骨科领域文献阅读汇编

GIM/FP/GP: [Formula: see text] Endocrinology: [Formula: see text] Geriatrics: [Formula: see text] Rheumatology: [Formula: see text].

Osteoporotic fractures pose a significant clinical challenge in aging societies due to the limited efficacy and high re-fracture risk associated with conventional treatments. To address this, we developed EXOs@ECM-SCS, a multifunctional bioactive hydrogel that encapsulates exosomes derived from induced pluripotent stem cell-induced mesenchymal stem cells within a hybrid matrix of decellularized extracellular matrix and methacrylated sulfated chitosan. This composite system promotes bone regeneration through a synergistic strategy that concurrently targets angiogenesis, immunomodulation, neurogenesis, and osteogenesis (AINO). Experimental results demonstrated that EXOs@ECM-SCS significantly enhanced osteogenic differentiation, angiogenic activity, and neural regeneration, while also driving macrophage polarization toward the M2 phenotype. These multifaceted effects collectively improved bone mass accumulation, mineralization, and fracture healing in an osteoporotic mouse model. Mechanistic insights from exosomal sequencing highlighted the involvement of key miRNAs such as miR-100-5p and miR-320a-3p, along with PI3K-Akt and MAPK signaling pathways. These findings underscore EXOs@ECM-SCS as an innovative therapeutic platform that leverages coordinated multimodal regulation to accelerate osteoporotic fracture repair.

Osteoporosis significantly challenges fracture healing, particularly in the regeneration of critical-size bone defects. It remains unclear whether osteoporotic woven bone weakness results from impaired intrinsic quality, reduced formation rate, or both, including its effect on the adjacent bone tissue. To address this question in a translational context, we employed an osteoporotic sheep model, widely recognized as one of the closest animal analogs to human bone biology and physiology. Using an ex vivo multimodal characterization, this study analyzed the woven tissue formed within the distraction callus and the adjacent cortical bone. Bone samples were harvested at 40 and 100 days of osteoporotic bone regeneration and analyzed by nanoindentation, Raman spectroscopy, μCT and chemical composition analyses. Osteoporotic data were compared with non-osteoporotic references. Results revealed that the intrinsic elastic mechanical properties, microstructure and chemical quality of the regenerated osteoporotic woven bone were preserved at the tissue level. However, composition analysis indicated a significantly higher water content and significantly lower bone matrix volume, apparently delayed by the disease. In contrast, cortical tissue adjacent to the defect showed significant mineral loss, likely due to mineral mobilization to support woven tissue formation, although the remaining bone matrix appears to be unaltered. These findings suggest that osteoporotic impairment in bone regeneration is driven by a logistical failure in the woven formation rate and adjacent tissue degradation, rather than an intrinsic woven quality deficiency. Consequently, therapies should prioritize anabolic acceleration of woven bone formation and antiresorptive protection of the adjacent bone tissue, whose fixation is compromised. STATEMENT OF SIGNIFICANCE: Treating large fractures in patients with osteoporosis is challenging due to impaired bone regeneration. This study aimed to determine whether compromised healing results from impaired material quality of newly formed bone, reduced bone formation rate, or both, and to evaluate effects on adjacent bone tissue. Using an osteoporotic sheep model, we found that new bone quality is comparable to healthy bone, but bone formation occurs at a significantly reduced rate. Furthermore, adjacent bone deteriorates structurally, likely mobilizing minerals to support repair, becoming porous and fragile. These results suggest that treatments should focus on accelerating bone formation while preserving bone integrity.

