Background: Tolerogenic dendritic cells (DCs) are associated with poor prognosis of sepsis. Matrix metalloproteinases (MMPs) have been shown to have immunomodulatory effects. However, whether MMPs are involved in the functional reprogramming of DCs is unknown. The study aims to investigate the role of MMPs in sepsis-induced DCs tolerance and the potential mechanisms. Methods: A murine model of late sepsis was induced by cecal ligation and puncture (CLP). The expression levels of members of the MMP family were detected in sepsis-induced tolerogenic DCs by using microarray assessment. The potential roles and mechanisms underlying MMP8 in the differentiation, maturation and functional reprogramming of DCs during late sepsis were assessed both in vitro and in vivo. Results: DCs from late septic mice expressed higher levels of MMP8, MMP9, MMP14, MMP19, MMP25 and MMP27, and MMP8 levels were the highest. MMP8 deficiency significantly alleviated sepsis-induced immune tolerance of DCs both in vivo and in vitro. Adoptive transfer of MMP8 knockdown post-septic bone marrow-derived DCs protected mice against sepsis-associated lethality and organ dysfunction, inhibited regulatory T-cell expansion and enhanced Th1 response. Furthermore, the effect of MMP8 on DC tolerance was found to be associated with the nuclear factor kappa-B p65/β-catenin pathway. Conclusions: Increased MMP8 levels in septic DCs might serve as a negative feedback loop, thereby suppressing the proinflammatory response and inducing DC tolerance.

Background: Hypoxia is the typical characteristic of keloids. The development of keloids is closely related to the abnormal phenotypic transition of macrophages. However, the role of exosomal microRNAs (miRNAs) derived from hypoxic macrophages in keloids remains unclear. This study aimed to explore the role of hypoxic macrophage-derived exosomes (HMDE) in the occurrence and development of keloids and identify the critical miRNA. Methods: The expression of CD206+ M2 macrophage in keloids and normal skin tissues was examined through immunofluorescence. The polarization of macrophages under a hypoxia environment was detected through flow cytometry. The internalization of macrophage-derived exosomes in human keloid fibroblasts (HKFs) was detected using a confocal microscope. miRNA sequencing was used to explore the differentially expressed miRNAs in exosomes derived from the normoxic and hypoxic macrophage. Subsequently, the dual-luciferase reporter assay verified that phosphatase and tension homolog (PTEN) was miR-26b-5p’s target. The biological function of macrophage-derived exosomes, miR-26b-5p and PTEN were detected using the CCK-8, wound-healing and Transwell assays. Western blot assay was used to confirm the miR-26b-5p’s underlying mechanisms and PTEN-PI3K/AKT pathway. Results: We demonstrated that M2-type macrophages were enriched in keloids and that hypoxia treatment could polarize macrophages toward M2-type. Compared with normoxic macrophages-derived exosomes (NMDE), HMDE promote the proliferation, migration and invasion of HKFs. A total of 38 differential miRNAs (18 upregulated and 20 downregulated) were found between the NMDE and HMDE. miR-26b-5p was enriched in HMDE, which could be transmitted to HKFs. According to the results of the functional assay, exosomal miR-26b-5p produced by macrophages facilitated HKFs’ migration, invasion and proliferation via the PTEN-PI3K/AKT pathway. Conclusions: The highly expressed miR-26b-5p in HMDE promotes the development of keloids via the PTEN-PI3K/AKT pathway.

Burn injuries can be devastating, with life-long impacts including an increased risk of hospitalization for a wide range of secondary morbidities. One area that remains not fully understood is the impact of burn trauma on the central nervous system (CNS). This review will outline the current findings on the physiological impact that burns have on the CNS and how this may contribute to the development of neural comorbidities including mental health conditions. This review highlights the damaging effects caused by burn injuries on the CNS, characterized by changes to metabolism, molecular damage to cells and their organelles, and disturbance to sensory, motor and cognitive functions in the CNS. This damage is likely initiated by the inflammatory response that accompanies burn injury, and it is often long-lasting. Treatments used to relieve the symptoms of damage to the CNS due to burn injury often target inflammatory pathways. However, there are non-invasive treatments for burn patients that target the functional and cognitive damage caused by the burn, including transcranial magnetic stimulation and virtual reality. Future research should focus on understanding the mechanisms that underpin the impact of a burn injury on the CNS, burn severity thresholds required to inflict damage to the CNS, and acute and long-term therapies to ameliorate deleterious CNS changes after a burn.

Background: Ionizing radiation (IR)-induced intestinal injury is a major side effect and dose-limiting toxicity in patients receiving radiotherapy. There is an urgent need to identify an effective and safe radioprotectant to reduce radiation-induced intestinal injury. Immunoregulation is considered an effective strategy against IR-induced injury. The purpose of this article was to investigate the protective effect of Nocardia rubra cell wall skeleton (Nr-CWS), an immunomodulator, on radiation-induced intestinal damage and to explore its potential mechanism. Methods: C57BL/6 J male mice exposed to 12 Gy whole abdominal irradiation (WAI) were examined for survival rate, morphology and function of the intestine and spleen, as well as the gut microbiota, to comprehensively evaluate the therapeutic effects of Nr-CWS on radiation-induced intestinal and splenetic injury. To further elucidate the underlying mechanisms of Nr-CWS-mediated intestinal protection, macrophages were depleted by clodronate liposomes to determine whether Nr-CWS-induced radioprotection is macrophage dependent, and the function of peritoneal macrophages stimulated by Nr-CWS was detected in vitro. Results: Our data showed that Nr-CWS promoted the recovery of intestinal barrier function, enhanced leucine-rich repeat-containing G protein-coupled receptor 5+ intestinal stem cell survival and the regeneration of intestinal epithelial cells, maintained intestinal flora homeostasis, protected spleen morphology and function, and improved the outcome of mice exposed to 12 Gy WAI. Mechanistic studies indicated that Nr-CWS recruited macrophages to reduce WAI-induced intestinal damage. Moreover, macrophage depletion by clodronate liposomes blocked Nr-CWS-induced radioprotection. In vitro, we found that Nr-CWS activated the nuclear factor kappa-B signaling pathway and promoted the phagocytosis and migration ability of peritoneal macrophages. Conclusions: Our study suggests the therapeutic effect of Nr-CWS on radiation-induced intestinal injury, and provides possible therapeutic strategy and potential preventive and therapeutic drugs to alleviate it.

Background: Laser therapy has emerged to play a valuable role in the treatment of paediatric burn scars; however, there is heterogeneity in the literature, particularly concerning optimal timing for initiation of laser therapy. This study aims to investigate the effect of factors such as scar age, type of laser and laser treatment interval on burn scar outcomes in children by meta-analysis of previous studies. Methods: A literature search was conducted across seven databases in May 2022 to understand the effects of laser therapy on burn scar outcomes in paediatric patients by metanalysis of standardized mean difference (SMD) between pre-and post-laser intervention. Meta-analyses were performed using the Comprehensive Meta-Analysis software version 4.0. Fixed models were selected when there was no significant heterogeneity, and the random effects model was selected for analysis when significant heterogeneity was identified. For all analyses, a p-value < 0.05 was considered significant. Results: Seven studies were included in the meta-analysis with a total of 467 patients. Laser therapy significantly improved Vancouver Scar Scale (VSS)/Total Patient and Observer Scar Assessment Scale (Total POSAS), vascularity, pliability, pigmentation and scar height of burn scars. Significant heterogeneity was found between the studies and thus subgroup analyses were performed. Early laser therapy (<12 months post-injury) significantly improved VSS/POSAS scores compared to latent therapy (>12 months post-injury) {SMD −1.97 [95% confidence interval (CI) = −3.08; −0.87], p < 0.001 vs −0.59 [95%CI = −1.10; −0.07], p = 0.03} as well as vascularity {SMD −3.95 [95%CI = −4.38; −3.53], p < 0.001 vs −0.48 [95%CI = −0.66; −0.30], p < 0.001}. Non-ablative laser was most effective, significantly reducing VSS/POSAS, vascularity, pliability and scar height outcomes compared to ablative, pulse dye laser and a combination of ablative and pulse dye laser. Shorter treatment intervals of <4 weeks significantly reduced VSS/POSAS and scar height outcomes compared to intervals of 4 to 6 weeks. Conclusions: Efficacy of laser therapy in the paediatric population is influenced by scar age, type of laser and interval between laser therapy application. The result of this study particularly challenges the currently accepted initiation time for laser treatment. Significant heterogeneity was observed within the studies, which suggests the need to explore other confounding factors influencing burn scar outcomes after laser therapy.

Metabolic reprogramming refers to the ability of a cell to alter its metabolism in response to different stimuli and forms of pressure. It helps cells resist external stress and provides them with new functions. Skin wound healing involves the metabolic reprogramming of nutrients, such as glucose, lipids, and amino acids, which play vital roles in the proliferation, differentiation, and migration of multiple cell types. During the glucose metabolic process in wounds, glucose transporters and key enzymes cause elevated metabolite levels. Glucose-mediated oxidative stress drives the proinflammatory response and promotes wound healing. Reprogramming lipid metabolism increases the number of fibroblasts and decreases the number of macrophages. It enhances local neovascularization and improves fibrin stability to promote extracellular matrix remodelling, accelerates wound healing, and reduces scar formation. Reprogramming amino acid metabolism affects wound re-epithelialization, collagen deposition, and angiogenesis. However, comprehensive reviews on the role of metabolic reprogramming in skin wound healing are lacking. Therefore, we have systematically reviewed the metabolic reprogramming of glucose, lipids, and amino acids during skin wound healing. Notably, we identified their targets with potential therapeutic value and elucidated their mechanisms of action.

Background: Hypertrophic scar (HS) is a common fibroproliferative skin disease that currently has no truly effective therapy. Given the importance of phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) in hypertrophic scar formation, the development of therapeutic strategies for endogenous inhibitors against PIK3CA is of great interest. Here, we explored the molecular mechanisms underlying the protective effects of miR-203a-3p (PIK3CA inhibitor) against excessive scar. Methods: Bioinformatic analysis, immunohistochemistry, immunofluorescence, miRNA screening and fluorescence in situ hybridization assays were used to identify the possible pathways and target molecules mediating HS formation. A series of in vitro and in vivo experiments were used to clarify the role of PIK3CA and miR-203a-3p in HS. Mechanistically, transcriptomic sequencing, immunoblotting, dual-luciferase assay and rescue experiments were executed. Results: Herein, we found that PIK3CA and the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway were upregulated in scar tissues and positively correlated with fibrosis. We then identified miR-203a-3p as the most suitable endogenous inhibitor of PIK3CA. miR-203a-3p suppressed the proliferation, migration, collagen synthesis and contractility as well as the transdifferentiation of fibroblasts into myofibroblasts in vitro, and improved the morphology and histology of scars in vivo. Mechanistically, miR-203a-3p attenuated fibrosis by inactivating the PI3K/AKT/mTOR pathway by directly targeting PIK3CA. Conclusions: PIK3CA and the PI3K/AKT/mTOR pathway are actively involved in scar fibrosis and miR-203a-3p might serve as a potential strategy for hypertrophic scar therapy through targeting PIK3CA and inactivating the PI3K/AKT/mTOR pathway.

Diabetic wound healing (DWH) represents a major complication of diabetes where inflammation is a key impediment to proper healing. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway has emerged as a central mediator of inflammatory responses to cell stress and damage. However, the contribution of cGAS-STING activation to impaired healing in DWH remains understudied. In this review, we examine the evidence that cGAS-STING-driven inflammation is a critical factor underlying defective DWH. We summarize studies revealing upregulation of the cGAS-STING pathway in diabetic wounds and discuss how this exacerbates inflammation and senescence and disrupts cellular metabolism to block healing. Partial pharmaceutical inhibition of cGAS-STING has shown promise in damping inflammation and improving DWH in preclinical models. We highlight key knowledge gaps regarding cGAS-STING in DWH, including its relationships with endoplasmic reticulum stress and metal-ion signaling. Elucidating these mechanisms may unveil new therapeutic targets within the cGAS-STING pathway to improve healing outcomes in DWH. This review synthesizes current understanding of how cGAS-STING activation contributes to DWH pathology and proposes future research directions to exploit modulation of this pathway for therapeutic benefit.

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, with ~50 million people experiencing TBI each year. Ferroptosis, a form of regulated cell death triggered by iron ion-catalyzed and reactive oxygen species-induced lipid peroxidation, has been identified as a potential contributor to traumatic central nervous system conditions, suggesting its involvement in the pathogenesis of TBI. Alterations in iron metabolism play a crucial role in secondary injury following TBI. This study aimed to explore the role of ferroptosis in TBI, focusing on iron metabolism disorders, lipid metabolism disorders and the regulatory axis of system Xc⁻/glutathione/glutathione peroxidase 4 in TBI. Additionally, we examined the involvement of ferroptosis in the chronic TBI stage. Based on these findings, we discuss potential therapeutic interventions targeting ferroptosis after TBI. In conclusion, this review provides novel insights into the pathology of TBI and proposes potential therapeutic targets.

