Background:Fibrotic scar formation constitutes a significant pathological obstacle that impedes neural regeneration and long-term functional recovery following spinal cord injury (SCI). However, the spatial distribution of key pro-fibrotic mediators within lesion scars and the upstream regulatory mechanisms driving fibroblast activation remain inadequately defined. This study aims to characterize CD36-associated fibrotic remodeling after SCI and to determine whether targeting the c-Jun-Irf8-CD36 axis could attenuate scar formation, improve the regenerative microenvironment, and promote functional recovery. Methods:This study integrated single-cell ribonucleic acid sequencing and spatial transcriptomic profiling to characterize CD36 expression patterns and identify fibroblast subpopulations within SCI scars. Pharmacological interventions were administered in mouse SCI models, using salvianolic acid B (SAB) to inhibit CD36 and T5224 to block AP-1/c-Jun activity. Histological and immunofluorescence analyses were performed to assess fibroblast accumulation, extracellular matrix deposition, angiogenesis, and axonal regeneration, alongside longitudinal behavioral evaluations of locomotor function. Mechanistic validation of the regulatory pathway was achieved through CUT&Tag and dual-luciferase reporter assays to investigate c-Jun-Irf8-CD36 transcriptional regulation, complemented by integrated single-cell/spatial analyses to assess fibroblast subcluster remodeling post-treatment. Results:Spatial and single-cell analyses demonstrated that CD36 is predominantly localized within lesion scars, correlating with fibrotic progression and preferentially upregulated in specific fibroblast subclusters. SAB-mediated CD36 inhibition markedly reduced P4HB+ fibroblast accumulation, alleviated fibrotic deposition, enhanced angiogenesis and axonal regeneration, and improved hindlimb functional recovery. Mechanistically, c-Jun was upregulated in scar regions and indirectly promoted CD36 transcription through Irf8 activation, establishing a c-Jun-Irf8-CD36 signaling axis. CUT&Tag and reporter assays confirmed c-Jun binding to the Irf8 promoter, leading to Irf8-driven CD36 transcription. Similarly, T5224 downregulated CD36 expression, reduced fibroblast aggregation and matrix deposition, facilitated vascular remodeling, and promoted early functional recovery. These findings demonstrate that modulating this signaling pathway can significantly inhibit pathological scar formation and facilitate approximately scar-free healing, thereby providing an ideal microenvironment for tissue regeneration. Multi-omic analyses further revealed that T5224 selectively inhibited the aberrant expansion of CD36+ fibroblast subclusters and reprogrammed their transcriptional states toward a less fibrotic phenotype. Conclusions:The c-Jun-Irf8-CD36 axis serves as a pivotal regulator of fibrotic scar formation after SCI. Targeting this pathway through CD36 inhibition (SAB) or AP-1/c-Jun blockade (T5224) attenuates fibrosis, remodels the scar microenvironment, enhances tissue repair, and promotes functional recovery, highlighting a promising therapeutic strategy for central nervous system injury.
The mitochondrial unfolded protein response (UPRmt) is a conserved mitochondrial stress response that is activated by mitochondrial dysfunction to maintain proteostasis. Although UPRmt has been extensively studied in aging and cancer, its role in trauma and critical illness remains poorly understood. Here, we propose a unifying conceptual framework in which UPRmt functions as a central stress-integration hub that senses and coordinates adaptive responses following acute injury. We systematically review the mechanisms of UPRmt activation triggered by diverse insults and highlight how UPRmt integrates mitochondrial-nuclear communication, and crosstalk with other stress-responses such as the integrated stress response and mitophagy. Beyond cell-autonomous regulation, UPRmt also coordinates systemic adaptation through mitokine-mediated interorgan signaling. Importantly, we emphasize the context-dependent role of UPRmt in trauma and critical illness. Moderate activation promotes mitochondrial recovery, limits reactive oxygen species accumulation, and supports immune cell function, thereby enhancing tissue resilience and repair. In contrast, sustained or dysregulated UPRmt contributes to mitochondrial failure, sterile inflammation, and the progression to systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). Furthermore, we discuss emerging evidence linking UPRmt to immune regulation and inflammatory responses, and propose that targeting key regulatory nodes within this stress-integration network may offer novel therapeutic strategies for a broad spectrum of human diseases. Crucially, we synthesize how UPRmt mechanisms contribute to post-traumatic mitochondrial damage, sterile inflammation, SIRS, and MODS. We propose that targeting key regulatory nodes within this stress-integration network may offer novel therapeutic strategies for trauma, burns, and critical illness.
