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Unveiling of the mechanism involved in the occurrence and development of trauma-induced heterotopic ossification (tHO) is highly demanding due to current ineffective clinical treatment for it. Previous studies proposed that hydrogen sulfide (H 2 S) was vital for fate determination of stem cells, suggesting a potential role in the regulation of tHO development. In the current study, We found that expression of metabolic enzyme within sulfur conversion pathway was enhanced after tendon injury, leading to H 2 S accumulation within the tHO region. Increased production of endogenous H 2 S was shown to promote aberrant osteogenic activity of tendon-derived stem cells (TDSCs), which accelerated tHO formation. The inhibition of metabolic enzyme of H 2 S production or directly absorption of H 2 S could abolished osteogenic induction of TDSCs and the formation of tHO. Mechanistically, through RNA sequencing combined with rescue experiments, we demonstrated that activation of Ca 2+ /ERK pathway was the downstream molecular event of H 2 S-induced osteogenic commitment of TDSCs and tHO. For treatment strategy exploration, zine oxide nanoparticles (ZnO) as an effective H 2 S elimination material was validated to ideally halt the tHO formation in this study. Furthermore, in terms of chirality of nanoparticles, D-ZnO or L-ZnO nanoparticles showed superiority over R-ZnO nanoparticles in both clearing of H 2 S and inhibition of tHO. Our study not only revealed the mechanism of tHO through the endogenous gas signaling event from a new perspective, but also presented a applicable platform for elimination of the inordinate gas production, thus aiding the development of clinical treatment for tHO., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Lymphocyte decline, particularly the depletion of NK cells, is a prominent feature of immunosuppression following severe tissue injury, heightening the susceptibility of severe trauma patients to life-threatening infections. Previous research indicates that the reduction in the number of NK cells is closely associated with the process of cell death. Nonetheless, the precise mechanism of NK cell death remains unknown. Here, we discovered that following severe traumatic injury, NK cells undergo several cell death pathways, dominated by apoptosis and pyroptosis with coexistence of necrotic cell death, immunogenic cell death, ferroptosis, and autophagy. These NK cells with different paradigms of death have diverse cytokine expression profiles and diverse interactions with other immune cells. Further exploration revealed that hypoxia was strongly associated with this diverse paradigm of NK cell death. Detailed investigation of paradigms of cell death may help to enhance comprehension of lymphopenia post-severe trauma, to develop new strategy in preventing immunosuppression, and then to improve outcome for severe trauma population., (© 2024. The Author(s).)

The increasing global prevalence of chronic wounds underscores the growing importance of developing effective animal models for their study. This review offers a critical evaluation of the strengths and limitations of rat models frequently employed in chronic wound research and proposes potential improvements. It explores these models in the context of key comorbidities, including diabetes, venous and arterial insufficiency, pressure-induced blood flow obstruction, and infections. Additionally, the review examines important wound factors including age, sex, smoking, and the impact of anesthetic and analgesic drugs, acknowledging their substantial effects on research outcomes. A thorough understanding of these variables is crucial for refining animal models and can provide valuable insights for future research endeavors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: Key wound environment parameters include pH, hydration, and the balance between tissue remodeling and deposition of new tissue. When prolonged inflammation is present, the proliferation phase of wound healing can be delayed because excessive protease production due to persistent inflammation can destroy newly formed tissue and prevent wounds from filling and reepithelializing., Objective: To conduct an in vitro study of the ability of polygalacturonic acid (PG), a natural pectin derivative present in ripening fruit, to inhibit 3 destructive wound proteases and prevent dehydration in environments in which significant evaporation can occur., Materials and Methods: In vitro enzyme inhibition assay kits were used to detect the ability of PG to inhibit key wound proteases matrix metalloproteinase (MMP)-2, MMP-9, and neutrophil elastase (NE). Transepidermal evaporative water loss from a polyvinyl alcohol skin substitute hydrogel was gravimetrically measured., Results: PG could partially inhibit MMP-2 (>50% inhibition relative to negative controls), MMP-9 (>50% inhibition relative to negative controls), and NE (>25% inhibition relative to negative controls) and thereby potentially blunt some of the destructive effects of excess proteases where prolonged inflammation is present. In an in vitro transepidermal evaporative water loss assay, PG also helped retain moisture and inhibited dehydration (>25% reduction relative to negative controls)., Conclusions: These findings suggest that PG can be a useful addition to ointments and dressings in wound care and warrants further in vivo testing.

In an aging society with common lifestyle-associated health issues such as obesity and diabetes, chronic wounds pose a frequent challenge that physicians face in everyday clinical practice. Therefore, nonhealing wounds have attracted much scientific attention. Several in vitro and in vivo models have been introduced to deepen our understanding of chronic wound pathogenesis and amplify therapeutic strategies. Understanding how wounds become chronic will provide insights to reverse or avoid chronicity. Although choosing a suitable model is of utmost importance to receive valuable outcomes, an ideal in vivo model capturing the complexity of chronic wounds is still missing and remains a translational challenge. This review discusses the most relevant mammalian models for wound healing studies and provides guidance on how to implement the hallmarks of chronic wounds. It highlights the benefits and pitfalls of established models and maps out future avenues for research., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Falls are the second most common cause of injury associated with mortality worldwide and an important type of blunt trauma, which forms a significant percentage of traumatic accidents and emergency department admissions. Falling from a tree is an important problem because of its effect on one's health owing to infirmity caused by injuries, most commonly spinal injuries, and the economic burden that accompanies it., Methods: A retrospective chart analysis was performed including all the patients with falls from heights who presented to a tertiary care hospital in South India during the summer months of 2018, 2019, and 2020. A structured case record form was used to capture information such as basic demographics, tree species, reason for climbing the tree, and mode of fall, along with the clinical profile, and outcomes from the cases selected from the emergency department registers and cross verified using ICD codes., Results: Despite the existing lockdown due to COVID, an unusual increase in the number of patients getting admitted to the triage with a fall from tree was noted in the year 2020 compared to 2019 and 2018. The most common type of injuries sustained were spinal injuries. Burst fractures were leading types of fractures in the patients with spinal injury. The second most common type of injuries involved were of extremities, with lower extremities more than upper extremities. Two patients had inhospital mortality within 30 days., Conclusions: Falls from a tree are a neglected and preventable mechanism of trauma with a significant socio-economic impact, as most of the patients are young or middle aged earning members of their families. The burden of this mode of injury is primarily on rural and agricultural communities. Pre-hospital services in areas with vast agroforestry cultivation require dedicated first response clinics. Lockdowns and geographic isolation during disasters or disease outbreaks must also factor in a supply of essential commodities and warrant treatment on an urgent basis to reduce the need and risk of injury from forestry and agricultural activities.

