channel mediated by membrane aquaporins. Aquaporin-4 (AQP4) plays an especially important role in this process, but the relationship between AQP4 and TBE remains unclear. The purpose of this study was to explore expression of AQP4 in the hippocampus after traumatic brain injury (TBI), as well as the effect of brain edema on skeletal protein and its function in hippocampal neurons. Methods: The adult male Wistar rats we divided into a sham group and a TBI group, the latter of which was further divided into 1, 3, 6, 12, 24 and 72 hours (h) and 15 days (d) post injury subgroups. A proper TBI model was established, and brain edema was assessed in each group by water content. We measured the abundance of various proteins, including hypoxia inducible factor-1α (HIF-1α), AQP4, microtubule-associated protein 2 (MAP2), tau-5 protein, phosphorylated level of TAU, synaptophysin, cyclic adenosine monophosphate response element binding protein (CREB), phosphorylated CREB and general control nonrepressed 2, in each group. Hippocampal neurons and spatial memory test were analyzed in different time points. Results: Compared with that in the sham group, the level of AQP4 in hippocampal neurons began to significantly increase at 1 h post TBI and then decreased at 15 d post TBI. During this time frame, AQP4 level peaked at 12 and 72 h, and these peaks were closely correlated with high brain water content. HIF-1α displayed a similar trend. Conversely, levels of MAP2 began to decrease at 1 h post TBI and then increase at 15 d post TBI. In addition, the most severe brain edema in rats was found at 24 h post TBI, with neuronal loss and hippocampal dendritic spine injury. Compared to those in the sham group, rats in the TBI groups had significantly prolonged latency and significantly shortened exploration time. Conclusions: AQP4 level was closely correlated with severity of brain edema, and abnormal levels thereof aggravated such severity after TBI.

Background: Traffic incidents are still a major contributor to hospital admissions and trauma-related mortality. The aim of this nationwide study was to examine risk-adjusted traffic injury mortality to determine whether hospital type was an independent survival factor. Methods: Data on all patients admitted to Swedish hospitals with traffic-related injuries, based on International Classification of Diseases codes, between 2001 and 2011 were extracted from the Swedish inpatient and cause of death registries. Using the binary outcome measure of death or survival, data were analysed using logistic regression, adjusting for age, sex, comorbidity, severity of injury and hospital type. The severity of injury was established using the International Classification of Diseases Injury Severity Score (ICISS). Results: The final study population consisted of 152,693 hospital admissions. Young individuals (0–25 years of age) were overrepresented, accounting for 41% of traffic-related injuries. Men were overrepresented in all age categories. Fatalities at university hospitals had the lowest mean (SD) ICISS 0.68 (0.19). Regional and county hospitals had mean ICISS 0.75 (0.15) and 0.77 (0.15), respectively, for fatal traffic incidents. The crude overall mortality in the study population was 1193, with a mean ICISS 0.72 (0.17). Fatalities at university hospitals had the lowest mean ICISS 0.68 (0.19). Regional and county hospitals had mean ICISS 0.75 (0.15) and 0.77 (0.15), respectively, for fatal traffic incidents. When regional and county hospitals were merged into one group and its risk-adjusted mortality compared with university hospitals, no significant difference was found. A comparison between hospital groups with the most severely injured patients (ICISS ≤0.85) also did not show a significant difference (odds ratio, 1.13; 95% confidence interval, 0.97–1.32). Conclusions: This study shows that, in Sweden, the type of hospital does not influence risk adjusted traffic related mortality, where the most severely injured patients are transported to the university hospitals and centralization of treatment is common.

Background: Traumatic injury is associated with increased concentrations of cell-free DNA (cfDNA) in the circulation, which contribute to post-injury complications. The endonuclease deoxyribonuclease 1 (DNase-1) is responsible for removing 90% of circulating cfDNA. Recently, DNase activity was reported to be significantly reduced following major non-traumatic brain injury (TBI), but the processes responsible were not investigated. Moreover, it is not known how quickly following injury DNase activity is reduced and whether this also occurs after TBI. Methods: At 3 post-injury time points (≤1, 4–12 and 48–72 hours), blood samples were obtained from 155 adult trauma patients that had sustained an isolated TBI (n = 21), TBI with accompanying extracranial injury (TBI+) (n = 53) or an extracranial injury only (ECI) (n = 81). In addition to measuring cfDNA levels and the activity and expression of DNase, circulating concentrations of monomeric globular action (G-actin), an inhibitor of DNase-1, and the actin scavenging proteins gelsolin (GSN) and vitamin D binding protein (VDBP) were determined and values compared to a cohort of healthy controls. Results: Significantly elevated concentrations of plasma cfDNA were seen in TBI, TBI+ and ECI patients at all study time points when compared to healthy controls. cfDNA levels were significantly higher at ≤1 hour post-injury in ECI patients who subsequently developed multiple organ dysfunction syndrome when compared to those who did not. Plasma DNase-1 protein was significantly elevated in all patient groups at all sampling time points. In contrast, DNase enzyme activity was significantly reduced, with this impaired function evident in TBI+ patients within minutes of injury. Circulating concentrations of G-actin were elevated in all patient cohorts in the immediate aftermath of injury and this was accompanied by a significant reduction in the levels of GSN and VDBP. Conclusions: The post-traumatic increase in circulating cfDNA that occurs following extracranial trauma and TBI is accompanied by reduced DNase activity. We propose that, secondary to reduced GSN and VDBP levels, elevated circulating concentrations of G-actin underlie the post-injury reduction in DNase activity. Reducing circulating cfDNA levels via therapeutic restoration of DNase-1 activity may improve clinical outcomes post-injury.

Burns, with their high incidence and mortality rates, have a devastating effect on patients. There are still huge challenges in the management of burns. Mesenchymal stem cells (MSCs), which have multidirectional differentiation potential, have aroused interest in exploring the capacity for treating different intractable diseases due to their strong proliferation, tissue repair, immune tolerance and paracrine abilities, among other features. Currently, several animal studies have shown that MSCs play various roles and have beneficial effects in promoting wound healing, inhibiting burn inflammation and preventing the formation of pathological scars during burn healing process. The substances MSCs secrete can act on peripheral cells and promote burn repair. According to preclinical research, MSC-based treatments can effectively improve burn wound healing and reduce pain. However, due to the small number of patients and the lack of controls, treatment plans and evaluation criteria vary widely, thus limiting the value of these clinical studies. Therefore, to better evaluate the safety and effectiveness of MSC-based burn treatments, standardization of the application scheme and evaluation criteria of MSC therapy in burn treatment is required in the future. In addition, the combination of MSC pretreatment and dressing materials are also conducive to improving the therapeutic effect of MSCs on burns. In this article, we review current animal research and clinical trials based on the use of stem cell therapy for treating burns and discuss the main challenges and coping strategies facing future clinical applications.

Background: Bombyx mori silk fibroin is a biomacromolecule that allows the assembly of scaffolds for tissue engineering and regeneration purposes due to its cellular adhesiveness, high biocompatibility and low immunogenicity. Earlier work showed that two types of 3D silk fibroin nonwovens (3D-SFnws) implanted into mouse subcutaneous tissue were promptly vascularized via undefined molecular mechanisms. The present study used nontumorigenic adult human dermal fibroblasts (HDFs) adhering to a third type of 3D-SFnws to assess whether HDFs release exosomes whose contents promote neoangiogenesis. Methods: Electron microscopy imaging and physical tests defined the features of the novel carded/hydroentangled 3D-SFnws. HDFs were cultured on 3D-SFnws and polystyrene plates in an exosome-depleted medium. DNA amounts and D-glucose consumption revealed the growth and metabolic activities of HDFs on 3D-SFnws. CD9-expressing total exosome fractions were from conditioned media of 3D-SFnws and 2D polystyrene plates HDF cultures. Angiogenic growth factors (AGFs) in equal amounts of the two groups of exosomal proteins were analysed via double-antibody arrays. A tube formation assay using human dermal microvascular endothelial cells (HDMVECs) was used to evaluate the exosomes’ angiogenic power. Results: The novel features of the 3D-SFnws met the biomechanical requirements typical of human soft tissues. By experimental day 15, 3D-SFnws-adhering HDFs had increased 4.5-fold in numbers and metabolized 5.4-fold more D-glucose than at day 3 in vitro. Compared to polystyrene-stuck HDFs, exosomes from 3D-SFnws-adhering HDFs carried significantly higher amounts of AGFs, such as interleukin (IL)-1α, IL-4 and IL-8; angiopoietin-1 and angiopoietin-2; angiopoietin-1 receptor (or Tie-2); growth-regulated oncogene (GRO)-α, GRO-β and GRO-γ; matrix metalloproteinase-1; tissue inhibitor metalloproteinase-1; and urokinase-type plasminogen activator surface receptor, but lesser amounts of anti-angiogenic tissue inhibitor metalloproteinase-2 and pro-inflammatory monocyte chemoattractant protein-1. At concentrations from 0.62 to 10 µg/ml, the exosomes from 3D-SFnws-cultured HDFs proved their angiogenic power by inducing HDMVECs to form significant amounts of tubes in vitro. Conclusions: The structural and mechanical properties of carded/hydroentangled 3D-SFnws proved their suitability for tissue engineering and regeneration applications. Consistent with our hypothesis, 3D-SFnws-adhering HDFs released exosomes carrying several AGFs that induced HDMVECs to promptly assemble vascular tubes in vitro. Hence, we posit that once implanted in vivo, the 3D-SFnws/HDFs interactions could promote the vascularization and repair of extended skin wounds due to burns or other noxious agents in human and veterinary clinical settings.