Background: Multiple surgical strategies have been developed for treating massive rotator cuff tears (mRCTs). However, there is still no consensus on the best surgical option for mRCTs. Through a network meta-analysis, we aimed to comprehensively and systematically analyse the evidence in randomized controlled trials to help clinicians make evidence-based clinical decisions for patients with mRCTs. Methods: Our study was a network meta-analysis of the surgical management of mRCTs (PROSPERO Registration ID: CRD42023397971). We searched PubMed, EMBASE, Cochrane and Web of Science for randomized controlled trials that examined the efficacy of surgical management for mRCTs up to 3 November 2022. A three-step method was employed for the study process. Study selection, data extraction and risk of bias evaluation were conducted by two independent reviewers. R software (version 4.2.1) and Stata (version 15.1) were used for the data analysis. Results: From 10,633 publications, we included 15 randomized controlled trials (996 participants) for the quantitative analysis. In terms of both long-term and short-term surgical effects, there were no statistically significant differences among surgical interventions such as patch-augmented rotator cuff repair (RCR), RCR with platelet-rich plasma, arthroscopic decompression, bridging reconstruction, arthroscopic RCR with platelet-leukocyte membrane, open RCR, mini-open RCR, arthroscopic debridement, superior capsular reconstruction, arthroscopic suture-spanning augmented repair, subacromial balloon spacer and latissimus dorsi tendon transfer. Based on algorithms, the probability ranking suggests that patch augmentation is the most highly ranked surgical intervention for achieving better short-term surgical outcomes. Furthermore, arthroscopic-associated mini-open RCR was ranked as the highest surgical intervention for achieving better long-term surgical effects. Conclusions: Based on the available data from the included studies, similar surgical efficacies were observed among the reported intervention measures for mRCTs. The patch augmentation technique was found to potentially achieve better short-term surgical outcomes, which is consistent with previous reports. However, the best surgical interventions for achieving long-term surgical effects remain unknown. More high-quality research is needed to evaluate the efficacy and safety of these interventions and to guide clinical practice.

Background: The breakdown of intestinal barrier integrity occurs after severe burn injury and is responsible for the subsequent reactions of inflammation and oxidative stress. A new protective strategy for the intestinal barrier is urgently needed due to the limitations of the traditional methods. Recently, the application of nanoparticles has become one of the promising therapies for many inflammation-related diseases or oxidative damage. Herein, we developed a new anti-inflammatory and antioxidant nanoparticle named luminol-conjugated cyclodextrin (LCD) and aimed to evaluate its protective effects in severe burn-induced intestinal injury. Methods: First, LCD nanoparticles, engineered with covalent conjugation between luminol and β-cyclodextrin (β-CD), were synthesized and examined. Then a mouse burn model was successfully established before the mouse body weight, intestinal histopathological manifestation, permeability, tight junction (TJ) expression and pro-inflammatory cytokines were determined in different groups. The proliferation, apoptosis, migration and reactive oxygen species (ROS) of intestinal epithelial cells (IECs) were assessed. Intraepithelial lymphocytes (IELs) were isolated and cultured for analysis by flow cytometry. Results: LCD nanoparticle treatment significantly relieved the symptoms of burn-induced intestinal injury in the mouse model, including body weight loss and intestinal permeability abnormalities. Moreover, LCD nanoparticles remarkably recovered the mechanical barrier of the intestine after severe burn, renewed TJ structures, promoted IEC proliferation and migration, and inhibited IEC apoptosis. Mechanistically, LCD nanoparticles dramatically alleviated pro-inflammation factors (tumor necrosis factor-α, IL-17A) and ROS accumulation, which could be highly involved in intestinal barrier disruption. Furthermore, an increase in IL-17A and the proportion of IL-17A+Vγ4+γδ T subtype cells was also observed in vitro in LPS-treated Vγ4+γδ T cells, but the use of LCD nanoparticles suppressed this increase. Conclusions: Taken together, these findings demonstrate that LCD nanoparticles have the protective ability to ameliorate intestinal barrier disruption and provide a therapeutic intervention for burn-induced intestinal injury.

Background: Prevention of diabetic heart myocardial ischemia–reperfusion (IR) injury (MIRI) is challenging. Propofol attenuates MIRI through its reactive oxygen species scavenging property at high doses, while its use at high doses causes hemodynamic instability. Salvianolic acid A (SAA) is a potent antioxidant that confers protection against MIRI. Both propofol and SAA affect metabolic profiles through regulating Adenosine 5‘-monophosphate-activated protein kinase (AMPK). The aim of this study was to investigate the protective effects and underlying mechanisms of low doses of propofol combined with SAA against diabetic MIRI. Methods: Diabetes was induced in mice by a high-fat diet followed by streptozotocin injection, and MIRI was induced by coronary artery occlusion and reperfusion. Mice were treated with propofol at 46 mg/kg/h without or with SAA at 10 mg/kg/h during IR. Cardiac origin H9c2 cells were exposed to high glucose (HG) and palmitic acid (PAL) for 24 h in the absence or presence of cluster of differentiation 36 (CD36) overexpression or AMPK gene knockdown, followed by hypoxia/reoxygenation (HR) for 6 and 12 h. Results: Diabetes-exacerbated MIRI is evidenced as significant increases in post-ischemic infarction with reductions in phosphorylated (p)-AMPK and increases in CD36 and ferroptosis. Propofol moderately yet significantly attenuated all the abovementioned changes, while propofol plus SAA conferred superior protection against MIRI to that of propofol. In vitro, exposure of H9c2 cells under HG and PAL decreased cell viability and increased oxidative stress that was concomitant with increased levels of ferroptosis and a significant increase in CD36, while p-AMPK was significantly reduced. Co-administration of low concentrations of propofol and SAA at 12.5 μM in H9c2 cells significantly reduced oxidative stress, ferroptosis and CD36 expression, while increasing p-AMPK compared to the effects of propofol at 25 μM. Moreover, either CD36 overexpression or AMPK silence significantly exacerbated HR-induced cellular injuries and ferroptosis, and canceled propofol-and SAA-mediated protection. Notably, p-AMPK expression was downregulated after CD36 overexpression, while AMPK knockdown did not affect CD36 expression. Conclusions: Combinational usage of propofol and SAA confers superior cellular protective effects to the use of high-dose propofol alone, and it does so through inhibiting HR-induced CD36 overexpression to upregulate p-AMPK.

Background: Tissue expansion, a technique in which skin regeneration is induced by mechanical stretch stimuli, is commonly used for tissue repair and reconstruction. In this study, we aimed to monitor the autophagy levels of expanded skin after the application of expansion stimuli and explore the effect of autophagy modulation on skin regeneration. Methods: A rat scalp expansion model was established to provide a stable expanded skin response to mechanical stretch. Autophagy levels at different time points (6, 12, 24, 48 and 72 h after the last expansion) were detected via western blotting. The effect of autophagy regulation on skin regeneration during tissue expansion was evaluated via skin expansion efficiency assessment, western blotting, immunofluorescence staining, TUNEL staining and laser Doppler blood flow imaging. Results: The autophagic flux reached its highest level 48 h after tissue expansion. Activating autophagy by rapamycin increased the area of expanded skin as well as the thicknesses of epidermis and dermis. Furthermore, activating autophagy accelerated skin regeneration during tissue expansion by enhancing the proliferation of cells and the number of epidermal basal and hair follicle stem cells, reducing apoptosis, improving angiogenesis, and promoting collagen synthesis and growth factor secretion. Conversely, the regenerative effects were reversed when autophagy was blocked. Conclusions: Autophagy modulation may be a promising therapeutic strategy for improving the efficiency of tissue expansion and preventing the incidence of the complication of skin necrosis.

Background: Refractory diabetic wounds are a common occurrence in patients with diabetes and epidermis-specific macroautophagy/autophagy impairment has been implicated in their pathogenesis. Therefore, identifying and developing treatment strategies capable of normalizing epidermis-specific macroautophagy/autophagy could facilitate diabetic wound healing. The study aims to investigate the potential of bone marrow mesenchymal stem cell-derived exosomes (BMSC-exos) from hypoxic conditions as a treatment to normalize epidermis-specific autophagy for diabetic wound healing. Methods: We compared the effects of bone marrow mesenchymal stem cell (BMSC)-sourced exosomes (BMSC-Exos) from hypoxic conditions to those of BMSC in normoxic conditions (noBMSC-Exos). Our studies involved morphometric assessment of the exosomes, identification of the microRNA (miRNA) responsible for the effects, evaluation of keratinocyte functions and examination of effects of the exosomes on several molecules involved in the autophagy pathway such as microtubule-associated protein 1 light chain 3 beta, beclin 1, sequestosome 1, autophagy-related 5 and autophagy-related 5. The experiments used human BMSCs from the American Type Culture Collection, an in vivo mouse model of diabetes (db/db) to assess wound healing, as well as the human keratinocyte HaCaT cell line. In the methodology, the authors utilized an array of approaches that included electron microscopy, small interfering RNA (siRNA) studies, RNA in situ hybridization, quantitative real-time reverse transcription PCR (qRT-PCR), the isolation, sequencing and differential expression of miRNAs, as well as the use of miR-4645-5p-specific knockdown with an inhibitor. Results: Hypoxia affected the release of exosomes from hypoxic BMSCs (hy-BMSCs) and influenced the size and morphology of the exosomes. Moreover, hyBMSC-Exo treatment markedly improved keratinocyte function, including keratinocyte autophagy, proliferation and migration. miRNA microarray and bioinformatics analysis showed that the target genes of the differentially expressed miRNAs were mainly enriched in ‘autophagy’ and ‘process utilizing autophagic mechanism’ in the ‘biological process’ category and miR-4645-5p as a major contributor to the pro-autophagy effect of hyBMSC-Exos. Moreover, mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2) was identified as a potential target of exosomal miR-4645-5p; this was confirmed using a dual luciferase assay. Exosomal miR-4645-5p mediates the inactivation of the MAPKAPK2-induced AKT kinase group (comprising AKT1, AKT2, and AKT3), which in turn suppresses AKT-mTORC1 signaling, thereby facilitating miR-4645-5p-mediated autophagy. Conclusions: Overall, the results of this study showed that hyBMSC-Exo-mediated transfer of miR-4645-5p inactivated MAPKAPK2-induced AKT-mTORC1 signaling in keratinocytes, which activated keratinocyte autophagy, proliferation and migration, resulting in diabetic wound healing in mice. Collectively, the findings could aid in the development of a novel therapeutic strategy for diabetic wounds.

The efficient management of skin wounds for rapid and scarless healing represents a major clinical unmet need. Nonhealing skin wounds and undesired scar formation impair quality of life and result in high healthcare expenditure worldwide. The skin-colonizing microbiota contributes to maintaining an intact skin barrier in homeostasis, but it also participates in the pathogenesis of many skin disorders, including aberrant wound healing, in many respects. This review focuses on the composition of the skin microbiome in cutaneous wounds of different types (i.e. acute and chronic) and with different outcomes (i.e. nonhealing and hypertrophic scarring), mainly based on next-generation sequencing analyses; furthermore, we discuss the mechanistic insights into host–microbe and microbe–microbe interactions during wound healing. Finally, we highlight potential therapeutic strategies that target the skin microbiome to improve healing outcomes.

Acne is a common chronic inflammatory dermatosis that can lead to pathological scars (PSs, divided into hypertrophic scars and keloids). These kinds of abnormal scars seriously reduce the quality of life of patients. However, their mechanism is still unclear, resulting in difficult clinical prevention, unstable treatment effects and a high risk of recurrence. Available evidence supports inflammatory changes caused by infection as one of the keys to abnormal proliferation of skin fibroblasts. In acne-induced PSs, increasing knowledge of the immunopathology indicates that inflammatory cells directly secrete growth factors to activate fibroblasts and release pro-inflammatory factors to promote the formation of PSs. T helper cells contribute to PSs via the secretion of interleukin (IL)-4 and IL-13, the pro-inflammatory factors; while regulatory T cells have anti-inflammatory effects, secrete IL-10 and prostaglandin E2, and suppress fibrosis production. Several treatments are available, but there is a lack of combination regimens to target different aspects of acne-induced PSs. Overall, this review indicates that the joint involvement of inflammatory response and fibrosis plays a crucial role in acne-induced PSs, and also analyzes the interaction of current treatments for acne and PS.

Second-degree burns are the most common type of burn in clinical practice and hard to manage. Their treatment requires not only a consideration of the different outcomes that may arise from the dressing changes or surgical therapies themselves but also an evaluation of factors such as the burn site, patient age and burn area. Meanwhile, special attention should be given to the fact that there is no unified standard or specification for the diagnosis, classification, surgical procedure, and infection diagnosis and grading of second-degree burn wounds. This not only poses great challenges to the formulation of clinical treatment plans but also significantly affects the consistency of clinical studies. Moreover, currently, there are relatively few guidelines or expert consensus for the management of second-degree burn wounds, and no comprehensive and systematic guidelines or specifications for the treatment of second-degree burns have been formed. Therefore, we developed the Consensus on the Treatment of Second-Degree Burn Wounds (2024 edition), based on evidence-based medicine and expert opinion. This consensus provides specific recommendations on prehospital first aid, nonsurgical treatment, surgical treatment and infection treatment for second-degree burns. The current consensus generated a total of 58 recommendations, aiming to form a standardized clinical treatment plan.

Background: Oxidative stress (OS) and inflammatory reactions play pivotal roles in secondary brain injury after traumatic brain injury (TBI). Histone deacetylase 3 (HDAC3) controls the acetylation of histones and non-histones, which has a significant impact on the central nervous system’s reaction to damage. This research determined the implications of RGFP966, a new and specific inhibitor of HDAC3, for the antioxidant (AO) systems mediated by nuclear factor erythroid2-related factor 2 (Nrf2) and the Nod-like receptor protein 3 (NLRP3) inflammasome in TBI. The study also studied the underlying mechanisms of RGFP966’s actions. Our objective was to examine the impacts and underlying RGFP966 mechanisms in TBI. Methods: In vitro, a rat cortical neuron OS model was induced by H₂O₂, followed by the addition of RGFP966 to the culture medium. Neurons were collected after 24 h for western blot (WB), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and 2′-7′-dichlorodihydrofluorescein diacetate staining. In vivo, RGFP966 (10 mg/kg) was administered post-TBI. Brain tissue water content and modified neurological severity scores were assessed 72 h post-injury. Cortical tissues surrounding the focal injury were subjected to western blot, TUNEL staining, Nissl staining and immunofluorescence/immunohistochemistry staining, and malondialdehyde level, hindered glutathione content and superoxide dismutase activity were measured. Serum was collected for the enzyme-linked immunosorbent assay. Nrf2-specific shRNA lentivirus was injected into the lateral ventricle of rats for 7 days, and cerebral cortex tissue was analyzed by WB and real-time polymerase chain reaction. Results: During in vitro and in vivo experiments, RGFP966 suppressed HDAC3 expression, promoted Nrf2 nuclear translocation, activated downstream AO enzymes, mitigated excessive reactive oxygen species production and alleviated nerve cell apoptosis. RGFP966 effectively reduced brain edema and histological damage and enhanced neurological and cognitive function in rats with TBI. RGFP966 markedly inhibited NLRP3 inflammasome activation mediated by high-mobility group box 1 (HMGB1)/toll-like receptor 4 (TLR4). Nrf2 knockdown in TBI rats attenuated the AO and anti-inflammatory, neuroprotective impacts of RGFP966. Conclusions: Overall, our findings demonstrate that RGFP966 can mitigate the first brain damage and neurological impairments in TBI. The underlying mechanism involves triggering the Nrf2-mediated AO system and negatively regulating the HMGB1/TLR4-mediated NLRP3 inflammasome pathway.