Chronic non-healing wounds, particularly diabetic foot ulcers, persist as a significant clinical challenge due to the limited availability of therapeutic options and the complexity of their pathological microenvironments. Plant-derived extracellular vesicles (PDEVs), which are nanoscale lipid carriers rich in bioactive molecules, have emerged as a promising therapeutic approach due to their low immunogenicity, antioxidant, anti-inflammatory properties, and their ability to promote angiogenesis. Structurally, the biomaterial protects the integrity of PDEVs and extends their residency through modulated release. Biologically, PDEVs enhance the regenerative potential of the material by profoundly reprogramming the local cellular and immune microenvironments. However, their clinical application is severely impeded by their inherent instability in the dynamic wound microenvironment, which includes susceptibility to enzymatic degradation, disruption due to pH fluctuations, and rapid clearance by wound exudate. These factors collectively lead to premature cargo loss and reduced therapeutic efficacy. This review synthesizes how engineered biomaterials, serving as tailored structural platforms for controlled delivery, can overcome these stability challenges specific to PDEVs. By examining loading strategies and design principles, we demonstrate how composite systems surpass single-component therapies in wound models. Lastly, we address translational challenges and propose a development framework that integrates artificial intelligence-driven design with mechanism-guided material optimization. This work lays the groundwork for the rational development of next-generation vesicle-enabled wound therapeutics.
Diabetic foot ulcers (DFUs) represent a growing clinical challenge, driven by an aging global population and the increasing prevalence of diabetes. Affecting millions worldwide, DFUs remain one of the most serious complications of diabetes, frequently progressing to infection, amputation, and elevated mortality. Standard treatments typically include pressure offloading, circulation improvement, infection control, and topical wound care; however, many chronic DFUs fail to respond to these interventions due to persistent inflammation, impaired vascularization, and microbial burden. These challenges have accelerated interest in regenerative medicine approaches, including stem cells, growth factors, and skin substitutes. Among these, skin substitutes have shown particular promise; among Food and Drug Administration-approved options, products such as the collagen-Manuka honey-hydroxyapatite patch from SweetBio (Apis®) have demonstrated improved outcomes in patients with chronic ulcers. Silk fibroin (SF), a natural biopolymer with established clinical use, has emerged as a promising platform for chronic wound management due to its biocompatibility, tunable degradation, and capacity for controlled bio-additive delivery. SF scaffolds can be fabricated through various methods tailored to wound-healing applications: electrospun fibrous mats with high surface-area-to-volume ratio, freeze-dried porous constructs with interconnected architecture, and hydrogels designed for controlled drug delivery. In this review, we critically examine how SF scaffolds enhanced with bio-additives modulate cellular responses, redirect dysregulated healing pathways, accelerate wound closure, and promote tissue regeneration in diabetic wounds. We synthesize recent advances in preclinical and clinical studies, identify key translational barriers, and outline future directions for advancing SF-based dressings toward clinical adoption. Collectively, this review positions bio-enhanced SF scaffolds as next-generation, disease-informed candidates for improving outcomes in chronic DFU care.
Diabetic wound healing is a common yet challenging problem in clinical practice that involves complex pathophysiological processes and frequently progresses to chronic nonhealing wounds, imposing substantial burdens on both healthcare systems and patients while markedly decreasing quality of life. Persistent inflammatory responses represent a fundamental pathological feature of this condition. Accumulating evidence highlights the key role of neutrophil extracellular traps (NETs) in the chronic inflammatory response characteristic of diabetic wounds. As components of the innate immune system, NETs play pivotal roles in both host defence and tissue repair. Neutrophil extracellular trap formation (NETosis) is currently classified as vital NETosis or lytic NETosis. In this review, we synthesize existing evidence on the mechanistic heterogeneity of NETosis and further refine lytic NETosis subtypes on the basis of distinct molecular mechanisms and temporal dynamics-namely, NADPH oxidase 2 (NOX2)-dependent classical lytic NETosis and mitochondrial reactive oxygen species-driven rapid lytic NETosis. We also highlight the functional outcomes of NETs in response to specific stimuli within the diabetic wound milieu. Therapeutic strategies targeting NET formation, degradation, or neutralization have shown considerable promise in preclinical studies; however, their clinical translation will require standardized biomarkers for NET quantification, localized delivery approaches to minimize systemic immunosuppression, and biomarker-guided frameworks to balance the risk of infection against healing benefits.
