Radiotherapy is one of the main cancer treatments, but it may damage normal tissue and cause various side effects. At present, radioprotective agents used in clinics have side effects such as nausea, vomiting, diarrhea and hypotension, which limit their clinical application. It has been found that exosomes play an indispensable role in radiation injury. Exosomes are lipid bilayer vesicles that carry various bioactive substances, such as proteins, lipids and microRNA (miRNA), that play a key role in cell-to-cell communication and affect tissue injury and repair. In addition, studies have shown that radiation can increase the uptake of exosomes in cells and affect the composition and secretion of exosomes. Here, we review the existing studies and discuss the effects of radiation on exosomes and the role of exosomes in radiation injury, aiming to provide new insights for the treatment of radiation injury.

The development of 3D bioprinting in recent years has provided new insights into the creation of in vitro microenvironments for promoting stem cell-based regeneration. Sweat glands (SGs) are mainly responsible for thermoregulation and are a highly differentiated organ with limited regenerative ability. Recent studies have focused on stem cell-based therapies as strategies for repairing SGs after deep dermal injury. In this review, we highlight the recent trend in 3D bioprinted native-like microenvironments and emphasize recent advances in functional SG regeneration using this technology. Furthermore, we discuss five possible regulatory mechanisms in terms of biochemical factors and structural and mechanical cues from 3D bioprinted microenvironments, as well as the most promising regulation from neighbor cells and the vascular microenvironment.

Chronic wounds (e.g. diabetic wounds, pressure wounds, vascular ulcers, etc.) do not usually heal in a timely and orderly manner but rather last for years and may lead to irreversible adverse events, resulting in a substantial financial burden for patients and society. Recently, a large amount of evidence has proven that cellular senescence has a crucial influence on chronic nonhealing wounds. As a defensive mechanism, cell senescence is a manner of cell-cycle arrest with increased secretory phenotype to resist death, preventing cells from stress-induced damage in cancer and noncancer diseases. A growing amount of research has advanced the perception of cell senescence in various chronic wounds and focuses on pathological and physiological processes and therapies targeting senescent cells. However, previous reviews have failed to sum up novel understandings of senescence in chronic wounds and emerging strategies targeting senescence. Herein, we discuss the characteristics and mechanisms of cellular senescence and the link between senescence and chronic wounds as well as some novel antisenescence strategies targeting other diseases that may be applied for chronic wounds.

Chronic wounds are defined as wounds that fail to proceed through the normal phases of wound healing in an orderly and timely manner. The most common and inevitable impairment to wound healing is the installation of an infection, usually in the case of chronic wounds. Therefore, the objective of the present review was to identify the importance of copper nanoparticles in dressings for wound healing. Nanoparticles such as silver, gold and copper combat infectious processes through the inhibition of protein synthesis, peroxidation of the cell membrane and destroying the nucleic acids of bacteria and viruses. Among bioactive nanoparticles, copper plays a complex role in various cells, it modulates several cytokines and growth factor mechanisms of action and is essentially involved in all stages of the wound healing process. More importantly, copper plays a key role in skin regeneration and angiogenesis and accelerates the healing process through induction of vascular endothelial growth factor (VEGF) and angiogenesis by hypoxia-induced factor-1-alpha (HIF-1α) action where copper enhances HIF-1α expression and HIF-1α binding to the critical motifs in the promoter and putative enhancer regions of HIF-1-regulated genes.

Dermal substitutes provide a template for dermal regeneration and reconstruction. They constitute an ideal clinical treatment for deep skin defects. However, rapid vascularization remains as a major hurdle to the development and application of dermal substitutes. Several bioactive factors play an important regulatory role in the process of angiogenesis and an understanding of the mechanism of achieving their effective delivery and sustained function is vital. Nanomaterials have great potential for tissue engineering. Effective delivery of bioactive factors (including growth factors, peptides and nucleic acids) by nanomaterials is of increasing research interest. This paper discusses the process of dermal substitute angiogenesis and the roles of related bioactive factors in this process. The application of nanomaterials for the delivery of bioactive factors to enhance angiogenesis and accelerate wound healing is also reviewed. We focus on new systems and approaches for delivering bioactive factors for enhancing angiogenesis in dermal substitutes.

Background: Red cell distribution width (RDW) and serum albumin concentration are associated with postoperative outcomes. However, the usefulness of the RDW/albumin ratio in burn surgery remains unclear. Therefore, we evaluated the association between RDW/albumin ratio and 90-day mortality after burn surgery. Methods: Between 2013 and 2020, a retrospective review of patients in a burn intensive care unit (ICU) was performed. Receiver operating characteristic curve, multivariate Cox logistic regression, multivariate logistic regression and Kaplan–Meier analyses were conducted to evaluate the associ-ation between RDW/albumin ratio and 90-day mortality after burn surgery. Additionally, prolonged ICU stay rate (>60 days) and ICU stay were assessed. Results: Ninety-day mortality was 22.5% (210/934) in burn patients. Risk factors for 90-day mortality were RDW/albumin ratio at postoperative day 1, age, American Society of Anesthesiologists physical status, diabetes mellitus, inhalation injury, total body surface area burned, hypotensive event and red blood cell transfusion volume. The area under the curve of the RDW/albumin ratio at postoperative day 1 to predict 90-day mortality, after adjusting for age and total body surface area burned, was 0.875 (cut-off value, 6.8). The 90-day mortality was significantly higher in patients with RDW/albumin ratio >6.8 than in those with RDW/albumin ratio ≤6.8 (49.2% vs 12.3%, p < 0.001). Prolonged ICU stay rate and ICU stay were significantly higher and longer in patients with RDW/albumin ratio >6.8 than in those with RDW/albumin ratio ≤6.8 (34.5% vs 26.5%; 21 [11– 38] vs 18 [7–32] days). Conclusion: RDW/albumin ratio >6.8 on postoperative day 1 was associated with higher 90-day mortality, higher prolonged ICU stay rate and longer ICU stay after burn surgery.

Background: Gelatin methacryloyl (GelMA) hydrogels loaded with stem cells have proved to be an effective clinical treatment for wound healing. Advanced glycation end product (AGE), interacting with its particular receptor (AGER), gives rise to reactive oxygen species (ROS) and apoptosis. Curcumin (Cur) has excellent antioxidant activity and regulates intracellular ROS production and apoptosis. In this study, we developed a Cur-incorporated 3D-printed GelMA to insert into adipose-derived stem cells (ADSCs) and applied it to diabetic wounds. Methods: GelMA hydrogels with Cur were fabricated and their in vitro effects on ADSCs were investigated. We used structural characterization, western blot, ROS and apoptosis assay to evaluate the antioxidant and anti-apoptotic activity, and assessed the wound healing effects to investigate the mechanism underlying regulation of apoptosis by Cur via the AGE/AGER/nuclear factor-κB (NF-κB) p65 pathway. Results: A 10% GelMA scaffold exhibited appropriate mechanical properties and biocompatibility for ADSCs. The circular mesh structure demonstrated printability of 10% GelMA and Cur-GelMA bioinks. The incorporation of Cur into the 10% GelMA hydrogel showed an inhibitory effect on AGEs/AGER/NF-κB p65-induced ROS generation and ADSC apoptosis. Furthermore, Cur-GelMA scaffold promoted cell survival and expedited in vivo diabetic wound healing. Conclusions: The incorporation of Cur improved the antioxidant activity of 3D-printed GelMA hydrogel and mitigated AGE/AGER/p65 axis-induced ROS and apoptosis in ADSCs. The effects of scaffolds on wound healing suggested that Cur/GelMA-ADSC hydrogel could be an effective biological material for accelerating wound healing.

Background: Promoting wound healing is crucial to restore the vital barrier function of injured skin. Growth factor products including epidermal growth factor (EGF), fibroblast growth factor (FGF) and granulocyte-macrophage colony stimulating factor (GM-CSF) have been used for decades although no systematic evaluation exists regarding their effectiveness and safety issues in treating acute skin wounds. This has resulted in a lack of guidelines and standards for proper application regimes. Therefore, this systematic review and meta-analysis was performed to critically evaluate the effectiveness and safety of these growth factors on skin acute wounds and provide guidelines for application regimes. Methods: We searched PubMed/Medline (1980–2020), Cochrane Library (1980–2020), Cochrane CENTRAL (from establishment to 2020), ClinicalTrials.gov (from establishment to 2020), Chinese Journal Full-text Database (CNKI, 1994–2020), China Biology Medicine disc (CBM, 1978–2019), Chinese Scientific Journal Database (VIP, 1989–2020) and Wanfang Database (WFDATA, 1980–2019). Randomized controlled trials (RCTs), quasi-RCTs and controlled clinical trials treating patients with acute skin wounds from various causes and with those available growth factors were included. Results: A total of 7573 papers were identified through database searching; 229 papers including 281 studies were kept after final screening. Administering growth factors significantly shortened the healing time of acute skin wounds, including superficial burn injuries [mean difference (MD) = −3.02; 95% confidence interval (CI):−3.31 ~−2.74; p < 0.00001], deep burn injuries (MD = −5.63; 95% CI:−7.10 ~−4.17; p < 0.00001), traumata and surgical wounds (MD = −4.50; 95% CI:−5.55 ~−3.44; p < 0.00001). Growth factors increased the healing rate of acute skin wounds and decreased scar scores. The incidence of adverse reactions was lower in the growth factor treatment group than in the non-growth factor group. Conclusions: The studied growth factors not only are effective and safe for managing acute skin wounds, but also accelerate their healing with no severe adverse reactions.

Autophagy is a lysosome-dependent, self-renewal mechanism that can degrade and recycle cellular components in eukaryotic cells to maintain the stability of the intracellular environment and the cells ability to cope with unfavorable environments. Numerous studies suggest that autophagy participates in regulating various cellular functions and is closely associated with the onset and progression of various diseases. Wound healing is a complex, multistep biological process that involves multiple cell types. Refractory wounds, which include diabetic skin ulcers, can seriously endanger human health. Previous studies have confirmed that autophagy plays an essential role in various phases of wound healing. Specifically, in the inflammatory phase, autophagy has an anti-infection effect and it negatively regulates the inflammatory response, which prevents excessive inflammation from causing tissue damage. In the proliferative phase, local hypoxia in the wound can induce autophagy, which plays a role in anti-apoptosis and anti-oxidative stress and promotes cell survival. Autophagy of vascular endothelial cells promotes wound angiogenesis and that of keratinocytes promotes their differentiation, proliferation and migration, which is conducive to the completion of wound re-epithelialisation. In the remodeling phase, autophagy of fibroblasts affects the formation of hypertrophic scars. Additionally, a refractory diabetic wound may be associated with increased levels of autophagy, and the regulation of mesenchymal stem cell autophagy may improve its application to wound healing. Therefore, understanding the relationship between autophagy and skin wound healing and exploring the molecular mechanism of autophagy regulation may provide novel strategies for the clinical treatment of wound healing.