Background: Prospective randomized trials in severely burned children have shown the positive effects of oxandrolone (OX), beta blockers (BB) and a combination of the two (BBOX) on hypermetabolism, catabolism and hyperinflammation short-and long-term post-burn. Although data on severely burned adults are lacking in comparison, BB, OX and BBOX appear to be commonly employed in this patient population. In this study, we perform a secondary analysis of an international prospective randomized trial dataset to provide descriptive evidence regarding the current utilization patterns and potential treatment effects of OX, BB and BBOX. Methods: The RE-ENERGIZE (RandomizEd Trial of ENtERal Glutamine to minimIZE Thermal Injury, NCT00985205) trial included 1200 adult patients with severe burns. We stratified patients according to their receipt of OX, BB, BBOX or none of these drugs (None) during acute hospitalization. Descriptive statistics describe the details of drug therapy and unadjusted analyses identify predisposing factors for drug use per group. Association between OX, BB and BBOX and clinical outcomes such as time to discharge alive and 6-month mortality were modeled using adjusted multivariable Cox regressions. Results: More than half of all patients in the trial received either OX (n = 138), BB (n = 293) or BBOX (n = 282), as opposed to None (n = 487, 40.6%). Per study site and geographical region, use of OX, BB and BBOX was highly variable. Predisposing factors for the use of OX, BB and BBOX included larger total body surface area (TBSA) burned, higher acute physiology and chronic health evaluation (APACHE) II scores on admission and younger patient age. After adjustment for multiple covariates, the use of OX was associated with a longer time to discharge alive [hazard ratio (HR) 0.62, confidence interval (CI) (0.47–0.82) per 100% increase, p = 0.001]. A higher proportion of days on BB was associated with lower in-hospital-mortality (HR: 0.5, CI 0.28–0.87, p = 0.015) and 6-month mortality (HR: 0.44, CI 0.24–0.82, p = 0.01). Conclusions: The use of OX, BB and BBOX is common within the adult burn patient population, with its use varying considerably across sites worldwide. Our findings found mixed associations between outcomes and the use of BB and OX in adult burn patients, with lower acute and 6-month-mortality with BB and longer times to discharge with OX. Further research into these pharmacological modulators of the pathophysiological response to severe burn injury is indicated.

Background: Hypertrophic scarring is the most serious and unmet challenge following burn and trauma injury and often leads to pain, itching and even loss of function. However, the demand for ideal scar prevention and treatment is difficult to satisfy. We aimed to discover the effects and mechanisms of adipose-derived stem cell (ADSC) exosomes in hypertrophic scarring. Methods: ADSC exosomes were isolated from the culture supernatant of ADSCs and identified by nanoparticle tracking analysis, transmission electron microscopy and western blotting. The effect of ADSC exosomes on wound healing and scar formation was detected by the wound model of BALB/c mice. We isolated myofibroblasts from hypertrophic scar tissue and detected the cell viability, proliferation and migration of myofibroblasts. In addition, collagen formation and fibrosis-related molecules were also detected. To further disclose the mechanism of ADSC exosomes on fibrosis in myofibroblasts, we detected the expression of Smad2 in hypertrophic scar tissue and normal skin and the regulatory mechanism of ADSC exosomes on Smad2. Injection of bleomycin was performed in male BALB/c mice to establish an in vivo fibrosis model while ADSC exosomes were administered to observe their protective effect. The tissue injury of mice was observed via hematoxylin and eosin and Masson staining and related testing. Results: In this study, we found that ADSC exosomes could not only speed up wound healing and improve healing quality but also prevent scar formation. ADSC exosomes inhibited expression of fibrosis-related molecules such as α-smooth muscle actin, collagen I (COL1) and COL3 and inhibited the transdifferentiation of myofibroblasts. In addition, we verified that Smad2 is highly expressed in both hypertrophic scar tissue and hypertrophic fibroblasts, while ADSC exosomes downregulated the expression of Smad2 in hypertrophic fibroblasts. Further regulatory mechanism analysis revealed that microRNA-125b-5p (miR-125b-5p) is highly expressed in ADSC exosomes and binds to the 3′ untranslated region of Smad2, thus inhibiting its expression. In vivo experiments also revealed that ADSC exosomes could alleviate bleomycin-induced skin fibrosis and downregulate the expression of Smad2. Conclusions: We found that ADSC exosomes could alleviate hypertrophic scars via the suppression of Smad2 by the specific delivery of miR-125b-5p.

Background: Adipose mesenchymal stem cell-derived exosomes (ADSC-Exos) have great potential in the field of tissue repair and regenerative medicine, particularly in cases of refractory diabetic wounds. Interestingly, autophagy plays a role in wound healing, and recent research has demonstrated that exosomes are closely associated with intracellular autophagy in biogenesis and molecular signaling mechanisms. Therefore, this study aimed to investigate whether ADSC-Exos promote the repair of diabetic wounds by regulating autophagy to provide a new method and theoretical basis for the treatment of diabetic wounds. Methods: Western blot analysis and autophagy double-labelled adenovirus were used to monitor changes in autophagy flow in human immortalized keratinocyte cell line (HaCaT) cells. ADSC-Exos were generated from ADSC supernatants via ultracentrifugation. The effectiveness of ADSC-Exos on HaCaT cells was assessed using a live-cell imaging system, cell counting kit-8 and cell scratch assays. The cells were treated with the autophagy inhibitor bafilomycin A1 to evaluate the effects of autophagy on cell function. The recovery of diabetic wounds after ADSC-Exo treatment was determined by calculating the healing rates and performing histological analysis. High-throughput transcriptome sequencing was used to analyze changes in mRNA expression after the treatment of HaCaT cells with ADSC-Exos. Results: ADSC-Exos activated autophagy in HaCaT cells, which was inhibited by high glucose levels, and potentiated their cellular functions. Moreover, ADSC-Exos in combination with the autophagy inhibitor bafilomycin A1 showed that autophagy defects further impaired the biological function of epidermal cells under high-glucose conditions and partially weakened the healing effect of ADSC-Exos. Using a diabetes wound model, we found that ADSC-Exos promoted skin wound healing in diabetic mice, as evidenced by increased epidermal autophagy and rapid re-epithelialization. Finally, sequencing results showed that increased expression of autophagy-related genes nicotinamide phosphoribosyltransferase (NAMPT), CD46, vesicle-associated membrane protein 7 (VAMP7), VAMP3 and eukaryotic translation initiation factor 2 subunit alpha (EIF2S1) may contribute to the underlying mechanism of ADSC-Exo action. Conclusions: This study elucidated the molecular mechanism through which ADCS-Exos regulate autophagy in skin epithelial cells, thereby providing a new theoretical basis for the treatment and repair of skin epithelial damage by ADSC-Exos.

Sebaceous glands (SGs), as holocrine-secreting appendages, lubricate the skin and play a central role in the skin barrier. Large full-thickness skin defects cause overall architecture disruption and SG loss. However, an effective strategy for SG regeneration is lacking. Organoids are 3D multicellular structures that replicate key anatomical and functional characteristics of in vivo tissues and exhibit great potential in regenerative medicine. Recently, considerable progress has been made in developing reliable procedures for SG organoids and existing SG organoids recapitulate the main morphological, structural and functional features of their in vivo counterparts. Engineering approaches empower researchers to manipulate cell behaviors, the surrounding environment and cell–environment crosstalk within the culture system as needed. These techniques can be applied to the SG organoid culture system to generate functionally more competent SG organoids. This review aims to provide an overview of recent advancements in SG organoid engineering. It highlights some potential strategies for SG organoid functionalization that are promising to forge a platform for engineering vascularized, innervated, immune-interactive and lipogenic SG organoids. We anticipate that this review will not only contribute to improving our understanding of SG biology and regeneration but also facilitate the transition of the SG organoid from laboratory research to a feasible clinical application.

Background: Extracellular cold-inducible RNA-binding protein (eCIRP) plays a vital role in the inflammatory response during cerebral ischaemia. However, the potential role and regulatory mechanism of eCIRP in traumatic brain injury (TBI) remain unclear. Here, we explored the effect of eCIRP on the development of TBI using a neural-specific CIRP knockout (KO) mouse model to determine the contribution of eCIRP to TBI-induced neuronal injury and to discover novel therapeutic targets for TBI. Methods: TBI animal models were generated in mice using the fluid percussion injury method. Microglia or neuron lines were subjected to different drug interventions. Histological and functional changes were observed by immunofluorescence and neurobehavioural testing. Apoptosis was examined by a TdT-mediated dUTP nick end labelling assay in vivo or by an annexin-V assay in vitro. Ultrastructural alterations in the cells were examined via electron microscopy. Tissue acetylation alterations were identified by non-labelled quantitative acetylation via proteomics. Protein or mRNA expression in cells and tissues was determined by western blot analysis or real-time quantitative polymerase chain reaction. The levels of inflammatory cytokines and mediators in the serum and supernatants were measured via enzyme-linked immunoassay. Results: There were closely positive correlations between eCIRP and inflammatory mediators, and between eCIRP and TBI markers in human and mouse serum. Neural-specific eCIRP KO decreased hemispheric volume loss and neuronal apoptosis and alleviated glial cell activation and neurological function damage after TBI. In contrast, eCIRP treatment resulted in endoplasmic reticulum disruption and ER stress (ERS)-related death of neurons and enhanced inflammatory mediators by glial cells. Mechanistically, we noted that eCIRP-induced neural apoptosis was associated with the activation of the protein kinase RNA-like ER kinase-activating transcription factor 4 (ATF4)-C/EBP homologous protein signalling pathway, and that eCIRP-induced microglial inflammation was associated with histone H3 acetylation and the α7 nicotinic acetylcholine receptor. Conclusions: These results suggest that TBI obviously enhances the secretion of eCIRP, thereby resulting in neural damage and inflammation in TBI. eCIRP may be a biomarker of TBI that can mediate the apoptosis of neuronal cells through the ERS apoptotic pathway and regulate the inflammatory response of microglia via histone modification.

Background: Despite being a stable component of burn rehabilitation at later stages of recovery, exercise training is not commonly provided during the acute phase of burns. A lack of evidence surrounding its efficacy and safety in severely burned adults has hampered its implementation in acute burn care. The aim of this study was to investigate the capacity of early exercise training to modulate parameters of postburn muscle wasting and quality of life. Methods: Adults <65 years of age with burns ≥40% total burn surface area (TBSA) were randomly allocated to either receive early exercise (n = 29) in addition to standard care or standard care alone (n = 29). Early exercise involved resistance and aerobic training, which commenced as early as possible and lasted for a duration of 6 to 12 weeks, in line with burn center length of stay. Ultrasound-derived quadriceps muscle layer thickness (QMLT) and rectus femoris cross-sectional area (RF-CSA), lower limb muscle force, Eurocol Quality of Life-5 Dimensions and Burn Specific Health Scale Brief (BSHS-B) were assessed 6 and 12 weeks after baseline. Mixed models were fitted to compare between-group changes over time. Results: A total of 58 adults [42 (95% confidence interval 40–45) years old; 40–94% TBSA range, 86% previously mechanically ventilated] participated in this study. Exercise commenced 7 days [IQR (interquartile range) 5–9] after burn center admission with an attendance rate of 93%. Allocation to the exercise group had a protective effect on the loss of muscle size from baseline to 6 weeks of follow-up (QMLT: β-coefficient: 0.05 cm, p = 0.010; RF-CSA: β-coefficient: 0.05 cm², p = 0.045), and resulted in an improved recovery from 6 to 12 weeks (QMLT: β-coefficient: 0.04 cm, p = 0.01; RF-CSA: β-coefficient: 0.06 cm², p < 0.001). Muscle force increased significantly more in the exercise group than in the control group (β-coefficient: 3.102 N, p < 0.001) between 6 and 12 weeks. Besides a marginally significant effect for the BSHS-B domains ‘affect’ and ‘interpersonal relationships’ between 6 and 12 weeks, no benefits were observed in the other assessed quality-of-life measures. No serious adverse events were reported in the exercise group. Conclusions: The results of this study support the use of early exercise training as a feasible and efficacious therapeutic strategy to manage burn-related changes in muscle size and strength in adults with acute severe burn injury.