Background:Sepsis-related myocardial dysfunction significantly increases the mortality risk of sepsis. However, its underlying mechanism remains incompletely understood, and effective therapeutic strategies are still lacking. Transcriptomic profiling from septic patients showed endoplasmic reticulum stress (ERS) were the main pathways participating in the occurrence of sepsis myocardial dysfunction. Therefore, this study aimed to explore the protective effect of 4-phenylbutyric acid (4-PBA) on sepsis-induced myocardial injury and specify its molecular regulatory mechanism, to provide experimental basis for clinical intervention of septic myocardial dysfunction. Methods:In vivo and in vitro models of sepsis were used, and 4-PBA (5 mg/kg) was administered for intervention. Mitochondria-associated ER-membrane (MAM) formation, mitochondrial dynamics, mitochondrial function, glycolytic metabolism, and protein lactylation were systematically examined. Molecular docking and site-directed mutation were applied to verify the direct binding and catalytic sites of 4-PBA. Results:4-PBA significantly alleviated sepsis-induced myocardial dysfunction (SIMD). The mechanism was closely related to 4-PBA inhibiting MAM formation and improving the mitochondrial dynamic balance and mitochondrial function. 4-PBA inhibited MAM formation mainly via decreasing the lactate production and lactylation of Arpc1b-K308 by inhibiting the glycolysis limiting enzyme HK2, and 4-PBA inhibited HK2 activity by binding K621 and K624 catalytic sites. Conclusions:The results indicate that 4-PBA protects cardiac function following sepsis by recovering mitochondrial dynamics balance. This finding provides a novel therapeutic strategy and potential target for SIMD.
The integrity of the intestinal mucosal barrier is essential for maintaining normal gut physiology, and its disruption is associated with a wide range of conditions, including trauma- and burn-related intestinal injury, which remain difficult to manage clinically. Intestinal organoid-on-a-chip systems have emerged as advanced in vitro models that reproduce key features of the intestinal microenvironment and physiological function. These systems have shown promise for studying mucosal injury and repair, assessing therapeutic strategies, and supporting translational research. This review summarizes the basic principles of intestinal organoid-on-a-chip technology and examines its use in modeling intestinal barrier function, inflammatory responses, drug screening, regenerative approaches, and trauma-related barrier repair. It also reviews recent progress in preclinical studies, considers potential applications in gastrointestinal research, and discusses current technical challenges, particularly those related to scalability and reproducibility. Future directions for the development of next-generation systems are also outlined. With the continued integration of advances across disciplines, these platforms may provide useful tools for studying and treating disorders involving the intestinal mucosal barrier, especially in the context of trauma and burns.
Background:Hypertrophic scars (HTSs) are characterized by excessive extracellular matrix deposition and impaired scar remodelling. Fibroblasts are central to HTS pathogenesis, yet clinical strategies remain limited by an incomplete understanding of fibroblast heterogeneity and transcriptional regulation. This study aimed to identify a key fibroblast subpopulation and its regulatory transcription factors to address this translational gap. Methods:Single-cell RNA sequencing was performed on dermal cells from freshly excised human HTS and normal skin (NS) tissues. Fibroblast subsets and transcriptional regulators were identified using Seurat, pseudotime, transcription factor prediction, and cell-cell communication analyses. Functional validation involved lentiviral overexpression of Yin Yang 1 (YY1) in fibroblasts derived from patients with hypertrophic scars, followed by bulk RNA sequencing, western blotting, CUT&Tag, and immunofluorescence assays. Results:Clinical HTS specimens showed characteristic collagen overproduction and vascular hyperplasia. Single-cell analysis of 43 303 cells revealed disease-specific shifts in cellular composition, including pronounced pericyte expansion and reduced fibroblast abundance. Notably, fibroblast subcluster Fib_5 (ADAM12+ COMP+ POSTNhi) increased despite the overall fibroblast decline in HTS and exhibited upregulated fibrotic gene expression. Cross-validation using combined public datasets comprising 21 samples indicated that the Fib_5-like subcluster is conserved across fibrotic conditions. Pseudotime analyses placed Fib_5 within an HTS-dominant branch, State 6; transcription factor prediction from branch-dependent differentially expressed genes identified YY1 as the only predicted transcription factor also differentially expressed in State 6. Functional validation showed that YY1 overexpression in fibroblasts derived from patients with HTS reversed fibrotic gene expression profiles, with Fib_5 identified as a primary responder by Scissor. CUT&Tag analysis validated these findings at the epigenomic level. Cell-cell communication analyses further revealed marked reprogramming of fibroblast-pericyte signalling across multiple fibrosis-related pathways in HTS. Conclusion:This work establishes the Fib_5-YY1 axis as a central hub in HTS pathogenesis, with YY1-mediated fibroblast plasticity as a key transcriptional mechanism underlying skin fibrogenesis.