Background: Microbial dysbiosis in critically ill patients is a leading cause of mortality and septic complications. Probiotics and synbiotics have emerged as novel therapy on gut microbiota to prevent septic complications. However, current evidence on their effects is conflicting. This work aims to systematically review the impact of probiotics or synbiotics in critically ill adult patients. Methods: A comprehensive search of the PubMed, CBM, Embase, CENTRAL, ISI, and CNKI databases was performed to identify randomized controlled trials that evaluate probiotics or synbiotics in critically ill patients. The quality assessment was based on the modified Jadad’s score scale and the Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1. The major outcome measure was mortality. Secondary outcomes included incidence of septic complications, sepsis incidence, length of intensive care unit (ICU) stay, incidence of non-septic complication, and ventilator day. Data synthesis was conduct by Review Manager 5.4. Results: A total of 25 randomized controlled trials reporting on 5049 critically ill patients were included. In the intervention group, 2520 participants received probiotics or synbiotics, whereas 2529 participants received standard care or placebo. Pooling data from randomized controlled trials demonstrated a significant reduction in the incidence of ventilator-associated pneumonia (VAP) in the treatment group [(risk ratio (RR) 0.86; 95% confidence interval (CI): 0.78–0.95; p <0.003, I 2=85%)]. However, in the subgroup analysis, the reduction of incidence of VAP was only significant in patients receiving synbiotics (RR=0.61, 95% CI: 0.47–0.80, p=0.0004, I 2=40%) and not significant in those receiving only probiotics (RR=0.91, 95% CI: 0.82–1.01, p=0.07, I 2=65%). Moreover, sepsis incidence of critically ill patients was only significantly reduced by the addition of synbiotics (RR=0.41; 95% CI: 0.22–0.72, p=0.005, I 2=0%). The incidence of ICU-acquired infections was significantly reduced by the synbiotics therapy (RR=0.72; 95% CI: 0.58–0.89, p=0.0007, I 2=79%). There was no significant difference in mortality, diarrhea, or length of ICU stay between the treatment and control groups. Conclusions: Synbiotics is an effective and safe nutrition therapy in reducing septic complications in critically ill patients. However, in such patients, administration of probiotics alone compared with placebo resulted in no difference in the septic complications.

Following injury, tissue autonomously initiates a complex repair process, resulting in either partial recovery or regeneration of tissue architecture and function in most organisms. Both the repair and regeneration processes are highly coordinated by a hierarchy of interplay among signal transduction pathways initiated by different growth factors, cytokines and other signaling molecules under normal conditions. However, under chronic traumatic or pathological conditions, the reparative or regenerative process of most tissues in different organs can lose control to different extents, leading to random, incomplete or even flawed cell and tissue reconstitution and thus often partial restoration of the original structure and function, accompanied by the development of fibrosis, scarring or even pathogenesis that could cause organ failure and death of the organism. Ample evidence suggests that the various combinatorial fibroblast growth factor (FGF) and receptor signal transduction systems play prominent roles in injury repair and the remodeling of adult tissues in addition to embryonic development and regulation of metabolic homeostasis. In this review, we attempt to provide a brief update on our current understanding of the roles, the underlying mechanisms and clinical application of FGFs in tissue injury repair.

Tetrahedral DNA nanostructures (TDNs) are molecules with a pyramidal structure formed by folding four single strands of DNA based on the principle of base pairing. Although DNA has polyanionic properties, the special spatial structure of TDNs allows them to penetrate the cell membrane without the aid of transfection agents in a caveolin-dependent manner and enables them to participate in the regulation of cellular processes without obvious toxic side effects. Because of their stable spatial structure, TDNs resist the limitations imposed by nuclease activity and innate immune responses to DNA. In addition, TDNs have good editability and biocompatibility, giving them great advantages for biomedical applications. Previous studies have found that TDNs have a variety of biological properties, including promoting cell migration, proliferation and differentiation, as well as having anti-inflammatory, antioxidant, anti-infective and immune regulation capabilities. Moreover, we confirmed that TDNs can promote the regeneration and repair of skin, blood vessels, muscles and bone tissues. Based on these findings, we believe that TDNs have broad prospects for application in wound repair and regeneration. This article reviews recent progress in TDN research and its applications.

Background: Diabetes significantly delays wound healing through oxidative stress, inflammation and impaired re-epithelialization that lead to defective regulation of the healing process, although the related mechanism remains unclear. Here, we aim to investigate the potential role and mechanism for the beneficial effect of betulinic acid (BA) on diabetic wound healing. Methods: The molecular effect of BA on hyperglycemia-mediated gene expression, oxidative stress, inflammation and glucose uptake was evaluated in endothelial, fibroblast and muscle cells. Burn injury was introduced to streptozotocin-induced diabetic rats and BA administration through either an intraperitoneal (IP) or topical (TOP) technique was used for wound treatment. Glucose tolerance was evaluated in both muscle tissue and fibroblasts, while oxidative stress and inflammation were determined in both the circulatory system and in wound tissues. The effect of BA on the wound healing process was also evaluated. Results: BA treatment reversed hyperglycemia-induced glucose transporter type 4 (GLUT4) sup-pression in both muscle and fibroblast cells. This treatment also partly reversed hyperglycemia-mediated suppression of endothelial nitric oxide synthase (eNOS), nuclear factor erythroid 2-related factor 2 (Nrf2) signaling and nuclear factor NFκB p65 subunit (NFκB p65) activation in endothelial cells. An in vivo rat study showed that BA administration ameliorated diabetes-mediated glucose intolerance and partly attenuated diabetes-mediated oxidative stress and inflam-mation in both the circulatory system and wound tissues. BA administration by both IP and TOP techniques significantly accelerated diabetic wound healing, while BA administration by either IP or TOP methods alone had a significantly lower effect. Conclusions: BA treatment ameliorates hyperglycemia-mediated glucose intolerance, endothelial dysfunction, oxidative stress and inflammation. Administration of BA by both IP and TOP tech-niques was found to significantly accelerate diabetic wound healing, indicating that BA could be a potential therapeutic candidate for diabetic wound healing.

Background: Acute lung injury (ALI) is a common complication following severe burns. The underlying mechanisms of ALI are incompletely understood; thus, available treatments are not sufficient to repair the lung tissue after ALI. Methods: To investigate the relationship between the Notch pathway and burn-induced lung injury, we established a rat burn injury model by scalding and verified lung injury via lung injury evaluations, including hematoxylin and eosin (H&E) staining, lung injury scoring, bronchoalveolar lavage fluid and wet/dry ratio analyses, myeloperoxidase immunohistochemical staining and reactive oxygen species (ROS) accumulation analysis. To explore whether burn injury affects Notch1 expression, we detected the expression of Notch1 and Hes1 after burn injury. Then, we extracted pulmonary microvascular endothelial cells (PMVECs) and conducted Notch pathway inhibition and activation experiments, via a γ-secretase inhibitor (GSI) and OP9-DLL1 coculture, respectively, to verify the regulatory effect of the Notch pathway on ROS accumulation and apoptosis in burn-serum-stimulated PMVECs. To investigate the regulatory effect of the Notch pathway on ROS accumulation, we detected the expression of oxidative-stress-related molecules such as superoxide dismutase, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) 2, NOX4 and cleaved caspase-3. NOX4-specific small interfering RNA (siRNA) and the inhibitor GKT137831 were used to verify the regulatory effect of the Notch pathway on ROS via NOX4. Results: We successfully established a burn model and revealed that lung injury, excessive ROS accumulation and an inflammatory response occurred. Notch1 detection showed that the expression of Notch1 was significantly increased after burn injury. In PMVECs challenged with burn serum, ROS and cell death were elevated. Moreover, when the Notch pathway was suppressed by GSI, ROS and cell apoptosis levels were significantly increased. Conversely, these parameters were reduced when the Notch pathway was activated by OP9-DLL1. Mechanistically, the inhibition of NOX4 by siRNA and GKT137831 showed that the Notch pathway reduced ROS production and cell apoptosis by downregulating the expression of NOX4 in PMVECs. Conclusions: The Notch pathway reduced ROS production and apoptosis by downregulating the expression of NOX4 in burn-stimulated PMVECs. The Notch–NOX4 pathway may be a novel therapeutic target to treat burn-induced ALI.

Background: Circular RNA (circRNA) plays key regulatory roles in the development of many diseases. However the biological functions and potential molecular mechanisms of circRNA in the injury and repair of intestinal mucosa in mice after severe burns are yet to be elucidated. Methods: Cell counting kit-8 (CCK-8), 5-ethynyl-2′-deoxyuridine (EdU), wound healing and transwell assays were used to detect cell proliferation and migration ability. Real-time quantitative PCR was used to identify the expression of circRNA, microRNA and messenger RNA. Nuclear and cytoplasmic separation experiments were employed to perceive the location of circRNA_Maml2. Finally, in vitro and in vivo experiments were conducted to study the repairing effect of circRNA_Maml2 on the intestinal mucosa of mice after severe burns. Results: When compared with the control group, the expression of circRNA_Maml2 was significantly reduced in the severe burn group. Furthermore, overexpression of circRNA_Maml2 promoted the proliferation and migration of CT26.wt cells in vivo and the repair of damaged intestinal mucosa in vitro. CircRNA_Maml2 acted as a sponge adsorption molecule for miR-93-3p to enhance the expression of frizzled class receptor 7 and activate the downstream Wnt/β-catenin pathway, thereby promoting the repair of the intestinal mucosa. Conclusions: Our findings demonstrate that circRNA_Maml2 regulates the miR-93-3p/FZD7/Wnt/β-catenin pathway and promotes the repair of damaged intestinal mucosa. Hence, circRNA_Maml2 is a potential therapeutic target to promote intestinal mucosal repair.