Osteoporosis, a common orthopedic disease predominantly caused by estrogen deficiency in postmenopausal women, continues to pose a significant public health challenge due to the poorly understood molecular mechanisms. While cuproptosis has been implicated in various pathological conditions, its concrete role in the pathogenesis of osteoporosis remains unknown. Equally ambiguous remains the functional role of Sirtuin 5 (SIRT5), a mitochondrial deacylase with well-characterized involvement in aging and bone formation, in estrogen deficiency-associated osteoporosis. In the present study, we identified a novel potential Estrogen/SIRT5/Ferredoxin 1 regulatory axis that modulates both cuproptosis and the lineage commitment of mesenchymal stem cells. Using an ovariectomized mouse model, we observed that serum copper levels were reduced, whereas copper accumulation was elevated in bone tissue. Estrogen deficiency down-regulated SIRT5 expression, promoted cuproptosis, and induced obvious bone loss. Cuproptosis directly impaired the osteogenic differentiation in mesenchymal stem cells, while SIRT5 overexpression partially rescued this lineage commitment defect. Mechanistically, we showed that estrogen up-regulated SIRT5 expression, which in turn mediated Ferredoxin 1 demalonylation and enhanced its lysosomal degradation. This dual regulatory mechanism may effectively suppress cuproptosis and restore the osteogenic potential of mesenchymal stem cells. Our findings suggest that the novel Estrogen/SIRT5/FDX1 axis may function as a key regulator of bone homeostasis, and identify SIRT5 as a potential therapeutic candidate for postmenopausal osteoporosis, likely through its capacity to reduce the cuproptosis-like features of mesenchymal stem cells.

Glucocorticoids (GCs) are essential endocrine regulators coordinating stress responsiveness, metabolic flexibility, inflammatory resolution, and circadian physiology. While acute GC fluctuations are adaptive, sustained exposure (arising from psychosocial stress, circadian disruption, obesity, chronic inflammation, neoplasms, or steroid therapy) elicits pleiotropic effects that overlap with biological aging. Prolonged GC signaling intersects with multiple hallmarks of aging by altering nutrient sensing, suppressing autophagy, impairing mitochondrial quality control, and promoting cellular senescence. In this context, the GC-responsive polypeptide ACBP/DBI (acyl-coenzyme A [CoA]-binding protein/diazepam-binding inhibitor) has emerged as a stress-induced inhibitor of macroautophagy that amplifies several metabolic and immune consequences of GC excess linked to aging phenotypes. Clinically, chronic GC elevation is associated with earlier and more severe manifestations of age-related diseases, including metabolic syndrome, osteoporosis, sarcopenia, neurodegeneration, cardiovascular disease, immunosenescence, and cancer. Here, we review mechanistic links between GC signaling and systemic aging and discuss strategies to mitigate the age-accelerating consequences of persistent GC exposure.

The treatment of osteoporosis remains a critical challenge due to the limitations of current therapies in simultaneously restoring homeostasis of bone metabolism and modulating the chronic inflammation of bone microenvironment. While the acidic microenvironment greatly exacerbates bone resorption, it also lays the foundation for the application of responsive therapeutic nanoplatforms. Herein, inspired by the rocket-like responsive cascade release principle-defined by a "booster-payload" mechanism, in which a metal ion-doped mesoporous silica shell serves as an early-release booster and a calcium sulfide core acts as a sustained-release payload-a bone-targeted nanoplatform (CSM3P) was developed. This platform integrates calcium sulfide nanoparticles with magnesium/manganese-doped mesoporous silica for bone targeting. It leverages the pathological acidic microenvironment of osteoporosis to enable stimuli-responsive and stepwise release of multiple mineral ions (Mg2+/Mn2+/Ca2+) and hydrogen sulfide (H2S), coordinates bone regeneration and regulation of the osteoimmunological microenvironment and thereby achieves metal-gas targeted therapy for osteoporosis. This acidic responsive and sequential ion/gas release model establishes a self-reinforcing therapeutic cycle, where the pathological acidity itself drives a synergistic and adaptive treatment regimen. Both in vitro and in vivo evaluations demonstrate the superior efficacy of CSM3P in ameliorating the inflammatory bone microenvironment and rebalancing bone remodeling. This work offers a novel paradigm for intelligent, feedback-driven nanotherapy against osteoporosis and other microenvironment-associated diseases.

