Pelvic hematoma: The same complication with different etiology after patent foramen ovale closure.

Well-known complication associated with patent foramen ovale (PFO) closure include infection, acute cardiac tamponade, and local complications such as adjacent arterial or nerve damage, hemorrhage, and thrombophlebitis. Pelvic hematoma is rare and potentially fatal complication. This paper reports two cases of severe hemorrhagic shock within1 day after PFO closure. Both female patients presented to our department with history of headaches and were diagnosed with PFO. Both patients underwent percutaneous PFO closure from the right femoral vein. One day after the procedure, both patients experienced pelvic hematoma and were successfully rescued by compression hemostasis and uterine artery embolization. Both patients recovered well during follow-up. Life-threatening pelvic hematoma associated with PFO closure has a certain incidence and should be considered. Peripheral vascular complications after PFO closure can be safely treated but should not be ignored. We believe that the prevention of vascular mechanical damage during surgery is important. The possibility of spontaneous uterine artery rupture should be considered for unexplained pelvic hematoma. Although it is a rare complication, severe bleeding after PFO closure remains unpredictable. Timely and correct diagnosis and appropriate treatment are required. If the timing is delayed, there could be serious consequences.

Regulation of metabolic microenvironment with a nanocomposite hydrogel for improved bone fracture healing.

Bone nonunion poses an urgent clinical challenge that needs to be addressed. Recent studies have revealed that the metabolic microenvironment plays a vital role in fracture healing. Macrophages and bone marrow-derived mesenchymal stromal cells (BMSCs) are important targets for therapeutic interventions in bone fractures. Itaconate is a TCA cycle metabolite that has emerged as a potent macrophage immunomodulator that limits the inflammatory response. During osteogenic differentiation, BMSCs tend to undergo aerobic glycolysis and metabolize glucose to lactate. Copper ion (Cu2+) is an essential trace element that participates in glucose metabolism and may stimulate glycolysis in BMSCs and promote osteogenesis. In this study, we develop a 4-octyl itaconate (4-OI)@Cu@Gel nanocomposite hydrogel that can effectively deliver and release 4-OI and Cu2+ to modulate the metabolic microenvironment and improve the functions of cells involved in the fracture healing process. The findings reveal that burst release of 4-OI reduces the inflammatory response, promotes M2 macrophage polarization, and alleviates oxidative stress, while sustained release of Cu2+ stimulates BMSC glycolysis and osteogenic differentiation and enhances endothelial cell angiogenesis. Consequently, the 4-OI@Cu@Gel system achieves rapid fracture healing in mice. Thus, this study proposes a promising regenerative strategy to expedite bone fracture healing through metabolic reprogramming of macrophages and BMSCs.

Microenvironment-sensitive nanozymes for tissue regeneration.

Tissue defect is one of the significant challenges encountered in clinical practice. Nanomaterials, including nanoparticles, nanofibers, and metal-organic frameworks, have demonstrated an extensive potential in tissue regeneration, offering a promising avenue for future clinical applications. Nonetheless, the intricate landscape of the inflammatory tissue microenvironment has engendered challenges to the efficacy of nanomaterial-based therapies. This quandary has spurred researchers to pivot towards advanced nanotechnological remedies for overcoming these therapeutic constraints. Among these solutions, microenvironment-sensitive nanozymes have emerged as a compelling instrument with the capacity to reshape the tissue microenvironment and enhance the intricate process of tissue regeneration. In this review, we summarize the microenvironmental characteristics of damaged tissues, offer insights into the rationale guiding the design and engineering of microenvironment-sensitive nanozymes, and explore the underlying mechanisms that underpin these nanozymes' responsiveness. This analysis includes their roles in orchestrating cellular signaling, modulating immune responses, and promoting the delicate process of tissue remodeling. Furthermore, we discuss the diverse applications of microenvironment-sensitive nanozymes in tissue regeneration, including bone, soft tissue, and cartilage regeneration. Finally, we shed our sights on envisioning the forthcoming milestones in this field, prospecting a future where microenvironment-sensitive nanozymes contribute significantly to the development of tissue regeneration and improved clinical outcomes.