Background: Patients with hemorrhagic shock and trauma (HS/T) are vulnerable to the endotheliopathy of trauma (EOT), characterized by vascular barrier dysfunction, inflammation, and coagulopathy. Cellular therapies such as mesenchymal stem cells (MSCs) and MSC extracellular vesicles (EVs) have been proposed as potential therapies targeting the EOT. In this study we investigated the effects of MSCs and MSC EVs on endothelial and epithelial barrier integrity in vitro and in vivo in a mouse model of HS/T. This study addresses the systemic effects of HS/T on multiorgan EOT., Methods: In vitro, pulmonary endothelial cell (PEC) and Caco-2 intestinal epithelial cell monolayers were treated with control media, MSC conditioned media (CM), or MSC EVs in varying doses and subjected to a thrombin or hydrogen peroxide (H 2 O 2 ) challenge, respectively. Monolayer permeability was evaluated with a cell impedance assay, and intercellular junction integrity was evaluated with immunofluorescent staining. In vivo, a mouse model of HS/T was used to evaluate the effects of lactated Ringer's (LR), MSCs, and MSC EVs on endothelial and epithelial intercellular junctions in the lung and small intestine as well as on plasma inflammatory biomarkers., Results: MSC EVs and MSC CM attenuated permeability and preserved intercellular junctions of the PEC monolayer in vitro, whereas only MSC CM was protective of the Caco-2 epithelial monolayer. In vivo, both MSC EVs and MSCs mitigated the loss of endothelial adherens junctions in the lung and small intestine, though only MSCs had a protective effect on epithelial tight junctions in the lung. Several plasma biomarkers including MMP8 and VEGF were elevated in LR- and EV-treated but not MSC-treated mice., Conclusions: In conclusion, MSC EVs could be a potential cell-free therapy targeting endotheliopathy after HS/T via preservation of the vascular endothelial barrier in multiple organs early after injury. Further research is needed to better understand the immunomodulatory effects of these products following HS/T and to move toward translating these therapies into clinical studies., (© 2024. The Author(s).)

Background: Wound healing involves the repair of skin and other soft tissues after an injury. Royal jelly, a product of bees, possesses antioxidant, anti-inflammatory, antibacterial, and antiviral properties. Melatonin, a circadian indoleamine, is produced in the pineal gland and other organs. This study explores the effects of melatonin and royal jelly, both individually and combined, on wound healing in geriatric and young mice., Methods: The study includes 90 Balb/C mice divided into ten groups to assess the effects of royal jelly and melatonin on wound healing. Royal jelly was applied topically at a concentration of 300 mg/kg. Melatonin was formulated in a vaseline-based pomade at a concentration of 5 mg/kg. The substances were applied either separately or in combination to wounds created on the mice., Results: Both substances significantly enhanced wound healing at a macroscopic level in both age groups. Melatonin was found to be more effective during the initial wound formation process, whereas royal jelly was more beneficial during the granulation phase. However, significant results at a histopathological level were observed only in geriatric animals., Conclusion: The findings suggest a potential new therapeutic approach to enhance wound healing, particularly in elderly individuals. However, these findings need to be supported through further research and clinical trials.

In forensic medical investigations, physical injuries are documented with photographs accompanied by written reports. Automatic segmentation and classification of wounds on these photographs could provide forensic pathologists with a tool to improve the assessment of injuries and accelerate the reporting process. In this pilot study, we trained and compared several preexisting deep learning architectures for image segmentation and wound classification on forensically relevant photographs in our database. The best scores were a mean pixel accuracy of 69.4% and a mean intersection over union (IoU) of 48.6% when evaluating the trained models on our test set. The models had difficulty distinguishing the background from wounded areas. As an example, image pixels showing subcutaneous hematomas or skin abrasions were assigned to the background class in 31% of cases. Stab wounds, on the other hand, were reliably classified with a pixel accuracy of 93%. These results can be partially attributed to undefined wound boundaries for some types of injuries, such as subcutaneous hematoma. However, despite the large class imbalance, we demonstrate that the best trained models could reliably distinguish among seven of the most common wounds encountered in forensic medical investigations., (© 2023. The Author(s).)

Heterotopic ossification is the inappropriate formation of bone in soft tissues of the body. It can manifest spontaneously in rare genetic conditions or as a response to injury, known as acquired heterotopic ossification. There are several experimental models for studying acquired heterotopic ossification from different sources of damage. However, their tenuous mechanistic relevance to the human condition, invasive and laborious nature and/or lack of amenability to chemical and genetic screens, limit their utility. To address these limitations, we developed a simple zebrafish injury model that manifests heterotopic ossification with high penetrance in response to clinically emulating injuries, as observed in human myositis ossificans traumatica. Using this model, we defined the transcriptional response to trauma, identifying differentially regulated genes. Mutant analyses revealed that an increase in the activity of the potassium channel Kcnk5b potentiates injury response, whereas loss of function of the interleukin 11 receptor paralogue (Il11ra) resulted in a drastically reduced ossification response. Based on these findings, we postulate that enhanced ionic signalling, specifically through Kcnk5b, regulates the intensity of the skeletogenic injury response, which, in part, requires immune response regulated by Il11ra., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Wound management for acute and chronic wounds has become a serious clinical problem worldwide, placing considerable pressure on public health systems. Owing to the high-precision, adjustable pore structure, and repeatable manufacturing process, 3D-printed electrospun fibre (3DP-ESF) has attracted widespread attention for fabricating wound dressing. In addition, in comparison with 2D electrospun fibre membranes fabricated by traditional electrospinning, the 3D structures provide additional guidance on cell behaviour. In this perspective article, we first summarise the basic manufacturing principles and methods to fabricate 3DP-ESF. Then, we discuss the function of 3DP-ESF in manipulating the different stages of wound healing, including anti-bacteria, anti-inflammation, and promotion of cell migration and proliferation, as well as the construction of tissue-engineered scaffolds. In the end, we provide the current challenge faced by 3DP-ESF in the application of skin wound regeneration and its promising future directions., (© 2023 The Wound Healing Society.)

Despite advances in the treatment and care of severe physical injuries, trauma remains one of the main reasons for disability-adjusted life years worldwide. Trauma patients often suffer from disturbances in energy utilization and metabolic dysfunction, including hyperglycemia and increased insulin resistance. White adipose tissue plays an essential role in the regulation of energy homeostasis and is frequently implicated in traumatic injury due to its ubiquitous body distribution but remains poorly studied. Initial triggers of the trauma response are mainly damage-associated molecular patterns (DAMPs) such as histones. We hypothesized that DAMP-induced adipose tissue inflammation contributes to metabolic dysfunction in trauma patients. Therefore, we investigated whether histone release during traumatic injury affects adipose tissue. Making use of a murine polytrauma model with hemorrhagic shock, we found increased serum levels of histones accompanied by an inflammatory response in white adipose tissue. In vitro, extracellular histones induced an inflammatory response in human adipocytes. On the molecular level, this inflammatory response was mediated via a MYD88-IRAK1-ERK signaling axis as demonstrated by pharmacological and genetic inhibition. Histones also induced lytic cell death executed independently of caspases and RIPK1 activity. Importantly, we detected increased histone levels in the bloodstream of patients after polytrauma. Such patients might benefit from a therapy consisting of activated protein C and the FDA-approved ERK inhibitor trametinib, as this combination effectively prevented histone-mediated effects on both, inflammatory gene activation and cell death in adipocytes. Preventing adipose tissue inflammation and adipocyte death in patients with polytrauma could help minimize posttraumatic metabolic dysfunction., (© 2024. The Author(s).)