Background: Delayed wound healing remains a common but challenging problem in patients with acute or chronic wound following accidental scald burn injury. However, the systematic and detailed evaluation of the scald burn injury, including second-degree deep scald (SDDS) and third-degree scald (TDS), is still unclear. The present study aims to analyze the wound-healing speed, the formation of granulation tissue, and the healing quality after cutaneous damage. Methods: In order to assess SDDS and TDS, the models of SDDS and TDS were established using a scald instrument in C57BL/6 mice. Furthermore, an excisional wound was administered on the dorsal surface in mice (Cut group). The wound-healing rate was first analyzed at days 0, 3, 5, 7, 15 and 27, with the Cut group as a control. Then, on the full-thickness wounds, hematoxylin and eosin (H&E) staining, Masson staining, Sirius red staining, Victoria blue staining and immunohistochemistry were performed to examine re-epithelialization, the formation of granulation tissue, vascularization, inflammatory infiltration and the healing quality at different time points in the Cut, SDDS and TDS groups. Results: The presented data revealed that the wound-healing rate was higher in the Cut group, when compared with the SDDS and TDS groups. H&E staining showed that re-epithelialization, formation of granulation tissue and inflammatory infiltration were greater in the Cut group, when compared with the SDDS and TDS groups. Immunohistochemistry revealed that the number of CD31, vascular endothelial growth factor A, transforming growth factor-β and α-smooth muscle actin reached preferential peak in the Cut group, when compared with other groups. In addition, Masson staining, Sirius red staining, Victoria blue staining, Gordon-Sweets staining and stress analysis indicated that the ratio of collagen I to III, reticular fibers, failure stress, Young’s modulus and failure length in the SDDS group were similar to those in the normal group, suggesting that healing quality was better in the SDDS group, when compared with the Cut and TDS groups. Conclusion: Overall, the investigators first administered a comprehensive analysis in the Cut, SDDS and TDS groups through in vivo experiments, which further proved that the obstacle of the formation of granulation tissue leads to delayed wound healing after scald burn injury in mice.

Background: Scar assessment plays a key role during burns aftercare, to monitor scar remodelling and patients’ psychosocial well-being. To aid assessment, subjective scar assessment scales are available that use health-care professionals’ and patients’ opinions to score scar characteristics. The subjective scales are more widely used in clinical practice over objective scar measures. To date, there is no research that considers patients’ views on scar assessment and the role of subjective and objective assessment tools. Therefore, the aim of this qualitative study was to explore patients’ perspectives on scar assessment and the utility of scar assessment tools during burns rehabilitation. Methods: Semi-structured interviews were conducted with 10 adult burn patients who were being reviewed in clinic for scarring. Participants were recruited via their clinical care team and research nurses at the Queen Elizabeth Hospital, Birmingham, UK. Topics covered during interview included patient experience of scar assessment, the use of scar assessment tools and discussion surrounding important factors to be addressed when assessing scars. A thematic analysis using the Framework Method was conducted. Results: Participants identified key subthemes that contribute towards the overarching theme of patient-centred scar assessment. These are: patient-led care; continuity in care; learning how to self-manage scarring; and psychological assessment. Links were demonstrated between these subthemes and the remaining themes that describe scar assessment strategies, indicating their potential patient-centred contributions. The subjective opinions of clinicians were found to be valued above the use of subjective or objective scar assessment tools. Scar assessment scales were perceived to be a beneficial method for self-reflection in relation to psychosocial functioning. However, minimal feedback and review of completed assessment scales led to uncertainty regarding their purpose. Patients perceived objective tools to be of primary use for health-care professionals, though the measures may aid patients’ understanding of scar properties. Conclusions: Scar assessment tools should be used to support, rather than replace, health-care professionals’ subjective judgements of scarring. Adapting the way in which clinicians introduce and use scar assessment tools, according to patient needs, can support a patient-centred approach to scar assessment.

Coronavirus disease 2019 (COVID-19) has been around for over a year since December 2019, and the global outlook is not optimistic. Because of its high transmissibility and high mortality, management of the COVID-19 pandemic has become a major challenge for health systems globally, especially for critical care. However, the level of demand for physicians and nurses in intensive care units (ICUs) to manage critical patients with highly infectious diseases (such as COVID-19) is still unclear [1, 2]. Care for critically ill patients with highly communicable diseases may require more intensive care personnel than for non-communicable diseases. Therefore, we investigated ICU staffing in this cross-sectional survey from January 18 to March 14, 2020. A total of 58 ICUs were invited to participate, including 41 ICUs from Hubei Province and 17 ICUs from the other 11 provinces or municipalities in China. All ICUs included were only applicable for COVID-19 adult patients. In addition, a descriptive analysis of the reinforcements for care of critically ill patients was carried out and the epidemiological data on COVID-19 in Hubei Province was overlaid with this survey. No personal data was analyzed in this study. The data used in this study are considered a part of the public health outbreak investigation. Informed consent and approval was waived by the Institutional Review Board. A total of 2635 COVID-19 patients were admitted to 58 ICUs with 1340 ICU beds. The number of physicians per bed and nurses per bed in these ICUs were 1.1(0.7, 1.8) and 3.5(2.3, 4.2), respectively. The average age of patients was 62.0 years (56.7 years, 65.0 years), and the proportion of male patients was 24.0% (12.0%, 43.0%). The overall mortality and 95% confidence interval (CI) was 23.6% (22.0%, 25.3%). Mortality in these ICUs ranged from 0.0% to 67.3%. This was divided into low mortality group (n = 19, mortality <7.7%), medium mortality group (n = 20, mortality 7.7–21.2%) and high mortality group (n = 19, mortality >21.2%). The differences in patient characteristics in the three groups were analysed (Table 1). The average age of the middle mortality and high mortality groups was significantly higher than that of the low mortality group (p = 0.04). The proportion of male patients, patients receiving mechanical ventilation (MV), or continuous renal replacement therapy (CRRT), and use of vasopressors also showed significant differences among the three groups. The ICU staffing is shown in Table 1.The higher mortality group showed more ICU beds (p = 0.022) and more ICU admissions (p < 0.001) than the low mortality group. The proportion of nurses per bed in the high mortality group was significantly lower than that in the low and middle mortality groups (p = 0.017). To explore the relationship between the mortality of COVID-19 patients and ICU staffing, two probit regression models were established. Potential confounding factors such as mean age, proportion of males, use of MVs or CRRT or vasopressors (considered to indicate severity of patient illness) and inpatients per bed per month (used as ICU beds) were adjusted (Table 2). Both models showed that there was a negative correlation between the number of physicians per bed or nurses per bed and the mortality of patients with severe COVID-19. In addition, the average age, proportion of males, MV ratios, and inpatients per bed per month were significant impact factors. The multivariable probit regression models were also used to estimate the allocation needs of ICU staff for COVID-19 patients (Figure 1a, b). The estimated numbers (95% CI) of physicians per bed and nurses per bed were 5.7 (3.9, 13.8), 3.8 (2.7, 8.5), 2.5 (1.9, 5.0), 1.5 (1.2, 2.3), and 15.8 (11.0, 35.4), 10.6 (7.7, 22.0), 7.0 (5.4, 13.0), 4.2 (3.3, 6.2), respectively, with an ICU mortality rate of 5%, 10%, 15%, and 20%, respectively. According to the reports from the National Health Commission of the People’s Republic of China (NHCPRC), the number of critically ill cases that remained in designated hospitals, the daily death toll and the daily death rate in Hubei Province as of March 14, 2020 are shown in Figure 2. The daily death rate varied from 20.5% in late January to 1.6% by March 14, 2020. The reinforcements of physicians and nurses at 41 ICUs in Hubei Province were recorded. A large number of ICU medical staff who were not responsible for the admission of COVID-19 patients were recruited nationwide. After the second reinforcement teams were dispatched to Hubei Province on January 28, 2020, the daily mortality of critically ill patients showed a downward trend. Our main finding was that the level of ICU staffing was associated with mortality in ICUs for critically ill COVID-19 patients. Mortality was negatively correlated with the proportion of physicians or nurses per bed in these ICUs. It is important to note that higher numbers of intensive care personnel may be needed to reduce mortality in patients with COVID-19 in ICUs. For instance, even if the target mortality is as high as 20%, the estimated demand for physicians and nurses per bed is 1.5 (95% CI: 1.2, 2.3) and 4.2 (95% CI: 3.3, 6.2), which is far higher than the recommended values (0.8–1:1 and 2.5–3:1) for conventional ICUs [3]. However, in the early stages of the COVID-19 epidemic in Hubei Province, intensive care personnel in designated hospitals were very scarce. In fact, according to the 2016 Hubei Provincial Critical Care Development Report, the percentage of ICU beds at that time was only 1.49% [4], which has not exceeded the national rate. However, intensive care comprised 2.1% of total bed numbers in China in 1999 [5]. The Guideline on the Construction and Management of Critical Care Units (Trial) issued by the Ministry of Health of China in 2009 requires that the ratio of ICU beds to hospital beds should be 2–8% [6]. However, intensive care comprised 8% of total bed numbers in the United States in 1991 [7]; compared with 1~2% in the United Kingdom [8]. A review showed that the mean ratio of ICU beds to hospital beds was 1.5% from 15 low-income countries [9]. In fact, the problem in Wuhan is that there are not enough physicians and nurses, and the number of ICU beds is estimated to be insufficient. Importantly, our findings further demonstrated that the trend in daily death rate decreased when reinforcement teams were introduced into designated hospitals in Hubei Province (Figure 2); while the number of patients and the proportion of professional ICU staffing were comparable, and mortality was negatively correlated with the ratio of physicians or nurses per bed in 58 ICUs, especially nationwide (Table 2). These findings confirmed that ICU staffing was one of the important determinants for mortality in ICUs during the epidemic of a highly infectious disease. Our aim was to estimate the number of ICU staff needed to reduce mortality in ICUs of hospitals designated for COVID-19. Based on the increasing data, the ICU design and management guidelines recommend that each bed be equipped with 0.8–1 physicians and 2.5–3 nurses [3, 10]. Meanwhile, there was limited evidence on the requirements of ICU staffing for a highly infectious disease. Management of COVID-19 patients may require more ICU staffing than management of ordinary critically ill patients. Based on probit regression models, the estimated values of physicians (nurses) per bed were 5.7 (15.8), 3.8 (10.6), 2.5 (7.0), and 1.5 (4.2), respectively, while ICU mortality rates were 5%, 10%, 15%, and 20%, respectively (Figure 2). In conclusion, our results showed a significant correlation between critical care staffing and the mortality of critically ill patients during the early COVID-19 epidemic in China. The COVID-19-specific ICUs required a higher number of intensive care personnel to reduce mortality. Finally, increasing the number of ICU beds is required in the development of ICUs in Hubei Province.