Glucocorticoid-induced osteoporosis (GIOP) is a prevalent and serious side effect of long-term glucocorticoid therapy, characterized by elevated oxidative stress and profound suppression of bone formation. There is a lack of therapies that effectively target the underlying oxidative stress and impaired osteogenesis simultaneously. In this study, we aimed to identify novel therapeutic agents from a library of quinonoid compounds. Using a high-throughput screen with Runx2 promoter-luciferase reporter cells, we identified decylubiquinone (DUB) as a potent candidate that counteracted dexamethasone (Dex)-induced oxidative stress and osteogenic suppression in bone marrow mesenchymal stem cells (BMSCs). In a murine GIOP model, DUB administration significantly alleviated bone loss, reduced oxidative stress, and inhibited osteoblast apoptosis. Mechanistically, DUB restored the glucocorticoid-impaired CD39/CD73/adenosine (ADO) axis, thereby elevating extracellular ADO levels. ADO subsequently exerted dual protective effects: it attenuated oxidative stress and apoptosis induced by glucocorticoids, and it activated the adenosine A2b receptor (A2bR), triggering the downstream cAMP/PKA/CREB signaling cascade to drive osteogenic gene expression. Genetic knockdown of CD39, CD73, or A2bR abolished the beneficial effects of both DUB and exogenous ADO. Furthermore, we developed bone-targeted DUB-loaded liposomes (DUB@TLip), which markedly enhanced the in vivo therapeutic efficacy of DUB. In summary, our study not only identifies DUB as a promising anabolic agent against GIOP but also reveals a novel mechanistic link between purinergic signaling and bone redox homeostasis, highlighting the therapeutic potential of targeting the CD39/CD73/ADO axis for treating this and potentially other oxidative stress-associated skeletal disorders.

Osteoclastogenesis is driven by tightly coordinated transcriptional programs downstream of receptor activator of nuclear factor-κB ligand (RANKL) signaling, in which reactive oxygen species (ROS) function as essential secondary messengers. Although extracellular peroxiredoxin 1 (PRDX1) has been implicated in the suppression of osteoclast differentiation, the role of intracellular PRDX1 in regulating osteoclastogenic signaling remains poorly understood. Here, we identify intracellular PRDX1 as a redox-sensitive negative regulator of osteoclastogenesis and bone resorption. PRDX1 deficiency markedly enhanced osteoclast differentiation, bone resorption activity, and osteoporotic phenotypes in vivo. Transcriptomic and mechanistic analyses revealed that PRDX1 attenuates osteoclastogenic gene transcription by blocking the nuclear factor kappa B (NF-κB)/p65 signaling axis. Loss of PRDX1 increased intracellular ROS accumulation, promoted p65 nuclear translocation and promoter occupancy, thereby amplifying osteoclastogenic transcriptional programs. Mechanistically, PRDX1 underwent TNF receptor associated factor 6 (TRAF6)-mediated Lys67-dependent ubiquitylation and lysosomal degradation in response to RANKL signaling. In addition, RANKL-induced Src activation promoted phosphorylation of PRDX1 at Tyr194, which enhanced TRAF6-mediated ubiquitylation without substantially altering overall TRAF6 binding. Together, these findings reveal a PRDX1-ROS feedback loop that modulates NF-κB activity during osteoclastogenesis and identify regulated PRDX1 degradation as a mechanism by which RANKL signaling amplifies osteoclastogenic responses. These findings establish intracellular PRDX1 as an important modulator of skeletal homeostasis, suggesting its potential relevance as a pharmacological target in diseases characterized by excessive bone resorption.