Cell membrane coated nanoparticles: cutting-edge drug delivery systems for osteoporosis therapy.

Osteoporosis, characterized by a reduction in bone mineral density, represents a prevalent skeletal disorder with substantial global health implications. Conventional therapeutic strategies, exemplified by bisphosphonates and hormone replacement regimens, though effective, encounter inherent limitations and challenges. Recent years have witnessed the surge of cell-membrane-coated nanoparticles (CMNPs) as a promising intervention for osteoporosis, leveraging their distinct attributes including refined biocompatibility, heightened pharmaceutical payload capacity, as well as targeted drug release kinetics. However, a comprehensive review consolidating the application of CMNPs-based therapy for osteoporosis remains absent within the existing literature. In this review, we provide a concise overview of the distinctive pathogenesis associated with osteoporosis, alongside an in-depth exploration of the physicochemical attributes intrinsic to CMNPs derived from varied cellular sources. Subsequently, we explore the potential utility of CMNPs, elucidating emerging trends in their deployment for osteoporosis treatment through multifaceted therapeutic approaches. By linking the notable attributes of CMNPs with their roles in mitigating osteoporosis, this review serves as a catalyst for further advances in the design of advanced CMNPs tailored for osteoporosis management. Ultimately, such progress is promising for enhancing outcomes in anti-bone loss interventions, paving the way for clinical translation in the near future.

[Research on Locating Device for the Entry Point of Intramedullary Nail Based on Inertial Navigation].

Objective: To introduce a locating device for the entry point of intramedullary nail based on the inertial navigation technology, which utilizes multi-dimensional angle information to assist in rapid and accurate positioning of the ideal direction of femoral anterograde intramedullary nails' entry point, and to verify its clinical value through clinical tests. Methods: After matching the locating module with the developing board, which are the two components of the locating device, they were placed on the skin surface of the proximal femur of the affected side. Anteroposterior fluoroscopy was performed. The developing angle corresponding to the ideal direction of entry point was selected based on the X-ray image, and then the yaw angle of the locating module was reset to zero. After resetting, the locating module was combined with the surgical instrument to guide the insertion angle of the guide wire. The ideal direction of entry point was accurately located based on the angle guidance. By setting up an experimental group and a control group for clinical surgical operations, the number of guide wire insertion times, surgical time, fluoroscopy frequency, and intraoperative blood loss with or without the locating device was recorded. Results: Compared to the control group, the experimental group showed significant improvement in the number of guide wire insertion times, surgical time, fluoroscopy frequency, and intraoperative blood loss, with a statistically significant difference (P<0.01). Conclusion: The locating device can assist doctors in quickly locating the entry point of intramedullary nail, effectively reducing the fluoroscopy frequency and surgical time by improving the success rate of the guide wire insertion with one shot, improving surgical efficiency, and possessing certain clinical value.

A distinct "repair" role of regulatory T cells in fracture healing.

Regulatory T cells (Tregs) suppress immune responses and inflammation. Here, we described the distinct nonimmunological role of Tregs in fracture healing. The recruitment from the circulation pool, peripheral induction, and local expansion rapidly enriched Tregs in the injured bone. The Tregs in the injured bone displayed superiority in direct osteogenesis over Tregs from lymphoid organs. Punctual depletion of Tregs compromised the fracture healing process, which leads to increased bone nonunion. In addition, bone callus Tregs showed unique T-cell receptor repertoires. Amphiregulin was the most overexpressed protein in bone callus Tregs, and it can directly facilitate the proliferation and differentiation of osteogenic precursor cells by activation of phosphatidylinositol 3-kinase/protein kinase B signaling pathways. The results of loss- and gain-function studies further evidenced that amphiregulin can reverse the compromised healing caused by Treg dysfunction. Tregs also enriched in patient bone callus and amphiregulin can promote the osteogenesis of human pre-osteoblastic cells. Our findings indicate the distinct and nonredundant role of Tregs in fracture healing, which will provide a new therapeutic target and strategy in the clinical treatment of fractures.