Objective: A comparison between Cinematic Rendering Technique (CRT) and Volume Rendering Technique (VRT) in cases with postmortem CT-angiography (PMCTA) was carried out., Methods: For different injuries seen in PMCTA, a VRT and a CRT image of exactly the same pathological section was generated. Two questionnaires were created, one with CRT and one with VRT reconstructions, with the same questions per 3D-image. The questionnaires were sent to forensic pathologists, lawyers and police officers. In total eleven different injuries had to be analyzed., Results: In total 109 questionnaires were answered fully. Of these returnees, 36 stated that they were forensic pathologists. Seventy-three people were assigned to the group of medical laypersons, in the study this group consists mainly of police officers, judges and lawyers. Between the two software programs CRT and VRT that were compared, no significant difference could be identified in any of the participating groups with regard to the assessment of the life-threatening nature of the injury images shown. When asked about the comprehensibility of pathology, there was a significant difference in favour of CRT. This advantage was apparent to named medical laypersons and to forensic pathologists., Conclusions: The study showed a positive trend that CRT may be more understandable than VRT. Not only the medical laypersons, but also the forensic physicians found CRT to be beneficial., Competing Interests: Declaration of competing interest N/A., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Wound closure is a fundamental process in many physiological and pathological processes, but the regulating effects of external force on the closure process are still unclear. Here, we systematically studied the closure process of wounds of different shape under cyclic stretching. We found that the stretching amplitude and direction had significant effect on the healing speed and healing mode. For instance, there was a biphasic dependence of the healing speed on the stretching amplitude. That is, the wound closure was faster under relatively small and large amplitude, while it was slower under intermediate amplitude. At the same time, the stretching could regulate the healing pattern. We showed that the stretching would increase the healing speed along the direction perpendicular to the stretching direction. Specifically, when the stretching was along the major axis of the wound, it accelerated the healing speed along the short axis, which induced a rosette to stitching-line mode transition. In contrast, stretching along the minor axis accelerated the healing speed along the long axis, inducing a stitching-line to rosette mode transition. Our theoretical analyses demonstrated that the wound closure process was coregulated by the mechanical factors including prestress in the cytoskeleton, the protrusion of cells, and the contraction of the actin ring, as well as the geometry of the wound. The cyclic stretch could further modulate the roles of these factors. For example, the stretching changed the stress field in the cell layer, and switched the direction of cell protrusions. This article reveals important cellular mechanisms of the wound healing process under cyclic stretching, and provides an insight into possible approaches of regulating cell collective behaviors via mechanical forces., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

With the worldwide prevalence of diabetes and considering the complicated microenvironment of diabetic wounds, the design and development of innovative multifunctional wound dressing materials are much wanted for the treatment of hard-to-heal wounds in diabetic patients. In the present study, anti-inflammatory ingredients loaded with nanofibrous wound dressing materials were manufactured by a promising blend-electrospinning strategy, and their capability for treating the diabetic wound was also systematically explored. A polymer blend consisting of Chitosan (CS) and polyvinyl alcohol (PVA) was electrospun into CS-PVA nanofibrous mats as control groups. In the meanwhile, a bioactive ingredient of Chinese medicine Pulsatilla , anemoside B4(ANE), with different contents were loaded into the electrospinning solution to construct CS-PVA-ANE nanofibrous mats. The developed CS-PVA-ANE wound dressing materials exhibited multifunctional properties including prominent water absorption, biomimetic elastic mechanical properties, and sustained ANE releasing behavior, as well as outstanding hemostatic properties. The in vitro studies showed that the CS-PVA-ANE nanofiber mats could significantly suppress lipopolysaccharide (LPS)-stimulated differentiation of pro-inflammatory (M1) macrophage subsets, and notably reduce the reactive oxygen species (ROS) generation, as well as obviously decrease inflammatory cytokine release. The in vivo animal studies showed that the CS-PVA-ANE nanofiber mats promoted the healing of diabetic wounds by significantly enhancing wound closure rates, accelerating excellent angiogenesis, promoting re-epithelization and collagen matrix deposition throughout all stages of wound healing. The present study demonstrated that CS-PVA-ANE nanofiber mats could effectively shorten the wound-healing time by inhibiting inflammatory activity, which makes them promising candidates for the treatment of hard-to-heal wounds caused by diabetes.

The refractory diabetic wound has remained a worldwide challenge as one of the major health problems. The impaired angiogenesis phase during diabetic wound healing partly contributes to the pathological process. MicroRNA (miRNA) is an essential regulator of gene expression in crucial biological processes and is a promising nucleic acid drug in therapeutic fields of the diabetic wound. However, miRNA therapies have limitations due to lacking an effective delivery system. In the present study, we found a significant reduction of miR-31-5p expression in the full-thickness wounds of diabetic mice compared to normal mice. Further, miR-31-5p has been proven to promote the proliferation, migration, and angiogenesis of endothelial cells. Thus, we conceived the idea of exogenously supplementing miR-31-5p mimics to treat the diabetic wound. We used milk-derived exosomes as a novel system for miR-31-5p delivery and successfully encapsulated miR-31-5p mimics into milk exosomes through electroporation. Then, we proved that the miR-31-5p loaded in exosomes achieved higher cell uptake and was able to resist degradation. Moreover, our miRNA-exosomal formulation demonstrated dramatically improved endothelial cell functions in vitro , together with the promotion of angiogenesis and enhanced diabetic wound healing in vivo . Collectively, our data showed the feasibility of milk exosomes as a scalable, biocompatible, and cost-effective delivery system to enhance the bioavailability and efficacy of miRNAs.

BACKGROUND Wound healing is a dynamic and complex process that is regulated by a variety of factors and pathways. This study sought to identify the mechanisms of the four-herb Chinese medicine ANBP in enhancing wound repair. MATERIAL AND METHODS By comparing the group treated with ANBP for 6 h (Z6h) with the corresponding control group (C6h), we used the new high-throughput differential acetylation proteomics method to explore the mechanism of ANBP treatment and analyse and identify new targets of ANBP for promoting wound healing. RESULTS ANBP promoted skin wound healing in mice; the wound healing process was accelerated and the wound healing time was shortened (P<0.05). The upregulated proteins were distributed mostly in the mitochondria to nuclear respiratory chain complexes and cytoplasmic vesicles. The dominant pathways for upregulated proteins were fatty acid metabolism, pyruvate metabolism, and tricarboxylic acid cycle. Pdha1 was upregulated with the most acetylation sites, while the downregulated Ncl, and Pfkm were most acetylated. CONCLUSIONS The findings from our study showed that ANBP improved cell aerobic respiration through enhanced glycolysis, pyruvic acid oxidative decarboxylation, and the Krebs cycle to produce more ATP for energy consumption, thus accelerating wound repair of skin.

To undertake a reliable analysis of injury severity in road traffic accidents, a complete understanding of important attributes is essential. As a result of the shift from traditional statistical parametric procedures to computer-aided methods, machine learning approaches have become an important aspect in predicting the severity of road traffic injuries. The paper presents a hybrid feature selection-based machine learning classification approach for detecting significant attributes and predicting injury severity in single and multiple-vehicle accidents. To begin, we employed a Random Forests (RF) classifier in conjunction with an intrinsic wrapper-based feature selection approach called the Boruta Algorithm (BA) to find the relevant important attributes that determine injury severity. The influential attributes were then fed into a set of four classifiers to accurately predict injury severity (Naive Bayes (NB), K-Nearest Neighbor (K-NN), Binary Logistic Regression (BLR), and Extreme Gradient Boosting (XGBoost)). According to BA's experimental investigation, the vehicle type was the most influential factor, followed by the month of the year, the driver's age, and the alignment of the road segment. The driver's gender, the presence of a median, and the presence of a shoulder were all found to be unimportant. According to classifier performance measures, XGBoost surpasses the other classifiers in terms of prediction performance. Using the specified attributes, the accuracy, Cohen's Kappa, F1-Measure, and AUC-ROC values of the XGBoost were 82.10%, 0.607, 0.776, and 0.880 for single vehicle accidents and 79.52%, 0.569, 0.752, and 0.86 for multiple-vehicle accidents, respectively., Competing Interests: The authors have declared that no competing interests exist.

Vehicle-tree collisions are the most common type of road crash with fixed obstacle in Czech Republic. Based on the literature review and using real world in-depth crash data, this paper aims to define factors, which significantly influence the injury severity of single vehicle-tree crashes. In-depth data provide a comprehensive view to the failure on the system infrastructure-human-vehicle related to crash, the in-depth crash database include very detailed information related to infrastructure, vehicle, human failure and crash participants characteristics and their medical condition and also crash reconstruction. Multinomial logistic regression and generalized linear mixed model were used to determine the individual effect of each predictor. The statistically significant variables were the day period, trunk diameter and impact speed. Using multinomial logistic regression shows also vehicle age as statistically significant. Obtained results can help to efficiently direct countermeasures not only on the road infrastructure-e.g. speed reduction in selected locations with specified tree character. However, the emphasis should be also focused on driver behaviour., Competing Interests: The authors have declared that no competing interests exist.