Regenerative medicine is undergoing a paradigm shift from live-cell therapies to cell-free strategies. Within this evolving field, mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as a leading platform. These nanoscale vesicles deliver bioactive cargo that mediates critical therapeutic functions, including immunomodulation, angiogenesis, and anti-fibrosis. Furthermore, they offer improved safety, greater potential for standardization, and enhanced scalability compared to traditional live-cell therapies. However, clinical translation remains constrained by several challenges, such as inherent vesicle heterogeneity, limited targeting specificity, and bottlenecks in large-scale manufacturing. This review systematically examines the biogenesis of MSC-EVs, focusing specifically on exosomes, microvesicles, and apoptotic vesicles. We evaluate their functional performance across diverse regeneration contexts, encompassing orofacial, barrier, musculoskeletal, and visceral tissue regeneration. We further highlight innovative engineering strategies designed to enhance therapeutic efficacy, such as surface modification, cargo loading, and biomaterial-integrated delivery systems. In addition, we introduce an emerging approach utilizing engineered MSC aggregate-derived EVs inspired by organ morphogenesis. Finally, this article details the strategic framework required for clinical translation. The framework encompasses scalable production, rigorous quality control, comprehensive non-clinical studies, evolving regulatory pathways, and the current clinical trial landscape. Collectively, this work provides an integrated roadmap for advancing MSC-EVs as a next-generation precision platform for cell-free therapeutics.
Background:Hypertrophic scars are a major clinical challenge with limited treatments. Adipose-derived stem cells (ADSCs) play an important role in inhibiting pathological scar formation. However, the underlying mechanisms remain unclear. In this study, we aimed to investigate the function, mechanism, and therapeutic potential of adipose-derived stem cell peptide 5 (ADSCP5), a novel peptide from adipose-derived stem cell-conditioned medium. Methods:We used in vitro hypertrophic scar fibroblast, macrophage-fibroblast coculture and human umbilical vein endothelial cell (HUVEC) assays, RNA sequencing, pathway analysis, peptide pull-down, molecular docking, cellular thermal shift assays, surface plasmon resonance, immunofluorescence colocalization analysis, western blotting, rescue experiments, reactive oxygen species (ROS), autophagy tests, and mitochondrial membrane potential assays and untargeted metabolomics. The efficacy of ADSCP5 was validated in rabbit and porcine scar models. Results:In hypertrophic scar fibroblasts, ADSCP5 significantly downregulated the expression of collagen genes (COL1A1, COL1A2, and COL3A1) and actin alpha 2, smooth muscle, without affecting cell proliferation, apoptosis, or migration. Transcriptomic, enrichment, and western blot analyses confirmed that ADSCP5 reduced the protein levels of phosphorylated p65 (p-p65, NF-κB subunit), p-PI3K, p-AKT, and p-mTOR. Moreover, ADSCP5 decreased IL-6 transcription. Mechanistically, ADSCP5 bound directly to pyruvate carboxylase or the NF-κB subunit p50. This interaction resulted in the downregulation of PC or the upregulation of p50, ultimately inhibiting collagen expression, a finding confirmed by rescue assays. Furthermore, ADSCP5 induced ROS generation and autophagy, altered global metabolism, and modulated macrophage-fibroblast crosstalk to suppress fibrosis. It also exhibited antiangiogenic effects in HUVECs. In both the rabbit and porcine scar models, ADSCP5 treatment effectively attenuated collagen deposition and scar hyperplasia, increased the number of macrophages (increased CD68), reduced angiogenesis (decreased VEGFA and CD34), and promoted autophagy (reduced p62). Conclusions:Overall, this study demonstrate that ADSCP5 alleviates hypertrophic scarring by directly binding to PC and p50, suppressing the PI3K/AKT/mTOR and NF-κB pathways, reducing IL-6 and collagen production, promoting ROS and autophagy, and modulating metabolic, macrophage and angiogenic responses. These findings position ADSCP5 as a promising therapeutic agent for hypertrophic scar prevention and treatment.