Background: Nerve transfer is an important clinical surgical procedure for nerve repair by the coaptation of a healthy donor nerve to an injured nerve. Usually, nerve transfer is performed in an end-to-end manner, which will lead to functional loss of the donor nerve. In this study, we aimed to evaluate the efficacy of 3D-printed branch nerve conduits in nerve transfer. Methods: Customized branch conduits were constructed using gelatine-methacryloyl by 3D printing. The nerve conduits were characterized both in vitro and in vivo. The efficacy of 3D-printed branch nerve conduits in nerve transfer was evaluated in rats through electrophysiology testing and histological evaluation. Results: The results obtained showed that a single nerve stump could form a complex nerve network in the 3D-printed multibranch conduit. A two-branch conduit was 3D printed for transferring the tibial nerve to the peroneal nerve in rats. In this process, the two branches were connected to the distal tibial nerve and peroneal nerve. It was found that the two nerves were successfully repaired with functional recovery. Conclusions: It is implied that the two-branch conduit could not only repair the peroneal nerve but also preserve partial function of the donor tibial nerve. This work demonstrated that 3D-printed branch nerve conduits provide a potential method for nerve transfer.

Organ fibrosis is a process in which cellular homeostasis is disrupted and extracellular matrix is excessively deposited. Fibrosis can lead to vital organ failure and there are no effective treatments yet. Although epithelial–mesenchymal transition (EMT) may be one of the key cellular mechanisms, the underlying mechanisms of fibrosis remain largely unknown. EMT is a cell phenotypic process in which epithelial cells lose their cell-to-cell adhesion and polarization, after which they acquire mesenchymal features such as infiltration and migration ability. Upon injurious stimulation in different organs, EMT can be triggered by multiple signaling pathways and is also regulated by epigenetic mechanisms. This narrative review summarizes the current understanding of the underlying mechanisms of EMT in fibrogenesis and discusses potential strategies for attenuating EMT to prevent and/or inhibit fibrosis. Despite better understanding the role of EMT in fibrosis development, targeting EMT and beyond in developing therapeutics to tackle fibrosis is challenging but likely feasible.

Background: Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection. Although fish oil has been used as an immunonutritional preparations for the treatment of sepsis patients, there is still controversy as to whether it is beneficial to them. We systematically reviewed published clinical trial data to evaluate the effectiveness of fish oil-containing nutrition supplementation in sepsis patients. Methods: A systematic search was undertaken in PubMed, Embase, Chinese Biomedicine Database, the Cochrane Library and the China Knowledge Resource Integrated Database to obtain clinical controlled trails. RCTs on nutrition therapy containing fish oil among adult sepsis patients were selected for analysis in comparison with routine therapy. Results: Twenty-five published trials were included in the meta-analysis. Fish oil-containing nutrition supplementation reduced the mortality compared with the control group (relative risk (RR) 0.74, I²= 0%). Fish oil also shortened the ICU stay (MD −3.57 days; 95% CI −4.54, −2.59; p<0.00001; I²= 76%), hospital stay (MD −9.92 days; 95% CI −15.37, −4.46; p= 0.0004; I²= 91%) and the duration of mechanical ventilation support (MD −2.26; 95% CI −4.27, −0.26; p= 0.03; I²= 83%). A subgroup analysis based on the route of administration revealed that parenteral administration of fish oil could reduce mortality in septic patients (RR =0.68, I²= 0%), but no significant difference in mortality was observed in the fish oil group administered by enteral route (RR = 0.80, I²= 0%). No statistically significant publication biases were detected for the above clinical endpoints (p>0.05). Conclusions: Parenteral nutrition containing fish oil could significantly decrease mortality in sepsis patients while enteral administration could not. Fish oil-containing nutrition supplementation.

Background: A keloid is a disease of excessive fibrosis that is characterized by the aberrant proliferation of fibroblasts. However, the molecular mechanisms of fibroblasts during the development of keloids remain unclear. This study aims to identify new molecular targets that promote the proliferation and migration of keloid fibroblasts, providing new ideas for the prevention and treatment of keloids. Methods: We utilized bioinformatics tools to analyze data from keloid fibroblasts (KFs) available in the Gene Expression Omnibus (GEO) database to identify the key genes involved in keloid development. Homeobox C6 (HOXC6) emerged as a hub gene in KFs from the GEO database was verified in keloid tissue samples and KFs using reverse transcription-quantitative polymerase chain reaction, western blot (WB) and immunohistochemistry. Subsequently, the effects of down-regulated HOXC6 expression on the cellular behaviors of KFs were examined by performing Cell Counting Kit-8, flow cytometry, transwell migration and WB assays. Meanwhile, we performed transcriptome sequencing and gene set enrichment analysis (GSEA) to further explore HOXC6-related mechanisms and validated the signaling pathways by performing a series of experiments. Results: HOXC6 was the top-ranking hub gene of KFs in microarray datasets from GEO and was upregulated in keloid tissue samples and KFs. Downregulation of HOXC6 inhibited proliferation, migration and extracellular matrix (ECM) accumulation and promoted KF apoptosis. GSEA predicted that the hypoxia signaling pathway was associated with HOXC6 in KFs. Transcriptome sequencing suggested that the extracellular regulated protein kinase (ERK) pathway was one of the downstream pathways of HOXC6 in KFs. Our experiments confirmed that hypoxia-inducible factor-1α (HIF-1α) upregulates HOXC6, contributing to KFs proliferation, migration, apoptosis inhibition and collagen accumulation through the ERK signaling pathway. Conclusions: Our findings first revealed that HOXC6 acts as an oncogenic driver in the molecular mechanisms of fibroblasts in keloids. The HIF-1α/HOXC6/ERK axis promotes proliferation, migration and ECM production by KFs, contributing to the progression of keloids. Taken together, HOXC6 may serve as a promising novel therapeutic target and new focus for research designed to understand the pathogenesis of keloids.

Acute and chronic wound infection has become a major worldwide healthcare burden leading to significantly high morbidity and mortality. The underlying mechanism of infections has been widely investigated by scientist, while standard wound management is routinely been used in general practice. However, strategies for the diagnosis and treatment of wound infections remain a great challenge due to the occurrence of biofilm colonization, delayed healing and drug resistance. In the present review, we summarize the common microorganisms found in acute and chronic wound infections and discuss the challenges from the aspects of clinical diagnosis, non-surgical methods and surgical methods. Moreover, we highlight emerging innovations in the development of antimicrobial peptides, phages, controlled drug delivery, wound dressing materials and herbal medicine, and find that sensitive diagnostics, combined treatment and skin microbiome regulation could be future directions in the treatment of wound infection.

Background: Hypertrophic scars (HS) represent one of the most common clinical challenges due to unsatisfactory therapeutic results. HS formation is associated with the abnormal activation of fibroblasts and their excessive fibrotic behavior. Glycolysis dysregulation has been shown to participate in the incidence and progression of various fibrotic diseases and shows potential as a means of controlling HS formation. This work aimed to discuss the impact of augmented glycolysis on HS and to propose a method for controlling HS formation through glycolysis regulation. Methods: Here, augmented glycolysis was confirmed together with enhanced fibrotic activity in both HS fibroblasts (HFs) and HS tissues, and the suppression of glycolysis also attenuated fibroblast activation. We also introduced IR780, a heptamethine cyanine dye, to regulate glycolysis for the control of HS formation. Results: In vitro, cell studies indicated that IR780 significantly down-regulated glycolysis and suppressed the fibrotic activity of HFs. In vivo, the intralesional injection of IR780 into rabbit HS models led to the downregulation of glycolysis and the control of HS formation. Furthermore, IR780 accumulated preferentially in activated fibroblasts in both in vitro and in vivo studies, and thus specifically downregulated glycolysis and efficiently controlled fibrosis by targeting activated fibroblasts. Conclusions: This work identified a strategy for controlling fibrosis and HS formation from the perspective of glycolysis regulation with IR780 targeting of activated fibroblasts.

Background: Recent evidence suggests that burn patients are at increased risk of hospital admission for infection, mental health conditions, cardiovascular disease and cancer for many years after discharge for the burn injury itself. Burn injury has also been shown to induce sustained immune system dysfunction. This change to immune function may contribute to the increased risk of chronic disease observed. However, the mechanisms that disrupt long-term immune function in response to burn trauma, and their link to long-term morbidity, remain unknown. In this study we investigated changes to immune function after burn injury using a murine model of non-severe injury. Methods: An established mouse model of non-severe burn injury (full thickness burn equivalent to 8% total body surface area) was used in combination with an orthotopic model of B16 melanoma to investigate the link between burns and cancer. Considering that CD8⁺ T cells are important drivers of effective tumour suppression in this model, we also investigated potential dysregulation of this immune population using mouse models of burn injury in combination with herpes simplex virus infection. Flow cytometry was used to detect and quantify cell populations of interest and changes in immune function. Results: We demonstrate that 4 weeks after a non-severe burn injury, mice were significantly more susceptible to tumour development than controls using an orthotopic model of B16 melanoma. In addition, our results reveal that CD8⁺ T cell expansion, differentiation and memory potential is significantly impaired at 1 month post-burn. Conclusions: Our data suggests that CD8⁺ T cell-mediated immunity may be dysfunctional for a sustained period after even non-severe burn injury. Further studies in patients to validate these findings may support clinical intervention to restore or protect immunity in patients after burn injury and reduce the increased risk of secondary morbidities observed.

Background: For professional athletes, sports injury has been considered one of the most influential factors determining their athletic careers’ duration and quality. High-intensity training and competitiveness of the sports competition are perhaps critical causes of sports-related stress. This article reviews the relevant research on sports injuries and stressor-related disorders. Further, it explores the following three issues in depth: (1) Do physical injuries caused by competitive sports lead to acute or posttraumatic stress disorder for athletes? What are the abnormal stress responses? (2) What diagnoses are currently available for sports injury related traumatic stress disorder? (3) What kinds of psychological rehabilitation are available for trauma-related symptoms in sports injury? How efficient are they in alleviating these symptoms? Methods: The study searched electronic databases, including PubMed, MEDLINE, CINAHL, etc. And reference lists of included papers were also screened. Two researchers selected the literature strictly according to the inclusion criteria and sorted them out. Based on the proved conclusions, the study established a new framework to manage traumatic stress disorders after the injury occurred. Results: 16 articles were included in the study. (Q1: N = 10; Q2: N = 3; Q3: N = 3 ) The findings of this review suggested that athletes who suffer from sports injuries are more likely to experience abnormal physiological or psychological stress responses, which may become a massive challenge for athletes to continue their sports careers at a competitive level. However, there is a minimal understanding of addressing sports injury-related traumatic stress disorder from a biological perspective. Thus, it is challenging to build a scientific basis for diagnosis, screening, and treatment. In addition, the current diagnostic tool for athletes stress disorder still heavily relies on subjective measurement, and the treatment plan is not different from that of the general population. Conclusions: It highlighted that sports-related stress disorder could be the greatest challenge to return to competition for injured athletes. The present study indicated the importance of systematically identifying the symptoms of sports-related stress disorder and improving the current diagnosis and treatment system.