Background: Following combat-related, extensive soft tissue injury from gunshot wounds or blasts, prolonged duration from injury to full wound closure is associated with infection, increased morbidity and mortality, failure to mobilize, poor functional outcome and increased cost. The purpose of this study was to evaluate a novel treatment enabling early primary closure of combat wounds. Methods: This was a retrospective study of 10 soldiers and civilians with extensive combat-related soft tissue limb injuries (5 gunshot wounds, 5 blasts) treated using the TopClosure^® Tension Relief System (TRS) with simultaneous administration of regulated oxygen-enriched and irrigation negative pressure-assisted wound therapy (ROINPT) via the Vcare α^® device. Results: Nine patients were treated during the acute phase of injury and one was treated following removal of a flap due to deep infection 20 years after injury and flap reconstruction. Two patients had upper limb injury and the rest lower limb injury. With the aid of the TRS and/or ROINPT, immediate primary closure during reconstruction was achieved in 6 patients and delayed primary closure in three. Only one patient required a skin graft to close a small area of the wound after most of the wound had been closed by delayed primary closure. Wound closure was achieved within 0–37 days (median: 12.5 days, interquartile range: 2.75–19.75) from injury. Conclusions: The TRS is a novel device for effective, early skin stretching and secure wound closure through the application of stress relaxation and mechanical creep, achieving primary closure of large defects using a simplified surgical technique and reducing the need for closure using skin grafts and flaps and the use of tissue expanders. Delivering supplemental oxygen to the wound by ROINPT reverses the reduced oxygen levels inherent in conventional negative pressure-assisted wound therapy, mitigating anaerobic contamination and reducing infection. Irrigation may accelerate the evacuation of infectious material from the wound and provide a novel method for antibiotic administration. The combination of TRS and ROINPT devices allow for early primary closure with improved functionality of combat-related limb injuries.

Background: Epidermal stem cells (EpSCs) that reside in cutaneous hair follicles and the basal layer of the epidermis are indispensable for wound healing and skin homeostasis. Little is known about the effects of photochemical activation on EpSC differentiation, proliferation and migration during wound healing. The present study aimed to determine the effects of photodynamic therapy (PDT) on wound healing in vivo and in vitro. Methods: We created mouse full-thickness skin resection models and applied 5-aminolevulinic acid (ALA) for PDT to the wound beds. Wound healing was analysed by gross evaluation and haematoxylin–eosin staining in vivo. In cultured EpSCs, protein expression was measured using flow cytometry and immunohistochemistry. Cell migration was examined using a scratch model; apoptosis and differentiation were measured using flow cytometry. Results: PDT accelerated wound closure by enhancing EpSC differentiation, proliferation and migration, thereby promoting re-epithelialization and angiogenesis. PDT inhibited inflammatory infiltration and expression of proinflammatory cytokines, whereas the secretion of growth factors was greater than in other groups. The proportion of transient amplifying cells was significantly greater in vivo and in vitro in the PDT groups. EpSC migration was markedly enhanced after ALA-induced PDT. Conclusions: Topical ALA-induced PDT stimulates wound healing by enhancing re-epithelialization, promoting angiogenesis as well as modulating skin homeostasis. This work provides a preliminary theoretical foundation for the clinical administration of topical ALA-induced PDT in skin wound healing.

The epidermis is the outermost layer of skin and the first barrier against invasion. Dendritic epidermal T cells (DETCs) are a subset of γ δ T cells and an important component of the epidermal immune microenvironment. DETCs are involved in skin wound healing, malignancy and autoimmune diseases. DETCs secrete insulin-like growth factor-1 and keratinocyte growth factor for skin homeostasis and re-epithelization and release inflammatory factors to adjust the inflammatory microenvironment of wound healing. Therefore, an understanding of their development, activation and correlative signalling pathways is indispensable for the regulation of DETCs to accelerate wound healing. Our review focuses on the above-mentioned molecular mechanisms to provide a general research framework to regulate and control the function of DETCs.

Background: Wound healing processes are influenced by macronutrient intake (protein, carbohydrate and fat). The most favourable diet for cutaneous wound healing is not known, although high-protein diets are currently favoured clinically. This experimental study investigates the optimal macronutrient balance for cutaneous wound healing using a mouse model and the Geometric Framework, a nutrient modelling method, capable of analyzing the individual and interactive effects of a wide spectrum of macronutrient intake. Methods: Two adjacent and identical full-thickness skin excisions (1 cm²) were surgically created on the dorsal area of male C57BL/6 mice. Mice were then allocated to one of 12 high-energy diets that varied in protein, carbohydrate and fat content. In select diets, wound healing processes, cytokine expression, energy expenditure, body composition, muscle and fat reserves were assessed. Results: Using the Geometric Framework, we show that a low-protein intake, coupled with a balanced intake of carbohydrate and fat is optimal for wound healing. Mice fed a low-protein diet progressed quickly through wound healing stages with favourable wound inflammatory cytokine expression and significantly accelerated collagen production. These local processes were associated with an increased early systemic inflammatory response and a higher overall energy expenditure, related to metabolic changes occurring in key macronutrient reserves in lean body mass and fat depots. Conclusions: The results suggest that a low-protein diet may have a greater potential to accelerate wound healing than the current clinically used high-protein diets.

Nerve guide conduits (NGCs), as alternatives to nerve autografts and allografts, have been widely explored as an advanced tool for the treatment of peripheral nerve injury. However, the repairing efficiency of NGCs still needs significant improvements. Functional NGCs that provide a more favorable microenvironment for promoting axonal elongation and myelination are of great importance. In recent years, 3D printing technologies have been widely applied in the fabrication of customized and complex constructs, exhibiting great potential for tissue engineering applications, especially for the construction of functional NGCs. In this review, we introduce the 3D printing technologies for manufacturing functional NGCs, including inkjet printing, extrusion printing, stereolithography-based printing and indirect printing. Further, we summarize the current methods and strategies for constructing functional NGCs, such as designing special conduit architectures, using appropriate materials and co-printing with different biological cues. Finally, the challenges and prospects for construction of functional NGCs are also presented.

Background: Scar comorbidities seriously affect the physical and mental health of patients, but few studies have reported the exact epidemiological characteristics of scar comorbidities in China. This study aimed to investigate the prevalence of scar comorbidities in China. Methods: The data of 177,586 scar cases between 2013 and 2018 were obtained from the Hospital Quality Monitoring System based on the 10th edition of the International Classification of Diseases coding system. The total distribution of scar comorbidities and their relationship with age, aetiology and body regions were analysed. Results: Six comorbidities (contracture, malformation, ocular complications, adhesion, infection and others) were the main focus. In general, male patients outnumbered females and urban areas outnumbered rural areas. The proportion of contractures was the highest at 59,028 (33.24%). Students, workers and farmers made up the majority of the occupation. Han Chinese accounted for the majority of the ethnic. The highest proportion of scar contracture occurred at 1–1.9 years of age (58.97%), after which a significant downward trend was observed. However, starting from 50 years of age, ocular complications increased gradually and significantly, eventually reaching a peak of 34.49% in those aged >80 years. Scar contracture was the most common comorbidity according to aetiology, and the highest proportion was observed in patients who were scalded (29.33%). Contractures were also the most frequent comorbidity in hands (10.30%), lower limbs (6.97%), feet (6.80%) and upper limbs (6.02%). The mean and median hospitalization durations were 12.85 and 8 days, respectively. Conclusions: Contractures were the most common comorbidities, and different comorbidities tended to occur at different ages and with different causative factors.

