Correction: Janus N,N-dimethylformamide as a solvent for a gradient porous wound dressing of poly(vinylidene fluoride) and as a reducer for in situ nano-silver production: anti-permeation, antibacterial and antifouling activities against multi-drug-resistant bacteria both in vitro and in vivo.

[This corrects the article DOI: 10.1039/C8RA03234C.].

Comparison of inferior vena cava puncture under continuous cardiac perfusion with cardiac puncture in blood acquisition of the laboratory mouse.

Obtaining sufficient blood volume from mice significantly facilitates experimental research. This study explored the inferior vena cava puncture under continuous cardiac perfusion (IVCP-UCCP) technique and evaluated its efficiency in comparison with conventional cardiac puncture (CP). In an initial dose-finding study, 50 mice were randomly assigned to one of 10 groups with escalating perfusion volume from 0.5 to 4.5 ml in 0.5-ml increments. The minimum perfusion volume was determined to be 2 ml in collecting whole circulating blood. In the next comparison using the conventional method, 40 mice were randomly assigned to one of two groups denoting different blood collection methods: Group 1: CP, Group 2: IVCP-UCCP. The results showed 1) that the cells and undiluted blood volume collected via IVCP-UCCP was over twofold higher than that by CP (p < 0.001), confirmed by the cell counts and hematoxylin-eosin staining of different tissues slides (p < 0.001); 2) the new technique did not alter the cellular composition or viability, which was verified by routine blood tests and flow cytometry (p > 0.05); 3) the blood collected via the novel technique was diluted 2.1 times: the hemato-biochemical indicator results multiplied by 2.1 were identical with the test results of blood from CP (p > 0.05). Together, the refined blood collection method of IVCP-UCCP completely extracted the limited blood resources in mice, significantly enhanced the utilization of each mouse, and thus offered scientific and ethical benefits. This technique may be also applicable for other small animal models.

Mitochondrial dysfunction in sepsis: mechanisms and therapeutic perspectives.

Sepsis is a severe medical condition characterized by a systemic inflammatory response, often culminating in multiple organ dysfunction and high mortality rates. In recent years, there has been a growing recognition of the pivotal role played by mitochondrial damage in driving the progression of sepsis. Various factors contribute to mitochondrial impairment during sepsis, encompassing mechanisms such as reactive nitrogen/oxygen species generation, mitophagy inhibition, mitochondrial dynamics change, and mitochondrial membrane permeabilization. Damaged mitochondria actively participate in shaping the inflammatory milieu by triggering key signaling pathways, including those mediated by Toll-like receptors, NOD-like receptors, and cyclic GMP-AMP synthase. Consequently, there has been a surge of interest in developing therapeutic strategies targeting mitochondria to mitigate septic pathogenesis. This review aims to delve into the intricate mechanisms underpinning mitochondrial dysfunction during sepsis and its significant impact on immune dysregulation. Moreover, we spotlight promising mitochondria-targeted interventions that have demonstrated therapeutic efficacy in preclinical sepsis models.

Macrophage plasticity: signaling pathways, tissue repair, and regeneration.

Macrophages are versatile immune cells with remarkable plasticity, enabling them to adapt to diverse tissue microenvironments and perform various functions. Traditionally categorized into classically activated (M1) and alternatively activated (M2) phenotypes, recent advances have revealed a spectrum of macrophage activation states that extend beyond this dichotomy. The complex interplay of signaling pathways, transcriptional regulators, and epigenetic modifications orchestrates macrophage polarization, allowing them to respond to various stimuli dynamically. Here, we provide a comprehensive overview of the signaling cascades governing macrophage plasticity, focusing on the roles of Toll-like receptors, signal transducer and activator of transcription proteins, nuclear receptors, and microRNAs. We also discuss the emerging concepts of macrophage metabolic reprogramming and trained immunity, contributing to their functional adaptability. Macrophage plasticity plays a pivotal role in tissue repair and regeneration, with macrophages coordinating inflammation, angiogenesis, and matrix remodeling to restore tissue homeostasis. By harnessing the potential of macrophage plasticity, novel therapeutic strategies targeting macrophage polarization could be developed for various diseases, including chronic wounds, fibrotic disorders, and inflammatory conditions. Ultimately, a deeper understanding of the molecular mechanisms underpinning macrophage plasticity will pave the way for innovative regenerative medicine and tissue engineering approaches.