Background: In vivo cell tracking after transplantation in regenerative medicine remains an unmet challenge and limits current understanding of the wound healing mechanism through cell-based therapies. This study investigated tracking of human Wharton’s jelly stem cells (hWJSCs) seeded onto an acellular dermal matrix (ADM) and labeled with superparamagnetic iron oxide nanoparticles (SPIONs) by magnetic resonance imaging (MRI) in burn injury. Method: The hWJSCs were characterized and assessed for growth kinetics. A total of 30 rats were enrolled in three equal groups. Group 1 underwent scald burn injury left without treatment, the group 2 was treated by an ADM that was prepared from cosmetic surgery skin samples and the group 3 received hWJSCs labeled with SPIONs seeded onto an ADM. Tensile strength was evaluated before and after interventions, real time PCR assessed apoptosis, and Prussian blue staining, scanning electron microscopy (SEM) and MRI were used for the tracking of labeled cells. Results: The hWJSCs exhibited mesenchymal stem cell properties. Population doubling time was 40.1 hours. SPIONs did not show any toxic effect. The hWJSCs seeded onto an ADM decreased Bax and increased Bcl-2 gene expression. Internalization of SPIONs within hWJSCs was confirmed by Prussian blue staining, SEM and MRI until day 21. There was a significant difference between the Young’s moduli of normal skin and the group receiving hWJSCs seeded onto an ADM. Histological observations and SEM imaging confirmed that MRI is an accurate method to track SPION-labeled hWJSCs in vivo. Conclusions: This study showed that SPION labeling coupled with MRI can be used to further understand the fate of stem cells after transplantation in a burn model.

Background: Most traditional wound dressings only partially meet the needs of wound healing because of their single function. Patients usually suffer from the increasing cost of treatment and pain resulting from the frequent changing of wound dressings. Herein, we have developed a mutifunctional cryogel to promote bacterial infected wound healing based on a biocompatible polysaccharide. Methods: The multifunctional cryogel is made up of a compositive scaffold of chitosan (CS), gelatin (Gel) and tannic acid (TA) and in situ formed silver nanoparticles (Ag NPs). A liver bleeding rat model was used to evaluate the dynamic hemostasis performance of the various cryogels. In order to evaluate the antibacterial properties of the prepared cryogels, gram-positive bacterium Staphylococcus aureus (S. aureus) and gram-negative bacterium Escherichia coli (E. coli) were cultured with the cryogels for 12 h. Meanwhile, S. aureus was introduced to cause bacterial infection in vivo. After treatment for 2 days, the exudates from wound sites were dipped for bacterial colony culture. Subsequently, the anti-inflammatory effect of the various cryogels was evaluated by western blotting and enzyme-linked immunosorbent assay. Finally, full-thickness skin defect models on the back of SD rats were established to assess the wound healing performances of the cryogels. Results: Due to its porous structure, the multifunctional cryogel showed fast liver hemostasis. The introduced Ag NPs endowed the cryogel with an antibacterial efficiency of >99.9% against both S. aureus and E. coli. Benefited from the polyphenol groups of TA, the cryogel could inhibit nuclear factor-κB nuclear translocation and down-regulate inflammatory cytokines for an anti-inflammatory effect. Meanwhile, excessive reactive oxygen species could also be scavenged effectively. Despite the presence of Ag NPs, the cryogel did not show cytotoxicity and hemolysis. Moreover, in vivo experiments demonstrated that the biocompatible cryogel displayed effective bacterial disinfection and accelerated wound healing. Conclusions: The multifunctional cryogel, with fast hemostasis, antibacterial and anti-inflammation properties and the ability to promote cell proliferation could be widely applied as a wound dressing for bacterial infected wound healing.

Background: Topical local analgesic and anaesthetic agents have been used both pre-and immediately post-harvest on split-thickness skin graft (STSG) donor site wounds (DSW). There is no systematic review of their effectiveness in providing post-harvest analgesia, or of the possible toxic effects of systemic absorption. This study is designed to address the question of which agent, if any, is favoured over the others and whether there are any safety data regarding their use. Methods: Systematic literature review of randomised controlled trials of topical agents applied to STSG DSWs, with a view to providing analgesia. Studies identified via search of Cochrane and EBSCO databases. No restrictions on language or publication year. Primary outcomes: pain at the time of (awake) STSG, and post-harvest pain (up to first dressing change). Secondary outcome was serum medication levels relative to published data on toxic doses. Cochrane risk of bias assessment tool utilised in assessment of included studies. At least 2 reviewers screened and reviewed included studies. A narrative review is presented. Results: There were 11 studies meeting inclusion criteria. Overall methodological quality and patient numbers were low. Topical eutectic mixture of lidocaine and prilocaine pre-harvest affords good local anaesthesia in awake STSG harvesting. Topical bupivacaine (5 studies) or lidocaine (1 study) gave significantly better post-harvest anaesthesia/analgesia than placebo. Topical morphine performs no better than placebo. Topical local anaesthetic agents at reported doses were all well below toxic serum levels. Conclusions: Topical local anaesthetics (lidocaine or bupivacaine) provide good analgesia, both during and after STSG harvest, at well below toxic serum levels, but there are no good data determining the best local anaesthetic agent to use. There is no evidence morphine performs better than placebo.

Background: The Latarjet procedure is an effective technique for the treatment of recurrent anterior shoulder dislocation with glenoid bone loss. However, the inevitable destruction of the coracoacromial arch may result in humeral head translation. The aim of the study is to introduce a modified Latarjet technique with coracoacromial arch preservation as well as its short term clinical outcomes. Methods: We propose a novel individualized flexible arthroscopic suture button fixation Latarjet technique called ‘LUtarjet’ with video. Precise measurements of the coracoid process, glenoid deficiency and osteotomy plane were made preoperatively. Only three arthroscopic portals were needed and limit unique coracoid osteotomy was performed with coracoacromial arch preservation. The mini window splitting of the subscapularis was performed from the posterior to the anterior direction and the split window was as small as 8–10 mm in length. Results: A total of 27 patients (25.6 ± 5.4 years) were included in the study. The average surgical duration was 55.6 ± 6.3 min and the mean follow-up time was 8.1 ± 1.5 months. The functional score was significantly improved at the last follow-up. Radiologic evidence showed that the bone graft healing was placed in the desired position. No complications were found. Conclusions: We present a fast, easy, accurate, safe arthroscopic ‘LUtarjet’ technique called FEAST that can simplify the arthroscopic Latarjet process and achieve a satisfactory bone graft position and satisfactory short-term clinical outcomes. Level of evidence: IV, case series.

Hair follicle stem cells (HFSCs) reside in the bulge region of the outer root sheath of the hair follicle. They are considered slow-cycling cells that are endowed with multilineage differentiation potential and superior proliferative capacity. The normal morphology and periodic growth of HFSCs play a significant role in normal skin functions, wound repair and skin regeneration. The HFSCs involved in these pathophysiological processes are regulated by a series of cell signal transduction pathways, such as lymphoid enhancer factor/T-cell factor, Wnt/β-catenin, transforming growth factor-β/bone morphogenetic protein, Notch and Hedgehog. The mechanisms of the interactions among these signaling pathways and their regulatory effects on HFSCs have been previously studied, but many mechanisms are still unclear. This article reviews the regulation of hair follicles, HFSCs and related signaling pathways, with the aims of summarizing previous research results, revealing the regulatory mechanisms of HFSC proliferation and differentiation and providing important references and new ideas for treating clinical diseases.

Background: Keloid scarring is a fibroproliferative disease caused by aberrant genetic activation with an unclear underlying mechanism. Genetic predisposition, aberrant cellular responses to environmental factors, increased inflammatory cytokines and epithelial–mesenchymal transition (EMT) phenomena are known as major contributors. In this study, we aimed to identify the molecular drivers that initiate keloid pathogenesis. Methods: Bulk tissue RNA sequencing analyses of keloid and normal tissues along with ex vivo and in vitro tests were performed to identify the contributing genes to keloid pathogenesis. An animal model of inflammatory keloid scarring was reproduced by replication of a skin fibrosis model with intradermal bleomycin injection in C57BL/6 mice. Results: Gene set enrichment analysis revealed upregulation of Wnt family member 5A (WNT5A) expression and genes associated with EMT in keloid tissues. Consistently, human keloid tissues and the bleomycin-induced skin fibrosis animal model showed significantly increased expression of WNT5A and EMT markers. Increased activation of the interleukin (IL)-6/Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway and subsequent elevation of EMT markers was also observed in keratinocytes co-cultured with WNT5A-activated fibroblasts or keloid fibroblasts. Furthermore, WNT5A silencing and the blockage of IL-6 secretion via neutralizing IL-6 antibody reversed hyperactivation of the STAT pathway and EMT markers in keratinocytes. Lastly, STAT3 silencing significantly reduced the EMT-like phenotypes in both keratinocytes and IL-6-stimulated keratinocytes. Conclusions: Intercellular communication via the WNT5A and STAT pathways possibly underlies a partial mechanism of EMT-like phenomena in keloid pathogenesis. IL-6 secreted from WNT5A-activated fibroblasts or keloid fibroblasts activates the JAK/STAT signaling pathway in adjacent keratinocytes which in turn express EMT markers. A better understanding of keloid development and the role of WNT5A in EMT will promote the development of next-generation targeted treatments for keloid scars.