Background: Sweat glands (SGs) and hair follicles (HFs) are two important cutaneous appendages that play crucial roles in homeostatic maintenance and thermoregulation, and their interaction is involved in wound healing. SGs can be regenerated from mesenchymal stem cell-laden 3D bioprinted scaffolds, based on our previous studies, whereas regeneration of HFs could not be achieved in the same model. Due to the lack of an in vitro model, the underlying molecular mechanism of the interaction between SGs and HFs in regeneration could not be fully understood. The purpose of the present study was to establish an in vitro model of skin constructs with SGs and HFs and explore the interaction between these two appendages in regeneration. Methods: To investigate the interaction effects between SGs and HFs during their regeneration processes, a combined model was created by seeding HF spheroids on 3D printed SG scaffolds. The interaction between SG scaffolds and HF spheroids was detected using RNA expression and immunofluorescence staining. The effects of microenvironmental cues on SG and HF regeneration were analysed by altering seed cell types and plantar dermis homogenate in the scaffold. Results: According to this model, we overcame the difficulties in simultaneously inducing SG and HF regeneration and explored the interaction effects between SG scaffolds and HF spheroids. Surprisingly, HF spheroids promoted both SG and HF differentiation in SG scaffolds, while SG scaffolds promoted SG differentiation but had little effect on HF potency in HF spheroids. Specifically, microenvironmental factors (plantar dermis homogenate) in SG scaffolds effectively promoted SG and HF genesis in HF spheroids, no matter what the seed cell type in SG scaffolds was, and the promotion effects were persistent. Conclusions: Our approach elucidated a new model for SG and HF formation in vitro and provided an applicable platform to investigate the interaction between SGs and HFs in vitro. This platform might facilitate 3D skin constructs with multiple appendages and unveil the spatiotemporal molecular program of multiple appendage regeneration.

The accurate and objective evaluation of burn depth is a significant challenge in burn wound care. Herein, we used near infrared spectroscopy (NIRS) technology to measure the different depth of thermal burns in ex vivo porcine models. Based on the intensity of the spectral signals and the diffuse reflection theory, we extracted the optical parameters involved in functional (total hemoglobin and water content) and structural (tissue scattered size and scattered particles) features that reflect the changes in burn depth. Next, we applied support vector regression to construct a model including the optical property parameters and the burn depth. Finally, we histologically verified the burn depth data collected via NIRS. The results showed that our inversion model could achieve an average relative error of about 7.63%, while the NIRS technology diagnostic accuracy was in the range of 50 μm. For the first time, this novel technique provides physicians with real-time burn depth information objectively and accurately.

Burn injuries and their treatments result in severe pain. Unlike traumatic injuries that are characterized by a discrete episode of pain followed by recovery, burn-injured patients endure pain for a prolonged period that lasts through wound closure (e.g. background pain, procedural pain, breakthrough pain, neuropathic pain and itch). Regional anesthesia, including peripheral nerve blocks and neuraxial/epidural anesthesia, offers significant benefits to a multimodal approach in pain treatment. A ‘regional-first’ approach to pain management can be incorporated into the workflow of burn centers through engaging regional anesthesiologists and pain medicine practitioners in the care of burn patients. A detailed understanding of peripheral nerve anatomy frames the burn clinician’s perspective when considering a peripheral nerve block/catheter. The infra/supraclavicular nerve block provides excellent coverage for the upper extremity, while the trunk can be covered with a variety of blocks including erector spinae plane and quadratus lumborum plane blocks. The lower extremity is targeted with fascia iliaca plane and sciatic nerve blocks for both donor and recipient sites. Burn centers that adopt regional anesthesia should be aware of potential complications and contraindications to prevent adverse events, including management of local anesthetic toxicity and epidural infections. Management of anticoagulation around regional anesthesia placement is crucial to prevent hematoma and nerve damage. Ultimately, regional anesthesia can facilitate a better patient experience and allow for early therapy and mobility goals that are hallmarks of burn care and rehabilitation.

Background: Hypertrophic scars are one of the main complications that affect the quality of life of patients after burns. Many methods have been shown to be effective in the treatment of hypertrophic scars, such as ablative fractional CO₂ laser (AFCL) and platelet-rich plasma (PRP). However, there are few studies on the effect of the combined application of these measures. The purpose of this study was to explore the therapeutic effect of AFCL combined with PRP on hypertrophic burn scars. Methods: A retrospective clinical observation study was conducted on 50 patients with hyper-trophic burn scars. The AFCL+PRP group included 31 patients who received AFCL combined with PRP treatment; the AFCL group included 19 patients who received AFCL treatment only. The University of North Carolina 4P Scar Scale (UNC4P) and the Vancouver Scar Scale (VSS) scores that were collected before each treatment were used as indicators of the effectiveness of the previous treatment. The scores recorded at the second, fourth and seventh months were analysed. Results: The demographic data of the 2 groups were not significantly different. Before treatment, there was no difference in the UNC4P and VSS scores between the 2 groups. There was a significant decline in the UNC4P and VSS total scores over 6 months in both groups (p < 0.05) and scores in the 2 groups were comparable after 3 and 6 months (p < 0.05). UNC4P scores in the AFCL+PRP group decreased from a mean of 8.26 to 2.61 (p < 0.05) with a concomitant drop in VSS scores from a mean of 11.74 to 6.06 (p < 0.01). In the AFCL group UNC4P and VSS scores decreased from 7.68 to 4.63 (p < 0.05) and from 10.89 to 8.16 (p < 0.05), respectively. The sub-items of these 2 assessments were analysed and the results suggest that AFCL combined with PRP can comprehensively improve scarring. Conclusions: This study shows that PRP is an effective adjunct for AFCL in the treatment of hypertrophic burn scars and that the combination of PRP and AFCL proved to be more useful than AFCL alone. This combination may be a new and effective clinical practice for the treatment of scars. However, larger and higher-level clinical studies are still needed to determine its efficacy and possible mechanisms.

Severe burns often cause various systemic complications and multiple organ dysfunction syndrome, which is the main cause of death. The lungs and kidneys are vulnerable organs in patients with multiple organ dysfunction syndrome after burns. Extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) have been gradually applied in clinical practice and are beneficial for severe burn patients with refractory respiratory failure or renal dysfunction. However, the literature on ECMO combined with CRRT for the treatment of severe burns is limited. Here, we focus on the current status of ECMO combined with CRRT for the treatment of severe burns and the associated challenges, including the timing of treatment, nutrition support, heparinization and wound management, catheter-related infection and drug dosing in CRRT. With the advancement of medical technology, ECMO combined with CRRT will be further optimized to improve the outcomes of patients with severe burns.

Because China is becoming an aging society, the incidence of diabetes and diabetic foot have been increasing. Diabetic foot has become one of the main health-related killers due to its high disability and mortality rates. Negative pressure wound therapy (NPWT) is one of the most effective techniques for the treatment of diabetic foot wounds and great progress, both in terms of research and its clinical application, has been made in the last 20 years of its development. However, due to the complex pathogenesis and management of diabetic foot, irregular application of NPWT often leads to complications, such as infection, bleeding and necrosis, that seriously affect its treatment outcomes. In 2020, under the leadership of Burns, Trauma and Tissue Repair Committee of the Cross-Straits Medicine Exchange Association, the writing group for ‘Consensus on the application of negative pressure wound therapy of diabetic foot wounds’was established with the participation of scholars from the specialized areas of burns, endocrinology, vascular surgery, orthopedics and wound repair. Drawing on evidence-based practice suggested by the latest clinical research, this consensus proposes the best clinical practice guidelines for the application and prognostic evaluation of NPWT for diabetic foot. The consensus aims to support the formation of standardized treatment schemes that clinicians can refer to when treating cases of diabetic foot.

Blood plays an essential role in the human body. Hemorrhage is a critical cause of both military and civilian casualties. The human body has its own hemostatic mechanism that involves complex processes and has limited capacity. However, in emergency situations such as battlefields and hospitals, when the hemostatic mechanism of the human body itself cannot stop bleeding effectively, hemostatic materials are needed for saving lives. In this review, the hemostatic mechanisms and performance of the most commonly used hemostatic materials, (including fibrin, collagen, zeolite, gelatin, alginate, chitosan, cellulose and cyanoacrylate) and the commercial wound dressings based on these materials, will be discussed. These materials may have limitations, such as poor tissue adhesion, risk of infection and exothermic reactions, that may lessen their hemostatic efficacy and cause secondary injuries. High-performance hemostatic materials, therefore, have been designed and developed to improve hemostatic efficiency in clinical use. In this review, hemostatic materials with advanced performances, such as antibacterial capacity, superhydrophobicity/superhydrophilicity, superelasticity, high porosity and/or biomimicry, will be introduced. Future prospects of hemostatic materials will also be discussed in this review.