STING coordinates resolution of inflammation during wound repair by modulating macrophage trafficking through STAT3.

Efficient cutaneous wound healing requires a coordinated transition between inflammatory phases mediated by dynamic changes in leukocyte subset populations. Here, we identify STING as a key innate immune mediator governing timely resolution of inflammation by regulating macrophage dynamics during skin repair. Using a mouse model, we show STING deficiency caused delayed wound closure associated with abnormal persistence of TNF-α+ leukocytes. This resulted from the impaired macrophage recruitment. STING controlled the trafficking of bone marrow myeloid cells into blood and wounds, intrinsically enhancing macrophage migratory capacity through STAT3 activation. Specifically, STING modulated the production of monocyte chemokines and their receptors CCR2/CCR5 to enable efficient egress and wound infiltration. Consequently, disrupted systemic and local STING-STAT3-chemokine signaling combine to delay macrophage influx. This study elucidates STING as a critical rheostat tuning macrophage responses through STAT3 to orchestrate inflammatory resolution necessary for efficient wound healing. Our findings have broad implications for targeting STING therapeutically in both regenerative medicine and inflammatory disease contexts. STING regulates the macrophage trafficking through STAT3 in wound healing.

Nanomaterial-Based Repurposing of Macrophage Metabolism and Its Applications.

Macrophage immunotherapy represents an emerging therapeutic approach aimed at modulating the immune response to alleviate disease symptoms. Nanomaterials (NMs) have been engineered to monitor macrophage metabolism, enabling the evaluation of disease progression and the replication of intricate physiological signal patterns. They achieve this either directly or by delivering regulatory signals, thereby mapping phenotype to effector functions through metabolic repurposing to customize macrophage fate for therapy. However, a comprehensive summary regarding NM-mediated macrophage visualization and coordinated metabolic rewiring to maintain phenotypic equilibrium is currently lacking. This review aims to address this gap by outlining recent advancements in NM-based metabolic immunotherapy. We initially explore the relationship between metabolism, polarization, and disease, before delving into recent NM innovations that visualize macrophage activity to elucidate disease onset and fine-tune its fate through metabolic remodeling for macrophage-centered immunotherapy. Finally, we discuss the prospects and challenges of NM-mediated metabolic immunotherapy, aiming to accelerate clinical translation. We anticipate that this review will serve as a valuable reference for researchers seeking to leverage novel metabolic intervention-matched immunomodulators in macrophages or other fields of immune engineering.

Orchestration of Macrophage Polarization Dynamics by Fibroblast-Secreted Exosomes during Skin Wound Healing.

Macrophages undertake pivotal yet dichotomous functions during skin wound healing, mediating both early proinflammatory immune activation and late anti-inflammatory tissue remodeling processes. The timely phenotypic transition of macrophages from inflammatory M1 to proresolving M2 activation states is essential for efficient healing. However, the endogenous mechanisms calibrating macrophage polarization in accordance with the evolving tissue milieu remain undefined. In this study, we reveal an indispensable immunomodulatory role for fibroblast-secreted exosomes in directing macrophage activation dynamics. Fibroblast-derived exosomes permitted spatiotemporal coordination of macrophage phenotypes independent of direct intercellular contact. Exosomes enhanced macrophage sensitivity to both M1 and M2 polarizing stimuli, yet they also accelerated timely switching from M1 to M2 phenotypes. Exosome inhibition dysregulated macrophage responses, resulting in aberrant inflammation and impaired healing, whereas provision of exogenous fibroblast-derived exosomes corrected defects. Topical application of fibroblast-derived exosomes onto chronic diabetic wounds normalized dysregulated macrophage activation to resolve inflammation and restore productive healing. Our findings elucidate fibroblast-secreted exosomes as remote programmers of macrophage polarization that calibrate immunological transitions essential for tissue repair. Harnessing exosomes represents a previously unreported approach to steer productive macrophage activation states with immense therapeutic potential for promoting healing in chronic inflammatory disorders.

Peceleganan Spray for the Treatment of Skin Wound Infections: A Randomized Clinical Trial.