Septic shock is a severe form of sepsis characterized by high global mortality rates and significant heritability. Clinicians have long been perplexed by the differential expression of genes, which poses challenges for early diagnosis and prompt treatment of septic shock. Genetic polymorphisms play crucial roles in determining susceptibility to, mortality from, and the prognosis of septic shock. Research indicates that pathogenic genes are known to cause septic shock through specific alleles, and protective genes have been shown to confer beneficial effects on affected individuals. Despite the existence of many biomarkers linked to septic shock, their clinical use remains limited. Therefore, further investigation is needed to identify specific biomarkers that can facilitate early prevention, diagnosis and risk stratification. Septic shock is closely associated with multiple signaling pathways, including the toll-like receptor 2/toll-like receptor 4, tumor necrosis factor-α, phosphatidylinositol 3-kinase/protein kinase B, mitogen-activated protein kinase, nuclear factor κB, Janus kinase/signal transducer and activator of transcription, mammalian target of rapamycin, NOD-like receptor thermal protein domain-associated protein 3 and hypoxia-induced-factor-1 pathways. Understanding the regulation of these signaling pathways may lead to the identification of therapeutic targets for the development of novel drugs to treat sepsis or septic shock. In conclusion, identifying differential gene expression during the development of septic shock allows physicians to stratify patients according to risk at an early stage. Furthermore, auxiliary examinations can assist physicians in identifying therapeutic targets within relevant signaling pathways, facilitating early diagnosis and treatment, reducing mortality and improving the prognosis of septic shock patients. Although there has been significant progress in studying the genetic polymorphisms, specific biomarkers and signaling pathways involved in septic shock, the journey toward their clinical application and widespread implementation still lies ahead.

Background: Severe burn injury causes a hypermetabolic response, resulting in muscle protein catabolism and multiple organ damage syndrome. However, this response has not yet been continuously characterized by metabolomics in patients. This study aims to quantify temporal changes in the metabolic processes of patients with severe burns. Methods: We employed¹H-nuclear magnetic resonance (NMR) spectroscopy to scrutinize metabolic alterations during the initial 35 days following burn injury in a cohort of 17 adult patients with severe burns, with 10 healthy individuals included as controls. Plasma specimens were collected from patients on postburn days 1, 3, 7, 14, 21, 28 and 35. After performing multivariate statistical analysis, repeated-measures analysis of variance and time-series analysis, we quantified changes in metabolite concentrations. Results: Among the 36 metabolites quantified across 119 samples from burn patients, branched-chain amino acids, glutamate, glycine, glucose, pyruvate, lactate, trimethylamine N-oxide and others exhibited obvious temporal variations in concentration. Notably, these metabolites could be categorized into three clusters based on their temporal characteristics. The initial response to injury was characterized by changes in lactate and amino acids, while later changes were driven by an increase in fatty acid catabolism and microbial metabolism, leading to the accumulation of ketone bodies and microbial metabolites. Conclusions: Metabolomics techniques utilizing NMR have the potential to monitor the intricate processes of metabolism in patients with severe burns. This study confirmed that the third day after burn injury serves as the boundary between the ebb phase and the flow phase. Furthermore, identification of three distinct temporal patterns of metabolites revealed the intrinsic temporal relationships between these metabolites, providing clinical data for optimizing therapeutic strategies.

Background: Small-diameter vascular grafts have become the focus of attention in tissue engineering. Thrombosis and aneurysmal dilatation are the two major complications of the loss of vascular access after surgery. Therefore, we focused on fabricating 3D printed electrospun vascular grafts loaded with tetramethylpyrazine (TMP) to overcome these limitations. Methods: Based on electrospinning and 3D printing, 3D-printed electrospun vascular grafts loaded with TMP were fabricated. The inner layer of the graft was composed of electrospun poly(L-lactic-co-caprolactone) (PLCL) nanofibers and the outer layer consisted of 3D printed polycaprolactone (PCL) microfibers. The characterization and mechanical properties were tested. The blood compatibility and in vitro cytocompatibility of the grafts were also evaluated. Additionally, rat abdominal aortas were replaced with these 3D-printed electrospun grafts to evaluate their biosafety. Results: Mechanical tests demonstrated that the addition of PCL microfibers could improve the mechanical properties. In vitro experimental data proved that the introduction of TMP effectively inhibited platelet adhesion. Afterwards, rat abdominal aorta was replaced with 3D-printed electrospun grafts. The 3D-printed electrospun graft loaded with TMP showed good biocompatibility and mechanical strength within 6 months and maintained substantial patency without the occurrence of acute thrombosis. Moreover, no obvious aneurysmal dilatation was observed. Conclusions: The study demonstrated that 3D-printed electrospun vascular grafts loaded with TMP may have the potential for injured vascular healing.

Background: Given the significant impact on human health, it is imperative to develop novel treatment approaches for diabetic wounds, which are prevalent and serious complications of diabetes. The diabetic wound microenvironment has a high level of reactive oxygen species (ROS) and an imbalance between proinflammatory and anti-inflammatory cells/factors, which hamper the healing of chronic wounds. This study aimed to develop poly(L-lactic acid) (PLLA) nanofibrous membranes incorporating curcumin and silver nanoparticles (AgNPs), defined as PLLA/C/Ag, for diabetic wound healing. Methods: PLLA/C/Ag were fabricated via an air-jet spinning approach. The membranes underwent preparation and characterization through various techniques including Fourier-transform infrared spectroscopy, measurement of water contact angle, X-ray photoelectron spectroscopy, X-ray diffraction, scanning electron microscopy, assessment of in vitro release of curcumin and Ag⁺, testing of mechanical strength, flexibility, water absorption and biodegradability. In addition, the antioxidant, antibacterial and anti-inflammatory properties of the membranes were evaluated in vitro, and the ability of the membranes to heal wounds was tested in vivo using diabetic mice. Results: Loose hydrophilic nanofibrous membranes with uniform fibre sizes were prepared through air-jet spinning. The membranes enabled the efficient and sustained release of curcumin. More importantly, antibacterial AgNPs were successfully reduced in situ from AgNO₃. The incorporation of AgNPs endowed the membrane with superior antibacterial activity, and the bioactivities of curcumin and the AgNPs gave the membrane efficient ROS scavenging and immunomodulatory effects, which protected cells from oxidative damage and reduced inflammation. Further results from animal studies indicated that the PLLA/C/Ag membranes had the most efficient wound healing properties, which were achieved by stimulating angiogenesis and collagen deposition and inhibiting inflammation. Conclusions: In this research, we successfully fabricated PLLA/C/Ag membranes that possess properties of antioxidants, antibacterial agents and anti-inflammatory agents, which can aid in the process of wound healing. Modulating wound inflammation, these new PLLA/C/Ag membranes serve as a novel dressing to enhance the healing of diabetic wounds.

Background: Diabetic chronic wounds are among the most common and serious complications of diabetes and are associated with significant morbidity and mortality. Endothelial-to-mesenchymal transition (EndMT) is a specific pathological state in which endothelial cells are transformed into mesenchymal cells in response to various stimuli, such as high glucose levels and high oxidative stress. Acidic fibroblast growth factor (aFGF), which is a member of the fibroblast growth factor family, possesses strong antioxidant properties and can promote the differentiation of mesenchymal stem cells into angiogenic cells. Therefore, we investigated the role of aFGF in EndMT in diabetic wounds and analysed the underlying mechanisms. Methods: A diabetic mouse model was used to verify the effect of aFGF on wound healing, and the effect of aFGF on vascular endothelial cells in a high-glucose environment was examined in vitro. We examined the expression of miR-155-5p in a high-glucose environment and the miR-155 downstream target gene SIRT1 by luciferase reporter assays. Results: aFGF promoted wound closure and neovascularization in a mouse model of type 2 diabetes. In vitro, aFGF inhibited the production of total and mitochondrial reactive oxygen species (ROS) in vascular endothelial cells and alleviated epithelial–mesenchymal transdifferentiation in a high-glucose environment. Mechanistically, aFGF promoted the expression of SIRT1 and the downstream targets Nrf2 and HO-1 by negatively regulating miR-155-5p, thereby reducing ROS generation. Conclusions: In conclusion, our results suggest that aFGF inhibits ROS-induced epithelial–mesenchymal transdifferentiation in diabetic vascular endothelial cells via the miR-155-5p/SIRT1/Nrf2/HO-1 axis, thereby promoting wound healing.

Background: It is challenging to repair wide or irregular defects with traditional skin flaps, and anterolateral thigh (ALT) lobulated perforator flaps are an ideal choice for such defects. However, there are many variations in perforators, so good preoperative planning is very important. This study attempted to explore the feasibility and clinical effect of digital technology in the use of ALT lobulated perforator flaps for repairing complex soft tissue defects in limbs. Methods: Computed tomography angiography (CTA) was performed on 28 patients with complex soft tissue defects of the limbs, and the CTA data were imported into Mimics 20.0 software in DICOM format. According to the perforation condition of the lateral circumflex femoral artery and the size of the limb defect, one thigh that had two or more perforators from the same source vessel was selected for 3D reconstruction of the ALT lobulated perforator flap model. Mimics 20.0 software was used to visualize the vascular anatomy, virtual design and harvest of the flap before surgery. The intraoperative design and excision of the ALT lobulated perforator flap were guided by the preoperative digital design, and the actual anatomical observations and measurements were recorded. Results: Digital reconstruction was successfully performed in all patients before surgery; this reconstruction dynamically displayed the anatomical structure of the flap vasculature and accu-rately guided the design and harvest of the flap during surgery. The parameters of the harvested flaps were consistent with the preoperative parameters. Postoperative complications occurred in 7 patients, but all flaps survived uneventfully. All of the donor sites were closed directly. All patients were followed up for 13–27 months (mean, 19.75 months). The color and texture of each flap were satisfactory and each donor site exhibited a linear scar. Conclusions: Digital technology can effectively and precisely assist in the design and harvest of ALT lobulated perforator flaps, provide an effective approach for individualized evaluation and flap design and reduce the risk and difficulty of surgery.

The hypoxic environment is among the most important factors that complicates the healing of chronic wounds, such as venous leg ulcers, pressure injuries and diabetic foot ulcers, which seriously affects the quality of life of patients. Various oxygen supply treatments are used in clinical practice to improve the hypoxic environment at the wound site. However, problems still occur, such as insufficient oxygen supply, short oxygen infusion time and potential biosafety risks. In recent years, artificial photosynthetic systems have become a research hotspot in the fields of materials and energy. Photosynthesis is expected to improve the oxygen level at wound sites and promote wound healing because the method provides a continuous oxygen supply and has good biosafety. In this paper, oxygen treatment methods for wounds are reviewed, and the oxygen supply principle and construction of artificial photosynthesis systems are described. Finally, research progress on the photosynthetic oxygen production system to promote wound healing is summarized.

The unique ability of piezoelectric materials to generate electricity spontaneously has attracted widespread interest in the medical field. In addition to the ability to convert mechanical stress into electrical energy, piezoelectric materials offer the advantages of high sensitivity, stability, accuracy and low power consumption. Because of these characteristics, they are widely applied in devices such as sensors, controllers and actuators. However, piezoelectric materials also show great potential for the medical manufacturing of artificial organs and for tissue regeneration and repair applications. For example, the use of piezoelectric materials in cochlear implants, cardiac pacemakers and other equipment may help to restore body function. Moreover, recent studies have shown that electrical signals play key roles in promoting tissue regeneration. In this context, the application of electrical signals generated by piezoelectric materials in processes such as bone healing, nerve regeneration and skin repair has become a prospective strategy. By mimicking the natural bioelectrical environment, piezoelectric materials can stimulate cell proliferation, differentiation and connection, thereby accelerating the process of self-repair in the body. However, many challenges remain to be overcome before these concepts can be applied in clinical practice, including material selection, biocompatibility and equipment design. On the basis of the principle of electrical signal regulation, this article reviews the definition, mechanism of action, classification, preparation and current biomedical applications of piezoelectric materials and discusses opportunities and challenges for their future clinical translation.

Background: Chronic skin wounds are a leading cause of hospital admissions and reduced life expectancy among older people and individuals with diabetes. Delayed wound healing is often attributed to a series of cellular abnormalities. Matrine, a well-studied component found in Sophora flavescens, is recognized for its anti-inflammatory effects. However, its impact on wound healing still remains uncertain. This study aims to explore the potential of matrine in promoting wound healing. Methods: In this study, we utilized gradient extrusion to produce fibroblast-derived exosome-mimetic vesicles as carriers for matrine (MHEM). MHEM were characterized using transmission electron microscopy and dynamic light scattering analysis. The therapeutic effect of MHEM in wound healing was explored in vitro and in vivo. Results: Both matrine and MHEM enhanced the cellular activity as well as the migration of fibroblasts and keratinocytes. The potent anti-inflammatory effect of matrine diluted the inflammatory response in the vicinity of wounds. Furthermore, MHEM worked together to promote angiogenesis and the expression of transforming growth factor β and collagen I. MHEM contained growth factors of fibroblasts that regulated the functions of fibroblasts, keratinocytes and monocytes, which synergistically promoted wound healing with the anti-inflammatory effect of matrine. Conclusions: MHEM showed enhanced therapeutic efficacy in the inflammatory microenvironment, for new tissue formation and angiogenesis of wound healing.

Background: Platelets play a critical role in hemostasis and inflammatory diseases. Low platelet count and activity have been reported to be associated with unfavorable prognosis. This study aims to explore the relationship between dynamics in platelet count and in-hospital morality among septic patients and to provide real-time updates on mortality risk to achieve dynamic prediction. Methods: We conducted a multi-cohort, retrospective, observational study that encompasses data on septic patients in the eICU Collaborative Research Database (eICU-CRD) and the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. The joint latent class model (JLCM) was utilized to identify heterogenous platelet count trajectories over time among septic patients. We assessed the association between different trajectory patterns and 28-day in-hospital mortality using a piecewise Cox hazard model within each trajectory. We evaluated the performance of our dynamic prediction model through area under the receiver operating characteristic curve, concordance index (C-index), accuracy, sensitivity, and specificity calculated at predefined time points. Results: Four subgroups of platelet count trajectories were identified that correspond to distinct in-hospital mortality risk. Including platelet count did not significantly enhance prediction accuracy at early stages (day 1 C-indexDynamic vs C-indexWeibull: 0.713 vs 0.714). However, our model showed superior performance to the static survival model over time (day 14 C-indexDynamic vs C-indexWeibull: 0.644 vs 0.617). Conclusions: For septic patients in an intensive care unit, the rapid decline in platelet counts is a critical prognostic factor, and serial platelet measures are associated with prognosis.