Background: The clinical features of keloids consist of aberrant proliferation, secretion, differentiation and apoptosis of keloid dermis-derived fibroblasts (KFBs). Notably, the apoptosis rate of KFBs is lower than the proliferation rate. Though the anti-fibrotic effect of adipose-derived stem cells (ADSCs) on keloids has become a hot topic of research, the exact anti-fibrotic mechanism of the paracrine effect remains unclear. This study aimed to find out how the conditioned medium of ADSCs (ADSC-CM) exerts an anti-fibrotic effect in KFBs. Methods: KFBs and ADSCs were extracted and cultured. Then, ADSC-CM was prepared. Whether ADSC-CM could inhibit KFB growth and induce apoptosis was verified by the use of a cell counting kit-8, an 5-Ethynyl-2-deoxyuridine (Edu) kit and flow cytometry. The expressions of cyclooxygenase-1 (COX-1), COX-2, caspase 3 and B-cell lymphoma-2 (Bcl-2) in ADSC-CM-cultured KFBs were tested by real-time PCR and western blotting. To clarify the role of COX-2 in ADSC-CM-induced KFB apoptosis, a specific COX-2 inhibitor, celecoxib, was applied to KFBs cultured in ADSC-CM. Moreover, we tested the production of arachidonic acid (AA) and prostaglandin E₂ (PGE₂) by ELISA. Then, we established a keloid transplantation model in a nude mouse to validate the therapeutic effect in vivo. Results: The proliferation ability of KFBs cultured in ADSC-CM was found to be weakened and apoptosis was significantly increased. Caspase 3 expression was significantly upregulated and Bcl-2 was downregulated in ADSC-CM-cultured KFBs. Furthermore, ADSC-CM strikingly elevated COX-2 mRNA and protein expressions, but COX-1 expression was unaltered. COX-2 inhibitors reduced ADSC-CM-induced apoptosis. Additionally, COX-2 inhibition blocked the elevation of caspase 3 and reversed the decrease in Bcl-2 expression. ADSC-CM increased PGE₂ levels by 1.5-fold and this effect was restrained by COX-2 inhibition. In the nude mouse model, expressions of AA, COX-2 and PGE₂ were higher in the translated keloid tissues after ADSC-CM injection than in the controls. Conclusions: We showed activation of the COX-2/PGE₂ cascade in KFBs in response to ADSC-CM. By employing a specific COX-2 inhibitor, COX-2/PGE₂ cascade activation played a crucial role in mediating the ADSC-CM-induced KFB apoptosis and anti-proliferation effects.

Background: Following recent findings from our group that curcumin preconditioning augments the therapeutic efficacy of adipose-derived stem cells in the healing of diabetic wounds in rats, we aimed to investigate the regenerative effects of curcumin preconditioned adipose-derived mesenchymal stem cells (ASCs) for better recovery of acid inflicted burns in this study. Methods: ASCs were preconditioned with 5 μM curcumin for 24 hours and assessed for proliferation, migration, paracrine release potential and gene expression comparative to naïve ASCs. Subsequently, the healing capacity of curcumin preconditioned ASCs (Cur-ASCs) versus naïve ASCs was examined using acidic wounds in rats. For this, acid inflicted burns of 20 mm in diameter were made on the back of male Wistar rats. Then, 2 × 10⁶ cells of Cur-ASCs and naïve ASCs were intradermally injected in the wound periphery (n = 6) for comparison with an untreated saline control. Post-transplantation, wounds were macroscopically analysed and photographed to evaluate the percentage of wound closure and period of re-epithelization. Healed wound biopsies were excised and used for histological evaluation and expression analysis of wound healing markers at molecular level by quantitative PCR and western blotting. Results: We found that Cur-ASCs exhibited greater proliferation, migration and paracrine potential in vitro. Further, Cur-ASCs showed more effective recovery than naïve ASCs as exhibited by gross morphology, faster wound closure and earlier re-epithelialization. Masson’s trichrome and hematoxylin and eosin staining demonstrated the improved architecture of the healing burns, as evidenced by reduced infiltration of inflammatory cells, compact collagen and marked granulation in Cur-ASC treated rats. Corroborating these findings, molecular assessment showed significantly reduced expressions of pro-inflammatory factors (interleukin-1 beta, interleukin-6, tumor necrosis factor alpha) a with striking upsurge of an oxidative marker (superoxide dismutase 1), pro-angiogenic factors (vascular endothelial growth factor, hepatocyte growth factor, hypoxia-inducible factor-1 alpha) and collagen markers (transforming growth factor beta 1, fibroblast growth factor-2, collagen type 1 alpha 1), verifying that Cur-ASCs modulate the regulation of pro-inflammatory and healing markers at burn sites. Conclusions: Treatment with Cur-ASCs resulted in faster re-epithelization of acid inflicted burns compared to the treatment with naïve ASCs. Based on observed findings, we suggest the transplantation of Cur-ASCs is a valuable therapy for the potent clinical management of acidic burns.

Background: Artificial intelligence (AI) is an innovative field with potential for improving burn care. This article provides an updated review on machine learning in burn care and discusses future challenges and the role of healthcare professionals in the successful implementation of AI technologies. Methods: A systematic search was carried out on MEDLINE, Embase and PubMed databases for English-language articles studying machine learning in burns. Articles were reviewed quantitatively and qualitatively for clinical applications, key features, algorithms, outcomes and validation methods. Results: A total of 46 observational studies were included for review. Assessment of burn depth (n = 26), support vector machines (n = 19) and 10-fold cross-validation (n = 11) were the most common application, algorithm and validation tool used, respectively. Conclusion: AI should be incorporated into clinical practice as an adjunct to the experienced burns provider once direct comparative analysis to current gold standards outlining its benefits and risks have been studied. Future considerations must include the development of a burn-specific common framework. Authors should use common validation tools to allow for effective comparisons. Level I/II evidence is required to produce robust proof about clinical and economic impacts.

Background: Poor sleep quality is associated with a decrease in quality of life in patients with major burn scars, combined with pruritus and pain. Few interventions have been reported to improve the sleep quality of patients with scars. In the current prospective cohort study, we investigated the efficacy of CO₂-ablative fractional laser (AFL) surgery vs conventional surgery in post-burn patients with hypertrophic scars with sleep quality as the primary study outcome. Methods: In total 68 consecutive patients undergoing scar surgical treatment were recruited, including a CO₂-AFL surgery cohort (n = 35) and a conventional surgery cohort (n = 33). A subgroup from the AFL cohort was selected. Sleep quality, pain and pruritus were evaluated. Multiple linear regression analyses were performed to reveal the effect of CO₂-AFL surgery. Results: The CO₂-AFL surgery cohort had significantly lower Pittsburgh sleep quality index (PSQI) global scores than the conventional surgery cohort after the last surgical treatment. In the subgroup of patients receiving hardware sleep monitoring, CO₂-AFL markedly increased deep sleep time, deep sleep efficiency and reduced initial sleep latency. Compared to the conventional surgery cohort, the CO₂-AFL cohort presented significantly lower pain and pruritus scores. Correlation analysis showed pain and pruritus were significantly associated with PSQI scores, and there were also significant correlations between pain and pruritus scores. Multiple linear regression analysis showed that surgery method was negatively linearly correlated with visual analog scale (VAS) pain score, brief pain inventory (BPI) total, VAS pruritus score, 5-D itch scale total, four-item itch questionnaire (FIIQ) total and PSQI total. Conclusions: CO₂-AFL surgery significantly improved sleep quality and reduced pain and pruritus of hypertrophic scar patients. The alleviation of sleep disorder was associated with improvement of deep sleep quality including deep sleep time and deep sleep deficiency. Trial registration: The Chinese Clinical Trial Registry (ChiCTR200035268) approved retrospectively registration on 5 Aug 2020.

The complex lower extremity wound is frequently encountered by orthopedic and plastic surgeons. Innovations in wound care, soft tissue coverage and surgical fixation techniques allow for improved functional outcomes in this patient population with highly morbid injuries. In this review, the principles of reconstruction of complex lower extremity traumatic wounds are outlined. These principles include appropriate initial evaluation of the patient and mangled extremity, as well as appropriate patient selection for limb salvage. The authors emphasize proper planning for reconstruction, timing of reconstruction and the importance of an understanding of the most appropriate reconstructive option. The role of different reconstructive and wound care modalities is discussed, notably negative pressure wound therapy and dermal substitutes. The role of pedicled flaps and microvascular free-tissue transfer are discussed, as are innovations in understanding of perforator anatomy and perforator flap surgery that have broadened the reconstruction surgeon’s armamentarium. Finally, the importance of a multidisciplinary team is highlighted via the principle of the orthoplastic approach to management of complex lower extremity wounds. Upon completion of this review, the reader should have a thorough understanding of the principles of contemporary lower extremity reconstruction.

Preventing microbial colonization or infections that cause offensive smells may lead to odor reduction. As both anaerobic and aerobic bacteria cause the release of malodor from wounds, the most direct way of avoiding or eliminating wound odor is to prevent or eradicate the responsible infection through the debridement of necrotic tissues. However, some burn patients with malodorous wounds are unable to undergo debridement due to systemic conditions, especially in the acute stage. Moreover, the optimal drug doses and dressings to ensure the efficacy and cost-effectiveness of odorous burn wound management is unclear. The purpose of this commentary is to outline the odor management options available for burn patients, focusing on topical strategies. Numerous potential therapies for treating odorous wounds after burn injuries are suggested.