Background: Nowadays, a wide range of wound dressings is already commercially available. The selection of the dressing is of paramount importance as inappropriate wound management and dressing selection can delay the wound healing process. Not only can this be distressing for the patient, but it can also contribute to complications such as maceration and subsequent infection. Many researchers are targeting the design of dressings with superior properties over existing commercial dressings. However, reported results in the state-of-the-art are rarely benchmarked against commercial dressings. The aim of this study was to determine several characteristics of a large variety of the most frequently used commercial wound dressings, providing an overview for both practitioners and researchers. Methods: For this comparative study, 11 frequently used commercial wound dressings were selected, representing the different types. The morphology was studied using scanning electron microscopy. The dressings were characterized in terms of swelling capacity (water, phosphate buffered saline and simulated wound fluid), moisture vapour transmission rate (MVTR) and moisture uptake capacity (via dynamic vapour sorption) as well as mechanical properties using tensile testing and texturometry. Results: The selected dressings showed distinctive morphological differences (fibrous, porous and/or gel) which was reflected in the different properties. Indeed, the swelling capacities ranged between 1.5 and 23.2 g/g (water), 2.1 and 17.6 g/g (phosphate buffered saline) or 2.9 and 20.8 g/g (simulated wound fluid). The swelling capacity of the dressings in water increased even further upon freeze-drying, due to the formation of pores. The MVTR values varied between 40 and 930 g/m²/24 h. The maximal moisture uptake capacity varied between 5.8% and 105.7% at 95% relative humidity. Some commercial dressings exhibited a superior mechanical strength, due to either being hydrophobic or multi-layered. Conclusions: The present work not only offers insight into a valuable toolbox of suitable wound dressing characterization techniques, but also provides an extensive landscaping of commercial dressings along with their physico-chemical properties, obtained through reproducible experimental protocols. Furthermore, it ensures appropriate benchmark values for commercial dressings in all forthcoming studies and could aid researchers with the development of novel modern wound dressings. The tested dressings either exhibited a high strength or a high swelling capacity, suggesting that there is still a strong potential in the wound dressings market for dressings that possess both.

Keloid scarring is a kind of pathological healing manifestation after skin injury and possesses various tumor properties, such as the Warburg effect, epithelial–mesenchymal transition (EMT), expression imbalances of apoptosis-related genes and the presence of stem cells. Abnormal expression of tumor signatures is critical to the initiation and operation of these effects. Although previous experimental studies have recognized the potential value of a single or several tumor biomolecules in keloids, a comprehensive evaluation system for multiple tumor signatures in keloid scarring is still lacking. This paper aims to summarize tumor biomolecules in keloids from the perspectives of liquid biopsy, genetics, proteomics and epigenetics and to investigate their mechanisms of action and feasibility from bench to bedside. Liquid biopsy is suitable for the early screening of people with keloids due to its noninvasive and accurate performance. Epigenetic biomarkers do not require changes in the gene sequence and their reversibility and tissue specificity make them ideal therapeutic targets. Nonetheless, given the ethnic specificity and genetic predisposition of keloids, more large-sample multicenter studies are indispensable for determining the prevalence of these signatures and for establishing diagnostic criteria and therapeutic efficacy estimations based on these molecules.

Background: Robot-assisted gait training (RAGT) is more effective in the range of motion (ROM) and isometric strength in patients with burns than conventional training. However, concerns have been raised about whether RAGT might negatively affect the scars of patients with burns. Therefore, we investigated the effects of RAGT-induced mechanical load on the biomechanical properties of burn scars. Methods: This was a single-blind, randomized clinical trial conducted on inpatients admitted to the Department of Rehabilitation Medicine between September 2020 and August 2021. RAGT was conducted for 30 min per day, five days a week for 12 weeks and the control group received conventional gait training for 12 weeks. The pre-training ROM of lower extremity joints was evaluated and the levels of melanin, erythema, trans-epidermal water loss, scar distensibility and elasticity were assessed before training and at 4 and 12 weeks after training. Finally, 19 patients in the gait assistance robot (GAR) group and 20 patients in the control group completed the 12-week trial and all evaluations. Results: There were no significant differences in the epidemiologic characteristics, pre-training ROM of joints and pre-training biomechanical properties of the burn scar between the groups (p > 0.05 for all). None of the patients experienced skin abrasion around the burn scar where the fastening belts were applied or musculoskeletal or cardiovascular adverse events during the training. Scar thickness significantly increased in both groups (p = 0.037 and p = 0.019) and scar distensibility significantly decreased in the control group (p = 0.011) during the training. Hysteresis was significantly decreased in the GAR group during the training (p = 0.038). The GAR and control groups showed significant difference in the change in the values of hysteresis between pre-training and 12 weeks after training (p = 0.441 and p = 0.049). Conclusions: RAGT significantly decreased hysteresis in hypertrophic burn scars and did not cause a significant decrease in skin distensibility. Moreover, no skin complications around the burn scars were detected during RAGT.

Background: P311, a highly conserved 8 kDa intracellular protein, has recently been reported to play an important role in aggravating hypertrophic scaring by promoting the differentiation and secretion of fibroblasts. Nevertheless, how P311 regulates the differentiation and function of fibroblasts to affect granulation tissue formation remains unclear. In this work, we studied the underlying mechanisms via which P311 affects fibroblasts and promotes acute skin wound repair. Methods: To explore the role of P311, both in vitro and in vivo wound-healing models were used. Full-thickness skin excisional wounds were made in wild-type and P311−/− C57 adult mice. Wound healing rate, re-epithelialization, granulation tissue formation and collagen deposition were measured at days 3, 6 and 9 after skin injury. The biological phenotypes of fibroblasts, the expression of target proteins and relevant signaling pathways were examined both in vitro and in vivo. Results: P311 could promote the proliferation and differentiation of fibroblasts, enhance the ability of myofibroblasts to secrete extracellular matrix and promote cell contraction, and then facilitate the formation of granulation tissue and eventually accelerate skin wound closure. Importantly, we discovered that P311 acts via up-regulating the expression of type II transforming growth factor-β receptor (TGF-βRII) in fibroblasts and promoting the activation of the TGF-βRII-Smad signaling pathway. Mechanistically, the mammalian target of rapamycin signaling pathway is closely implicated in the regulation of the TGF-βRII-Smad pathway in fibroblasts mediated by P311. Conclusions: P311 plays a critical role in activation of the TGF-βRII-Smad pathway to promote fibroblast proliferation and differentiation as well as granulation tissue formation in the process of skin wound repair.

Adipose-derived stem cells (ADSCs) have promising applications in tissue regeneration. Currently, there are only a few ADSC products that have been approved for clinical use. The clinical application of ADSCs still faces many challenges. Here, we review emerging strategies to improve the therapeutic efficacy of ADSCs in tissue regeneration. First, a great quantity of cells is often needed for the stem cell therapies, which requires the advanced cell expansion technologies. In addition cell-derived products are also required for the development of ‘cell-free’ therapies to overcome the drawbacks of cell-based therapies. Second, it is necessary to strengthen the regenerative functions of ADSCs, including viability, differentiation and paracrine ability, for the tissue repair and regeneration required for different physiological and pathophysiological conditions. Third, poor delivery efficiency also restricts the therapeutic effect of ADSCs. Effective methods to improve cell delivery include alleviating harsh microenvironments, enhancing targeting ability and prolonging cell retention. Moreover, we also point out some critical issues about the sources, effectiveness and safety of ADSCs. With these advanced strategies to improve the therapeutic efficacy of ADSCs, ADSC-based treatment holds great promise for clinical applications in tissue regeneration.

Background: Minimal data exist on anticoagulation use and timing and the dose of heparin in patients with sepsis, and whether heparin use improves sepsis survival remains largely unclear. This study was performed to assess whether heparin administration would provide a survival advantage in critically ill patients with sepsis. Methods: A retrospective cohort study of patients with sepsis in the Medical Information Mart for Intensive Care (MIMIC)-IV database was conducted. Cox proportional hazards model and propensity score matching (PSM) were used to evaluate the outcomes of prophylactic anticoagulation with heparin administered by subcutaneous injection within 48 h of intensive care unit (ICU) admission. The primary outcome was in-hospital mortality. Secondary outcomes included 60-day mortality, length of ICU stay, length of hospital stay and incidence of acute kidney injury (AKI) on day 7. E-Value analysis were used for unmeasured confounding. Results: A total of 6646 adult septic patients were included and divided into an early prophylactic heparin group (n = 3211) and a nonheparin group (n = 3435). In-hospital mortality in the heparin therapy group was significantly lower than that in the nonheparin group (prematched 14.7 vs 20.0%, hazard ratio (HR) 0.77, 95% confidence interval (CI) [0.68–0.87], p < 0.001, and postmatched 14.9 vs 18.3%, HR 0.78, 95% CI [0.68–0.89], p < 0.001). Secondary endpoints, including 60-day mortality and length of ICU stay, differed between the heparin and nonheparin groups (p < 0.01). Early prophylactic heparin administration was associated with in-hospital mortality among septic patients in different adjusted covariates (HR 0.71–0.78, p < 0.001), and only administration of five doses of heparin was associated with decreased in-hospital mortality after PSM (HR 0.70, 95% CI 0.56–0.87, p < 0.001). Subgroup analysis showed that heparin use was significantly associated with reduced in-hospital mortality in patients with sepsis-induced coagulopathy, septic shock, sequential organ failure assessment score ≥ 10, AKI, mechanical ventilation, gram-positive bacterial infection and gram-negative bacterial infection, with HRs of 0.74, 0.70, 0.58, 0.74, 0.73, 0.64 and 0.72, respectively (p <0.001). E-Value analysis suggested robustness to unmeasured confounding. Conclusions: This study found an association between early administration prophylactic heparin provided to patients with sepsis and reduced risk-adjusted mortality. A prospective randomized-controlled study should be designed to further assess the relevant findings.

Background: Anisotropic topologies are known to regulate cell-oriented growth and induce cell differentiation, which is conducive to accelerating nerve regeneration, while co-culture of endothelial cells (ECs) and Schwann cells (SCs) can significantly promote the axon growth of dorsal root ganglion (DRG). However, the synergistic regulation of EC and SC co-culture of DRG behavior on anisotropic topologies is still rarely reported. The study aims to investigate the effect of anisotropic topology co-cultured with Schwann cells and endothelial cells on dorsal root ganglion behavior for promoting peripheral nerve regeneration. Methods: Chitosan/artemisia sphaerocephala (CS/AS) scaffolds with anisotropic topology were first prepared using micro-molding technology, and then the surface was modified with dopamine to facilitate cell adhesion and growth. The physical and chemical properties of the scaffolds were characterized through morphology, wettability, surface roughness and component variation. SCs and ECs were co-cultured with DRG cells on anisotropic topology scaffolds to evaluate the axon growth behavior. Results: Dopamine-modified topological CS/AS scaffolds had good hydrophilicity and provided an appropriate environment for cell growth. Cellular immunofluorescence showed that in contrast to DRG growth alone, co-culture of SCs and ECs could not only promote the growth of DRG axons, but also offered a stronger guidance for orientation growth of neurons, which could effectively prevent axons from tangling and knotting, and thus may significantly inhibit neurofibroma formation. Moreover, the co-culture of SCs and ECs could promote the release of nerve growth factor and vascular endothelial growth factor, and up-regulate genes relevant to cell proliferation, myelination and skeletal development via the PI3K-Akt, MAPK and cytokine and receptor chemokine pathways. Conclusions: The co-culture of SCs and ECs significantly improved the growth behavior of DRG on anisotropic topological scaffolds, which may provide an important basis for the development of nerve grafts in peripheral nerve regeneration.