Importance: Peceleganan spray is a novel topical antimicrobial agent targeted for the treatment of skin wound infections. However, its efficacy and safety remain unclear. Objective: To assess the safety and efficacy of peceleganan spray for the treatment of wound infections. Design, Setting, and Participants: This multicenter, open-label, phase 3 randomized clinical trial recruited and followed up 570 adult patients diagnosed with secondary open wound infections from 37 hospitals in China from August 23, 2021, to July 16, 2022. Interventions: Patients were randomized to 2 groups with a 2:1 allocation. One group received treatment with 2% peceleganan spray (n = 381) and the other with 1% silver sulfadiazine (SSD) cream (n = 189). Main Outcomes and Measures: The primary efficacy outcome was the clinical efficacy rate (the number of patients fulfilling the criteria for efficacy of the number of patients receiving the treatment) on the first day following the end of treatment (day 8). The secondary outcomes included the clinical efficacy rate on day 5 and the bacterial clearance rate (cases achieving negative bacteria cultures after treatment of all cases with positive bacteria cultures before treatment) on days 5 and 8. The safety outcomes included patients' vital signs, physical examination results, electrocardiographic findings, blood test results, and adverse reactions. Results: Among the 570 patients randomized to 1 of the 2 groups, 375 (98.4%) in the 2% peceleganan treatment group and 183 (96.8%) in the 1% SSD control group completed the trial (n = 558). Of these, 361 (64.7%) were men, and the mean (SD) age was 48.6 (15.3) years. The demographic characteristics were similar between groups. On day 8, clinical efficacy was achieved by 339 patients (90.4%) in the treatment group and 144 (78.7%) in the control group (P < .001). On day 5, clinical efficacy was achieved by 222 patients (59.2%) in the treatment group and 90 (49.2%) in the control group (P = .03). On day 8, bacterial clearance was achieved by 80 of 334 patients (24.0%) in the treatment group and in 75 of 163 (46.0%) in the control group (P < .001). On day 5, bacterial clearance was achieved by 55 of 334 patients (16.5%) in the treatment group and 50 of 163 (30.7%) in the control group (P < .001). The adverse events related to the application of peceleganan spray and SSD cream were similar. Conclusions and Relevance: This randomized clinical trial found that peceleganan spray is a safe topical antimicrobial agent with a satisfactory clinical efficacy rate for the treatment of skin wound infections, while the effectiveness of bacterial clearance remains uncertain. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2100047202.

Comparing collagenase and silver sulfadiazine in deep second-degree burn treatment.

The indications for collagenase ointment (CO) and its efficacy are not clearly established in the treatment of second-degree burn wounds. To evaluate the efficacy of CO versus silver sulfadiazine ointment (SSD) in the treatment of second-degree burn wounds. A total of 170 eligible patients with deep second-degree burns, aged 18-65 years, with injuries occurring within 48-96 h, and having a total wound area of less than 30% of the total body surface area were included from 5 centers in China. The primary outcome was the wound healing time, and the secondary outcomes were the clearance time of wound necrotic tissues, wound healing rate, and wound inflammation. The study included 85 patients in SSD group and 84 in CO group in the modified intention-to-treat (mITT) population. The median time of wound healing was comparable in both groups (10 days vs. 10.5 days P = 0.16). The time for wound necrotic tissue removal was significantly shortened by CO compared with SSD (5 vs. 10 days P < 0.01). Wound inflammation, pain, wound healing rate, and scar were compared with SSD (all P-values > 0.05). No adverse events, such as infection or allergic reactions to the drugs and materials used, were reported. Both CO and SSD could heal the burn wounds at 10 days of treatment. However, CO significantly shortened the time of wound necrotic tissue removal by 5 days. Trial Registration: ChiCTR2100046971.

Spatiotemporal orchestration of macrophage activation trajectories by Vγ4 T cells during skin wound healing.