Traumatic injury is a major cause of morbidity and mortality worldwide, despite significant advances in treatments. Most deaths occur either very early, through massive head trauma/CNS injury or exsanguination (despite advances in transfusion medicine), or later after injury often through multiple organ failure and secondary infection. Extracellular vesicles (EVs) are known to increase in the circulation after trauma and have been used to limited extent as diagnostic and prognostic markers. More intriguingly, EVs are now being investigated as both causes of pathologies post trauma, such as trauma-induced coagulopathy, and as potential treatments. In this review, we highlight what is currently known about the role and effects of EVs in various aspects of trauma, as well as exploring current literature from investigators who have begun to use EVs therapeutically to alter the physiology and pathology of traumatic insults. The potential effectiveness of using EVs therapeutically in trauma is supported by a large number of experimental studies, but there is still some way to go before we understand the complex effects of EVs in what is already a complex disease process., (©2021 Society for Leukocyte Biology.)

Skin substitutes can provide a temporary or permanent treatment option for chronic wounds. The selection of skin substitutes depends on several factors, including the type of wound and its severity. Full-thickness skin grafts (SGs) require a well-vascularised bed and sometimes will lead to contraction and scarring formation. Besides, donor sites for full-thickness skin grafts are very limited if the wound area is big, and it has been proven to have the lowest survival rate compared to thick- and thin-split thickness. Tissue engineering technology has introduced new advanced strategies since the last decades to fabricate the composite scaffold via the 3D-bioprinting approach as a tissue replacement strategy. Considering the current global donor shortage for autologous split-thickness skin graft (ASSG), skin 3D-bioprinting has emerged as a potential alternative to replace the ASSG treatment. The three-dimensional (3D)-bioprinting technique yields scaffold fabrication with the combination of biomaterials and cells to form bioinks. Thus, the essential key factor for success in 3D-bioprinting is selecting and developing suitable bioinks to maintain the mechanisms of cellular activity. This crucial stage is vital to mimic the native extracellular matrix (ECM) for the sustainability of cell viability before tissue regeneration. This comprehensive review outlined the application of the 3D-bioprinting technique to develop skin tissue regeneration. The cell viability of human skin cells, dermal fibroblasts (DFs), and keratinocytes (KCs) during in vitro testing has been further discussed prior to in vivo application. It is essential to ensure the printed tissue/organ constantly allows cellular activities, including cell proliferation rate and migration capacity. Therefore, 3D-bioprinting plays a vital role in developing a complex skin tissue structure for tissue replacement approach in future precision medicine.

To explore the regulation of keratinocyte growth factor (KGF) in the process of repairing rat skin wounds by taspine hydrochloride (TA/HCl), 45 male Sprague-Dawley (SD) rats were purchased and divided into an experimental group, a dimethyl sulfoxide (DMSO) control group, and a basic fibroblast growth factor (bFGF) control group, each with 15 only. A back trauma model was innovatively adopted to prevent rats from biting and contaminating. The wound healing time and healing rate of the rat, and the Hydroxyproline (Hyp) and KGF expressions were observed. Morphological changes of wound tissue and the number of capillaries were observed after hematoxylin-eosin (HE) staining. The results showed that wound healing rate of experimental group and bFGF group was significantly higher than that of DMSO group ( P < 0.05) after 2-15 days, and wound healing time of experimental group was 18 days, which was significantly lower than that of the DMSO group ( P < 0.05). Expression levels of Hyp and KGF in the granulation tissue of rats in the experimental group were much higher than those in the DMSO control group after trauma ( P < 0.05). In early stage of wound tissue repair, the number of new capillaries formed in experimental group was significantly higher than that in DMSO control group ( P < 0.05). In summary, this study innovatively focused on KGF. The mechanism of TA/HCL promoting rat skin wound healing was closely related to KGF.

Chronic wound is a serious medical issue due to its high prevalence and complications; hyperbaric oxygen therapy (HBOT) is also considered in comprehensive treatment. Clinical trials, including large meta-analyses bring inconsistent results about HBOT efficacy. This review is summarizing the possible effect of HBOT on the healing of chronic wound models at the cellular level. HBOT undoubtedly escalates the production of reactive oxygen and nitrogen radicals (ROS and RNS), which underlie both the therapeutic and toxic effects of HBOT on certain tissues. HBOT paradoxically elevates the concentration of Hypoxia inducible factor (HIF) 1 by diverting the HIF-1 degradation to pathways that are independent of the oxygen concentration. Elevated HIF-1 stimulates the production of different growth factors, boosting the healing process. HBOT supports synthesis of Heat shock proteins (HSP), which are serving as chaperones of HIF-1. HBOT has antimicrobial effect, increases the effectiveness of some antibiotics, stimulates fibroblasts growth, collagen synthesis and suppresses the activity of proteolytic enzymes like matrix metalloproteinases. All effects of HBOT were investigated on cell cultures and animal models, the limitation of their translation is discussed at the end of this review.

Targeted disruption of E2f2 in mice causes T-cell hyperactivation and a disproportionate cell cycle entry upon stimulation. However, E2f2 -/- mice do not develop a lymphoproliferative condition. We report that E2f2 plays a Fas-dependent anti-apoptotic function in vitro and in vivo. TCR-stimulated murine E2f2 -/- T cells overexpress the proapoptotic genes Fas and FasL and exhibit enhanced apoptosis, which is prevented by treatment with neutralizing anti-FasL antibodies. p53 pathway is activated in TCR-stimulated E2f2 -/- lymphocytes, but targeted disruption of p53 in E2f2 -/- mice does not abrogate Fas/FasL expression or apoptosis, implying a p53-independent apoptotic mechanism. We show that E2f2 is recruited to Fas and FasL gene promoters to repress their expression. in vivo, E2f2 -/- mice are prone to develop immune-mediated liver injury owing to an aberrant lymphoid Fas/FasL activation. Taken together, our results suggest that E2f2-dependent inhibition of Fas/FasL pathway may play a direct role in limiting the development of immune-mediated pathologies.

Significance: Negative pressure wound therapy (NPWT) has become a valuable adjunct in the treatment of acute and chronic wounds in several surgical disciplines. Retained foams are among its side effects, and they pose a rare but devastating complication at the site of this therapy, which might be associated with wound-healing complications, infection persistence, repeated surgical revisions, and prolonged antibiotic courses. Recent Advances: In the past 15 years, an increasing number of studies have identified this potential problem. Although the exact incidence remains unknown, initial studies have indicated rates of up to 10% in large collectives being treated by NPWT. Critical Issues: The lack of radiopaque markers does not allow for the visual control of retained foams using plain radiographs. Further imaging methods ( e.g ., CT and MRI) also do not help in adequate differential diagnosis. The lack of routine documentation of the number, type, and localization of the inserted foam(s) and unplanned surgery with a different surgical team pose risk factors for foam retainment. Future Directions: Introducing new documentation records for wounds treated with NPWT is recommended. At foam removal, all dressing materials should be examined for integrity. The development of foams with radiopaque markers by the industry, such as those routinely used in surgical gauze swabs, might also be a useful step to minimize the risk of foam retainment within wounds.