Background: In this systematic review, we summarize the aetiology as well as the current knowledge regarding thermo(dys)regulation and hypothermia after severe burn trauma and aim to present key concepts of pathophysiology and treatment options. Severe burn injuries with >20% total body surface area (TBSA) affected commonly leave the patient requiring several surgical procedures, prolonged hospital stays and cause substantial changes to body composition and metabolism in the acute and long-term phase. Particularly in severely burned patients, the loss of intact skin and the dysregulation of peripheral and central thermoregulatory processes may lead to substantial complications. Methods: A systematic and protocol-based search for suitable publications was conducted following the PRISMA guidelines. Articles were screened and included if deemed eligible. This encompasses animal-based in vivo studies as well as clinical studies examining the control-loops of thermoregulation and metabolic stability within burn patients. Results: Both experimental animal studies and clinical studies examining thermoregulation and metabolic functions within burn patients have produced a general understanding of core concepts which are, nonetheless, lacking in detail. We describe the wide range of pathophysiological alterations observed after severe burn trauma and highlight the association between thermoregulation and hypermetabolism as well as the interactions between nearly all organ systems. Lastly, the current clinical standards of mitigating the negative effects of thermodysregulation and hypothermia are summarized, as a comprehensive understanding and implementation of the key concepts is critical for patient survival and long-term well-being. Conclusions: The available in vivo animal models have provided many insights into the interwoven pathophysiology of severe burn injury, especially concerning thermoregulation. We offer an outlook on concepts of altered central thermoregulation from non-burn research as potential areas of future research interest and aim to provide an overview of the clinical implications of temperature management in burn patients.

Background: Amphibian-derived peptides exhibit considerable potential in the discovery and development of new therapeutic interventions for clinically challenging chronic skin wounds. MicroRNAs (miRNAs) are also considered promising targets for the development of effective therapies against skin wounds. However, further research in this field is anticipated. This study aims to identify and provide a new peptide drug candidate, as well as to explore the underlying miRNA mechanisms and possible miRNA drug target for skin wound healing. Methods: A combination of Edman degradation, mass spectrometry and cDNA cloning were adopted to determine the amino acid sequence of a peptide that was fractionated from the secretion of Odorrana andersonii frog skin using gel-filtration and reversed-phase high-performance liquid chromatography. The toxicity of the peptide was evaluated by Calcein-AM/propidium iodide (PI) double staining against human keratinocytes (HaCaT cells), hemolytic activity against mice blood cells and acute toxicity against mice. The stability of the peptide in plasma was also evaluated. The prohealing potency of the peptide was determined by MTS, scratch healing and a Transwell experiment against HaCaT cells, full-thickness injury wounds and scald wounds in the dorsal skin of mice. miRNA transcriptome sequencing analysis, enzyme-linked immunosorbent assay, real-time polymerase chain reaction and western blotting were performed to explore the molecular mechanisms. Results: A novel peptide homodimer (named OA-GL17d) that contains a disulfide bond between the 16th cysteine residue of the peptide monomer and the sequence ‘GLFKWHPRCGEEQSMWT’ was identified. Analysis showed that OA-GL17d exhibited no hemolytic activity or acute toxicity, but effectively promoted keratinocyte proliferation and migration and strongly stimulated the repair of full-thickness injury wounds and scald wounds in the dorsal skin of mice. Mechanistically, OA-GL17d decreased the level of miR-663a to increase the level of transforming growth factor-β1 (TGF-β1) and activate the subsequent TGF-β1/Smad signaling pathway, thereby resulting in accelerated skin wound re-epithelialization and granular tissue formation. Conclusions: Our results suggest that OA-GL17d is a new peptide drug candidate for skin wound repair. This study emphasizes the importance of exogenous peptides as molecular probes for exploring competing endogenous RNA mechanisms and indicates that miR-663a may be an effective target for promoting skin repair.

Bioadhesives act as a bridge in wound closure by forming an effective interface to protect against liquid and gas leakage and aid the stoppage of bleeding. To their credit, tissue adhesives have made an indelible impact on almost all wound-related surgeries. Their unique properties include minimal damage to tissues, low chance of infection, ease of use and short wound-closure time. In contrast, classic closures, like suturing and stapling, exhibit potential additional complications with long operation times and undesirable inflammatory responses. Although tremendous progress has been made in the development of tissue adhesives, they are not yet ideal. Therefore, highlighting and summarizing existing adhesive designs and synthesis, and comparing the different products will contribute to future development. This review first provides a summary of current commercial traditional tissue adhesives. Then, based on adhesion interaction mechanisms, the tissue adhesives are categorized into three main types: adhesive patches that bind molecularly with tissue, tissue-stitching adhesives based on pre-polymer or precursor solutions, and bioinspired or biomimetic tissue adhesives. Their specific adhesion mechanisms, properties and related applications are discussed. The adhesion mechanisms of commercial traditional adhesives as well as their limitations and shortcomings are also reviewed. Finally, we also discuss the future perspectives of tissue adhesives.

Background: Robotic assistance has been increasingly employed to improve the operative precision in modern knee surgery. The purpose of the study was to evaluate the trauma effect of one of the first domestically developed orthopedic surgical robots in China in a clinical trial of robot-assisted total knee arthroplasty (RA-TKA). Methods: A total of 33 patients who underwent unilateral TKA for end-stage osteoarthritis were randomized to receive RA-TKA (17 cases) or conventional manual TKA (CM-TKA) in our institution in 2020. The trauma effects of the 4 main indicators with 48 sub-indicators in terms of subsectional operative time, inflammation and coagulation markers, physical and radiographical analyses of osteotomy deviation, and postoperative comfort were analyzed. Results: Subsectional operative time analysis showed that the times for bone cutting and gap balancing with RA-TKA were 5.3 and 2.2 min shorter than those with CM-TKA (p = 0.010, p = 0.02), respectively. Arterial blood gas indicators (partial pressure of carbon dioxide, partial pressure of oxygen and SO₂) 24 h after RA-TKA, as well as the white blood cell count and neutrophil ratio, were significantly lower than those after CM-TKA (p < 0.05). Inflammatory markers at 72 h after surgery showed the increments of C-reactive protein, erythrocyte sedimentation rate and D-dimer of RA-TKA declined by 180.7, 22.0 and 1050.0% (p < 0.05), respectively, referenced to the preoperative baseline values, as compared to CM-TKA. Mechanical deviation distribution exhibited percentages of region I errors for RA-TKA and CM-TKA of 76.5% and 27.1% (p = 0.000), respectively, and the success rates of one-time osteotomy were 94.1% and 62.5% (p = 0.039), respectively. Radiographical verification showed RA-TKA was more conducive to achieving mechanical alignment and ideal tibial component azimuths. Postoperative efficacy showed that patients were more comfortable after RA-TKA in terms of reduced administration of tranexamic acid, hydrocortisone and the utilization rate of temporary intensive opioid analgesics. No statistical difference in patient-reported outcome measures and complications were recorded between the two groups during continuous observation. Conclusions: Compared with CM-TKA, RA-TKA decreases rather than increases trauma. It might shorten the time required for bone cutting and gap balancing, reduce mechanical errors related to the osteotomy and prosthesis position, and improve the accuracy of the mechanical alignment reconstruction. RA-TKA is also favorable in promoting postoperative comfort and minimizing inflammatory response and drug consumption. Trial registration: The Chinese Clinical Trial Registry (ChiCTR2000031282) approved registration on 26 March 2020.

Background: Sweat glands (SGs) have low regenerative potential after severe burns or trauma and their regeneration or functional recovery still faces many obstacles. In practice, restoring SG function requires not only the structural integrity of the gland itself, but also its neighboring tissues, especially blood vessels. Collagen triple helix repeat containing-1 (CTHRC1) was first identified in vascular repair, and increasing reports showed a close correlation between cutaneous appendage specification, patterning and regeneration. The purpose of the present study was to clarify the role of CTHRC1 in SGs and their adjacent microvessels and find therapeutic strategies to restore SG function. Methods: The SGs and their adjacent microvascular network of Cthrc1^−/− mice were first investigated using sweat test, laser Doppler imaging, tissue clearing technique and transcriptome analysis. The effects of CTHRC1 on dermal microvascular endothelial cells (DMECs) were further explored with cell proliferation, DiI-labeled acetylated low-density lipoprotein uptake, tube formation and intercellular junction establishment assays. The effects of CTHRC1 on SG function restoration were finally confirmed by replenishing the protein into the paws of Cthrc1^−/− mice. Results: CTHRC1 is a key regulator of SG function in mice. At the tissue level, Cthrc1 deletion resulted in the disorder and reduction of the microvascular network around SGs. At the molecular level, the knockout of Cthrc1 reduced the expression of vascular development genes and functional proteins in the dermal tissues. Furthermore, CTHRC1 administration considerably enhanced SG function by inducing adjacent vascular network reconstruction. Conclusions: CTHRC1 promotes the development, morphogenesis and function execution of SGs and their neighboring vasculature. Our study provides a novel target for the restoration or regeneration of SG function in vivo.

Pathological scarring imposes a major clinical and social burden worldwide. Human cutaneous wounds are responsive to mechanical forces and convert mechanical cues to biochemical signals that eventually promote scarring. To understand the mechanotransduction pathways in cutaneous scarring and develop new mechanotherapy approaches to achieve optimal scarring, the current study highlights the mechanical behavior of unwounded and scarred skin as well as intra-and extracellular mechanisms behind keloid and hypertrophic scars. Additionally, the therapeutic interventions that promote optimal scar healing by mechanical means at the molecular, cellular or tissue level are extensively reviewed. The current literature highlights the significant role of fibroblasts in wound contraction and scar formation via differentiation into myofibroblasts. Thus, understanding myofibroblasts and their responses to mechanical loading allows the development of new scar therapeutics. A review of the current clinical and preclinical studies suggests that existing treatment strategies only reduce scarring on a small scale after wound closure and result in poor functional and aesthetic outcomes. Therefore, the perspective of mechanotherapies needs to consider the application of both mechanical forces and biochemical cues to achieve optimal scarring. Moreover, early intervention is critical in wound management; thus, mechanoregulation should be conducted during the healing process to avoid scar maturation. Future studies should either consider combining mechanical loading (pressure) therapies with tension offloading approaches for scar management or developing more effective early therapies based on contraction-blocking biomaterials for the prevention of pathological scarring.