Expert consensus on Prospective Precision Diagnosis and Treatment Strategies for Osteoporotic Fractures.

Osteoporotic fractures are the most severe complications of osteoporosis, characterized by poor bone quality, difficult realignment and fixation, slow fracture healing, and a high risk of recurrence. Clinically managing these fractures is relatively challenging, and in the context of rapid aging, they pose significant social hazards. The rapid advancement of disciplines such as biophysics and biochemistry brings new opportunities for future medical diagnosis and treatment. However, there has been limited attention to precision diagnosis and treatment strategies for osteoporotic fractures both domestically and internationally. In response to this, the Chinese Medical Association Orthopaedic Branch Youth Osteoporosis Group, Chinese Geriatrics Society Geriatric Orthopaedics Committee, Chinese Medical Doctor Association Orthopaedic Physicians Branch Youth Committee Osteoporosis Group, and Shanghai Association of Integrated Traditional Chinese and Western Medicine Osteoporosis Professional Committee have collaborated to develop this consensus. It aims to elucidate emerging technologies that may play a pivotal role in both diagnosis and treatment, advocating for clinicians to embrace interdisciplinary approaches and incorporate these new technologies into their practice. Ultimately, the goal is to improve the prognosis and quality of life for elderly patients with osteoporotic fractures.

Corpus callosum and cerebellum participate in semantic dysfunction of Parkinson's disease: a diffusion tensor imaging-based cross-sectional study.

Language dysfunction is common in Parkinson's disease (PD) patients, among which, the decline of semantic fluency is usually observed. This study aims to explore the relationship between white matter (WM) alterations and semantic fluency changes in PD patients. 127 PD patients from the Parkinson's Progression Markers Initiative cohort who received diffusion tensor imaging scanning, clinical assessment and semantic fluency test (SFT) were included. Tract-based special statistics, automated fiber quantification, graph-theoretical and network-based analyses were performed to analyze the correlation between WM structural changes, brain network features and semantic fluency in PD patients. Fractional anisotropy of corpus callosum, anterior thalamic radiation, inferior front-occipital fasciculus, and uncinate fasciculus, were positively correlated with SFT scores, while a negative correlation was identified between radial diffusion of the corpus callosum, inferior longitudinal fasciculus, and SFT scores. Automatic fiber quantification identified similar alterations with more details in these WM tracts. Brain network analysis positively correlated SFT scores with nodal efficiency of cerebellar lobule VIII, and nodal local efficiency of cerebellar lobule X. WM integrity and myelin integrity in the corpus callosum and several other language-related WM tracts may influence the semantic function in PD patients. Damage to the cerebellum lobule VIII and lobule X may also be involved in semantic dysfunction in PD patients.

Macrophage-mediated fracture healing: Unraveling molecular mechanisms and therapeutic implications using hydrogel-based interventions.

Fracture healing is a complex biological process that involves the orchestrated interplay of various cells and molecular signaling pathways. Among the key players, macrophages have emerged as critical regulators of fracture repair, influencing inflammation, tissue remodeling, and angiogenesis. Recent advances in hydrogel-based therapeutics have provided exciting opportunities to leverage the modulatory effects of macrophages for improving fracture healing outcomes. In the present study, we review the importance of macrophages in fracture repair and their potential therapeutic role in hydrogel-based interventions. We discuss the molecular mechanisms underlying macrophage-mediated effects on fracture healing, and how hydrogels can be utilized as a platform for macrophage modulation. Furthermore, we highlight the translation of hydrogel-based therapies from bench to bedside, including preclinical and clinical studies, and the challenges and opportunities in harnessing the therapeutic potential of macrophages in fracture repair. Overall, understanding the importance of macrophages in fracture healing and the potential of hydrogel-based therapeutics to modulate macrophage responses can pave the way for developing innovative approaches to improve fracture healing outcomes.