Dysregulated macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 phenotypes underlies impaired cutaneous wound healing. This study reveals Vγ4+ γδ T cells spatiotemporally calibrate macrophage trajectories during skin repair via sophisticated interferon-γ (IFN-γ) conditioning across multiple interconnected tissues. Locally within wound beds, infiltrating Vγ4+ γδ T cells directly potentiate M1 activation and suppress M2 polarization thereby prolonging local inflammation. In draining lymph nodes, infiltrated Vγ4+ γδ T cells expand populations of IFN-γ-competent lymphocytes which disseminate systemically and infiltrate into wound tissues, further enforcing M1 macrophages programming. Moreover, Vγ4+γδ T cells flushed into bone marrow stimulate increased IFN-γ production, which elevates the output of pro-inflammatory Ly6C+monocytes. Mobilization of these monocytes continually replenishes the M1 macrophage pool in wounds, preventing phenotypic conversion to M2 activation. Thus, multi-axis coordination of macrophage activation trajectories by trafficking Vγ4+ γδ T cells provides a sophisticated immunological mechanism regulating inflammation timing and resolution during skin repair.

Construction of programmed time-released multifunctional hydrogel with antibacterial and anti-inflammatory properties for impaired wound healing.

The successful reprogramming of impaired wound healing presents ongoing challenges due to the impaired tissue microenvironment caused by severe bacterial infection, excessive oxidative stress, as well as the inappropriate dosage timing during different stages of the healing process. Herein, a dual-layer hydrogel with sodium alginate (SA)-loaded zinc oxide (ZnO) nanoparticles and poly(N-isopropylacrylamide) (PNIPAM)-loaded Cu5.4O ultrasmall nanozymes (named programmed time-released multifunctional hydrogel, PTMH) was designed to dynamically regulate the wound inflammatory microenvironment based on different phases of wound repairing. PTMH combated bacteria at the early phase of infection by generating reactive oxygen species through ZnO under visible-light irradiation with gradual degradation of the lower layer. Subsequently, when the upper layer was in direct contact with the wound tissue, Cu5.4O ultrasmall nanozymes were released to scavenge excessive reactive oxygen species. This neutralized a range of inflammatory factors and facilitated the transition from the inflammatory phase to the proliferative phase. Furthermore, the utilization of Cu5.4O ultrasmall nanozymes enhanced angiogenesis, thereby facilitating the delivery of oxygen and nutrients to the impaired tissue. Our experimental findings indicate that PTMHs promote the healing process of diabetic wounds with bacterial infection in mice, exhibiting notable antibacterial and anti-inflammatory properties over a specific period of time.

Hyaluronidase-Responsive Bactericidal Cryogel for Promoting Healing of Infected Wounds: Inflammatory Attenuation, ROS Scavenging, and Immune Regulation.

Wounds infected with multidrug-resistant (MDR) bacteria are increasingly threatening public health and challenging clinical treatments because of intensive bacterial colonization, excessive inflammatory responses, and superabundant oxidative stress. To overcome this malignant burden and promote wound healing, a multifunctional cryogel (HA/TA2/KR2) composed of hyaluronic acid (HA), tannic acid (TA), and KR-12 peptides is designed. The cryogel exhibited excellent shape-memory properties, strong absorption performance, and hemostatic capacity. In vitro experiments demonstrated that KR-12 in the cryogel can be responsively released by stimulation with hyaluronidase produced by bacteria, reaching robust antibacterial activity against Escherichia coli (E. coli), MDR Pseudomonas aeruginosa (MDR-PA), and methicillin-resistant Staphylococcus aureus (MRSA) by disrupting bacterial cell membranes. Furthermore, the synergetic effect of KR-12 and TA can efficiently scavenge ROS and decrease expression of pro-inflammatory cytokines (tumor necrosis factor (TNF)-α & interleukin (IL)-6), as well as modulate the macrophage phenotype toward the M2 type. In vivo animal tests indicated that the cryogel can effectively destroy bacteria in the wound and promote healing process via accelerating angiogenesis and re-epithelialization. Proteomic analysis revealed the underlying mechanism by which the cryogel mainly reshaped the infected wound microenvironment by inhibiting the Nuclear factor kappa B (NF-κB) signaling pathway and activating the Janus kinase-Signal transducer and activator of transcription (JAK-STAT6) signaling pathway. Therefore, the HA/TA2/KR2 cryogel is a promising dressing candidate for MDR bacteria-infected wound healing.

Platelet Vesicles Synergetic with Biosynthetic Cellulose Aerogels for Ultra-Fast Hemostasis and Wound Healing.