Wound healing refers to the healing process that occurs after the skin and other tissues are separated or damaged by internal or external forces. It is a complex combination of tissue regeneration, granulation tissue hyperplasia, and scar formation, and shows the synergistic effects of these processes. After skin damage, the environment around the wound and the cells at site of the damage respond immediately, and a range of cytokines and growth factors are released. In cutaneous injury, extracellular vesicle (EV) signaling plays a vital role in the healing process via paracrine and endocrine mechanisms. EVs are natural intercellular and inter-organ communication tools that carry various bioactive substances for message exchange. Stem cells and stem cell EVs facilitate tissue repair, showing promising potential in regenerative medicine. Nevertheless, EVs derived from specific skin tissue cells, such as epidermal cells, fibroblasts, vascular endothelial cells and inflammatory cells, also play important roles in cutaneous tissue repair. Here, we describe the characteristics of wound healing, concentrating on the production and functions of EVs derived from specific skin cells, and provide new ideas for wound therapy using EVs.

Since the discovery of silicate bioactive glass (BG) by Larry Hench in 1969, different classes of BGs have been researched over decades mainly for bone regeneration. More recently, validating the beneficial influence of BGs with tailored compositions on angiogenesis, immunogenicity and bacterial infection, the applicability of BGs has been extended to soft tissue repair and wound healing. Particularly, fibrous wound dressings comprising BG particle reinforced polymer nanofibers and cotton-candy-like BG fibers have been proven to be successful for wound healing applications. Such fibrous dressing materials imitate the physical structure of skin's extracellular matrix and release biologically active ions e.g. regenerative, pro-angiogenic and antibacterial ions, e.g. borate, copper, zinc, etc., that can provoke cellular activities to regenerate the lost skin tissue and to induce new vessels formation, while keeping an anti-infection environment. In the current review, we discuss different BG fibrous materials meant for wound healing applications and cover the relevant literature in the past decade. The production methods for BG-containing fibers are explained and as fibrous wound dressing materials, their wound healing and bactericidal mechanisms, depending on the ions they release, are discussed. The present gaps in this research area are highlighted and new strategies to address them are suggested.

Background: Burn injuries place a heavy burden on the global healthcare system. However, there is still a lack of nationwide studies on the epidemiological characteristics of burn patients in mainland China. The present study aims to accurately analyze the clinical characteristics of burn patients by collecting data in mainland China from 2009 to 2018, which will provide effective strategies for healthcare systems and the government in mainland China. Methods: Patients admitted for burn injuries to 196 hospitals in 31 provinces, autonomous regions and municipalities in mainland China from 2009 to 2018 were included. The data collected included sex, age, month distribution, etiology, region, clinical outcome, injury anatomical location, total burn surface area and mortality. SPSS 19.0 software was used to analyze the data. Results: From 2009 to 2018, the burn patients were 333,995 (0.76%), which included 222,480 (66.61%) males and 111,515 (33.39%) females. From 2009 to 2018, the number of individuals admitted to hospitals for burns showed a downward trend year by year. The burn patients accounted for the highest proportion of inpatients in 0–10 years (38.10%), followed by 40–50 years (13.14%). The highest cure ratio of burn inpatients was in the 20–30 age group (31 394, 71.53%). Among 31 provinces, autonomous regions and municipalities, the province with the highest proportion of total inpatients caused by burns was Inner Mongolia (4.61%), followed by Zhejiang (3.17%), Hainan (2.88%) and Xinjiang (2.64%). Summer (29.16%) was the season with the highest incidence of burn patients admitted to hospitals, followed by spring (25.6%). Scalding (60.19%) was the most frequent kind of burn treated, followed by fire (20.45%). The patients had multiple burn sites (68.89%) most often, followed by burns on the lower limbs (10.91%). From 0% to 10% total body surface area (TBSA) accounted for the highest ratio (37.19%), followed by 90–100% TBSA (21.74%). Conclusions: The present study is the first to describe the associated situation and trends of burn patients in mainland China from 2009 to 2018. Our findings will serve as the latest clinical evidence for healthcare planning and prevention efforts in China and other countries.

Background: Hypertrophic scars are skin fibrotic diseases, characterized by fibroblast hyperproliferation and excessive accumulation of extracellular matrix. However, topical drug application for hypertrophic scars are unsatisfactory. The purpose of this study was to explore the permeability of silk nanofiber hydrogels (SNFs) loaded with rhodamine 6G (R6G) and rhodamine 110 (R110) mediated by CO₂ fractional laser irradiation into hypertrophic scar tissues. Methods: In this work, R6G and R110 were chosen as hydrophilic and hydrophobic model molecules. They were loaded inside SNFs. In vivo rabbit ear hypertrophic scars were treated with CO₂ fractional laser irradiation and then R6G/R110-laden SNFs were applied to the scars to evaluate their synergetic effect on drug penetration efficiency. Their permeability was quantified by fluorescence intensity and measured by confocal laser scanning microscopy on days 1, 3, 5 and 7. More specifically, the thermal coagulation zone (CZ) and its surrounding area (peri-CZ) caused by the thermal coagulation of the laser were discussed separately. Results: Our data indicated that the SNFs promoted the penetration of R6G but not that of R110 in the peri-CZ on day 1 when combined with laser irradiation. Interestingly, both R6G and R110 were abundant in the CZ and remained stable on days 1, 3 and 5. Moreover, rapid re-epithelialization hindered the long-term permeability of both drugs. Conclusion: Combining CO₂ fractional laser irradiation with SNF drug delivery could improve the efficiency of hydrophilic drug delivery within 24 h before total re-epithelialization.

Background: Alternative (M2)-activated macrophages drive the anti-inflammatory response against sepsis, a leading cause of death in patients suffering from burn injury. Macrophage M2 polarization is intrinsically linked with dominant oxidative phosphorylation (OXPHOS). Glutamine serves as a major anaplerotic source to fuel OXPHOS, but it remains unknown whether glutamine can modulate metabolic checkpoints in OXPHOS that favour M2 polarization. The study aims to explore whether glutamine essentially supports M2 polarization in IL-4-stimulated murine macrophages by sustaining the activity of PDH and whether glutamine augments macrophage M2 polarization and thus alleviates inflammation and organ injury in a murine burn sepsis model. Methods: To understand how glutamine promotes M2 activation in interleukin (IL-4)-treated murine macrophages, we detected glutamine-dependent M2 polarization and its relationship with the pyruvate dehydrogenase (PDH) complex by RT-PCR, flow cytometry and western blot. To explore how glutamine modulates PDH activity and thus supports M2 polarization, we compared the expression, phosphorylation and succinylation status of PDHA1 and then examined sirtuin SIRT5-dependent desuccinylation of PDHA1 and the effects of SIRT5 overexpression on M2 polarization by RT-PCR, flow cytometry and western blot. To determine whether glutamine or its metabolites affect M2 polarization, macrophages were cocultured with metabolic inhibitors, and then SIRT5 expression and M2 phenotype markers were examined by RT-PCR, flow cytometry and western blot. Finally, to confirm the in vivo effect of glutamine, we established a burn sepsis model by injecting Pseudomonas aeruginosainto burn wounds and observing whether glutamine alleviated proinflammatory injuries by RT-PCR, flow cytometry, western blot, immunofluorescent staining, hematoxylin-eosin staining and enzyme-linked immuno sorbent assay. Results: We showed that consumption of glutamine supported M2 activation in IL-4-treated murine macrophages by upregulating the activity of PDH. Mechanistically, glutamine did not affect the expression or alter the phosphorylation status of PDHA1 but instead downregulated the expression of SIRT5 and repressed SIRT5-dependent desuccinylation on PDHA1, which in turn recovered PDH activity and supported M2 polarization. This effect was implemented by its secondary metabolite α-ketoglutarate (αKG) rather than glutamine itself. Finally, we demonstrated that glutamine promoted macrophage M2 polarization in a murine burn sepsis model, thereby repressing excessive inflammation and alleviating organ injury in model mice. Conclusions: Glutamine mitigates murine burn sepsis by essentially supporting macrophage M2 polarization, with a mechanism involving the repression of the SIRT5-mediated desuccinylation of pyruvate dehydrogenase that replenishes OXPHOS and sustains M2 macrophages.

Background: Enteral nutrition (EN) is an important treatment for burn patients. However, severe gastrointestinal damage caused by major burns often leads to EN intolerance. Trophic EN solves this problem basically, but how to transition from trophic EN to standard EN smoothly is still a challenge in burn clinical nutrition. The aim of this study is to investigate the effects of EN with different energy supplies on metabolic changes, organ damage and prognosis in burned rats. Methods: Different feeding regimens were designed based on the continuous monitoring of resting energy expenditure in rats. Thirty-two Sprague–Dawley rats were randomly divided into a normal control group, burn +50% REE group, burn +75% REE group and burn +100% REE group. At the end of a nutritional treatment cycle (14th day), nuclear magnetic resonance spectroscopy, blood biochemistry analysis and quantification of subscab bacteria were performed to explore the differences in metabolic changes, degrees of organ damage and prognoses between the groups. Results: Sixteen metabolites involving seven metabolic pathways were identified from the different energy supply groups. After burn injury, resting energy consumption and body weight loss increased obviously. Meanwhile, weight loss was inversely related to energy supply. The greatest changes in the degree of organ damage, the level of plasma proteins, lipids and endotoxins, as well as the quantification of subscab bacteria were observed in the 50% REE group, followed by the 75 and 100% groups. Conclusions: Achieving an early balance between energy supply and expenditure is conducive to mitigating metabolic disorders and improving prognosis after burn injury.