The rising global prevalence of chronic conditions, notably obesity and type 2 diabetes, demands innovative approaches to mitigate their health and economic impacts. Complications, including neuropathy and chronic limb-threatening ischemia (CLTI), dramatically increase the risk of lower limb amputation, cardiovascular events, and cerebrovascular events, underscoring the urgent need for effective interventions. Emerging neuromodulation and regenerative strategies provide novel approaches to addressing diabetes-related complications. High-frequency (10-kHz) spinal cord stimulation demonstrates marked pain relief and sensory improvement in patients with refractory painful diabetic neuropathy. Peripheral focused ultrasound, including splenic-targeted stimulation, shows promise in reducing systemic inflammation, accelerating wound repair, and enhancing vascular function. Remote ischemic conditioning leverages brief controlled ischemic reperfusion cycles to enhance microcirculation and promote diabetic foot ulcer (DFU) healing. In severe cases, surgical techniques such as tibial transverse transport and lateral tibial periosteum distraction stimulate angiogenesis and enhance distal limb perfusion. Integrated wound care protocols, incorporating these procedures alongside debridement, negative pressure wound therapy, and skin grafting, may further optimize outcomes. Collectively, these therapies address both local and systemic pathophysiology, frequently producing physiologic effects at sites distant from the primary intervention. These seemingly disparate therapies represent a single unifying concept: generating a physiologic effect at locations remote from the primary target. This systematic approach, engaging neural, vascular, and immune pathways, may be key to improving outcomes in DFUs and CLTI. Early clinical data appears promising; however, larger randomized trials are required to validate efficacy, refine patient selection, and determine optimal integration with standard care. If confirmed, these strategies may shift management toward patient-centered, regenerative interventions that preserve limbs, reduce recurrence, and enhance quality of life for the expanding global patient population. Further research is warranted to confirm or refute these early promising physiologic effects.
Background:Severe acute kidney injury (AKI) is associated with high mortality. Current blood purification technologies fail to replace the biological functions of renal tubular epithelial cells (RTECs), such as active transport, acid-base homeostasis, and endocrine regulation. The integration of viable RTECs into an extracorporeal circuit to construct a bioartificial kidney represents a potential strategy for renal functional support. However, its translation is constrained by the rapid loss of seed cell phenotypes, immune and coagulation activation triggered by conventional materials, and a lack of in vivo validation in large animal models. However, three key challenges hinder its clinical translation, which this study seeks to address: the rapid loss of seed cell phenotypes, immune and coagulation activation triggered by conventional materials, and a lack of in vivo validation in large animal models. Methods:We engineered a renal tubule assist device (RAD) that integrates viable cells with a functionalized interface. First, we established an immortalized human proximal tubule cell line [immortalized renal tubular epithelial cell line (iRTEC)] and achieved scalable expansion using a microcarrier system. Second, we fabricated a cell-supporting interface [chlorogenic acid/poly-L-lysine-modified pristine nanofibrous membrane (CA/PLL-PNF)] with antioxidant properties and enhanced hemocompatibility via the layer-by-layer self-assembly of PLL and CA onto polyacrylonitrile nanofibrous membranes. Finally, we assembled these components into a flat-plate bioreactor and evaluated its extracorporeal performance in a Bama miniature pig model after bilateral nephrectomy. Results:iRTECs were stably expanded on microcarriers while maintaining a proximal tubule phenotype, and these cells outperformed existing cell lines in terms of amino acid hydrolysis and transmembrane transport, acid-base regulation, water transport, and endocrine responsiveness. With respect to the supporting interface, CA/PLL-PNF effectively scavenged diverse free radicals and mitigated cellular oxidative stress. Proteomic analysis confirmed that this modification remodeled the plasma protein corona, which significantly reduced the adsorption of complement and coagulation factors. In the bilaterally nephrectomized pig model, the RAD safely maintained extracorporeal circulation for 4 h-the duration of routine clinical dialysis-and preserved internal homeostasis. The antioxidant interface significantly attenuated circulating lipid peroxidation during treatment. Compared with hemofiltration alone, the RAD significantly enhanced the clearance of middle-molecule toxins (β2-microglobulin) and reduced proinflammatory cytokine levels at the outlet, demonstrating its capacity for the active modulation of local inflammation. Conclusions:This study established a renal support platform that integrates viable cells and functional materials. The device exhibited multidimensional biological efficacy in toxin clearance and internal homeostasis regulation and achieved stable extracorporeal circulation in a preclinical large animal model, which provides experimental evidence for advanced organ support strategies in the setting of severe AKI.