Nrf2 Inhibits GAPDH/Siah1 Axis to Reduce Inflammatory Reactions and Proliferation of Microglia After Simulating Spinal Cord Injury.

OBJECTIVE: To explore the effect of nuclear factor erythroid 2-related factor 2 (Nrf 2) on microglial inflammatory response and proliferation after spinal cord injury (SCI) through the glyceraldehyde phosphate dehydrogenase (GAPDH) / Seven in absentia homolog 1 (Siah 1) signaling pathway. METHODS: Human microglia HMC3 was induced by lipopolysaccharide (LPS) to establish a SCI cell model. Microglia morphology after LPS stimulation was observed by transmission electron microscope (TEM), and cellular Nrf2, GAPDH/Siah1 pathway expression and cell viability were determined. Subsequently, the Nrf2 overexpression plasmid was transfected into microglia to observe changes in cell viability and GAPDH/Siah1 pathway expression. RESULTS: Microglia, mostly amoeba-like, were found to have enlarged cell bodies after LPS stimulation, with an increased number of cell branches, highly expressed Nrf2, GAPDH and Siah1, and decreased cell viability (P<0.05). Up-regulating Nrf2 inhibited the GAPDH/Siah1 axis, decreased inflammatory responses, and enhanced activity in post-SCI microglia (P<0.05). CONCLUSION: Up-regulating Nrf2 expression can reverse the inflammatory reaction of microglia after LPS stimulation and enhance their activity by inhibiting the GAPDH/Siah1 axis.

Neddylation suppression by a macrophage membrane-coated nanoparticle promotes dual immunomodulatory repair of diabetic wounds.

Oxidative stress, infection, and vasculopathy caused by hyperglycemia are the main barriers for the rapid repair of foot ulcers in patients with diabetes mellitus (DM). In recent times, the discovery of neddylation, a new type of post-translational modification, has been found to regulate various crucial biological processes including cell metabolism and the cell cycle. Nevertheless, its capacity to control the healing of wounds in diabetic patients remains unknown. This study shows that MLN49224, a compound that inhibits neddylation at low concentrations, enhances the healing of diabetic wounds by inhibiting the polarization of M1 macrophages and reducing the secretion of inflammatory factors. Moreover, it concurrently stimulates the growth, movement, and formation of blood vessel endothelial cells, leading to expedited healing of wounds in individuals with diabetes. The drug is loaded into biomimetic macrophage-membrane-coated PLGA nanoparticles (M-NPs/MLN4924). The membrane of macrophages shields nanoparticles from being eliminated in the reticuloendothelial system and counteracts the proinflammatory cytokines to alleviate inflammation in the surrounding area. The extended discharge of MLN4924 from M-NPs/MLN4924 stimulates the growth of endothelial cells and the formation of tubes, along with the polarization of macrophages towards the anti-inflammatory M2 phenotype. By loading M-NPs/MLN4924 into a hydrogel, the final formulation is able to meaningfully repair a diabetic wound, suggesting that M-NPs/MLN4924 is a promising engineered nanoplatform for tissue engineering.

Contact lens sensor for ocular inflammation monitoring.

Contact lens sensors have been emerging as point-of-care devices in recent healthcare developments for ocular physiological condition monitoring and diagnosis. Fluorescence sensing technologies have been widely applied in contact lens sensors due to their accuracy, high sensitivity, and specificity. As ascorbic acid (AA) level in tears is closely related to ocular inflammation, a fluorescent contact lens sensor incorporating a BSA-Au nanocluster (NC) probe is developed for in situ tear AA detection. The NCs are firstly synthesized to obtain a fluorescent probe, which exhibits high reusability through the quench/recover (KMnO4/AA) process. The probe is then encapsulated with 15 wt% of poly(vinyl alcohol) (PVA) and 1.5 wt% of citric acid (CA) film, and implemented on a closed microfluidic contact lens sensing region. The laser-ablated microfluidic channel in contact lens sensors allows for tear fluid to flow through the sensing region, enabling an in-situ detection of AA. Meanwhile, a smartphone application accompanied by a customized 3D printed readout box is developed for image caption and algorism to quantitative analysis of AA levels. The contact lens sensor is tested within the readout box and the emission signal is collected through the smartphone camera at room temperature with an achieved LOD of 0.178 mmol L-1 (0.0-1.2 mmol L-1). The operational and storage lifetime is also evaluated to characterize the sensor properties and resulted in 20 h and 10 days, respectively. The reusable AA contact lens sensor is promising to lead to an alternative accessible diagnostic method for ocular inflammation in point-of-care settings.