Moderate or severe burns are potentially devastating injuries that can even cause death, and many of them occur every year. Infection prevention, anti-inflammation, pain management and administration of growth factors play key roles in the treatment of burn wounds. Novel therapeutic strategies under development, such as nanotherapeutics, are promising prospects for burn wound treatment. Nanotherapeutics, including metallic and polymeric nanoformulations, have been extensively developed to manage various types of burns. Both human and animal studies have demonstrated that nanotherapeutics are biocompatible and effective in this application. Herein, we provide comprehensive knowledge of and an update on the progress of various nanoformulations for the treatment of burn wounds.

Background: Blood-based biomarkers have proven to be a reliable measure of the severity and outcome of traumatic brain injury (TBI) in both murine models and patients. In particular, neuron-specific enolase (NSE), neurofilament light (NFL) and S100 beta (S100B) have been investigated in the clinical setting post-injury. Ethanol intoxication (EI) remains a significant comorbidity in TBI, with 30–40% of patients having a positive blood alcohol concentration post-TBI. The effect of ethanol on blood-based biomarkers for the prognosis and diagnosis of TBI remains unclear. In this study, we investigated the effect of EI on NSE, NFL and S100B and their correlation with blood–brain barrier integrity in a murine model of TBI. Methods: We used ultra-sensitive single-molecule array technology and enzyme-linked immunosorbent assay methods to measure NFL, NSE, S100B and claudin-5 concentrations in plasma 3 hours post-TBI. Results: We showed that NFL, NSE and S100B were increased at 3 hours post-TBI. Interestingly, ethanol blood concentrations showed an inverse correlation with NSE but not with NFL or S100B. Claudin-5 levels were increased post-injury but no difference was detected compared to ethanol pretreatment. The increase in claudin-5 post-TBI was correlated with NFL but not with NSE or S100B. Conclusions: Ethanol induces an effect on biomarker release in the bloodstream that is different from TBI not influenced by alcohol. This could be the basis of investigations into humans.

Background: Hypertrophic scarring after burn injury is one of the greatest unmet challenges in patients with burn injuries. A better understanding of the characteristics of scar maturation and early prediction of the long-term outcome of scarring are prerequisites for improving targeted therapies and pivotal for patient counselling. Methods: Repeated measurements of scar stiffness in 11 pediatric patients were performed over the course of 1 year using 2 suction devices, the Cutometer and the Nimble. In addition, the observer pliability score of the Patient and Observer Scar Assessment Scale was applied. This longitudinal study allowed quantification of the ability of each of the measured parameters to reflect scar maturation, as indicated by change in skin pliability/stiffness, over time (using linear regression); the ability to distinguish individual patients (intraclass correlation coefficient (ICC)); the correlation of the devices (Spearman correlation coefficient); and the ability to predict long-term scar maturation based on early scar assessment (using receiver operating characteristic). Results: All the tools used showed significant longitudinal decrease of scar stiffness from 3 months until 12 months after the injury. The Nimble (ICC_{patientNimble} = 0.99) and the Cutometer (ICC_patientCuto = 0.97) demonstrated an excellent ability to distinguish between individual patients. The Nimble seemed to be able to predict the 12-month pliability of scars based on early (3-month) measurements (area under the curve (AUC)_12mPOSAS = 0.67; AUC_12mC = 0.46; AUC_12mN = 0.79). Conclusions: The results of this preliminary study suggest that all 3 tools provide suitable means to quantify alterations in scar stiffness over time. Initial evidence suggests the Nimble is most favorable for predicting changes in stiffness associated with long-term scar maturation. Further studies with a larger sample size are required to validate tissue suction as a clinical tool for analysis of changes of scar stiffness over time.

Background: Human epidermal stem cells (hESCs) play an important role in re-epithelialization and thereby in facilitating wound healing, while an effective way to activate hESCs remains to be explored. Calcium silicate (CS) is a form of bioceramic that can alter cell behavior and promote tissue regeneration. Here, we have observed the effect of CS on hESCs and investigated its possible mechanism. Methods: Using a mouse full-thickness skin excision model, we explored the therapeutic effect of CS on wound healing and re-epithelialization. In vitro, hESCs were cultured with diluted CS ion extracts (CSIEs), and the proliferation, migration ability and stemness of hESCs were evaluated. The effects of CS on the epidermal growth factor (EGF), epidermal growth factor receptor (EGFR) and extracellular signal-related kinase (ERK) signaling pathway were also explored. Results: In vivo, CS accelerated wound healing and re-epithelialization. Immunohistochemistry demonstrated that CS upregulated cytokeratin 19 and integrin β1 expression, indicating that CS improved hESCs stemness. In vitro studies confirmed that CS improved the biological function of hESCs. And the possible mechanism could be due to the activation of the EGF/EGFR/ERK signaling pathway. Conclusion: CS can promote re-epithelialization and improve the biological functions of hESCs via activating the EGF/EGFR/ERK signaling pathway.

Background: Burn shock caused by vascular leakage is one of the main causes of high mortality in severe burn injury. However, the pathophysiological mechanism of vascular leakage is still unclear. The purpose of this study was to explore the molecular mechanism of vascular leakage in the early stage of severe burn and provide a new target for the treatment of severe burns. Methods: Neutrophils were isolated from human peripheral blood by magnetic beads sorting. ELISA was used to detect neutrophil-derived granule proteins and glycocalyx injury products in plasma. The vascular leakage and neutrophil movement were assessed by in vivo laser confocal imaging in mice, and high-quality video were provided. Adhesion-related molecules were investigated by qRT-PCR. The damage to glycocalyx of mice vascular endothelial cells was observed by transmission electron microscope and scanning electron microscope. Proteomic analysis, flow cytometry and immunofluorescence were used to further study the relationship between human peripheral blood neutrophil-derived hypochlorite (HOCl) and CD44 of human vascular endothelial cells. Results: In this study, we found that rapidly increasing activated neutrophils secrete heparin binding protein (HBP) and myeloperoxidase (MPO) after severe burn injury. Increased HBP triggers vascular leakage with synergy of MPO, results in systemic edema and burn shock. Furthermore, we found that the MPO catalytic product HOCl but not MPO triggers CD44 extracellular domain shedding from vascular endothelial cells to damage the glycocalyx. Damage to the glycocalyx results in firm adhesion of neutrophils and increases vascular leakage. However, MPO inhibitors partially protect the glycocalyx of vascular endothelial cells. The combination of HBP and MPO inhibitors markedly reduces vascular leakage and systemic edema in the early stage of severe burns. Conclusions: Taken together, these data reveal that neutrophil-derived HBP and MPO play an important synergies role in triggering vascular leakage at the early stage of severe burns. Targeted intervention in these two biomolecules may introduce new strategies for helping to reduce large amount of fluid loss and subsequent burn shock.

Background: Diabetic foot ulcers characterized by delayed healing are one of the main complications of diabetes. Epidermal keratinocyte dysfunction has been found to play a pivotal role in the poor healing ability of diabetic wounds. In this study, we aimed to explore the relationship between c-Myc and its O-linked N-acetylglucosamine (O-GlcNAc) glycosylation (O-GlcNAcylation) modification and keratinocyte dysfunction in diabetic wounds. Methods: Clinical wound samples were collected and a full-thickness skin defect wound model of diabetic rats was established. Re-epithelialization of wounds was observed by H&E staining and expressions of proliferating cell nuclear antigen, transglutaminase 1, loricrin, c-Myc and O-GlcNAc were measured by immunohistochemistry. The functional changes of proliferation, migration and differentiation of human immortalized epidermal cells (HaCaT) cells after overexpression or knockdown of c-Myc were observed. O-GlcNAcylation of c-Myc was confirmed using immunoprecipitation and proximity ligation assay. Stability of the c-Myc protein was measured using cycloheximide. Wound healing was observed after topical application of compounds that inhibited c-Myc or O-GlcNAc on diabetic wounds. Results: Keratinocytes at the diabetic wound margin were characterized by active proliferation and division, slow migration and poor differentiation. Similar phenomena were observed in HaCaT cells cultured in 30 mM glucose and keratinocytes at the wound margin of the diabetic rats. The expression of c-Myc was increased in keratinocytes at the wound margin of diabetic rats, patients, and in HaCaT cells cultured with 30 mM glucose. Increased expression of c-Myc promoted the proliferation while inhibiting the migration and differentiation of the HaCaT cells, and inhibition of c-Myc promoted diabetic wound healing. Increased O-GlcNAcylation of c-Myc with 30 mM glucose stabilized the c-Myc proteins. Inhibition of O-GlcNAc ameliorated keratinocyte dysfunction and promoted diabetic wound healing. Conclusions: Increased expression of c-Myc promoted abnormal proliferation and inhibited migration and differentiation of keratinocytes at the diabetic wound margin. Increased O-GlcNAcylation of c-Myc with 30 mM glucose stabilized the c-Myc proteins. Inhibition of c-Myc or O-GlcNAc alleviated delayed diabetic wound healing. These findings make c-Myc and O-GlcNAc potential therapeutic targets for diabetic wounds.