Osteoarthritis (OA) is a multifactorial joint disease characterized by progressive cartilage degeneration and chronic inflammation of the synovial membrane. A critical hallmark of OA is the depletion of high-molecular-weight hyaluronan (HA), which impairs lubrication and perpetuates a catabolic microenvironment. To restore endogenous HA biosynthesis, we engineered a cadherin-11 (CDH11)-targeted, pH-responsive nanocarrier (CMN-CDH11) based on amphiphilic carboxymethyl-hexanoyl chitosan-poly(ethylene glycol)-maleimide for the intracellular delivery of hyaluronan synthase 2 (HAS2). These nanocarriers (∼350 nm) leveraged a pH-triggered charge-reversal mechanism, transitioning from -10.88 mV at pH 7.0 to a positive potential of +34.40 mV at pH 4.5. Confocal imaging confirmed that this strategy facilitated endosomal escape, enabling cytosolic delivery of enzymatically active HAS2 for subsequent HA biosynthesis. In vitro results in fibroblast-like synoviocytes demonstrated that CDH11-mediated targeting enhanced cellular association by 2.5-fold, leading to a significant upregulation of HAS2 expression and secretion of bioactive HA with a weight-average molecular weight of 2.05 MDa. In a rabbit ACLT model with three animals per group, HAS2@CMN-CDH11 treatment promoted superior matrix regeneration and sulfated glycosaminoglycan deposition compared with conventional HA injections. We further demonstrated that the HAS2@CMN-CDH11 platform transitioned OA therapy from exogenous HA supplementation to cell-mediated HA production within a 6-week observation period, highlighting its potential as a therapeutic strategy for osteoarthritis.

Osteoarthritis (OA) is a degenerative joint disease driven by a complex interplay of inflammation, extracellular matrix degradation, subchondral bone remodeling, and chronic pain. Purinergic signaling has emerged as a key regulator of OA pathogenesis, where dysregulated extracellular nucleotide-mediated P2 receptor activation and impaired adenosine-mediated P1 receptor signaling disrupt joint homeostasis. Excessive activation of P2X and P2Y receptors amplifies inflammatory cascades, promotes chondrocyte apoptosis, enhances matrix metalloproteinase activity, and sensitizes nociceptive pathways, while reduced P1 receptor signaling, particularly via A2A and A3, compromises anti-inflammatory and chondroprotective mechanisms. Additionally, disruptions in extracellular nucleotide metabolism exacerbate disease progression by perpetuating synovial fibrosis, cartilage destruction, and persistent pain. This review provides a mechanistic overview of purinergic receptor dysregulation in OA, detailing its roles in synovial inflammation, cartilage homeostasis, subchondral bone remodeling, and pain transmission. Furthermore, this review explores emerging therapeutic strategies targeting purinergic receptors, particularly P2 receptor antagonists and P1 receptor agonists, which are being developed as selective ligands to restore joint homeostasis and attenuate disease progression. Understanding the intricate molecular crosstalk between the P2 and P1 receptor pathways will be critical for the development of precision therapies aimed at modifying OA pathophysiology and improving clinical outcomes.

The development of cell scaffolds with unique mechanical properties and their interaction with stem cells will substantially advance stem cell bioengineering. In this study, mechanically sensitized microspheres with a self-prestressed mechanical structure were developed using oxidized bacterial nanocellulose (OBNC) as a scaffold. This study is the first to demonstrate that mechanical stress can trigger membrane receptor switch, enhancing the sensitivity of cells to the microenvironment and promoting interactions between stem cells and cell scaffolds for cartilage repair and regeneration. OBNC microspheres use local mechanical stress stimulation of stem cells through a self-stressing mechanical structure to trigger membrane receptor switch, thereby increasing the sensitivity of integrin receptors to the extracellular matrix (ligand). Moreover, OBNC microspheres can self-adapt to fill irregular cartilage injury sites and integrate cell scaffolds based on the strong adhesion of loaded stem cells following activation. Triggering of membrane receptor switch by nanoliposomes carrying OBNC scaffolds promotes the chondrogenic differentiation of stem cells, which repair and regenerate cartilage. In vitro and in vivo experiments revealed that the interaction between OBNC microspheres and stem cells effectively repaired cartilage damage caused by osteoarthritis. The results of this study provide new insights into the application of mechanical properties in stem cell bioengineering.