miRNAs are broad participants in vertebrate biological processes, and they are also the major players in pathological processes. miR-125a-5p was recently found a modulator in the progression of osteoarthritis (OA). Our study was aimed to explore the role and underlying mechanisms of miR-125a-5p-abundant exosomes derived from mesenchymal stem cells (MSC) on OA progression. We separated bone marrow mesenchymal stem cells (BMSCs) as well as the exosomes from traumatic OA patients. The immunofluorescence and cartilage staining were implemented for the observation and the assessment on endocytosis of chondrocytes and exosomal miR-125a-5p efficacy to cartilage degradation. Dual luciferase reporter assay was performed to verified the relationship between miR-125a-5p and E2F2. Then, the function of exosomal miR-125a-5p were examined on chondrocyte degeneration in vitro and in vivo . Our findings indicated that E2F2 expression was elevated while the miR-125a-5p was down in traumatic OA cartilage tissue, showing a negative correlation of the former and the latter. miR-125a-5p targets E2F2 in traumatic OA cartilage tissue and leads to the down-expression of E2F2. The E2F2 expression in chondrocytes was decreased after internalization of exosomes. We additionally found that BMSCs-derived exosomes were rich in miR-125a-5p content and chondrocytes can have it internalized. miR-125a-5p is endowed with a trait of accelerating chondrocytes migration, which is going along with the up-expressions of Collagen II, aggrecan and SOX9 and the down-expression of MMP-13 in vitro . Besides that, the mice model with post-traumatic OA turned out that exosomal miR-125a-5p might beget an alleviation in chondrocyte extracellular matrix degradation. All these outcomes revealed that BMSCs-derived exosomal miR-125a-5p is a positive regulator for chondrocyte migration and inhibit cartilage degeneration We thus were reasonable to believe that transferring of exosomal miR-125a-5p is a prospective strategy for OA treatment.

ABSTRACT Melioidosis is a serious infectious disease endemic in Southeast Asia, Northern Australia and has been increasingly reported in other tropical and subtropical regions in the world. Percutaneous inoculation through cuts and wounds on the skin is one of the major modes of natural transmission. Despite cuts in skin being a major route of entry, very little is known about how the causative bacterium Burkholderia pseudomallei initiates an infection at the skin and the disease manifestation at the skin known as cutaneous melioidosis. One key issue is the lack of suitable and relevant infection models. Employing an in vitro 2D keratinocyte cell culture, a 3D skin equivalent fibroblast-keratinocyte co-culture and ex vivo organ culture from human skin, we developed infection models utilizing surrogate model organism Burkholderia thailandensis to investigate Burkholderia -skin interactions. Collectively, these models show that the bacterial infection was largely limited at the wound's edge. Infection impedes wound closure, triggers inflammasome activation and cellular extrusion in the keratinocytes as a potential way to control bacterial infectious load at the skin. However, extensive infection over time could result in the epidermal layer being sloughed off, potentially contributing to formation of skin lesions.

Injury to the optic nerve, termed, traumatic optic neuropathy (TON) is a known comorbidity of traumatic brain injury (TBI) and is now known to cause chronic and progressive retinal thinning up to 35 years after injury. Although animal models of TBI have described the presence of optic nerve degeneration and research exploring acute mechanisms is underway, few studies in humans or animals have examined chronic TON pathophysiology outside the retina. We used a closed-head weight-drop model of TBI/TON in 6-week-old male C57BL/6 mice. Mice were euthanized 7-, 14-, 30-, 90-, and 150-days post-injury (DPI) to assess histological changes in the visual system of the brain spanning a total of 12 regions. We show chronic elevation of FluoroJade-C, indicative of neurodegeneration, throughout the time course. Intriguingly, FJ-C staining revealed a bimodal distribution of mice indicating the possibility of subpopulations that may be more or less susceptible to injury outcomes. Additionally, we show that microglia and astrocytes react to optic nerve damage in both temporally and regionally different ways. Despite these differences, astrogliosis and microglial changes were alleviated between 14-30 DPI in all regions examined, perhaps indicating a potentially critical period for intervention/recovery that may determine chronic outcomes.

Childhood trauma (ChT) is a risk factor for psychosis. Negative lifestyle factors such as rumination, negative schemas, and poor diet and exercise are common in psychosis. The present study aimed to perform a network analysis of interactions between ChT and negative lifestyle in patients and controls. We used data of patients with early-stage psychosis (n = 500) and healthy controls (n = 202). Networks were constructed using 12 nodes from five scales: the Brief Core Schema Scale (BCSS), Brooding Scale (BS), Dietary Habits Questionnaire, Physical Activity Rating, and Early Trauma Inventory Self Report-Short Form (ETI). Graph metrics were calculated. The nodes with the highest predictability and expected influence in both patients and controls were cognitive and emotional components of the BS and emotional abuse of the ETI. The emotional abuse was a mediator in the shortest pathway connecting the ETI and negative lifestyle for both groups. The negative others and negative self of the BCSS mediated emotional abuse to other BCSS or BS for patients and controls, respectively. Our findings suggest that rumination and emotional abuse were central symptoms in both groups and that negative others and negative self played important mediating roles for patients and controls, respectively.Trial Registration: ClinicalTrials.gov identifier: CUH201411002., (© 2021. The Author(s).)

Introduction: The interaction of increasing age, Injury Severity Score (ISS), and complications is not well described in geriatric trauma patients. We hypothesized that failure to rescue rate from any complication worsens with age and injury severity., Methods: The National Trauma Data Bank (NTDB) was queried for injured patients aged 65 years or older from January 1, 2013 through December 31, 2016. Demographics and injury characteristics were used to compare groups. Mortality rates were calculated across subgroups of age and ISS, and captured with heatmaps. Multivariable logistic regression was performed to identify independent predictors of mortality., Results: 614,496 geriatric trauma patients were included; 151,880 (24.7%) experienced a complication. Those with complications tended to be older, female, non-white, have non-blunt mechanism, higher ISS, and hypotension on arrival. Overall mortality was highest (19%) in the oldest (≥86 years old) and most severely injured (ISS ≥ 25) patients, with constant age increasing across each ISS group was associated with a 157% increase in overall mortality ( P < .001, 95% CI: 148-167%). Holding ISS stable, increasing age group was associated with a 48% increase in overall mortality ( P < .001, 95% CI: 44-52%). After controlling for standard demographic variables at presentation, the existence of any complication was an independent predictor of overall mortality in geriatric patients (OR: 2.3; 95% CI: 2.2-2.4)., Conclusions: Any complication was an independent risk factor for mortality, and scaled with increasing age and ISS in geriatric patients. Differences in failure to rescue between populations may reflect critical differences in physiologic vulnerability that could represent targets for interventions.