Background: Due to vasculature injury and increased oxygen consumption, the early wound microenvironment is typically in a hypoxic state. We observed enhanced cell migration ability under early short-term hypoxia. CCL2 belongs to the CC chemokine family and was found to be increased in early hypoxic wounds and enriched in the extracellular signal-regulated kinase (ERK)1/2 pathway in our previous study. However, the underlying mechanism through which the CCL2-ERK1/2 pathway regulates wound healing under early short-term hypoxia remains unclear. Activation of epithelial–mesenchymal transition (EMT) is a key process in cancer cell metastasis, during which epithelial cells acquire the characteristics of mesenchymal cells and enhance cell motility and migration ability. However, the relationship between epithelial cell migration and EMT under early short-term hypoxia has yet to be explored. Methods: HaCaT cells were cultured to verify the effect of early short-term hypoxia on migration through cell scratch assays. Lentiviruses with silenced or overexpressed CCL2 were used to explore the relationship between CCL2 and migration under short-term hypoxia. An acute full-thickness cutaneous wound rat model was established with the application of an ERK inhibitor to reveal the hidden role of the ERK1/2 pathway in the early stage of wound healing. The EMT process was verified in all the above experiments through western blotting. Results: In our study, we found that short-term hypoxia promoted cell migration. Mechanistically, hypoxia promoted cell migration through mediating CCL2. Overexpression of CCL2 via lentivirus promoted cell migration, while silencing CCL2 via lentivirus inhibited cell migration and the production of related downstream proteins. In addition, we found that CCL2 was enriched in the ERK1/2 pathway, and the application of an ERK inhibitor in vivo and in vitro verified the upstream and downstream relationships between the CCL2 pathway and ERK1/2. Western blot results both in vivo and in vitro demonstrated that early short-term hypoxia promotes epidermal cell migration by activating the CCL2-ERK1/2 pathway and EMT during wound healing. Conclusions: Our work demonstrated that hypoxia in the early stage serves as a stimulus for triggering wound healing through activating the CCL2-ERK1/2 pathway and EMT, which promote epidermal cell migration and accelerate wound closure. These findings provide additional detailed insights into the mechanism of wound healing and new targets for clinical treatment.

Background: Bacterial infections pose a considerable threat to skin wounds, particularly in the case of challenging-to-treat diabetic wounds. Systemic antibiotics often struggle to penetrate deep wound tissues and topically applied antibiotics may lead to sensitization, necessitating the development of novel approaches for effectively treating germs in deep wound tissues. Neutrophils, the predominant immune cells in the bloodstream, rapidly release an abundance of molecules via degranulation upon activation, which possess the ability to directly eliminate pathogens. This study was designed to develop novel neutrophil cell engineered nanovesicles (NVs) with high production and explore their bactericidal properties and application in promoting infectious wound healing. Methods: Neutrophils were isolated from peripheral blood and activated in vitro via phorbol myristate acetate (PMA) stimulation. Engineered NVs were prepared by sequentially extruding activated neutrophils followed by ultracentrifugation and were compared with neutrophil-derived exosomes in terms of morphology, size distribution and protein contents. The bactericidal effect of NVs in vitro was evaluated using the spread plate technique, LIVE/DEAD backlight bacteria assay and observation of bacterial morphology. The therapeutic effects of NVs in vivo were evaluated using wound contraction area measurements, histopathological examinations, assessments of inflammatory factors and immunochemical staining. Results: Activated neutrophils stimulated with PMA in vitro promptly release a substantial amount of bactericidal proteins. NVs are similar to exosomes in terms of morphology and particle size, but they exhibit a significantly higher enrichment of bactericidal proteins. In vitro, NVs demonstrated a significant bactericidal effect, presumably mediated by the enrichment of bactericidal proteins such as lysozyme. These NVs significantly accelerated wound healing, leading to a marked reduction in bacterial load, downregulation of inflammatory factors and enhanced collagen deposition in a full-thickness infectious skin defect model. Conclusions: We developed engineered NVs derived from activated neutrophils to serve as a novel debridement method targeting bacteria in deep tissues, ultimately promoting infectious wound healing.

Burns are an underestimated serious injury negatively impacting survivors physically, psychologically and economically, and thus are a considerable public health burden. Despite significant advancements in burn treatment, many burns still do not heal or develop serious complications/sequelae. The nucleotide-binding oligomerization domain-like receptors (NLRs) family pyrin domain-containing 3 (NLRP3) inflammasome is a critical regulator of wound healing, including burn wound healing. A better understanding of the pathophysiological mechanism underlying the healing of burn wounds may help find optimal therapeutic targets to promote the healing of burn wounds, reduce complications/sequelae following burn, and maximize the restoration of structure and function of burn skin. This review aimed to summarize current understanding of the roles and regulatory mechanisms of the NLRP3 inflammasome in burn wound healing, as well as the preclinical studies of the involvement of NLRP3 inhibitors in burn treatment, highlighting the potential application of NLRP3-targeted therapy in burn wounds.

The healing process at a wound is made up of many types of cells, growth factors, the extracellular matrix, nerves and blood vessels all interacting with each other in complex and changing ways. Microbial colonization and proliferation are possible at the place of injury, which makes infection more likely. Because of this, any cut has a chance of getting an infection. Researchers have found that wound infections make patients more upset and cost the healthcare system a lot of money. Surgical site infections happen a lot to people who have recently had surgery. This study shows that such surgical infection is linked to a high rate of illness and death. This is shown by the fact that 25% of patients get serious sepsis and need to be transferred to an intensive care unit. In both animal models and people, mesenchymal stem cells (MSCs) play an active role in all stages of wound healing and have positive effects. Exosomes are one of the main things MSCs release. They have effects that are similar to those of the parent MSCs. Various effector proteins, messenger RNA and microRNAs can be transported by extracellular vesicles to control the activity of target cells. This has a big impact on the healing process. These results suggest that using MSC-exosomes as a new type of cell-free therapy could be a better and safer option than whole cell therapy. This review is mostly about how to use parts of MSC-exosomes to help wound infections heal.

Integrins are heterodimers composed of α and β subunits that are bonded through non-covalent interactions. Integrins mediate the dynamic connection between extracellular adhesion molecules and the intracellular actin cytoskeleton. Integrins are present in various tissues and organs where these heterodimers participate in diverse physiological and pathological responses at the molecular level in living organisms. Wound healing is a crucial process in the recovery from traumatic diseases and comprises three overlapping phases: inflammation, proliferation and remodeling. Integrins are regulated during the entire wound healing process to enhance processes such as inflammation, angiogenesis and re-epithelialization. Prolonged inflammation may result in failure of wound healing, leading to conditions such as chronic wounds. Bacterial colonization of a wound is one of the primary causes of chronic wounds. Integrins facilitate the infectious effects of bacteria on the host organism, leading to chronic inflammation, bacterial colonization, and ultimately, the failure of wound healing. The present study investigated the role of integrins as bridges for bacteria–cell interactions during wound healing, evaluated the role of integrins as nodes for bacterial inhibition during chronic wound formation, and discussed the challenges and prospects of using integrins as therapeutic targets in wound healing.

Diabetic foot ulcer (DFU), characterized by high recurrence rate, amputations and mortality, poses a significant challenge in diabetes management. The complex pathology involves dysregulated glucose homeostasis leading to systemic and local microenvironmental complications, including peripheral neuropathy, micro-and macro-angiopathy, recurrent infection, persistent inflammation and dysregulated re-epithelialization. Novel approaches to accelerate DFU healing are actively pursued, with a focus on utilizing exosomes. Exosomes are natural nanovesicles mediating cellular communication and containing diverse functional molecular cargos, including DNA, mRNA, microRNA (miRNA), lncRNA, proteins, lipids and metabolites. While some exosomes show promise in modulating cellular function and promoting ulcer healing, their efficacy is limited by low yield, impurities, low loading content and inadequate targeting. Engineering exosomes to enhance their curative activity represents a potentially more efficient approach for DFUs. This could facilitate focused repair and regeneration of nerves, blood vessels and soft tissue after ulcer development. This review provides an overview of DFU pathogenesis, strategies for exosome engineering and the targeted therapeutic application of engineered exosomes in addressing critical pathological changes associated with DFUs.

Background: Keloid scarring is caused by a fibroproliferative disorder due to abnormal activation of genes, the underlying mechanism of which is still unclear. The basic helix–loop–helix transcription factor Twist-related protein 1 (TWIST1) controls cell proliferation and differentiation in tissue development and disease processes. In this study, we aimed to clarify the essential role of TWIST1 in the pathogenesis of keloids. Methods: Immunohistochemistry, cell counting kit-8 assays, western blotting, PCR, matrigel invasion assays and immunofluorescence assays were applied to demonstrate the effects and mechanisms of TWIST1 in fibroblasts derived from normal skin and keloids. Mass spectrometry, ubiquitination assays, chromatin immunoprecipitation and dual luciferase reporter assay were applied to explore the interaction of TWIST1 with downstream molecules. Results: In the present study, we confirmed that TWIST1 was upregulated in keloid tissue of patients and in keloid-derived fibroblasts (KFBs). In vitro, TWIST1 inhibition prevented KFB proliferation, invasion and activation. We also discovered a link between TWIST1 and the transforming growth factor β (TGF-β) signaling related molecules TGF-β receptor 1 (TBR1), SMAD family member 2 (Smad2) and Smad3, and the fibrosis markers α-smooth muscle actin, collagen type I and collagen type III in KFBs. Mechanistically, we uncovered a brand-new mechanism by which TWIST1 interacts with myocyte enhancer factor 2A (MEF2A) and suppresses its ubiquitination and degradation. Using chromatin immunoprecipitation and dual-luciferase reporter assay, TBR1 was identified as a novel downstream target of MEF2A, which directly binds to its promoter. Overexpression of TWIST1 promoted the recruitment of MEF2A to the TBR1 promoter and restored TBR1 functional expression. Conclusions: Our research highlights a significant function of TWIST1 in the development of keloid and its related fibroblasts, partially facilitated by elevated MEF2A-dependent TBR1 expression. Blocking the expression of TWIST1 in KFBs could potentially pave a novel therapeutic avenue for keloid treatment.

Background: Wound healing has always been a serious issue for doctors and primary health care systems. In addition, adipose stem cell-derived exosomes have been proven to play a positive and effective role in tissue repair and regeneration. A systematic review of these preclinical studies was performed to assess the efficacy of adipose stem cell-derived exosomes (ADSC-Exos) in treating wounds. This article aimed to study the effectiveness of ADSC-Exos for the treatment of animal skin wounds and includes a meta-analysis of exosomes from general wounds and diabetic ulcer wounds in in vitro models of animals to provide a theoretical basis for clinical translation. Methods: A total of 19 studies with 356 animals were identified by searching the PubMed, Cochrane, MEDLINE Complete, Web of Science, CNKI and Wanfang databases from inception to 15 November 2022. No language or time restrictions were applied. Stata17 was used for all the data analyses. Results: The meta-analysis showed that ADSC-Exo therapy significantly improved the wound healing rate in the control group, except in the diabetes group on day 7. Day 7 of general wounds [standard mean difference (SMD) 2.87, 95% confidence interval (CI) 1.91–3.83)] and day 14 (SMD 2.89, 95%CI 1.47–4.30). Day 14 (SMD 3.43, 95%CI 1.28–5.58) of diabetic wounds. Other outcomes, such as blood vessel density, collagen deposition and wound re-epithelization, improved with the administration of ADSC-Exos. Conclusions: A meta-analysis showed that ADSC-Exo therapy applied to general and diabetic wounds can promote neovascularization, improve epithelization and collagen fiber deposition, promote healing, and reduce scar formation. ADSC-Exos have broad potential in preclinical research and clinical fields.

Background: Wound haemostasis is an important part of clinical treatments, especially treatments for patients with avulsion injury, destructive injury and large-scale soft tissue injury. Therefore, developing fast and effective haemostatic materials is critical. This study aimed to design a novel and efficient silk fibroin–gelatine composite haemostatic sponge loaded with thrombin (SFG@TB) to assist in wound haemostasis. Methods: The SFG@TB composite haemostatic sponge was formed with gelatine, silk fibroin and thrombin through a freeze-drying technique. First, the material characteristics of SFG@TB were measured, including the elastic modulus, swelling rate and porosity. Second, in vitro cell coculture experiments, in vivo embedding experiments and haemolytic analyses were performed to evaluate the biocompatibility of SFG@TB. Then, coagulation experiments and femoral artery and liver bleeding models were used to evaluate the haemostatic performance of SFG@TB. Finally, the ability of SFG@TB to promote tissue healing was evaluated through experiments with Sprague–Dawley rat models of injury. Results: Compared with gelatine sponges, SFG@TB exhibited outstanding mechanical properties and water absorption properties. In addition, the excellent biosafety of the composite haemostatic sponge was confirmed by cell experiments, subcutaneous embedding experiments and haemolytic analysis. Based on the in vitro coagulation test results, SFG@TB exhibited greater adhesion of red blood cells and platelets and a shorter dynamic coagulation time. Compared to the use of silk fibroin–gelatine composite haemostatic sponges or gelatine sponges, the introduction of thrombin resulted in a shorter haemostasis time and a smaller bleeding volume, as revealed by in vivo coagulation tests. The experiments with Sprague–Dawley rat models of injury indicated that SFG@TB accelerated the wound healing process and reduced scar width, which was accompanied by thicker granulation tissue. Conclusions: Overall, the SFG@TB composite haemostatic sponge, which exhibits outstanding mechanical properties, good haemostatic performance and high biosafety, promoted wound haemostasis and tissue repair. Therefore, the SFG@TB composite haemostatic sponge could be a promising material for wound haemostasis.