Bone-targeting engineered small extracellular vesicles carrying anti-miR-6359-CGGGAGC prevent valproic acid-induced bone loss.

The clinical role and underlying mechanisms of valproic acid (VPA) on bone homeostasis remain controversial. Herein, we confirmed that VPA treatment was associated with decreased bone mass and bone mineral density (BMD) in both patients and mice. This effect was attributed to VPA-induced elevation in osteoclast formation and activity. Through RNA-sequencing, we observed a significant rise in precursor miR-6359 expression in VPA-treated osteoclast precursors in vitro, and further, a marked upregulation of mature miR-6359 (miR-6359) in vivo was demonstrated using quantitative real-time PCR (qRT-PCR) and miR-6359 fluorescent in situ hybridization (miR-6359-FISH). Specifically, the miR-6359 was predominantly increased in osteoclast precursors and macrophages but not in neutrophils, T lymphocytes, monocytes and bone marrow-derived mesenchymal stem cells (BMSCs) following VPA stimulation, which influenced osteoclast differentiation and bone-resorptive activity. Additionally, VPA-induced miR-6359 enrichment in osteoclast precursors enhanced reactive oxygen species (ROS) production by silencing the SIRT3 protein expression, followed by activation of the MAPK signaling pathway, which enhanced osteoclast formation and activity, thereby accelerating bone loss. Currently, there are no medications that can effectively treat VPA-induced bone loss. Therefore, we constructed engineered small extracellular vesicles (E-sEVs) targeting osteoclast precursors in bone and naturally carrying anti-miR-6359 by introducing of EXOmotif (CGGGAGC) in the 3'-end of the anti-miR-6359 sequence. We confirmed that the E-sEVs exhibited decent bone/osteoclast precursor targeting and exerted protective therapeutic effects on VPA-induced bone loss, but not on ovariectomy (OVX) and glucocorticoid-induced osteoporotic models, deepening our understanding of the underlying mechanism and treatment strategies for VPA-induced bone loss.

Sodium Carbonate-Promoted Formation of 5-Amino-1,2,4-thiadiazoles and 5-Amino-1,2,4-selenadiazoles with Elemental Sulfur and Selenium.

Sodium carbonate-promoted facile synthesis of 5-amino-1,2,4-thiadiazoles and 5-amino-1,2,4-selenadiazoles with elemental sulfur and selenium, respectively, was developed. This method was carried out with O2 in the air as the green oxidant, and it has several advantages, including low cost, low toxicity, and stable sulfur and selenium sources, good to excellent yields with water as the sole byproduct, simple operation, and a broad substrate scope. Preliminary mechanistic studies indicate that the formation of the 1,2,4-thiadiazole ring and the 1,2,4-selenadiazole ring undergoes different processes.

Metal-Organic Frameworks and Their Composites for Chronic Wound Healing: From Bench to Bedside.

Chronic wounds are characterized by delayed and dysregulated healing processes. As such, they have emerged as an increasingly significant threat. The associated morbidity and socioeconomic toll are clinically and financially challenging, necessitating novel approaches in the management of chronic wounds. Metal-organic frameworks (MOFs) are an innovative type of porous coordination polymers, with low toxicity and high eco-friendliness. Documented anti-bacterial effects and pro-angiogenic activity predestine these nanomaterials as promising systems for the treatment of chronic wounds. In this context, the therapeutic applicability and efficacy of MOFs remain to be elucidated. It is, therefore, reviewed the structural-functional properties of MOFs and their composite materials and discusses how their multifunctionality and customizability can be leveraged as a clinical therapy for chronic wounds.