Osteoarthritis (OA) is a common orthopedic disease characterized by cartilage degeneration, osteophyte formation, and synovial hyperplasia. Although dysregulated O-GlcNAcylation has been implicated in various musculoskeletal and inflammatory disorders, its specific role and molecular targets in OA pathogenesis remain largely unexplored. In this study, we aimed to conduct a multidimensional investigation to demonstrate and delineate the chondrocyte-specific functions and mechanisms of O-GlcNAc transferase (OGT) during OA progression. To explore the mechanisms of OA progression, we analyzed OGT expression using GEO data and clinical cartilage samples. Cartilage-specific OGT knockout mice (Acan-CreERT2; Ogtflox/flox) were generated and subjected to DMM surgery. To determine the effects of OGT in OA, histological and immunohistochemical studies were conducted. RNA-seq and CUT&Tag were were employed to elucidate the underlying molecular mechanisms. OGT expression is reduced in OA cartilage, and its overexpression delays cartilage degeneration, while cartilage-specific OGT deletion accelerates OA progression. Mechanistically, we found that OGT interacts with and O-GlcNAcylates KDM6B at serine 215, thereby inhibiting its ubiquitination, enhancing protein stability, and promoting extracellular matrix gene expression by demethylating H3K27me3 at Col2a1 and Col6a6 loci. OGT is a key regulator of OA that exerts its function by modulating the epigenetic state of chondrocytes. Loss of OGT in chondrocytes not only disrupts normal cartilage development but also accelerates OA progression under pathological conditions, thereby providing new experimental evidence for understanding OA pathogenesis and informing the development of potential therapeutic strategies.

Osteoarthritis (OA), a leading cause of joint dysfunction, is characterized by progressive cartilage degradation linked to chondrocyte pyroptosis, yet disease-modifying therapies remain elusive. In this study, we conducted the first systematic drug repurposing screen in chondrocytes, aiming at identifying drugs that may suppress pyroptosis and verifying the therapeutic effects on OA. Mitiglinide's effects on chondrocyte viability were quantified via CCK-8 assays and live/dead staining. Pyroptosis inhibition, extracellular matrix (ECM) homeostasis, and NF-κB activation were measured by western blot and immunofluorescence. Network pharmacology analysis and molecular docking were applied to predict the interacting protein of mitiglinide, while Nrf2 was knocked down by siRNAs to confirm its role in mitiglinide regulated pyroptosis and ECM. In vivo, destabilization of the medial meniscus (DMM) model -induced OA mice received mitiglinide for 8 weeks, with efficacy evaluated through X-ray, OARSI-graded histopathology, immunohistochemistry, Hematoxylin-Eosin and Safranin O-Fast green staining. Through high-throughput screening (HTS) of 1,228 FDA-approved drugs, we identified a list of pyroptosis inhibitors, and mitiglinide was suggested as one of the most potent pyroptosis inhibitors in chondrocyte. Mechanistic studies demonstrated that mitiglinide may directly target Nrf2 and suppress its downstream NF-κB-driven NLRP3 inflammasome activation; it may also promote ECM homeostasis in chondrocytes. In vivo study showed that mitiglinide may effectively attenuate OA pathology in mice. Mitiglinide, identified via FDA-drug-library screening, alleviates OA progression by suppressing NLRP3 inflammasome activation and ECM degradation via activation of the Nrf2/HO-1 signaling pathway. This positions mitiglinide as a repurposed disease-modifying OA drug candidate.