Background: There is controversy over the optimal early protein delivery in critically ill patients with acute kidney injury (AKI). This study aims to evaluate whether the association between early protein delivery and 28-day mortality was impacted by the presence of AKI in critically ill patients. Methods: This is a post hoc analysis of data from a multicenter cluster-randomised controlled trial enrolling newly admitted critically ill patients (n = 2772). Participants without chronic kidney disease and with complete data concerning baseline renal function were included in this study. The primary outcome was 28-day mortality. Cox proportional hazards models were used to analyze the association between early protein delivery, reflected by mean protein delivery from day 3–5 after enrollment, 28-day mortality and whether baseline AKI stages interacted with this association. Results: Overall, 2552 patients were included, among whom 567 (22.2%) had AKI at enrollment (111 stage I, 87 stage II, 369 stage III). Mean early protein delivery was 0.60 ± 0.38 g/kg/day among the study patients. In the overall study cohort, each 0.1 g/kg/day increase in protein delivery was associated with a 5% reduction in 28-day mortality[hazard ratio (HR) = 0.95; 95% confidence interval (CI) 0.92–0.98, p < 0.001]. The association between early protein delivery and 28-day mortality significantly interacted with baseline AKI stages (adjusted interaction p = 0.028). Each 0.1 g/kg/day increase in early protein delivery was associated with a 4% reduction in 28-day mortality (HR = 0.96; 95%CI 0.92–0.99, p = 0.011) among patients without AKI and 9% (HR = 0.91; 95%CI 0.84–0.99, p = 0.021) among those with AKI stage III. However, such associations cannot be observed among patients with AKI stages I and II. Conclusions: Increased early protein delivery (up to close to the guideline recommendation) was associated with reduced 28-day mortality in critically ill patients without AKI and with AKI stage III, but not in those with AKI stage I or II.

Background: We previously confirmed that mechanical stimulation is an important factor in the repair of tendon–bone insertion (TBI) injuries and that mechanoreceptors such as transient receptor potential ion-channel subfamily V member 4 (TRPV4; also known as transient receptor potential vanilloid 4) are key to transforming mechanical stimulation into intracellular biochemical signals. This study aims to elucidate the mechanism of mechanical stimulation regulating TRPV4. Methods: Immunohistochemical staining and western blotting were used to evaluate cartilage repair at the TBI after injury. The RNA expression and protein expression of mechanoreceptors and key pathway molecules regulating cartilage proliferation were analyzed. TBI samples were collected for transcriptome sequencing to detect gene expression. Calcium-ion imaging and flow cytometry were used to evaluate the function of TPRV4 and cellular communication network factor 2 (CCN2) after the administration of siRNA, recombinant adenovirus and agonists. Results: We found that treadmill training improved the quality of TBI healing and enhanced fibrochondrocyte proliferation. The transcriptome sequencing results suggested that the elevated expression of the mechanistically stimulated regulator CCN2 and the exogenous administration of recombinant human CCN2 significantly promoted TRPV4 protein expression and fibrochondrocyte proliferation. In vitro, under mechanical stimulation conditions, small interfering RNA (siRNA)-CCN2 not only inhibited the proliferation of primary fibrochondrocytes but also suppressed TRPV4 protein expression and activity. Subsequently, primary fibrochondrocytes were treated with the TRPV4 agonist GSK1016790A and the recombinant adenovirus TRPV4 (Ad-TRPV4), and GSK1016790A partially reversed the inhibitory effect of siRNA-CCN2. The phosphoinositide 3-kinase/ protein kinase B (PI3K/AKT) signaling pathway participated in the above process. Conclusions: Mechanical stimulation promoted fibrochondrocyte proliferation and TBI healing by activating TRPV4 channels and the PI3K/AKT signaling pathway, and CCN2 may be a key regulatory protein in maintaining TRPV4 activation.

Background: Acute kidney injury (AKI) is a common surgical complication and is associated with intraoperative hypotension. However, the total duration and magnitude of intraoperative hypotension associated with AKI remains unknown. In this study, the causal relationship between the intraoperative arterial pressure and postoperative AKI was investigated among chronic hyper-tension patients undergoing non-cardiac surgery. Methods: A retrospective cohort study of 6552 hypertension patients undergoing non-cardiac surgery (2011 to 2019) was conducted. The primary outcome was AKI as diagnosed with the Kidney Disease-Improving Global Outcomes criteria and the primary exposure was intraoperative hypotension. Patients’ baseline demographics, pre-and post-operative data were harvested and then analyzed with multivariable logistic regression to assess the exposure–outcome relationship. Results: Among 6552 hypertension patients, 579 (8.84%) had postoperative AKI after non-cardiac surgery. The proportions of patients admitted to ICU (3.97 vs. 1.24%, p < 0.001) and experiencing all-cause death (2.76 vs. 0.80%, p < 0.001) were higher in the patients with postoperative AKI. More-over, the patients with postoperative AKI had longer hospital stays (13.50 vs. 12.00 days, p < 0.001). Intraoperative mean arterial pressure (MAP) < 60 mmHg for >20 min was an independent risk factor of postoperative AKI. Furthermore, MAP <60 mmHg for >10 min was also an independent risk factor of postoperative AKI in patients whose MAP was measured invasively in the subgroup analysis. Conclusions: Our work suggested that MAP < 60 mmHg for >10 min measured invasively or 20 min measured non-invasively during non-cardiac surgery may be the threshold of postoperative AKI development in hypertension patients. This work may serve as a perioperative management guide for chronic hypertension patients. Trial registration: clinical trial number: ChiCTR2100050209 (8/22/2021). http://www.chictr.org.cn/showproj.aspx?proj=132277.

Diabetic wounds are among the most common complications of diabetes mellitus and their healing process can be delayed due to persistent inflammatory reactions, bacterial infections, damaged vascularization and impaired cell proliferation, which casts a blight on patients’ health and quality of life. Therefore, new strategies to accelerate diabetic wound healing are being positively explored. Exosomes derived from mesenchymal stem cells (MSC-Exos) can inherit the therapeutic and reparative abilities of stem cells and play a crucial role in diabetic wound healing. However, poor targeting, low concentrations of therapeutic molecules, easy removal from wounds and limited yield of MSC-Exos are challenging for clinical applications. Bioengineering techniques have recently gained attention for their ability to enhance the efficacy and yield of MSC-Exos. In this review, we summarise the role of MSC-Exos in diabetic wound healing and focus on three bioengineering strategies, namely, parental MSC-Exos engineering, direct MSC-Exos engineering and MSC-Exos combined with biomaterials. Furthermore, the application of bioengineered MSC-Exos in diabetic wound healing is reviewed. Finally, we discuss the future prospects of bioengineered MSC-Exos, providing new insights into the exploration of therapeutic strategies.

Background: Diagnosing sternal wound infection (SWI) following median sternotomy remains laborious and troublesome, resulting in high mortality rates and great harm to patients. Early intervention and prevention are critical and challenging. This study aimed to develop a simple risk prediction model to identify high-risk populations of SWI and to guide examination programs and intervention strategies. Methods: A retrospective analysis was conducted on the clinical data obtained from 6715 patients who underwent median sternotomy between January 2016 and December 2020. The least absolute shrink and selection operator (LASSO) regression method selected the optimal subset of predictors, and multivariate logistic regression helped screen the significant factors. The nomogram model was built based on all significant factors. Area under the curve (AUC), calibration curve and decision curve analysis (DCA) were used to assess the model’s performance. Results: LASSO regression analysis selected an optimal subset containing nine predictors that were all statistically significant in multivariate logistic regression analysis. Independent risk factors of SWI included female [odds ratio (OR) = 3.405, 95% confidence interval (CI) = 2.535–4.573], chronic obstructive pulmonary disease (OR = 4.679, 95% CI = 2.916–7.508), drinking (OR = 2.025, 95% CI = 1.437–2.855), smoking (OR = 7.059, 95% CI = 5.034–9.898), re-operation (OR = 3.235, 95% CI = 1.087–9.623), heart failure (OR = 1.555, 95% CI = 1.200–2.016) and repeated endotracheal intubation (OR = 1.975, 95% CI = 1.405–2.774). Protective factors included bone wax (OR = 0.674, 95% CI = 0.538–0.843) and chest physiotherapy (OR = 0.446, 95% CI = 0.248–0.802). The AUC of the nomogram was 0.770 (95% CI = 0.745–0.795) with relatively good sensitivity (0.798) and accuracy (0.620), exhibiting moderately good discernment. The model also showed an excellent fitting degree on the calibration curve. Finally, the DCA presented a remarkable net benefit. Conclusions: A visual and convenient nomogram-based risk calculator built on disease-associated predictors might help clinicians with the early identification of high-risk patients of SWI and timely intervention.

Background: Sepsis-induced acute lung injury (ALI) leads to severe hypoxemia and respiratory failure, contributing to poor prognosis in septic patients. Endotoxin dissemination triggers oxidative stress and the release of inflammatory cytokines in macrophages, initiating diffuse alveolar damage. The role of epigenetic histone modifications in organ injury is increasingly recognized. The present study aimed to investigate the use of a histone modification inhibitor to alleviate sepsis-induced ALI, revealing a new strategy for improving sepsis patient survival. Methods: In vivo models of ALI were established through the intraperitoneal injection of lipopolysaccharide and cecal ligation and puncture surgery. Furthermore, the disease process was simulated in vitro by stimulating Tamm-Horsfall protein-1 (THP-1) cells with lipopolysaccharide. Hematoxylin and eosin staining, blood gas analysis and pulmonary function tests were utilized to assess the extent of lung tissue damage. Western blot analysis, real-time polymerase chain reaction, enzyme-linked immunosorbent assay and immunofluorescence were used to measure the levels and distribution of the indicated indicators within cells and tissues. Reactive oxygen species and autophagic flux alterations were detected using specific probes. Results: BRD3308, which is a inhibitor of histone deacetylase 3, improved lung tissue damage, inflammatory infiltration and edema in ALI by inhibiting Nod-like receptor protein3-mediated pyroptosis in macrophages. By upregulating autophagy, BRD3308 improved the disruption of redox balance in macrophages and reduced the accumulation of reactive oxygen species. Mechanistically, BRD3308 inhibited histone deacetylase 3 activity by binding to it and altering its conformation. Following histone deacetylase 3 inhibition, acetylation of H3K27 was significantly increased. Moreover, the increase in H3K27Ac led to the upregulation of autophagy-related gene 5, a key component of autophagosomes, thereby activating autophagy. Conclusions: BRD3308 inhibits oxidative stress and pyroptosis in macrophages by modulating histone acetylation, thereby preventing sepsis-induced ALI. The present study provides a potential strategy and theoretical basis for the clinical treatment of sepsis-induced ALI.

Background: There are various treatment modalities for chronic subdural hematoma (CSDH) and there is extensive debate surrounding pharmaceutical interventions. There is no consensus regarding the relative efficacy and safety of multiple treatment modalities. This study aims to investigate this issue and offer potential clinical recommendations. Methods: We searched PubMed, Web of Science, Embase and the Cochrane Library from January 2000 to May 2023 to identify randomized and nonrandomized controlled studies reporting one or more outcomes associated with the pharmacologic management of CSDH. The primary outcomes of interest included recurrence, favorable prognosis and adverse events, while the secondary outcomes included a reduction in hematoma volume and mortality. Pooled estimates, credible intervals and odds ratios were calculated for all outcomes using a fixed effects model. Confidence in network meta-analysis judgments were employed to stratify the evidential quality. This study was registered with PROSPERO: CRD42023406599. Results: The search strategy yielded 656 references; ultimately, 36 studies involving 8082 patients fulfilled our predefined inclusion criteria. The findings suggested that statins + glucocorticoids (GCs) ranked highest for preventing recurrence, improving prognosis and facilitating hematoma absorption. Tranexamic acid ranked second highest for preventing recurrence. Statins were found to be the preferred drug intervention for decreasing mortality and preventing adverse events. Antithrombotic agents ranked lowest in terms of decreasing mortality and improving prognosis. Conclusions: Our findings indicate that statins + GCs may be the most effective treatment modality for preventing recurrence, improving patient prognosis and facilitating hematoma absorption. In terms of reducing mortality and preventing adverse events, statins may be superior to other pharmacological interventions. Routine use of GCs is not suggested for patients with CSDH. Further prospective research is needed to directly compare the efficacy and superiority of various pharmaceutical interventions targeting CSDH to reinforce and validate our findings.

Background: Ensuring the survival of the distal end of a random flap during hypoperfusion (ischaemia) is difficult in clinical practice. Effective prevention of programmed cell death is a potential strategy for inhibiting ischaemic flap necrosis. The activation of stimulator of interferon genes (STING) pathway promotes inflammation and leads to cell death. The epidermal growth factor family member neuregulin-1 (NRG1) reduces cell death by activating the protein kinase B (AKT) signalling pathway. Moreover, AKT signalling negatively regulates STING activity. We aimed to verify the efficacy of NRG1 injection in protecting against flap necrosis. Additionally, we investigated whether NRG1 effectively enhances ischemic flap survival by inhibiting pyroptosis and necroptosis through STING suppression. Methods: A random-pattern skin flap model was generated on the backs of C57BL/6 mice. The skin flap survival area was determined. The blood supply and vascular network of the flap was assessed by laser Doppler blood flow analysis. Cluster of differentiation 34 immunohistochemistry (IHC) and haematoxylin and eosin (H&E) staining of the flap sections revealed microvessels. Transcriptome sequencing analysis revealed the mechanism by which NRG1 promotes the survival of ischaemic flaps. The levels of angiogenesis, oxidative stress, necroptosis, pyroptosis and indicators associated with signalling pathways in flaps were examined by IHC, immunofluorescence and Western blotting. Packaging adeno-associated virus (AAV) was used to activate STING in flaps. Results: NRG1 promoted the survival of ischaemic flaps. An increased subcutaneous vascular network and neovascularization were found in ischaemic flaps after the application of NRG1. Transcriptomic gene ontology enrichment analysis and protein level detection indicated that necroptosis, pyroptosis and STING activity were reduced in the NRG1 group. The phosphorylation of AKT and forkhead box O3a (FOXO3a) were increased after NRG1 treatment. The increased expression of STING in flaps induced by AAV reversed the therapeutic effect of NRG1. The ability of NRG1 to phosphorylate AKT-FOXO3a, inhibit STING and promote flap survival was abolished after the application of the AKT inhibitor MK2206. Conclusions: NRG1 inhibits pyroptosis and necroptosis by activating the AKT-FOXO3a signalling pathway to suppress STING activation and promote ischaemic flap survival.