Achieving hemostasis in penetrating and irregular wounds is challenging because the hemostasis factor cannot arrive at the bleeding site, and substantial bleeding will wash away the blood clot. Since the inherently gradual nature of blood clot formation takes time, a physical barrier is needed before blood clot formation. Herein, an ultra-light and shape memory hemostatic aerogel consisting of oxidized bacterial cellulose (OBC) and platelet extracellular vesicles (pVEs) is reported. The OBC-pVEs aerogel provides a physical barrier for the bleeding site by self-expansion, absorbing the liquid from blood to concentrate platelets and clotting factors and accelerating the clot formation by activating platelets and transforming fibrinogen into fibrin. In the rat liver and tail injury models, the blood loss decreases by 73% and 59%, and the bleeding times are reduced by 55% and 62%, respectively. OBC-pVEs aerogel has also been shown to accelerate wound healing. In conclusion, this work introduces an effective tool for treating deep, non-compressible, and irregular wounds and offers valuable strategies for trauma bleeding and wound treatment.

Clinical profile, management and risk factors for seizure-related burn injuries among patients with epilepsy in southwest China.

Objective: The epidemiological information associated with seizure-related burn injuries is lacking in China. Therefore, this study aims to analyze the clinical profile, management, outcome, and risk factors of burns that are directly caused by seizures among epileptic patients, and identify the epidemiological characteristics to develop effective preventive strategies. Methods: This study was conducted between January 2002 and December 2022 in a large Chinese burn center. Data including clinical profile, wound treatment, and outcome were analyzed. A multiple linear regression was used to screen the risk factors for the length of hospital stay (LOS), and a multiple logistic regression was used to screen the contributory factors for the amputation. Results: A total of 184 burn patients (55.98 % females) were enrolled, with a 0.78 % incidence rate during the study period. The mean age of the patients was 36.16 years (SD: 17.93). Patients aged 20-29 were the most affected age groups (23.37 %). Most burns were caused by flame, accounting for 60.33 % (111/184) of all cases. In total, 76.09 % of the 184 patients underwent at least one operation, and 35 patients (19.02 %) still required amputation during the study period. Burn sites (hands) had the greatest impact on amputation (OR = 3.799), followed by flame burns (OR = 3.723). The mean LOS/TBSA was 6.90 ± 8.53 d, and a larger TBSA, full-thickness burns, and a higher number of operations were identified as the risk factors for a longer LOS. There was one death among the 184 patients, with a mortality rate of 0.54 %. Conclusion: This study demonstrates that burn injuries are extremely harmful to individuals with epilepsy in China because they are at high risk of amputation and disability. Effective healthcare education and preventive programs that focus on lifestyle modifications and seizure control should be implemented to reduce the burn incidence in these populations.

Glycosaminoglycans' Ability to Promote Wound Healing: From Native Living Macromolecules to Artificial Biomaterials.

Glycosaminoglycans (GAGs) are important for the occurrence of signaling molecules and maintenance of microenvironment within the extracellular matrix (ECM) in living tissues. GAGs and GAG-based biomaterial approaches have been widely explored to promote in situ tissue regeneration and repair by regulating the wound microenvironment, accelerating re-epithelialization, and controlling ECM remodeling. However, most approaches remain unacceptable for clinical applications. To improve insights into material design and clinical translational applications, this review highlights the innate roles and bioactive mechanisms of native GAGs during in situ wound healing and presents common GAG-based biomaterials and the adaptability of application scenarios in facilitating wound healing. Furthermore, challenges before the widespread commercialization of GAG-based biomaterials are shared, to ensure that future designed and constructed GAG-based artificial biomaterials are more likely to recapitulate the unique and tissue-specific profile of native GAG expression in human tissues. This review provides a more explicit and clear selection guide for researchers designing biomimetic materials, which will resemble or exceed their natural counterparts in certain functions, thereby suiting for specific environments or therapeutic goals.

Severe High-Voltage Electrical Injury: A Rare Case Report.