Skin shows distinct temporal dynamics and spatial heterogeneity during development, aging, disease, and regeneration. Although single-cell sequencing has revealed cellular diversity, its lack of spatial context limits the ability to characterize cells within their native tissue microenvironment. Factors such as acute injury and chronic wounds spatiotemporally disrupt skin homeostasis and induce complex remodeling and functional changes. Understanding these dynamic processes with spatiotemporal resolution remains a challenge in skin biology. Recent advances in spatiotemporal omics make it possible to integrate single-cell sequencing, spatial omics, and time series analyses, allowing the preservation of in situ cellular positions and revealing gene expression dynamics and intercellular networks. These technologies have reshaped the understanding of skin development and wound healing and have promoted advances in precision medicine and regenerative therapies. In this review, the applications of, recent advances in, and clinical translation potential of spatiotemporal omics in skin research are summarized. The construction of a high-resolution, spatiotemporal cellular atlas across the human skin life cycle will help identify key biomarkers, optimize regenerative strategies, and support personalized therapies.
Background:Diabetic foot ulcer (DFU) is a severe diabetic complication characterized by impaired healing, often involving fibroblast senescence and the senescence-associated secretory phenotype (SASP). The role of ribonucleic acid (RNA)-binding proteins (RBPs) in this process remains undefined. This study investigates the function and mechanism of the RBP interleukin enhancer-binding factor 2 (ILF2) in DFU pathogenesis. Methods:Differentially expressed RBPs were identified via bioinformatics analysis of public single-cell and bulk transcriptomic datasets. ILF2 downregulation was subsequently validated in clinical DFU samples and diabetic mouse models. Functional assays in high-glucose (HG)-treated fibroblasts evaluated proliferation, migration, and SASP. Mechanistically, RNA sequencing, RNA-binding protein immunoprecipitation, and RNA pull-down assays identified downstream targets, while co-IP and rescue experiments verified the NPM1/NF-κB axis. Finally, a diabetic mouse model was used to study the effects of ILF2 overexpression/knockdown and NPM1 knockdown on wound healing. Results:Bioinformatics analysis identified ILF2 as significantly downregulated in DFU. This reduction was consistently validated in DFU patient tissues, diabetic mouse wounds, and HG-treated fibroblasts. Functionally, ILF2 overexpression promoted fibroblast proliferation and migration while suppressing SASP, whereas knockdown exacerbated senescence. Mechanistically, ILF2 directly bound to nucleophosmin (NPM1) mRNA to promote its degradation. ILF2 deficiency led to aberrant NPM1 accumulation, enhancing the NPM1-phospho-p65 interaction and NF-κB pathway activation. Rescue experiments confirmed that NPM1 knockdown reversed ILF2 deficiency-induced cellular dysfunction. Crucially, these findings were validated in primary fibroblasts isolated from DFU patients. In vivo, ILF2 overexpression accelerated wound healing, while knockdown delayed the process. Furthermore, NPM1 knockdown effectively ameliorated the impaired healing phenotype and reduced SASP levels. Conclusions:This study elucidates a novel ILF2-NPM1-NF-κB regulatory axis. ILF2 acts as a critical suppressor of inflammatory senescence by destabilizing NPM1 mRNA, highlighting its potential as a therapeutic target for DFU treatment.
Necrotizing soft tissue infections (NSTIs) represent a group of rapidly progressing, life-threatening infections characterized by widespread tissue necrosis, systemic inflammation, and multiorgan failure. Early diagnosis remains a clinical challenge because of nonspecific initial manifestations and overlapping symptoms with other soft tissue infections. Diagnostic scoring systems such as the Laboratory Risk Indicator for Necrotizing Fasciitis score and its variants have been widely utilized to facilitate early recognition but are limited by variable sensitivity and insufficient predictive value across diverse clinical populations. Recent advances in multi-omics technologies and machine learning approaches have enabled the identification of molecular biomarkers and predictive patterns associated with NSTI onset and progression. Integration of high-dimensional omics data with clinical and imaging parameters holds potential for dynamic, real-time diagnostic support, and individualized risk stratification in the intensive care setting. This review summarizes the evolution of diagnostic strategies for NSTIs, critically appraises the limitations of conventional clinical scoring systems, and examines emerging omics-based and ML-driven approaches. Finally, we propose an integrated diagnostic roadmap that aligns clinical assessment, imaging, microbiologic evaluation, host-response biomarkers, and multi-omics data to guide future research and clinical translation.