Critical-sized bone defects represent a significant clinical challenge due to their inability to undergo spontaneous regeneration, necessitating graft interventions for effective treatment. The development of tissue-engineered scaffolds and regenerative medicine has made bone tissue engineering a highly viable treatment for bone defects. The physical and biological properties of nanocomposite biomaterials, which have optimized structures and the ability to simulate the regenerative microenvironment of bone, are promising for application in the field of tissue engineering. These biomaterials offer distinct advantages over traditional materials by facilitating cellular adhesion and proliferation, maintaining excellent osteoconductivity and biocompatibility, enabling precise control of degradation rates, and enhancing mechanical properties. Importantly, they can simulate the natural structure of bone tissue, including the specific microenvironment, which is crucial for promoting the repair and regeneration of bone defects. This manuscript provides a comprehensive review of the recent research developments and applications of structure-optimized and microenvironment-inspired nanocomposite biomaterials in bone tissue engineering. This review focuses on the properties and advantages these materials offer for bone repair and tissue regeneration, summarizing the latest progress in the application of nanocomposite biomaterials for bone tissue engineering and highlighting the challenges and future perspectives in the field. Through this analysis, the paper aims to underscore the promising potential of nanocomposite biomaterials in bone tissue engineering, contributing to the informed design and strategic planning of next-generation biomaterials for regenerative medicine.

Background: Calvatia gigantea (CG) is widely used as a traditional Chinese medicine for wound treatment. In this study, we aimed to determine the effects of CG extract (CGE) on diabetic wound healing and the commensal wound microbiome. Method: A wound model was established using leptin receptor-deficient db/db mice, with untreated mice as the control group and CGE-treated mice as the treatment group. The wound healing rate, inflammation and histology were analyzed. Additionally, wound microbiome was evaluated via 16S ribosomal RNA (rRNA) gene sequencing. Results: CGE significantly accelerated the healing of diabetic ulcer wounds, facilitated re-epithelialization, and downregulated the transcription levels of the inflammatory cytokines, interleukin-1β and tumor necrosis factor-α. Furthermore, CGE treatment positively affected the wound microbiome, promoting diversity of the microbial community and enrichment of Escherichia-Shigella bacteria in the CGE-treated group. Conclusions: Overall, CGE enhanced diabetic wound healing by modulating the wound microbiome and facilitating macrophage polarization during inflammation. These findings suggest modulation of the commensal wound microbiome using medicinal plants as a potential therapeutic strategy for diabetic wounds.

Background: Bacterial infection, tissue hypoxia and inflammatory response can hinder infected wound repair. This study aimed to develop a multifunctional specific therapeutic photo-activated release nanosystem [HMPB@MB@AuNPs@PMB@HA (HMAPH)] by loading photosensitizer methylene blue (MB) into hollow mesoporous Prussian blue nanostructures and modifying the surface with gold particles, polymyxin B (PMB) and hydrophilic hyaluronic acid. Methods: The HMAPH was characterized using transmission electron microscopy, UV–vis, Fourier-transform infrared spectroscopy, X-ray diffraction and X-ray photon spectroscopy. The photothermal performance, iron ion release and free radical generation of the HMAPH were measured under different conditions to investigate its thermo-responsive cascade reaction. The antibacterial ability of HMAPH was investigated using live/dead fluorescence tests. The morphology and membrane integrity of Pseudomonas aeruginosa (P. aeruginosa) were investigated using transmission electron microscopy. The anti-biofilm activity of HMAPH was evaluated using crystal violet and SYBR Green I staining. Finally, we established a mouse model of a skin wound infected by P. aeruginosa to confirm the in vivo effectiveness of HMAPH. We used immunofluorescent staining, hematoxylin–eosin staining, Masson staining and enzyme-linked immunosorbent assay to examine whether HMAPH promoted wound healing and reduced inflammatory damage. Results: In this study, hyaluronic acid was decomposed under the action of hyaluronidase. Also, the exposed nanomaterials specifically bound to the outer membrane of P. aeruginosa through PMB to increase the membrane sensitivity to photodynamic treatment. Under dual-light irradiation, a large amount of iron ions released by HMAPH underwent a Fenton reaction with H₂O₂ in bacteria to generate hydroxyl radicals (•OH), enabling direct killing of cells by hyperthermia. Additionally, the photodynamic activity of MB released by photo-induced activation led to the generation of reactive oxygen species, achieving synergistic and effective inhibition of P. aeruginosa. HMAPH also inhibited biofilm formation and downregulated the expression of virulence factors. In vivo experiments revealed that HMAPH accelerated the healing of P. aeruginosa-infected wounds by promoting angiogenesis and skin regeneration, inhibiting the inflammatory response and promoting M1 to M2 polarization. Conclusions: Our study proposed a strategy against bacteria and biofilms through a synergistic photothermal–photodynamic–Fenton reaction, opening up new prospects for combating biofilm-associated infections.

Vascularization is a major challenge in the field of tissue engineering and regenerative medicine. Mechanical factors have been demonstrated to play a fundamental role in vasculogenesis and angiogenesis and can affect the architecture of the generated vascular network. Through the regulation of mechanical factors in engineered tissues, various mechanical strategies can be used to optimize the preformed vascular network and promote its rapid integration with host vessels. Optimization of the mechanical properties of scaffolds, including controlling scaffold stiffness, increasing surface roughness and anisotropic structure, and designing interconnected, hierarchical pore structures, is beneficial for the in vitro formation of vascular networks and the ingrowth of host blood vessels. The incorporation of hollow channels into scaffolds promotes the formation of patterned vascular networks. Dynamic stretching and perfusion can facilitate the formation and maturation of preformed vascular networks in vitro. Several indirect mechanical strategies provide sustained mechanical stimulation to engineered tissues in vivo, which further promotes the vascularization of implants within the body. Additionally, stiffness gradients, anisotropic substrates and hollow channels in scaffolds, as well as external cyclic stretch, boundary constraints and dynamic flow culture, can effectively regulate the alignment of vascular networks, thereby promoting better integration of prevascularized engineered tissues with host blood vessels. This review summarizes the influence and contribution of both scaffold-based and external stimulus-based mechanical strategies for vascularization in tissue engineering and elucidates the underlying mechanisms involved.

The cutaneous lymphatic system regulates tissue inflammation, fluid balance and immunological responses. Lymphangiogenesis or lymphatic dysfunction may lead to lymphedema, immune deficiency, chronic inflammation etc. Tissue regeneration and healing depend on angiogenesis and lymphangiogenesis during wound healing. Tissue oedema and chronic inflammation can slow wound healing due to impaired lymphangiogenesis or lymphatic dysfunction. For example, impaired lymphangiogenesis or lymphatic dysfunction has been detected in nonhealing wounds such as diabetic ulcers, venous ulcers and bedsores. This review summarizes the structure and function of the cutaneous lymphatic vessel system and lymphangiogenesis in wounds. Furthermore, we review wound lymphangiogenesis processes and remodelling, especially the influence of the inflammatory phase. Finally, we outline how to control lymphangiogenesis to promote wound healing, assess the possibility of targeting lymphangiogenesis as a novel treatment strategy for chronic wounds and provide an analysis of the possible problems that need to be addressed.

Background: Photodynamic therapy (PDT) is a widely used therapeutic approach for eradicating bacterial biofilms in infected wound, but its effectiveness is limited by the hypoxic environment within the biofilm. This study aimed to investigate whether the efficiency of photodynamic removing biofilm is improving by providing oxygen (O₂), as well as the expression of cytokines involved in infected wound healing. Methods: Manganese dioxide (MnO₂) nanoparticles with catalase-like activity were grown in situ on graphitic phase carbon nitride (g-C₃N₄, CN) nanosheets to construct an all-in-one CN-MnO₂ nanozyme, which was then incorporated into poly-L-lactic acid (PLLA) to prepare CN-MnO₂/PLLA wound dressing by electrospinning. Subsequently, the in vitro antibacterial biofilm ratio and antibacterial ratio of CN-MnO₂/PLLA wound dressing were examined by spread plate and crystal violet staining under irradiation with 808 nm near-infrared light and 660 nm visible light. Meanwhile, the rat skin injury model was established, and hematoxylin and eosin (H&E), Masson’s, tumor necrosis factor-α (TNF-α), Arginase 1 (Arg-1), vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (BFGF) were evaluated in vivo to assess the effect of CN-MnO₂/PLLA wound dressing on wound healing. Results: Biofilm density caused by Staphylococcus aureus and Pseudomonas aeruginosa had elim-ination rates of 83 and 62%, respectively, when treated with CN-MnO₂/PLLA dressing. Additionally, the dressing exhibited high antibacterial efficacy against both bacteria, achieving 99 and 98.7% elimination of Staphylococcus aureus and Pseudomonas aeruginosa, respectively. Furthermore, in vivo experiments showed that the CN-MnO₂/PLLA wound dressing achieved complete healing of infected wounds on Day 14, with a wound healing rate of >99% by increasing collagen deposition, expression of anti-inflammatory cytokine Arg-1, vascularization cytokine VEGF, and epithelial cell BFGF, and inhibiting the expression of inflammatory cytokine TNF-α. Conclusions: The CN-MnO₂/PLLA wound dressing exhibited excellent antibacterial properties in vitro and in vivo. In addition, CN-MnO₂/PLLA wound dressing accelerated rapid wound healing through an anti-inflammatory, pro-vascular regeneration and skin tissue remodeling mechanism.

Background: Our previous research suggested that dexmedetomidine (Dex) promotes autophagy in cardiomyocytes, thus safeguarding them against apoptosis during sepsis. However, the underlying mechanisms of Dex-regulated autophagy have remained elusive. This study aimed to explore the role of exosomes and how they participate in Dex-induced cardioprotection in sepsis. The underlying microRNA (miRNA) mechanisms and possible therapeutic targets for septic myocardial injury were identified. Methods: We first collected plasma exosomes from rats with sepsis induced by caecal ligation and puncture (CLP) with or without Dex treatment, and then incubated them with H9c2 cells to observe the effect on cardiomyocytes. Subsequently, the differential expression of miRNAs in plasma exosomes from each group of rats was identified through miRNA sequencing. miR-29b-3p expression in circulating exosomes of septic or non-septic patients, as well as in lipopolysaccharide-induced macrophages after Dex treatment, was analysed by quantitative real-time polymerase chain reaction (qRT–PCR). The autophagy level of cardiomyocytes after macrophage-derived exosome treatment was assessed by an exosome tracing assay, western blotting, and an autophagic flux assay. Specific miRNA mimics and inhibitors or small interfering RNAs were used to predict and evaluate the function of candidate miRNA and its target genes by qRT-PCR, annexin V/propyl iodide staining, autophagy flux analysis, and western blotting. Results: We found that plasma-derived exosomes from Dex-treated rats promoted cardiomyocyte autophagy and exerted antiapoptotic effects. Additionally, they exhibited a high expression of miRNA, including miR-29b-3p. Conversely, a significant decrease in miR-29b-3p was observed in circulating exosomes from CLP rats, as well as in plasma exosomes from sepsis patients. Furthermore, Dex upregulated the lipopolysaccharide-induced decrease in miR-29b-3p expression in macrophage-derived exosomes. Exosomal miR-29b-3p from macrophages is thought to be transferred to cardiomyocytes, thus leading to the promotion of autophagy in cardiomyocytes. Database predictions, luciferase reporter assays, and small interfering RNA intervention confirmed that glycogen synthase kinase 3β (GSK-3β) is a target of miR-29b-3p. miR-29b-3p promotes cardiomyocyte autophagy by inhibiting GSK-3β expression and activation. Conclusions: These findings demonstrate that Dex attenuates sepsis-associated myocardial injury by modulating exosome-mediated macrophage–cardiomyocyte crosstalk and that the miR-29b-3p/GSK-3β signaling pathway represents a hopeful target for the treatment of septic myocardial injury.

Skin wound healing is a complicated biological process that mainly occurs in response to injury, burns, or diabetic ulcers. It can also be triggered by other conditions such as dermatitis and melanoma-induced skin cancer. Delayed healing or non-healing after skin injury presents an important clinical issue; therefore, further explorations into the occurrence and development of wound healing at the cellular and molecular levels are necessary. Single-cell sequencing (SCS) is used to sequence and analyze the genetic messages of a single cell. Furthermore, SCS can accurately detect cell expression and gene sequences. The use of SCS technology has resulted in the emergence of new concepts pertaining to wound healing, making it an important tool for studying the relevant mechanisms and developing treatment strategies. This article discusses the application value of SCS technology, the effects of the latest research on skin wound healing, and the value of SCS technology in clinical applications. Using SCS to determine potential biomarkers for wound repair will serve to accelerate wound healing, reduce scar formation, optimize drug delivery, and facilitate personalized treatments.

Acute kidney injury (AKI), a common kidney disease in which renal function decreases rapidly due to various etiologic factors, is an important risk factor for chronic kidney disease (CKD). The pathogenesis of AKI leading to CKD is complex, and effective treatments are still lacking, which seriously affects the prognosis and quality of life of patients with kidney disease. Nanomedicine, a discipline at the intersection of medicine and nanotechnology, has emerged as a promising avenue for treating kidney diseases ranging from AKI to CKD. Increasing evidence has validated the therapeutic potential of nanomedicine in AKI; however, little attention has been paid to its effect on AKI for patients with CKD. In this review, we systematically emphasize the major pathophysiology of the AKI-to-CKD transition and summarize the treatment effects of nanomedicine on this transition. Furthermore, we discuss the key role of nanomedicine in the regulation of targeted drug delivery, inflammation, oxidative stress, ferroptosis, and apoptosis during the transition from AKI to CKD. Additionally, this review demonstrates that the integration of nanomedicine into nephrology offers unprecedented precision and efficacy in the management of conditions ranging from AKI to CKD, including the design and preparation of multifunctional nanocarriers to overcome biological barriers and deliver therapeutics specifically to renal cells. In summary, nanomedicine holds significant potential for revolutionizing the management of AKI-to-CKD transition, thereby providing a promising opportunity for the future treatment of kidney diseases.