Bone-Targeted Biomimetic Nanogels Re-Establish Osteoblast/Osteoclast Balance to Treat Postmenopausal Osteoporosis.

Insufficient bone formation and excessive bone resorption caused by estrogen deficiency are the major factors resulting in the incidence of postmenopausal osteoporosis (PMOP). The existing drugs usually fail to re-establish the osteoblast/osteoclast balance from both sides and generate side-effects owing to the lack of bone-targeting ability. Here, engineered cell-membrane-coated nanogels PNG@mR&C capable of scavenging receptor activator of nuclear factor-κB ligand (RANKL) and responsively releasing therapeutic PTH 1-34 in the bone microenvironment are prepared from RANK and CXCR4 overexpressed bone mesenchymal stem cell (BMSC) membrane-coated chitosan biopolymers. The CXCR4 on the coated-membranes confer bone-targeting ability, and abundant RANK effectively absorb RANKL to inhibit osteoclastogenesis. Meanwhile, the release of PTH 1-34 triggered by osteoclast-mediated acid microenvironment promote osteogenesis. In addition, the dose and frequency are greatly reduced due to the smart release property, prolonged circulation time, and bone-specific accumulation. Thus, PNG@mR&C exhibits satisfactory therapeutic effects in the ovariectomized (OVX) mouse model. This study provides a new paradigm re-establishing the bone metabolic homeostasis from multitargets and shows great promise for the treatment of PMOP.

Engineered Extracellular Vesicles in Wound Healing: Design, Paradigms, and Clinical Application.

The severe quality of life and economic burden imposed by non-healing skin wounds, infection risks, and treatment costs are affecting millions of patients worldwide. To mitigate these challenges, scientists are relentlessly seeking effective treatment measures. In recent years, extracellular vesicles (EVs) have emerged as a promising cell-free therapy strategy, attracting extensive attention from researchers. EVs mediate intercellular communication, possessing excellent biocompatibility and stability. These features make EVs a potential tool for treating a plethora of diseases, including those related to wound repair. However, there is a growing focus on the engineering of EVs to overcome inherent limitations such as low production, relatively fixed content, and targeting capabilities of natural EVs. This engineering could improve both the effectiveness and specificity of EVs in wound repair treatments. In light of this, the present review will introduce the latest progress in the design methods and experimental paradigms of engineered EVs applied in wound repair. Furthermore, it will comprehensively analyze the current clinical research status and prospects of engineered EVs within this field.

Advances in Doxorubicin-based nano-drug delivery system in triple negative breast cancer.

Triple positive breast cancer (TPBC) is one of the most aggressive breast cancer. Due to the unique cell phenotype, aggressiveness, metastatic potential and lack of receptors or targets, chemotherapy is the choice of treatment for TNBC. Doxorubicin (DOX), one of the representative agents of anthracycline chemotherapy, has better efficacy in patients with metastatic TNBC (mTNBC). DOX in anthracycline-based chemotherapy regimens have higher response rates. Nano-drug delivery systems possess unique targeting and ability of co-load, deliver and release chemotherapeutic drugs, active gene fragments and immune enhancing factors to effectively inhibit or kill tumor cells. Therefore, advances in nano-drug delivery systems for DOX therapy have attracted a considerable amount of attention from researchers. In this article, we have reviewed the progress of nano-drug delivery systems (e.g., Nanoparticles, Liposomes, Micelles, Nanogels, Dendrimers, Exosomes, etc.) applied to DOX in the treatment of TNBC. We also summarize the current progress of clinical trials of DOX combined with immune checkpoint inhibitors (ICIS) for the treatment of TNBC. The merits, demerits and future development of nanomedicine delivery systems in the treatment of TNBC are also envisioned, with the aim of providing a new class of safe and efficient thoughts for the treatment of TNBC.