Background: Given the high prevalence of wounds and their challenging treatment, the research of therapies to improve wound healing is of great clinical interest. In addition, the general consequences of developing chronic wounds constitute a large health economic aspect, which underscores the interest in the development of efficient treatment strategies. Direct cold atmospheric plasma (di&#95;CAP) has been shown to have beneficial effects on microcirculation of human tissue (Kisch et al., 2016a). It also affects microbial settlements, which may have supportive effects on wound healing processes (Balzer et al., 2015). To treat these adequately, in our view, the positive effects on wound healing should be objectified by application on standardized wounds. However, wound healing is a complex process, depending on nutrient and oxygen supply by cutaneous blood circulation. In spite of microcirculation has been shown to improve in healthy skin by CAP, a quantification of the effect in a standardized wound model has never been evaluated (Kisch et al., 2016a). Based on this, we hypothesize that CAP also influences the microcirculation in standardized acute wounds in a prospective cohort study., Methods: Microcirculatory data of 20 healthy subjects (14 males, 6 females; mean age 40.85 ± 15.84 years; BMI 26.83 ± 7.27 kg/m2) were recorded continuously at a standardized acute wound after skin transplantation (donor site) at the thigh. Under standardized conditions, microcirculatory measurements were performed using a combined laser Doppler and photospectrometry system. After baseline measurement, CAP was applied by a dielectric barrier discharge (DBD) plasma device for 90 s to the acute wound area. Immediately after the application, cutaneous microcirculation was assessed for 30 min (min) at the same site., Results: After CAP application, tissue oxygen saturation immediately increased by 5% (92,66 ± 4,76% vs. Baseline 88,21 ± 6,52%, p < 0,01) in the first 60 s and remained significantly elevated for 4 min. Capillary blood flow increased by 19.3% within the first minute of CAP therapy (220.14 ± 65.91 AU vs. Baseline 184.52 ± 56.77 AU, p < 0.001). The statistically highly significant increase in blood flow continued over the entire measurement time. A maximum value was shown in the blood flow in the 15th minute (232.15 ± 58.90 AU, p < 0.001) according to CAP application. With regard to the output measurement, it represents a percentage increase of 25.8%. The measurement of post-capillary venous filling pressure at a tissue depth of 6-8 mm was 59.39 ± AU 12.94 at baseline measurement. After application, there were no significant changes., Conclusion: CAP increases cutaneous tissue oxygen saturation and capillary blood flow at the standardized acute wound healing model. These results support recently published data on wound healing after CAP treatment. However, further studies are needed to determine if this treatment can improve the reduced microcirculation in chronic wounds. Moreover, repetitive application protocols have to be compared with a single session treatment approach., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Significance: We introduce and evaluate emerging devices and modalities for wound size imaging and also promising image processing tools for smart wound assessment and monitoring. Recent Advances: Some commercial devices are available for optical wound assessment but with limited possibilities compared to the power of multimodal imaging. With new low-cost devices and machine learning, wound assessment has become more robust and accurate. Wound size imaging not only provides area and volume but also the proportion of each tissue on the wound bed. Near-infrared and thermal spectral bands also enhance the classical visual assessment. Critical Issues: The ability to embed advanced imaging technology in portable devices such as smartphones and tablets with tissue analysis software tools will significantly improve wound care. As wound care and measurement are performed by nurses, the equipment needs to remain user-friendly, enable quick measurements, provide advanced monitoring, and be connected to the patient data management system. Future Directions: Combining several image modalities and machine learning, optical wound assessment will be smart enough to enable real wound monitoring, to provide clinicians with relevant indications to adapt the treatments and to improve healing rates and speed. Sharing the wound care histories of a number of patients on databases and through telemedicine practice could induce a better knowledge of the healing process and thus a better efficiency when the recorded clinical experience has been converted into knowledge through deep learning.

The Emergency Medical Retrieval and Transfer Service for Wales launched in 2015. This service delivers senior pre-hospital doctors and advanced critical care practitioners to the scene of time-critical life- and limb-threatening incidents to provide advanced decision-making and pre-hospital clinical care. The impact of the service on 30-day mortality was evaluated retrospectively using a data linkage system. The study included patients who sustained moderate-to-severe blunt traumatic injuries (injury severity score ≥ 9) between 27 April 2015 and 30 November 2018. The association between pre-hospital management by the Emergency Medical Retrieval and Transfer Service and 30-day mortality was assessed using multivariable logistic regression. In total, data from 4035 patients were analysed, of which 412 (10%) were treated by the Emergency Medical Retrieval and Transfer Service. A greater proportion of patients treated by the Emergency Medical Retrieval and Transfer Service had an injury severity score ≥ 16 and Glasgow coma scale ≤ 12 (288 (70%) vs. 1435 (40%) and 126 (31%) vs. 325 (9%), respectively). The unadjusted 30-day mortality rate was 11.7% for patients managed by the Emergency Medical Retrieval and Transfer Service compared with 9.6% for patients managed by standard pre-hospital care services. However, after adjustment for differences in case-mix, the 30-day mortality rate for patients treated by the Emergency Medical Retrieval and Transfer Service was 37% lower (adjusted odds ratio 0.63 (95%CI 0.41-0.97); p = 0.037). The introduction of an emergency medical retrieval service was associated with a reduction in 30-day mortality for patients with blunt traumatic injury., (© 2021 The Authors. Anaesthesia published by John Wiley & Sons Ltd on behalf of Association of Anaesthetists.)

Limb wounds are common in horses and often develop complications. Intravenous multipotent mesenchymal stromal cell (MSC) therapy is promising but has risks associated with intravenous administration and unknown potential to improve cutaneous wound healing. The objectives were to determine the clinical safety of administering large numbers of allogeneic cord blood-derived MSCs intravenously, and if therapy causes clinically adverse reactions, accelerates wound closure, improves histologic healing, and alters mRNA expression of common wound cytokines. Wounds were created on the metacarpus of 12 horses. Treatment horses were administered 1.51-2.46 × 10 8 cells suspended in 50% HypoThermosol FRS, and control horses were administered 50% HypoThermosol FRS alone. Epithelialization, contraction, and wound closure rates were determined using planimetric analysis. Wounds were biopsied and evaluated for histologic healing characteristics and cytokine mRNA expression. Days until wound closure was also determined. The results indicate that 3/6 of treatment horses and 1/6 of control horses experienced minor transient reactions. Treatment did not accelerate wound closure or improve histologic healing. Treatment decreased wound size and decreased all measured cytokines except transforming growth factor-β3. MSC intravenous therapy has the potential to decrease limb wound size; however, further work is needed to understand the clinical relevance of adverse reactions.

Embryos repair wounds rapidly, with no inflammation or scarring, in a process that involves polarization of the actomyosin cytoskeleton. Actomyosin polarization results in the assembly of a contractile cable around the wound that drives wound closure. Here, we demonstrate that a contractile actomyosin cable is not sufficient for rapid wound repair in Drosophila embryos. We show that wounding causes activation of the serine/threonine kinase p38 mitogen-activated protein kinase (MAPK) in the cells adjacent to the wound. p38 activation reduces the levels of wound-induced reactive oxygen species in the cells around the wound, limiting wound size. In addition, p38 promotes an increase in volume in the cells around the wound, thus facilitating the collective cell movements that drive rapid wound healing. Our data indicate that p38 regulates cell volumes through the sodium-potassium-chloride cotransporter NKCC1. Our work reveals cell growth and cell survival as cell behaviors critical for embryonic wound repair., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Wound healing is impaired with advanced age and certain chronic conditions, such as diabetes and obesity. Moreover, common cancer treatments, including chemotherapy and radiation, can cause unintended tissue damage and impair wound healing. Available wound care treatments are not always effective, as some wounds fail to heal or recur after treatment. Hence, a more thorough understanding of the pathophysiology of chronic, nonhealing wounds may offer new ideas for the development of effective wound care treatments. Cancers are sometimes referred to as wounds that never heal, sharing mechanisms similar to wound healing. We describe in this review how cellular senescence and the senescence-associated secretory phenotype (SASP) contribute to chronic wounds versus cancer., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: To report the clinical outcomes of patients with chronic parotid sialadenitis treated with superficial parotidectomy, and to review the literature., Methods: A retrospective case series was conducted of all patients undergoing parotidectomy for chronic parotid sialadenitis at our institution between 2009 and 2018., Results: Eighteen superficial parotidectomies were performed, resulting in complete symptom resolution in 17 patients. There was only one recurrence, of a milder form of the disease, requiring no specific treatment. Eight temporary post-operative facial nerve palsies and one permanent palsy occurred. Further complications included post-operative wound haematoma, seroma, Frey's syndrome, neuropathic pain and wound infection., Conclusion: Superficial parotidectomy is sufficient to control patient symptoms, avoiding the increased morbidity associated with near-total parotidectomy. The literature does not point to a clear difference in either the incidence of recurrence or the risk of a facial nerve palsy between the two procedures. Furthermore, the symptoms attributed to recurrence are often not severe enough to warrant salvage near-total parotidectomy.