Background: Intestinal stem cells (ISCs) play a pivotal role in maintaining intestinal homeostasis and facilitating the restoration of intestinal mucosal barrier integrity. Glutamine (Gln) is a crucial energy substrate in the intestine, promoting the proliferation of ISCs and mitigating damage to the intestinal mucosal barrier after burn injury. However, the underlying mechanism has not yet been fully elucidated. The objective of this study was to explore the mechanism by which Gln facilitates the proliferation of ISCs. Methods: A mouse burn model was established to investigate the impact of Gln on intestinal function. Subsequently, crypts were isolated, and changes in TP53-induced glycolysis and apoptosis regulator (TIGAR) expression were assessed using real-time quantitative polymerase chain reaction (RT-qPCR), western blotting, immunohistochemistry, and immunofluorescence. The effects of TIGAR on cell proliferation were validated through CCK-8, EdU, and clonogenicity assays. Furthermore, the effect of TIGAR on Yes-associated protein (YAP) nuclear translocation and ferroptosis was examined by western blotting and immunofluorescence staining. Finally, dot blot analysis and methylation-specific PCR were performed to evaluate the effect of Gln on TIGAR promoter methylation. Results: The mRNA and protein levels of TIGAR decreased after burn injury, and supplementation with Gln increased the expression of TIGAR. TIGAR accelerates the nuclear translocation of YAP, thereby increasing the proliferation of ISCs. Concurrently, TIGAR promotes the synthesis of nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione to suppress ferroptosis in ISCs. Subsequent investigations demonstrated that Gln inhibits TIGAR promoter methylation by increasing the expression of the demethylase ten-eleven translocation. This change increased TIGAR transcription, increased NADPH synthesis, and reduced oxidative stress, thereby facilitating the restoration of intestinal mucosal barrier integrity post-burn injury. Conclusions: Our data confirmed the inhibitory effect of Gln on TIGAR promoter methylation, which facilitates YAP translocation into the nucleus and suppresses ferroptosis, ultimately promoting the proliferation of ISCs.

Considering the increasing abundance of antibiotic-resistant bacteria, novel antimicrobial approaches need to be investigated. Photothermal therapy (PTT), an innovative noninvasive therapeutic technique, has demonstrated significant potential in addressing drug-resistant bacteria and bacterial biofilms. However, when used in isolation, PTT requires higher-temperature conditions to effectively eradicate bacteria, thereby potentially harming healthy tissues and inducing new inflammation. This study aims to present a comprehensive review of nanomaterials with intrinsic antimicrobial properties, antimicrobial materials relying on photothermal action, and nanomaterials using drug delivery antimicrobial action, along with their applications in antimicrobials. Additionally, the synergistic mechanisms of these antimicrobial approaches are elucidated. The review provides a reference for developing multifunctional photothermal nanoplatforms for treating bacterially infected wounds.

Background: Epidermal stem cells (ESCs) are primarily located in the basal layer of the epidermis and play a crucial role in wound healing. ESCs-derived exosomes (ESCs-Exo) are emerging as promising candidates for skin regeneration and wound healing. However, the underlying mechanisms remain unclear. This study aims to investigate the role and mechanisms of ESCs-Exo in promoting the proliferation, migration, and collagen synthesis of human skin fibroblasts (HSFBs). Methods: This study generated, isolated, and characterized ESC-Exos. The effects of ESCs-Exo on the proliferation of human skin fibroblasts (HSFBs) were detected via Cell Counting Kit-8 (CCK8), 5-Ethynyl-2’-deoxyuridine (EdU), and Proliferating Cell Nuclear Antigen (PCNA) and Marker of Proliferation Ki-67 (MKI67) gene expression methods. The effect of ESCs-Exo on the migration of HSFBs was detected via a transwell assay and a scratch test. The concentrations of collagen secreted by the HSFBs and the mRNAs of the two kinds of collagen expressed by the HSFBs were analyzed. We also analyzed the phosphorylation of Protein Kinase N1 (PKN1) and the expression of cyclins via western blotting. Finally, the effect of ESCs-Exo on wound healing was verified by animal experiments, and the key genes and signaling pathways of ESCs-Exo were excavated by transcriptomic analysis. Results: Western blotting revealed that the exosomes of ESCs highly expressed established markers such as Alix, CD63, and CD9. ESC-Exos significantly promoted HSFB proliferation and migration in a dose-dependent manner, as well as HSFB collagen synthesis, and effectively increased the ratio of collagen III/I. In addition, bioinformatics analysis showed that the expression of key gene C-X-C motif chemokine ligand 9 was lower in the ESCs-Exo group, which may promote wound healing by regulating PKN1-cyclin and tumor necrosis factor signaling pathways. Animal experiments demonstrated that ESCs-Exo could reduce inflammation and accelerate wound healing. Conclusions: In this study, we found that ESCs-Exo may improve wound healing by promoting the proliferation and migration of HSFBs.

Background: The extracellular matrix (ECM) provides essential physical support and biochemical cues for diverse biological activities, including tissue remodelling and regeneration, and thus is commonly applied in the construction of artificial peripheral nerve grafts. Nevertheless, the specific functions of essential peripheral nerve ECM components have not been fully determined. Our research aimed to differentially represent the neural activities of main components of ECM on peripheral nerve regeneration. Methods: Schwann cells from sciatic nerves and neurons from dorsal root ganglia were isolated and cultured in vitro. The cells were seeded onto noncoated dishes, Matrigel-coated dishes, and dishes coated with the four major ECM components fibronectin, laminin, collagen I, and collagen IV. The effects of these ECM components on Schwann cell proliferation were determined via methylthiazolyldiphenyl-tetrazolium bromide (MTT), Cell Counting Kit-8, and 5-ethynyl-2’-deoxyuridine (EdU) assays, whereas their effects on cell migration were determined via wound healing and live-cell imaging. Neurite growth in neurons cultured on different ECM components was observed. Furthermore, the two types of collagen were incorporated into chitosan artificial nerves and used to repair sciatic nerve defects in rats. Immunofluorescence analysis and a behavioural assessment, including gait, electrophysiology, and target muscle analysis, were conducted. Results: ECM components, especially collagen I, stimulated the DNA synthesis and movement of Schwann cells. Direct measurement of the neurite lengths of neurons cultured on ECM components further revealed the beneficial effects of ECM components on neurite outgrowth. Injection of collagen I into chitosan and poly(lactic-co-glycolic acid) artificial nerves demonstrated that collagen I facilitated axon regeneration and functional recovery after nerve defect repair by stimulating the migration of Schwann cells and the formation of new blood vessels. In contrast, collagen IV recruited excess fibroblasts and inflammatory macrophages and thus had disadvantageous effects on nerve regeneration. Conclusions: These findings reveal the modulatory effects of specific ECM components on cell populations of peripheral nerves, reveal the contributing roles of collagen I in microenvironment construction and axon regeneration, and highlight the use of collagen I for the healing of injured peripheral nerves.

Background: Hypertrophic scars cause impaired skin appearance and function, seriously affecting physical and mental health. Due to medical ethics and clinical accessibility, the collection of human scar specimens is frequently restricted, and the establishment of scar experimental animal models for scientific research is urgently needed. The four most commonly used animal models of hypertrophic scars have the following drawbacks: the rabbit ear model takes a long time to construct; the immunodeficient mouse hypertrophic scar model necessitates careful feeding and experimental operations; female Duroc pigs are expensive to purchase and maintain, and their large size makes it difficult to produce a significant number of models; and mouse scar models that rely on tension require special skin stretch devices, which are often damaged and shed, resulting in unstable model establishment. Our group overcame the shortcomings of previous scar animal models and created a new mouse model of hypertrophic scarring induced by suture anchoring at the wound edge. Methods: We utilized suture anchoring of incisional wounds to impose directional tension throughout the healing process, restrain wound contraction, and generate granulation tissue, thus inducing scar formation. Dorsal paired incisions were generated in mice, with wound edges on the upper back sutured to the rib cage and the wound edges on the lower back relaxed as a control. Macroscopic manifestation, microscopic histological analysis, mRNA sequencing, bioinformatics, and in vitro cell assays were also conducted to verify the reliability of this method. Results: Compared with those in relaxed controls, the fibrotic changes in stretched wounds were more profound. Histologically, the stretched scars were hypercellular, hypervascular, and hyperproliferative with disorganized extracellular matrix deposition, and displayed molecular hallmarks of hypertrophic fibrosis. In addition, the stretched scars exhibited transcriptional overlap with mechanically stretched scars, and human hypertrophic and keloid scars. Phosphatidylinositol 3-kinase-serine/threonine-protein kinase B signaling was implicated as a profibrotic mediator of apoptosis resistance under suture-induced tension. Conclusions: This straightforward murine model successfully induces cardinal molecular and histological features of pathological hypertrophic scarring through localized suture tension to inhibit wound contraction. The model enables us to interrogate the mechanisms of tension-induced fibrosis and evaluate anti-scarring therapies.

Tissue engineering is a discipline based on cell biology and materials science with the primary goal of rebuilding and regenerating lost and damaged tissues and organs. Tissue engineering has developed rapidly in recent years, while scaffolds, growth factors, and stem cells have been successfully used for the reconstruction of various tissues and organs. However, time-consuming production, high cost, and unpredictable tissue growth still need to be addressed. Machine learning is an emerging interdisciplinary discipline that combines computer science and powerful data sets, with great potential to accelerate scientific discovery and enhance clinical practice. The convergence of machine learning and tissue engineering, while in its infancy, promises transformative progress. This paper will review the latest progress in the application of machine learning to tissue engineering, summarize the latest applications in biomaterials design, scaffold fabrication, tissue regeneration, and organ transplantation, and discuss the challenges and future prospects of interdisciplinary collaboration, with a view to providing scientific references for researchers to make greater progress in tissue engineering and machine learning.

Background: Ferroptosis plays an essential role in the development of diabetes and its complications, suggesting its potential as a therapeutic target. Stem cell-derived extracellular vesicles (EVs) are increasingly being developed as nano-scale drug carriers. The aim of this study was to determine the role of ferroptosis in the pathogenesis of diabetic wound healing and evaluate the therapeutic effects of coenzyme Q10 (Q10)-stimulated exosmes derived from mesenchymal stem cells (MSCs). Methods: Human keratinocytes (HaCaTs) were exposed to high glucose (HG) conditions in vitro to mimic diabetic conditions, and the ferroptosis markers and expression level of acyl-coenzyme A synthase long-chain family member 4 (ACSL4) were determined. Exosomes were isolated from control and Q10-primed umbilical cord mesenchymal stem cells (huMSCs) and characterized by tramsmission electron microscopy and immunofluorescence staining. The HG-treated HaCaTs were cultured in the presence of exosomes derived from Q10-treated huMSCs (Q10-Exo) and their in vitro migratory capacity was analyzed. Results: Q10-Exo significantly improved keratinocyte viability and inhibited ferroptosis in vitro. miR-548ai and miR-660 were upregulated in the Q10-Exo and taken up by HaCaT cells. Furthermore, miR-548ai and miR-660 mimics downregulated ACSL4-inhibited ferroptosis in the HG-treated HaCaT cells and enhanced their proliferation and migration. However, simultaneous upregulation of ACSL4 reversed their effects. Q10-Exo also accelerated diabetic wound healing in a mouse model by inhibiting ACSL4-induced ferroptosis. Conclusions: Q10-Exo promoted the proliferation and migration of keratinocytes and inhibited ferroptosis under hyperglycemic conditions by delivering miR-548ai and miR-660. Q10-Exo also enhanced cutaneous wound healing in diabetic mice by repressing ACSL4-mediated ferroptosis.

Titanium mesh exposure after cranioplasty is the most serious complication of this procedure. Although some clinical experience has been gradually accumulated over the years in the diagnosis and treatment of titanium mesh exposure, the treatment is often not standardized and it is difficult to achieve satisfactory repair results due to insufficient understanding of its pathogenesis and concurrent infections. To normalize the diagnosis and treatment of titanium mesh exposed wounds after cranioplasty and improve the therapeutic effect and the quality of life of patients, the Wound Repair Professional Committee of Chinese Medical Doctor Association organized an expert discussion based on the literature and current diagnosis and treatment status of titanium mesh exposed wounds after cranioplasty at home and abroad, and reached a consensus on the pathogenesis, preventive measures, and diagnosis and treatment strategies of titanium mesh exposed wounds after cranioplasty to provide reference for relevant clinicians.

Extracellular vesicles (EVs) are heterogeneous membrane-like vesicles secreted by living cells that are involved in many physiological and pathological processes and act as intermediaries of intercellular communication and molecular transfer. Recent studies have shown that EVs from specific sources regulate tissue repair and regeneration by delivering proteins, lipids, and nucleic acids to target cells as signaling molecules. Nanotechnology breakthroughs have facilitated the development and exploration of engineered EVs for tissue repair. Enhancements through gene editing, surface modification, and content modification have further improved their therapeutic efficacy. This review summarizes the potential of EVs in tissue repair and regeneration, their mechanisms of action, and their research progress in regenerative medicine. This review highlights their design logic through typical examples and explores the development prospects of EVs in tissue repair. The aim of this review is to provide new insights into the design of EVs for tissue repair and regeneration applications, thereby expanding their use in regenerative medicine.