Background: Low molecular-weight heparin (LMWH) is routinely administered to burn patients for thromboprophylaxis. Some studies have reported heparin resistance, yet the mechanism(s) and prevalence have not been systematically studied. We hypothesized that nucleosomes, composed of histone structures with associated DNA released from injured tissue and activated immune cells in the form of neutrophil extracellular traps (NETs or NETosis), neutralize LMWH resulting in suboptimal anticoagulation, assessed by reduction in anti-factor Xa activity. Methods: Blood was sampled from >15% total body surface area (TBSA) burn patients receiving LMWH on days 5, 10 and 14. Peak anti-factor Xa (AFXa) activity, anti-thrombin (ATIII) activity, cell-free DNA (cfDNA) levels and nucleosome levels were measured. Mixed effects regression was adjusted for multiple confounders, including injury severity and ATIII activity, and was used to test the association between nucleosomes and AFXa. Results: A total of 30 patients with severe burns were included. Mean TBSA 43% (SD 17). Twenty-three (77%) patients were affected by heparin resistance (defined by AFXa activity <0.2 IU/mL). Mean peak AFXa activity across samples was 0.18 IU/mL (SD 0.11). Mean ATIII was 81.9% activity (SD 20.4). Samples taken at higher LWMH doses were found to have significantly increased AFXa activity, though the effect was not observed at all doses, at 8000 IU no samples were heparin resistant. Nucleosome levels were negatively correlated with AFXa (r = −0.29, p = 0.050) consistent with the hypothesis. The final model, with peak AFXa as the response variable, was adjusted for nucleosome levels (p = 0.0453), ATIII activity (p = 0.0053), LMWH dose pre-sample (p = 0.0049), drug given (enoxaparin or tinzaparin) (p = 0.03), and other confounders including severity of injury, age, gender, time point of sample. Conclusions: Heparin resistance is a prevalent issue in severe burns. Nucleosome levels were increased post-burn, and showed an inverse association with AFXa consistent with the hypothesis that they may interfere with the anticoagulant effect of heparin in vivo and contribute to heparin resistance. Accurate monitoring of AFXa activity with appropriate therapy escalation plans are recommended with dose adjustment following severe burn injury.

Background: Acute skin wounds may compromise the skin barrier, posing a risk of infection. Small intestinal submucosa (SIS) is widely used to treat acute and chronic wounds. However, the efficacy of SIS to accelerate wound healing still needs to be improved to meet clinical demands. To tackle this problem, platelet-rich plasma (PRP) is used due to its potency to promote proliferation, migration and adhesion of target cells. In this study, we applied PRP and SIS to skin wounds to explore their effects on wound healing by evaluating re-epithelialization, collagen production, angiogenesis and the inflammatory response. Methods: A 1 × 1-cm full-thickness skin defect was established in mice. Sixty mice were divided into four treatment groups: PRP + SIS, PRP, SIS and control. On days 3, 5, 7, 10 and 14 post-surgery, tissue specimens were harvested. Haematoxylin and eosin, Masson’s trichrome, immunohistochemical and immunofluorescence double staining were used to visualize epidermal thickness, collagen and vascular regeneration and inflammation. Results: Wound contraction in the PRP and PRP + SIS groups was significantly greater, compared with the other groups, on days 3 and 5 post-surgery. A histological analysis showed higher collagen expression in the PRP and PRP + SIS groups on day 7, which was associated with a thicker epidermal layer on day 14. In addition, immunohistochemical staining showed that CD31-positive blood vessels and vascular endothelial growth factor expression in the PRP + SIS and PRP groups were significantly higher, compared with the control group. Furthermore, immunofluorescence double staining showed that the number of M1 and M2 macrophages in the PRP + SIS and PRP groups was higher, compared with the control and SIS groups alone, on day 3. However, on day 7, the number of M1 macrophages dramatically decreased in the PRP + SIS and PRP groups. The ratio of M2 to M1 macrophages in the PRP + SIS and PRP groups was 3.97 and 2.93 times that of the control group and 4.56 and 3.37 times that of the SIS group, respectively. Conclusion: Co-administration of SIS and PRP has a better effect on promoting angiogenesis, re-epithelialization and collagen regeneration in managing acute wound healing than either agent alone.

Background: It is unknown whether lung-protective ventilation is applied in burn patients and whether they benefit from it. This study aimed to determine ventilation practices in burn intensive care units (ICUs) and investigate the association between lung-protective ventilation and the number of ventilator-free days and alive at day 28 (VFD-28). Methods: This is an international prospective observational cohort study including adult burn patients requiring mechanical ventilation. Low tidal volume (V_T) was defined as V_T ≤8 mL/kg predicted body weight (PBW). Levels of positive end-expiratory pressure (PEEP) and maximum airway pressures were collected. The association between V_T and VFD-28 was analyzed using a competing risk model. Ventilation settings were presented for all patients, focusing on the first day of ventilation. We also compared ventilation settings between patients with and without inhalation trauma. Results: A total of 160 patients from 28 ICUs in 16 countries were included. Low V_T was used in 74% of patients, median V_T size was 7.3 [interquartile range (IQR) 6.2–8.3] mL/kg PBW and did not differ between patients with and without inhalation trauma (p = 0.58). Median VFD-28 was 17 (IQR 0–26), without a difference between ventilation with low or high V_T (p = 0.98). All patients were ventilated with PEEP levels ≥5 cmH₂O; 80% of patients had maximum airway pressures <30 cmH₂O. Conclusion: In this international cohort study we found that lung-protective ventilation is used in the majority of burn patients, irrespective of the presence of inhalation trauma. Use of low V_T was not associated with a reduction in VFD-28. Trial registration: Clinicaltrials.gov NCT02312869. Date of registration: 9 December 2014.

Spinal cord injury (SCI) often leads to permanent disability, which is mainly caused by the loss of functional recovery. In this review, we aimed to investigate why the healing process is interrupted. One of the reasons for this interruption is the formation of a glial scar around the severely damaged tissue, which is usually covered by reactive glia, macrophages and fibroblasts. Aiming to clarify this issue, we summarize the latest research findings pertaining to scar formation, tissue repair, and the divergent roles of blood-derived monocytes/macrophages, ependymal cells, fibroblasts, microglia, oligodendrocyte progenitor cells (OPCs), neuron-glial antigen 2 (NG2) and astrocytes during the process of scar formation, and further analyse the contribution of these cells to scar formation. In addition, we recapitulate the development of therapeutic treatments targeting glial scar components. Altogether, we aim to present a comprehensive decoding of the glial scar and explore potential therapeutic strategies for improving functional recovery after SCI.

Sepsis is an overwhelming inflammatory response to microbial infection. Sepsis management remains a clinical challenge. The role of the gut microbiome in sepsis has gained some attention. Recent evidence has demonstrated that gut microbiota regulate host physiological homeostasis mediators, including the immune system, gut barrier function and disease susceptibility pathways. Therefore, maintenance or restoration of microbiota and metabolite composition might be a therapeutic or prophylactic target against critical illness. Fecal microbiota transplantation and supplementation of probiotics are microbiota-based treatment methods that are somewhat limited in terms of evidence-based efficacy. This review focuses on the importance of the crosstalk between the gastrointestinal ecosystem and sepsis to highlight novel microbiota-targeted therapies to improve the outcomes of sepsis treatment.

Background: Burn injuries are a leading cause of morbidity and disability, with the burden of disease being disproportionately higher in low-and middle-income countries (LMIC). Burn prevention programmes have led to significant reductions in the incidence of burns in high-income countries. However, a previous systematic review published in 2015 highlighted that implementation and evaluation of similar programmes has been limited in LMIC. The objective of this scoping review and narrative synthesis was to summarise and understand the initiatives that have been carried out to reduce burn injuries in LMIC and their effectiveness. Methods: We aimed to identify publications that described studies of effectiveness of burn prevention interventions applied to any population within a LMIC and measured burn incidence or burns-related outcomes. Suitable publications were identified from three sources. Firstly, data was extracted from manuscripts identified in the systematic review published by Rybarczyk et al. We then performed a search for manuscripts on burn prevention interventions published between January 2015 and September 2020. Finally, we extracted data from two systematic reviews where burn evidence was not the primary outcome, which were identified by senior authors. A quality assessment and narrative synthesis of included manuscripts were performed. Results: In total, 24 manuscripts were identified and categorized according to intervention type. The majority of manuscripts (n = 16) described education-based interventions. Four manuscripts focused on environmental modification interventions and four adopted a mixed-methods approach. All of the education-based initiatives demonstrated improvements in knowledge relating to burn safety or first aid, however few measured the impact of their intervention on burn incidence. Four manuscripts described population-based educational interventions and noted reductions in burn incidence. Only one of the four manuscripts describing environmental modification interventions reported burns as a primary outcome measure, noting a reduction in burn incidence. All mixed-method interventions demonstrated some positive improvements in either burn incidence or burns-related safety practices. Conclusion: There is a lack of published literature describing large-scale burn prevention programmes in LMIC that can demonstrate sustained reductions in burn incidence. Population-level, collaborative projects are necessary to drive forward burn prevention through specific environmental or legislative changes and supplementary educational programmes.