Bacterial infection and its induced oxidative stress as major clinical challenge during wound healing call for an urgent response for the development of medical dressings with multi-functions, such as antioxidant and antibacterial. To meet this demand, copper metal organic framework nanoparticles (HKUST NPs) and carboxymethyl chitosan-g-glutathione (CMCs-GSH) were synthesized and characterized. By embedding HKUST NPs into PAM/CMCs-GSH hydrogel (AOH), we developed a novel hydrogel dressing (HKUST-Hs) with dual effects of antibacterial and antioxidant. The morphology, swelling behavior, oxidation resistance and antibacterial properties of HKUST-Hs were investigated as well as the slow-release behavior of copper ions. Full-thickness cutaneous wound model of rats was created to assess the promoting effect of HKUST-Hs on wound healing. We found that HKUST NPs could be well dispersed in HKUST-Hs by shielding the positive charge of copper ions, and thus copper ions released were uniformly distributed and chelated with CMCs-GSH to promote the swelling stability of HKUST-Hs. Also, HKUST-Hs exhibited good free radical scavenging ability in vitro antioxidant assay. Meanwhile, a gradient sustained-release system of copper ions was formed in HKUST-Hs owing to the inhibition of HKUST NPs to copper release and the chelation of CMCs-GSH, which effectively inhibited the explosive release of copper ions and prolonged the release period, thereby reducing cytotoxicity. In vitro antibacterial test demonstrated there was synergistic antibacterial effect between the slow-released copper ions and CMCs-GSH, which improved the antibacterial activity and antibacterial persistence of HKUST-Hs. Finally, HKUST-Hs accelerated wound healing in vivo by continuously killing bacteria and inhibiting oxidative stress., (Copyright © 2021 Elsevier B.V. All rights reserved.)

There have been reports of improved pregnancy rates after performing intentional endometrial injuries, also known as endometrial scratching, in patients with recurrent implantation failure. In our previous study on intentional endometrial injury, we found an increased expression of matrix metalloproteinase (MMP)-3 following induced injuries to the mice endometrium. In the current study, we further examine whether the rise in MMP-3 could contribute to increased angiogenesis. Female C57B1/6 mice were obtained at 12 weeks of age, and intentional endometrial injuries were induced mechanically in the left uterine horns. Using the appropriate media, uterine-washes were performed on the injured and uninjured (control) horns of the harvested uteri. The uterine tissues were further processed for tissue lysates, histopathology and immunohistochemistry. The results show that intentional endometrial injuries caused an increase in secreted LPA in the injured horns, which were detected in the uterine-washes. In addition, LPA induced increased production of TNF-α in human endometrial epithelial cells (hEEpCs). Furthermore, TNF-α appeared to induce differential and cell-specific upregulation of the MMPs: MMP-3 was upregulated in the epithelial (hEEpCs), while MMP-9 was upregulated in the endothelial cells (human endometrial endothelial cells; hEEnCs). The upregulation of MMP-3 appeared to be necessary for the activation of MMP-9, whose active form stimulated the formation of vessel-like structure by the hEEnCs. The results of this study suggest that there may be enhanced angiogenesis following intentional endometrial injuries, which is mediated in part by TNF-α-induced and MMP-3-activated MMP-9 production., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Biomaterials are being extensively used in regenerative medicine including tissue engineering applications, as these enhance tissue development, repair, and help in the process of angiogenesis. Wound healing is a crucial biological process of regeneration of ruptured tissue after getting injury to the skin and other soft tissue in humans and animals. Besides, the accumulation of microbial biofilms around the wound surface can increase the risk and physically obstruct the wound healing activity, and may even lead to amputation. Hence, in both acute and chronic wounds, prominent biomaterials are required for wound healing along with antimicrobial agents. This review comprehensively addresses the antimicrobial and wound healing effects of chitosan, chitin, cellulose acetate, hyaluronic acid, pullulan, bacterial cellulose, fibrin, alginate, etc. based wound dressing biomaterials fabricated with natural resources such as honey, plant bioactive compounds, and marine-based polymers. Due to their excellent biocompatibility and biodegradability, bioactive compounds derived from honey, plants, and marine resources are commonly used in biomedical and tissue engineering applications. Different types of polymer-based biomaterials including hydrogel, film, scaffold, nanofiber, and sponge dressings fabricated with bioactive agents including honey, curcumin, tannin, quercetin, andrographolide, gelatin, carrageenan, etc., can exhibit significant wound healing process in, diabetic wounds, diabetic ulcers, and burns, and help in cartilage repair along with good biocompatibility and antimicrobial effects. Among the reviewed biomaterials, carbohydrate polymers such as chitosan-based biomaterials are prominent and widely used for wound healing applications followed by hyaluronic acid and alginate-based biomaterials loaded with honey, plant, and marine compounds. This review first provides an overview of the vast natural resources used to formulate different biomaterials for the treatment of antimicrobial, acute, and chronic wound healing processes., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Abstract: The diagnosis homicide by unspecified means (HUM) is used to categorize deaths occurring under suspicious or criminal circumstances, but a specific cause of death cannot be identified. In 2010, Matshes and Lew (Am J Forensic Med Pathol. 2010;31(2):174-177) presented a HUM cases series, from which they derived 5 diagnostic criteria; however, the accuracy of these criteria has not been assessed.To identify a validation cohort, Cuyahoga County Medical Examiner's Office records were searched from 2008 to 2019 for cases certified as HUM. Thirteen cases were identified; on review, all cases fulfilled criteria 1, 4, and 5. Only 1 case had a potential anatomic cause of death identified (criterion 2).However, in 3 cases, toxicologic analyses could not be conducted because of skeletonization; in 2 cases, the decedents tested positive for cocaine/benzoylecgonine but were found in proximity to other victims for whom a specific violent cause of death was determined. By strict reading of criterion 3, these cases would have been excluded from the diagnosis of HUM. Perpetrators confessed to homicide in 7 cases, including the 5 cases that failed the toxicologic criterion. The 2010 diagnostic criteria are a reasonable foundation for the determination of HUM; modification of criterion 3 would provide improved flexibility based on clinical judgment., Competing Interests: The authors report no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Pain is a central feature of soft tissue trauma, which under certain contexts, results in aberrant osteochondral differentiation of tissue-specific stem cells. Here, the role of sensory nerve fibers in this abnormal cell fate decision is investigated using a severe extremity injury model in mice. Soft tissue trauma results in NGF (Nerve growth factor) expression, particularly within perivascular cell types. Consequently, NGF-responsive axonal invasion occurs which precedes osteocartilaginous differentiation. Surgical denervation impedes axonal ingrowth, with significant delays in cartilage and bone formation. Likewise, either deletion of Ngf or two complementary methods to inhibit its receptor TrkA (Tropomyosin receptor kinase A) lead to similar delays in axonal invasion and osteochondral differentiation. Mechanistically, single-cell sequencing suggests a shift from TGFβ to FGF signaling activation among pre-chondrogenic cells after denervation. Finally, analysis of human pathologic specimens and databases confirms the relevance of NGF-TrkA signaling in human disease. In sum, NGF-mediated TrkA-expressing axonal ingrowth drives abnormal osteochondral differentiation after soft tissue trauma. NGF-TrkA signaling inhibition may have dual therapeutic use in soft tissue trauma, both as an analgesic and negative regulator of aberrant stem cell differentiation., (© 2021. The Author(s).)