Background: Sepsis-induced cardiomyopathy (SIC) is an identified serious complication of sepsis that is associated with adverse outcomes and high mortality. Heat shock proteins (HSPs) have been implicated in suppressing septic inflammation. The aim of this study was to investigate whether HSP70 can attenuate cellular mitochondrial dysfunction, exuberated inflammation and inflammasome-mediated pyroptosis for SIC intervention. Methods: Mice with cecal ligation plus perforation (CLP) and lipopolysaccharide (LPS)-treated H9C2 cardiomyocytes were used as models of SIC. The mouse survival rate, gross profile, cardiac function, pathological changes and mitochondrial function were observed by photography, echocardiography, hematoxylin–eosin staining and transmission electron microscopy. In addition, cell proliferation and the levels of cardiac troponin I (cTnI), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were determined by Cell Counting Kit-8, crystal violet staining and enzyme-linked immunosorbent assay. Moreover, mitochondrial membrane potential was assessed by immunofluorescence staining, and dynamin-related protein 1 and pyroptosis-related molecules [nucleotide-binding domain, leucine-rich-repeat containing family pyrin domain-containing 3 (NLRP3), caspase-1, gasdermin-D (GSDMD), gasdermin-D N-terminal (GSDMD-N)] were measured by western blotting, immunoprecipitation and immunoblotting. Finally, hsp70.1 knockout mice with CLP were used to verify the effects of HSP70 on SIC and the underlying mechanism. Results: Models of SIC were successfully established, as reduced consciousness and activity with liparotrichia in CLP mice were observed, and the survival rate and cardiac ejection fraction (EF) were decreased; conversely, the levels of cTnI, TNF-α and IL-1β and myocardial tissue damage were increased in CLP mice. In addition, LPS stimulation resulted in a reduction in cell viability, mitochondrial destabilization and activation of NLRP3-mediated pyroptosis molecules in vitro. HSP70 treatment improved myocardial tissue damage, survival rate and cardiac dysfunction caused by CLP. Additionally, HSP70 intervention reversed LPS-induced mitochondrial destabilization, inhibited activation of the NLRP3 inflammasome, caspase-1, GSDMD and GSDMD-N, and decreased pyroptosis. Finally, knockout of hsp70.1 mice with CLP aggravated cardiac dysfunction and upregulated NLRP3 inflammasome activity, and exogenous HSP70 significantly rescued these changes. It was further confirmed that HSP70 plays a protective role in SIC by attenuating mitochondrial dysfunction and inactivating pyroptotic molecules. Conclusions: Our study demonstrated that mitochondrial destabilization and NLRP3 inflammasome activation-mediated pyroptosis are attributed to SIC. Interestingly, HSP70 ameliorates sepsis-induced myocardial dysfunction by improving mitochondrial dysfunction and inhibiting the activation of NLRP3 inflammasome-mediated pyroptosis, and such a result may provide approaches for novel therapies for SIC.

Background: Inflammation is an important factor in pathological scarring. The role of neutrophils, one of the most important inflammatory cells, in scar hyperplasia remains unclear. The purpose of this article is to study the correlation between neutrophil extracellular traps (NETs) and scar hyperplasia and identify a new target for inhibiting scar hyperplasia. Methods: Neutrophils were isolated from human peripheral blood by magnetic-bead sorting. NETs in plasma and scars were detected by enzyme-linked immunosorbent assays (ELISAs), immunofluorescence and flow cytometry. Immunohistochemistry was used to assess neutrophil (CD66B) infiltration in hypertrophic scars. To observe the entry of NETs into fibroblasts we used immunofluorescence and flow cytometry. Results: We found that peripheral blood neutrophils in patients with hypertrophic scars were more likely to form NETs (p < 0.05). Hypertrophic scars showed greater infiltration with neutrophils and NETs (p < 0.05). NETs activate fibroblasts in vitro to promote their differentiation and migration. Inhibition of NETs with cytochalasin in wounds reduced the hyperplasia of scars in mice. We induced neutrophils to generate NETs with different stimuli in vitro and detected the proteins carried by NETs. We did not find an increase in the expression of common scarring factors [interleukin (IL)-17 and transforming growth factor-β (TGF-β), p > 0.05]. However, inhibiting the production of NETs or degrading DNA reduced the differentiation of fibroblasts into myofibroblasts. In vitro, NETs were found to be mediated by Toll-like receptor 9 (TLR-9) in fibroblasts and further phosphorylated nuclear factor Kappa-B (NF-κB). We found that IL-6, which is downstream of NF-κB, was increased in fibroblasts. Additionally, IL-6 uses autocrine and paracrine signaling to promote differentiation and secretion. Conclusions: Our experiments found that NETs activate fibroblasts through the TLR-9/NF-κB/IL-6 pathway, thereby providing a new target for regulating hypertrophic scars.

Background: Currently, various external tissue expansion devices are becoming widely used. Considering the scarcity of relevant application standards, this systematic review was performed to explore the effectiveness and safety of external tissue expansion techniques for the reconstruction of soft tissue defects. Method: A systematic review and meta-analysis on the efficacy and safety of external tissue expansion technique was conducted. A comprehensive search was performed in the following electronic databases: PubMed/Medline, Embase, Cochrane Library (Wiley Online Library), and Web of Science. Studies reporting patients with soft tissue defects under the treatment of external tissue expansion technique were included. Results: A total of 66 studies with 22 different types of external tissue expansion devices met the inclusion criteria. We performed a descriptive analysis of different kinds of devices. A single-arm meta-analysis was performed to evaluate the efficacy and safety of the external tissue expansion technique for different aetiologies. The pooled mean wound healing time among patients with defects after fasciotomy was 10.548 days [95% confidence interval (CI) = 5.796–15.299]. The pooled median wound healing times of patients with defects after excisional surgery, trauma, chronic ulcers and abdominal defects were 11.218 days (95% CI = 6.183-16.253), 11.561 days (95% CI = 7.062-16.060), 15.956 days (95% CI = 11.916-19.996) and 12.853 days (95% CI=9.444-16.227), respectively. The pooled wound healing rates of patients with defects after fasciotomy, excisional surgery, trauma, chronic ulcers and abdominal defects were 93.8% (95% CI=87.1-98.2%), 97.2% (95%CI=92.2-99.7%), 97.0% (95%CI=91.2-99.8%), 99.5% (95%CI=97.6-100%), and 96.8% (95%CI=79.2-100%), respectively. We performed a subgroup analysis in patients with diabetic ulcers and open abdominal wounds. The pooled median wound healing time of patients with diabetic ulcers was 11.730 days (95% CI = 10.334-13.125). The pooled median wound healing time of patients with open abdomen defects was 48.810 days (95% CI = 35.557–62.063) and the pooled successful healing rate was 68.8% (95% CI = 45.9-88.1%). A total of 1686 patients were included, 265 (15.7%) of whom experienced complications. The most common complication was dehiscence (n = 53, 3.14%). Conclusions: Our systematic review is the first to demonstrate the efficacy and safety of external tissue expansion in the management of soft tissue defects. However, we must interpret the meta-analysis results with caution considering the limitations of this review. Large-scale randomized controlled trials and long-term follow-up studies are still needed to confirm the effectiveness and evaluate the quality of healing.

Background: Skin wound healing depends on the progress of different but overlapping stages of healing, including hemostasis, inflammatory, proliferative and remodeling. Failure of these stages to occur in a timely and gradual manner may result in non-healing pathological wounds. Macrophages and neutrophils have been shown to play an essential role in the inflammatory responses of wound tissue, and their active plasticity allows them to modulate tissue damage and repair functions. The ability of macrophages and neutrophils to regulate the occurrence and resolution of inflammatory processes is essential for the treatment of pathological wound healing. Methods: Mice were categorized into negative control, streptozotocin, streptozotocin + puerarin and puerarin groups. The traditional Chinese medicine extract puerarin was selected to treat different groups of mice with a full-thickness skin defect wound. Cells of the RAW264.7 cell line were stimulated under different puerarin conditions. Then, real time quantitative polymerase chain reaction (RT-qPCR), western blot, immunofluorescence and other assays were carried out to explore the effect of puerarin on wound healing and its molecular mechanism. Results: Animal experiments found that the wound healing of diabetic mice treated with puerarin was significantly accelerated, and histological analysis found that puerarin treatment markedly decreased the infiltration of macrophages and neutrophils in wound tissue. Through western blot, RT-qPCR and immunofluorescence experiments, it was observed that puerarin treatment remarkably inhibited nuclear factor kinase B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, downregulated the expression of inflammatory cytokines and induced the M2 polarization of macrophages. At the cellular level, we also observed that puerarin improved M2 macrophage polarization and inhibited inflammatory pathway activation in a high-glucose culture. Conclusion: Puerarin has a significant therapeutic effect on wound healing in diabetic mice. The therapeutic effect is achieved by regulating macrophage polarization through suppressing NF-κB and MAPK signaling cascades.

Burn wounds result from exposure to hot liquids, chemicals, fire, electric discharge or radiation. Wound severity ranges from first-degree injury, which is superficial, to fourth-degree injury, which exposes bone, tendons and muscles. Rapid assessment of burn depth and accurate wound management in the outpatient setting is critical to prevent injury progression into deeper layers of the dermis. Injury progression is of particular pertinence to second-degree burns, which are the most common form of thermal burn. As our understanding of wound healing advances, treatment options and technologies for second-degree burn management also evolve. Polymeric hydrogels are a class of burn wound dressings that adhere to tissue, absorb wound exudate, protect from the environment, can be transparent facilitating serial wound evaluation and, in some cases, enable facile removal for dressing changes. This review briefly describes the burn level classification and common, commercially available dressings used to treat second-degree burns, and then focuses on new polymeric hydrogel burn dressings under preclinical development analyzing their design, structure and performance. The review presents the follow key learning points: (1) introduction to the integument system and the wound-healing process; (2) classification of burns according to severity and clinical appearance; (3) available dressings currently used for second-degree burns; (4) introduction to hydrogels and their preparation and characterization techniques; and (5) pre-clinical hydrogel burn wound dressings currently being developed.

Impaired wound healing is one of the severe complications of diabetes. Macrophages have been shown to play a vital role in wound healing. In different wound environments, macrophages are classified into two phenotypes: classically activated macrophages and alternatively activated macrophages. Dysregulation of macrophage phenotypes leads to severely impaired wound healing in diabetes. Particularly, uncontrolled inflammation and abnormal macrophage phenotype are important reasons hindering the closure of diabetic wounds. This article reviews the functions of macrophages at various stages of wound healing, the relationship between macrophage phenotypic dysregulation and diabetic wound healing and the mechanism of macrophage polarization in diabetic wound healing. New therapeutic drugs targeting phagocyte polarization to promote the healing of diabetic wounds might provide a new strategy for treating chronic diabetic wound healing.