Background: MicroRNA-101 (miR-101) is a tumor suppressor microRNA (miRNA) and its loss is associated with the occurrence and progression of various diseases. However, the biological function and target of miR-101 in the pathogenesis of hypertrophic scars (HS) remains unknown. Methods: We harvested HS and paired normal skin (NS) tissue samples from patients and cultured their fibroblasts (HSF and NSF, respectively). We used quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), fluorescence in situ hybridization (FISH), enzyme-linked immunosorbent assays (ELISA) and Western blot analyses to measure mRNA levels and protein expression of miR-101, enhancer of zeste homolog 2 (EZH2), collagen 1 and 3 (Col1 and Col3) and α-smooth muscle actin (α-SMA) in different in vitro conditions. We also used RNA sequencing to evaluate the relevant signaling pathways and bioinformatics analysis and dual-luciferase reporter assays to predict miR-101 targets. We utilized a bleomycin-induced fibrosis mouse model in which we injected miR-101 mimics to evaluate collagen deposition in vivo. Results: We found low expression of miR-101 in HS and HSF compared to NS and NSF. Overexpressing miR-101 decreased Col1, Col3 and α-SMA expression in HSF. We detected high expression of EZH2 in HS and HSF. Knockdown of EZH2 decreased Col1, Col3 and α-SMA in HSF. Mechanistically, miR-101 targeted the 3′-untranslated region (3′UTR) of EZH2, as indicated by the decreased expression of EZH2. Overexpressing EZH2 rescued miR-101-induced collagen repression. MiR-101 mimics effectively suppressed collagen deposition in the bleomycin-induced fibrosis mouse model. Conclusions: Our data reveal that miR-101 targets EZH2 in HS collagen production, providing new insight into the pathological mechanisms underlying HS formation.

As an emerging type of adult stem cell featuring non-invasive acquisition, urine-derived stem cells (USCs) have shown great potential for applications in tissue engineering and regenerative medicine. With a growing amount of research on the topic, the effectiveness of USCs in various disease models has been shown and the underlying mechanisms have also been explored, though many aspects still remain unclear. In this review, we aim to provide an up-to-date overview of the biological characteristics of USCs and their applications in skin, bone and articular cartilage repair. In addition to the identification procedure of USCs, we also summarize current knowledge of the underlying repair mechanisms and application modes of USCs. Potential concerns and perspectives have also been summarized.

Background: The objective of this study was to evaluate the clinical efficacy of thiamine and vitamin C with or without hydrocortisone coadministration on the treatment of sepsis and septic shock. Methods: MEDLINE, EMBASE and CENTRAL databases were searched for randomized controlled trials (RCTs) that made a comparative study between the combination therapy of vitamin C and thiamine with or without hydrocortisone and the administration of placebo in patients with sepsis or septic shock. Two reviewers independently performed study selection, data extraction and quality assessment. Both short-term mortality and change in the sequential organ failure assessment (SOFA) score from baseline (delta SOFA) were set as the primary outcomes. Secondary endpoints included intensive care unit (ICU) mortality, new onset of acute kidney injury, total adverse events, ICU and hospital length of stay, duration of vasopressor usage and ventilator-free days. Meanwhile, trial sequential analysis was conducted for primary outcomes. Results: Eight RCTs with 1428 patients were included in the current study. The results showed no significant reduction of short-term mortality in sepsis and septic shock patients who received combination therapy of vitamin C and thiamine with or without hydrocortisone compared to those with placebo {risk ratio (RR), 1.02 [95% confidence interval (CI), 0.87 to 1.20], p = 0.81, I² = 0%; risk difference (RD), 0 [95% CI, −0.04 to 0.05]}. Nevertheless, the combination therapy was associated with significant reduction in SOFA score [mean difference (MD), −0.63, (95% CI, −0.96 to −0.29, p < 0.001, I² = 0%] and vasopressors duration (MD, −22.11 [95% CI, −30.46 to −13.77], p < 0.001, I² = 6%). Additionally, there were no statistical differences in the pooled estimate for other outcomes. Conclusions: In the current meta-analysis, the combination therapy of vitamin C and thiamine, with or without hydrocortisone had no impact on short-term mortality when compared with placebo, but was associated with significant reduction in SOFA score among patients with sepsis and septic shock.

Background: Polysaccharide-based hydrogels have been developed for many years to treat burn wounds. Essential oils extracted from aromatic plants generally exhibit superior biological activity, especially antibacterial properties. Studies have shown that antibacterial hydrogels mixed with essential oils have great potential for burn wound healing. This study aimed to develop an antibacterial polysaccharide-based hydrogel with essential oil for burn skin repair. Methods: Eucalyptus essential oil (EEO), ginger essential oil (GEO) and cumin essential oil (CEO) were employed for the preparation of effective antibacterial hydrogels physically crosslinked by carboxymethyl chitosan (CMC) and carbomer 940 (CBM). Composite hydrogels were prepared and characterized using antimicrobial activity studies, Fourier-transform infrared spectroscopy, X-ray diffraction, scanning electron microscopy, gas chromatography-mass spectrometery, rheological analysis, viscosity, swelling, water loss rate and water vapor transmission rate studies. In addition, the biocompatibility of hydrogels was evaluated in vivo by cytotoxicity and cell migration assays and the burn healing ability of hydrogels was tested in vivo using burn-induced wounds in mice. Results: The different essential oils exhibited different mixing abilities with the hydrogel matrix (CMC and CBM), which caused varying levels of reduction in essential oil hydrogel viscosity, swelling and water vapor transmission. Among the developed hydrogels, the CBM/CMC/EEO hydrogel exhibited optimal antibacterial activities of 46.26 ± 2.22% and 63.05 ± 0.99% against Staphylococcus aureus and Escherichia coli, respectively, along with cell viability (>92.37%) and migration activity. Furthermore, the CBM/CMC/EEO hydrogel accelerated wound healing in mouse burn models by promoting the recovery of dermis and epidermis as observed using a hematoxylin– eosin and Masson’s trichrome staining assay. The findings from an enzyme-linked immunosorbent assay demonstrated that the CBM/CMC/EEO hydrogel could repair wounds through interleukin-6 and tumor necrosis factor-α downregulation and transforming growth factor-β, vascular endothelial growth factor (VEGF) and epidermal growth factor upregulation. Conclusions: This study successfully prepared a porous CBM/CMC/EEO hydrogel with high antibac-terial activity, favorable swelling, optimal rheological properties, superior water retention and water vapor transmission performance and a significant effect on skin repair in vitro and in vivo. The results indicate that the CBM/CMC/EEO hydrogel has the potential for use as a promising burn dressing material for skin burn repair.

With advances in anatomical knowledge and technology, increased interest has been directed towards reconstruction with enhanced aesthetic and functional outcomes. A myriad of thinned perforator flap harvest approaches have been developed for this purpose; however, concerns about jeopardizing their vascularity remain. To ensure optimum reconstructive outcome without hampering the flap’s microcirculation, it is important to make good use of the existing advanced imaging modalities that can provide clear visualization of perforator branches, particularly in the adipose layer, and an accurate assessment of flap perfusion. Therefore, this review will highlight the imaging modalities that have been utilized for harvesting a thinned perforator flap from these two perspectives, along with future insights into creating both functionally and aesthetically satisfying, yet simultaneously safe, thinned perforator flaps for the best reconstructive outcomes for patients.

Background: The study aimed to develop consensus on the components of health education of home-based negative pressure wound therapy (NPWT) for patients with chronic wounds. Methods: A Delphi method was used to achieve consensus on the components of health education and 75% agreement and coefficient of variation (CV) <0.25 were used as cutoff. Sixteen experts were recruited purposefully to finish this study. Results: Two rounds of consultation were implemented. Consensus was achieved on 36 of the 42 statements. The final agreed list of statements represented three domains: health education before carrying out home-based NPWT, health education for the treatment day of NPWT at hospital and health education for NPWT at home. Conclusions: This study was the first attempt to develop consensus on the comprehensive components of health education of home-based NPWT for patients with chronic wounds. According to the established framework and components of health education, wound professionals can safely and effectively implement health education of home-based NPWT for patients with chronic wounds and improve their self-care ability and treatment experience at home.

Background: Fractional CO₂ laser plays an important role in scar management post split-thickness skin graft by loosening the graft contracture and restoring the smoothness of the surface. However, the optimal treatment protocol remains unknown. This study applied a dual-scan protocol to achieve both releasing and ablation of contracted skin graft. We comprehensively describe this treatment method and compare the efficacy and safety between this dual-scan method and the conventional mono-scan mode. Methods: A hypercontracted scar model after split-thickness skin grafting in red Duroc pigs was established. All scars meeting the inclusion criteria were randomly divided into four groups: high fluence–low density (HF–LD), low fluence–high density (LF–HD), combined group and control group. The energy per unit area was similar in the HF–LD and LF–HD groups. Two laser interventions were performed at a 6-week interval. The efficacy of the treatment was evaluated by objective measures of scar area, release rate, elasticity, thickness and flatness, while the safety was evaluated based on adverse reactions and melanin index. Collagen structure was observed histologically. The animals were followed up for a maximum of 126 days after modeling. Results: A total of 28 contracted scars were included, 7 in each group. At 18 weeks postoperatively, the HF–LD and the combined groups showed significantly increased scar release rate (p = 0.000) and elasticity (p = 0.036) and decreased type I/III collagen ratio (p = 0.002) compared with the control and LF–HD groups. In terms of flatness, the combined group was significantly better than the HF–LD group for elevations <1 mm (p = 0.019). No significant skin side effects, pigmentation or scar thickness changes were observed at 18 weeks. Conclusions: Dual-scan protocol could achieve superficial ablation and deep release of contracted split-thickness skin graft in a single treatment, with similar contraction release and texture improvement compared to a single deep scan. Its main advantage is to restore a smoother scar appearance. Adequate laser penetration was necessary for the release of contracted scars.