High-voltage electrical injury usually causes severe tissue damage and serious secondary complications. We report a case of treatment of severe high-voltage electrical injury. A series of personalized and effective treatment plans were created through repeated discussions, we successfully handled a series of acute and critical conditions, including severe limb damage, a very large area of full-thickness abdominal wall defect, abdominal viscera (stomach and liver) necrosis, abdominal infection, renal insufficiency, myocardial damage, and malignant arrhythmia (atrial fibrillation). Finally, the wounds were all closed, the functions of the abdominal organs were restored, and the course of the disease was successfully transitioned into the rehabilitation stage. It took a lot of twists and turns but ultimately saved the patient's life. The successful treatment of this patient provides an important reference for similar patients with serious electrical injury in the future.

Treatment of hypertrophic scars with ablative fractional carbon dioxide laser assisted with different topical triamcinolone delivery ways.

Objectives: Ablative fractional carbon dioxide laser has been used with triamcinolone to treat hypertrophic scars, resulting in promising success rates. However, there are different topical triamcinolone delivery methods used in scar treatment. To assess the efficacy among the different triamcinolone delivery methods, this study was designed to compare the efficacy and safety of ablative fractional carbon dioxide laser followed by penetration and injection of topical triamcinolone into thicker hypertrophic scars (height score of VSS ≥2). Study design/materials and methods: We performed a retrospective study of 155 thicker hypertrophic scar patients (height score of VSS ≥2), including 88 patients in the triamcinolone external application group and 67 patients in the triamcinolone intralesional injection group. One month after the patients had 3 treatment sessions at 4-week intervals, the scars were assessed by photography, the Vancouver Scar Scale (VSS), durometry and spectrocolorimetry. Any adverse effects were also evaluated. Results: The VSS scores and the hardness of the scars in both groups improved significantly compared to baseline. Moreover, the patients in the triamcinolone intralesional injection group had higher treatment efficacy (19.77 ± 21.25 %) based on their VSS scores than the patients in the triamcinolone external application group (5.94 ± 24.07 %), especially in the improvement of scar pliability, height and hardness. Meanwhile, in the triamcinolone injection group, more patients had mild and moderate improvement than in the triamcinolone application group. However, there were no differences in the distribution of the adverse effects in either group. Conclusions: This study demonstrated that using the ablative fractional carbon dioxide laser followed by different topical triamcinolone delivery methods is effective and safe for thicker hypertrophic scar improvement. The method of using the ablative fractional carbon dioxide laser assisted with triamcinolone injection had a better therapeutic outcome in thicker hypertrophic scars, as compared with triamcinolone penetration.

Indocyanine Green Fluorescence Imaging in the Surgical Management of Skin Squamous Cell Carcinoma.

Introduction: Indocyanine green (ICG) fluorescence imaging has been used in the resection surgery and sentinel lymph node biopsy of many tumors. The aim of the present study is to verify the feasibility and effectiveness of ICG fluorescence imaging used for guiding the biopsy and resection of skin squamous cell carcinoma (SSCC). Methods: Sixty patients were enrolled, including 18 patients of suspected SSCC and 42 patients of diagnosed SSCC on admission. The ICG fluorescence imaging-guided skin biopsy was performed preoperatively in the 18 cases of suspected SSCC. Fifty-three patients underwent ICG fluorescence imaging-guided radical excision. Results: The results showed that 138 skin tissue samples in 60 patients with preoperative or intraoperative ICG fluorescence imaging-guide biopsy were collected. For a total number of 138 biopsies, 122 specimens were squamous cell carcinoma, and the accuracy rate was 88.4%, which was significantly higher than that of the group without preoperative ICG fluorescence imaging (41/62, 66.1%, P < 0.05). Fifty-three patients underwent surgery guided with ICG fluorescence imaging. Residual fluorescent signals in 24 patients were intraoperatively found and the excision was then expanded until the signals disappeared. Follow-up to November 2022, 12 patients died, of which 5 cases died from the tumor recurrence, and the others died due to advanced ages or other reasons. The recurrence rate was 9.4%, which was not significantly different from that of the group received routine radical resection (4/35, 11.4%, P > 0.05). Moreover, sentinel lymph nodes were successfully detected under ICG fluorescence imaging in the 4 patients with suspected lymph node metastases, and the location of lymph nodes can be precisely identified. Conclusion: ICG fluorescence imaging technique can guide the pathology biopsy to improve the accuracy of pathological examination, and help to identify the boundaries of tumor tissues and sentinel lymph nodes to resect tumor radically during operation.