Specificity and timing of synapse disassembly in the CNS are essential to learning how individual circuits react to neurodegeneration of the postsynaptic neuron. In sensory systems such as the mammalian retina, synaptic connections of second-order neurons are known to remodel and reconnect in the face of sensory cell loss. Here we analyzed whether degenerating third-order neurons can remodel their local presynaptic connectivity. We injured adult retinal ganglion cells by transiently elevating intraocular pressure. We show that loss of presynaptic structures occurs before postsynaptic density proteins and accounts for impaired transmission from presynaptic neurons, despite no evidence of presynaptic cell loss, axon terminal shrinkage, or reduced functional input. Loss of synapses is biased among converging presynaptic neuron types, with preferential loss of the major excitatory cone-driven partner and increased connectivity with rod-driven presynaptic partners, demonstrating that this adult neural circuit is capable of structural plasticity while undergoing neurodegeneration., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

This review summarizes the four processes of wound healing in the human body (hemostasis, inflammatory, proliferation, and remodeling) and the most current research on the most important factors affecting cutaneous wound healing and the underlying cellular and/or molecular pathways. Local factors, including temperature, oxygenation, and infection, and systemic factors, such as age, diabetes, sex hormones, genetic components, autoimmune diseases, psychological stress, smoking and obesity are also addressed. A better understanding of the role of these factors in wound repair could result in the development of therapeutics that promote wound healing and resolve affected wounds. Additionally, natural products obtained from plants and animals are critical targets for the discovery of novel biologically significant pharmacophores, such as medicines and agrochemicals. This review outlines the most recent advances in naturally derived targeted treatment for wound healing. These are plant-derived natural products, insect-derived natural products, marine-derived natural products, nanomaterial-based wound-healing therapeutics (metal- and non-metal-based nanoparticles), and natural product-based nanomedicine to improve the future direction of wound healing. Natural products extracted from plants and animals have advanced significantly, particularly in the treatment of wound healing. As a result, the isolation and extraction of bioactive compounds from a variety of sources can continue to advance our understanding of wound healing. Undescribed bioactive compounds or unexplored formulations that could have a role in today's medicinal arsenal may be contained in the abundance of natural products and natural product derivatives., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Trauma remains a major public health problem worldwide, marked as the fourth leading cause of death among all diseases. Trauma patients who survived at initial stages in the Emergency Department (ED), have significantly higher chances of mortality due to sepsis associated complications in the ICU at the later stage. There is paucity of literature regarding the role of circulating monocytes subsets and development of sepsis complications following trauma haemorrhagic shock (THS). The study was conducted to investigate the circulating level of monocyte subsets (Classical, Inflammatory, and Patrolling) and its functions in patients with acute post-traumatic sepsis. A total 72, THS patients and 30 age matched healthy controls were recruited. Blood samples were collected at different time points on days 1, 7, and 14 to measure the serum levels of cytokines by Cytometric bead assay (CBA), for the immunophenotyping of monocytes subsets, and also for the cell sorting of monocytes subsets for the functional studies. The circulating levels of monocytes subsets were found to be significantly differs among THS patients, who developed sepsis when compared with others who did not. The levels of patrolling monocytes were elevated in THS patients who developed sepsis and showed negative correlation with Sequential organ failure assessment (SOFA) score on days 7 and 14. Classical monocytes responded strongly to bacterial TLR-agonist (LPS) and produced anti-inflammatory cytokines, whereas patrolling monocytes responded with viral TLR agonist TLR-7/8 (R848) and produced inflammatory cytokines in post-traumatic sepsis patients. In conclusion, this study shows disparity in the behaviour of monocytes subsets in patients with acute post-traumatic sepsis., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Under stress conditions, the metabolic demand for nutrients increases, which, if not met, may slow down or indeed stop the wound from healing, thus, becoming chronic wounds. This study aims to perform a systematic review and meta-analysis of the effect of arginine and glutamine supplementation on wound healing. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed for the systematic review and ten electronic databases were used. Five and 39 human studies met the inclusion criteria for arginine and glutamine, respectively. The overall meta-analysis demonstrated a significant effect of arginine supplementation on hydroxyproline content (MD: 4.49, 95% CI: 3.54, 4.45, p < 0.00001). Regarding glutamine supplementation, there was significant effect on nitrogen balance levels (MD: 0.39, 95% CI: 0.21, 0.58, p < 0.0001), IL-6 levels (MD: -5.78, 95% CI: -8.71, -2.86, p = 0.0001), TNFα levels (MD: -8.15, 95% CI: -9.34, -6.96, p < 0.00001), lactulose/mannitol (L/M) ratio (MD: -0.01, 95% CI: -0.02, -0.01, p < 0.00001), patient mortality (OR: 0.48, 95% CI: 0.32, 0.72, p = 0.0004), C-reactive protein (CRP) levels (MD: -1.10, 95% CI: -1.26, -0.93, p < 0.00001) and length of hospital stay (LOS) (MD: -2.65, 95% CI: -3.10, -2.21, p < 0.00001). Regarding T-cell lymphocytes, a slight decrease was observed, although it failed to reach significance (MD: -0.16, 95% CI: -0.33, 0.01, p = 0.07). Conclusion: The wound healing might be enhanced in one or at various stages by nutritional supplementation in the right dose.

Neutrophils are rapidly recruited to inflammatory sites where their coordinated migration forms clusters, a process termed neutrophil swarming. The factors that modulate early stages of neutrophil swarming are not fully understood, requiring the development of new in vivo models. Using transgenic zebrafish larvae to study endogenous neutrophil migration in a tissue damage model, we demonstrate that neutrophil swarming is a conserved process in zebrafish immunity, sharing essential features with mammalian systems. We show that neutrophil swarms initially develop around an individual pioneer neutrophil. We observed the violent release of extracellular cytoplasmic and nuclear fragments by the pioneer and early swarming neutrophils. By combining in vitro and in vivo approaches to study essential components of neutrophil extracellular traps (NETs), we provide in-depth characterisation and high-resolution imaging of the composition and morphology of these release events. Using a photoconversion approach to track neutrophils within developing swarms, we identify that the fate of swarm-initiating pioneer neutrophils involves extracellular chromatin release and that the key NET components gasdermin, neutrophil elastase, and myeloperoxidase are required for the swarming process. Together our findings demonstrate that release of cellular components by pioneer neutrophils is an initial step in neutrophil swarming at sites of tissue injury., Competing Interests: HI, CL, SA, FK, KH, AK, JH, CM, MK, VK, NH, GL, SR, PE No competing interests declared, (© 2021, Isles et al.)

Phospholipase D (PLD) isoforms PLD1 and PLD2 serve as the primary nodes where diverse signaling pathways converge. However, their isoform-specific functions remain unclear. We showed that PLD1 and PLD2 selectively couple to toll-like receptor 4 (TLR4) and interleukin 4 receptor (IL-4R) and differentially regulate macrophage polarization of M1 and M2 via the LPS-MyD88 axis and the IL-4-JAK3 signaling, respectively. Lipopolysaccharide (LPS) enhanced TLR4 or MyD88 interaction with PLD1; IL-4 induced IL-4R or JAK3 association with PLD2, indicating isozyme-specific signaling events. PLD1 and PLD2 are indispensable for M1 polarization and M2 polarization, respectively. Genetic and pharmacological targeting of PLD1 conferred protection against LPS-induced sepsis, cardiotoxin-induced muscle injury, and skin injury by promoting the shift toward M2; PLD2 ablation intensified disease severity by promoting the shift toward M1. Enhanced Foxp3 + regulatory T cell recruitment also influenced the anti-inflammatory phenotype of Pld1 LyzCre macrophages. We reveal a previously uncharacterized role of PLD isoforms in macrophage polarization, signifying potential pharmacological interventions for macrophage modulation., (© 2020 The Authors. Journal of Cellular Physiology published by Wiley Periodicals LLC.)