Bleeding, a critical complication in trauma, surgery, and conditions such as hemophilia, liver cirrhosis, and thrombocytopenia, often leads to shock or death. The limitations of traditional hemostatic methods-such as compression, suturing, and electrocautery-have prompted the development of advanced biomaterials. In modern research, intelligent, multi-mechanism systems have supplanted basic physical or chemical approaches. Biomimetic designs, such as platelet- and fibrin-inspired materials, alongside nanotechnology (e.g. nanoparticle carriers and electrospun fibers) and stimuli-responsive polymers (e.g. light- or temperature-triggered), enable targeted clotting, controlled drug release, and enhanced wound adhesion. Additionally, 3D printing and microfluidics allow precise material modification, further boosting hemostatic efficiency. Despite these advances, clinical translation faces challenges related to biocompatibility, mass production, and patient-specific customization. Future progress is likely to integrate multidisciplinary technologies, such as artificial intelligence, genetic engineering, smart regulation, and personalized therapies, to improve hemorrhage management. These innovations aim to bridge the gap between laboratory research and clinical application, offering safer, more effective solutions for trauma and surgical interventions.
Ischaemia-reperfusion injury (IRI) is a fundamental pathological process underlying acute and chronic damage associated with myocardial infarction, ischaemic stroke, and solid organ transplantation. Although timely reperfusion is indispensable for tissue salvage, it paradoxically promotes maladaptive immune activation and oxidative stress, which aggravate microvascular dysfunction and organ failure. Accumulating evidence indicates that sterile inflammation, endothelial injury, and immunothrombosis are the central drivers of IRI progression. Among innate immune effectors, neutrophils act as first responders that integrate chemotactic signalling, adhesion cascades, and metabolic rewiring. Upon activation, neutrophils release damage-associated molecular patterns and form neutrophil extracellular traps (NETs), which amplify inflammation, promote coagulation, and disrupt tissue repair across organs. However, the organ-specific roles, temporal dynamics, and translational relevance of neutrophils and NETs in IRI remain incompletely understood. In this review, we systematically dissect the neutrophil- and NET-mediated mechanisms involved in IRI across the heart, brain, kidney, liver, and transplanted organs, with a particular emphasis on endothelial crosstalk, immunothrombosis, and metabolic regulation. We further summarize emerging NET-associated biomarkers-including cell-free DNA and myeloperoxidase-DNA complexes-for IRI diagnosis and prognosis. Finally, we evaluate therapeutic strategies targeting neutrophil recruitment, immune metabolism, and NET clearance, highlighting challenges for clinical translation. In summary, this review provides a mechanistic and translational framework for targeting neutrophils and NETs in precision therapies for IRI.
Hypertrophic scars (HS) represent a significant clinical challenge due to their complex pathophysiology and resistance to conventional therapies, often resulting in persistent symptoms such as itching, pain, and impaired joint mobility that compromise patients' quality of life. Current treatment modalities, including compression therapy, pharmacological agents, radiation, silicone gel, and laser therapies, have faced limitations primarily due to inadequate drug penetration into the dense fibrotic scar tissue. In this context, microneedle-mediated controlled delivery systems have emerged as a promising pharmaceutical platform to enhance localized and sustained delivery of therapeutic agents, including small-molecule drugs, biologic proteins, small interfering RNA, and living cells, directly into HS. This article critically reviews the biological and formulation-related challenges associated with transdermal delivery in scar tissue and highlights recent innovations in microneedle design, material selection, and drug-loading techniques tailored for controlled release applications. Furthermore, it discusses the integration of proteins and cell-based therapies within microneedle platforms and their potential to modulate scar remodeling and inflammation. By addressing current limitations and exploring cutting-edge technologies, this review article aims to guide the development of effective microneedle-mediated strategies for pharmaceutical intervention in hypertrophic scar management.