Osteoarthritis (OA) is a debilitating joint disease characterized by progressive loss of boundary lubrication and disruption of cartilage homeostasis. Proteoglycan 4 (PRG4) is a critical boundary lubricant, but PRG4 function in OA may be compromised by reduced local expression, intra-articular clearance and protease-mediated processing within the inflamed joint microenvironment. Here we identified conserved downregulation of PRG4 in both human and mouse OA cartilage and developed a multifunctional lipid nanoparticle (LNP) platform, sa/A@E LNPs (PRG4 saRNA/AEBSF@EC12 LNPs), to achieve sustained lubrication and chondroprotection. In this system, PRG4 saRNA is delivered by LNPs formulated with a newly developed ionizable lipid, EC12, together with the broad serine protease inhibitor AEBSF. AEBSF is intended to shield endogenous and saRNA-expressed PRG4 from serine protease activity in the protease-rich OA microenvironment, whereas EC12 functions not only as a delivery component but also as an intrinsic activator of NRF2 signaling. Mechanistically, EC12 binds KEAP1, promotes NRF2 nuclear translocation, and increases NRF2 stability, thereby activating endogenous antioxidant responses. sa/A@E LNPs showed deep cartilage penetration. In a destabilization of the medial meniscus (DMM) mouse model, intra-articular administration of sa/A@E LNPs attenuated cartilage erosion and improved joint function. Together, these findings establish a multifunctional therapeutic strategy that integrates lubrication restoration, broad serine-protease shielding and antioxidant activation, supporting the further development of sa/A@E LNPs as a promising disease-modifying platform for OA treatment.

Obesity is a major risk factor for osteoarthritis (OA), yet the mechanisms linking excess adiposity to joint degeneration remain incompletely understood. Here, we identify adipocyte-derived extracellular vesicles enriched in mitochondrial components (EV-Mito) as pathogenic mediators that transfer mitochondrial DNA (mtDNA) to chondrocytes. The internalized mtDNA activates the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) cytosolic DNA-sensing pathway, inducing inflammatory signaling, metabolic dysfunction, senescence, and cartilage degeneration in murine and human models. Genetic and pharmacological inhibition of cGAS-STING signaling attenuates cartilage damage, pain behaviors, and gait abnormalities. Population-level and interventional data further show that body fat percentage, rather than body mass index, is more closely associated with OA risk and severity. In an exercise cohort, high-intensity interval training selectively reduced adiposity and was associated with lower mtDNA abundance in synovial EV fractions enriched for adipose-associated EV markers, reduced synovial 2',3'-cyclic GMP-AMP levels, and superior improvement in OA symptoms. These findings define a conserved EV-Mito-mtDNA-cGAS-STING axis linking adipose tissue to joint pathology and highlight fat-targeted interventions as mechanistically informed strategies for preventing and treating obesity-associated OA.

Pain arising after surgery and persisting beyond 3 months is termed 'chronic postsurgical pain' (CPSP). Prevention of CPSP is a research priority. Our objectives were to assess whether regional anaesthesia can reduce the incidence of CPSP and long-term opioid use and to determine which factors influence its effectiveness. We conducted a Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA)-compliant systematic review and network meta-analysis of randomised controlled trials assessing the effectiveness of regional anaesthesia for reduction of CPSP. We searched various databases up to October 2025. We performed pairwise meta-analysis and network meta-analysis to determine whether type, timing and method (catheter or single injection) of regional anaesthesia influenced the incidence of CPSP. We investigated the effect of surgery type, baseline risk, and sex via meta-regression. We used Grading of Recommendations Assessment, Development and Evaluation (GRADE)/ Confidence In Network Meta-Analysis (CINeMA) to assess certainty of evidence. We included 158 randomised controlled trials involving 18 794 subjects. Overall, regional anaesthesia reduced the incidence of CPSP compared with no block (risk ratio [RR]: 0.73, 95% confidence interval [CI]: 0.67-0.80), with effects observed up to 12 months after surgery. Reductions in CPSP were also observed within specific surgery types, including mastectomy (RR: 0.69, 95% CI: 0.59-0.79), thoracotomy (RR: 0.72, 95% CI: 0.55-0.96), video-assisted thoracoscopic surgery (RR: 0.73, 95% CI: 0.56-0.96), and knee arthroplasty (RR: 0.71, 95% CI: 0.52-0.97). Opioid use was not statistically significantly different between groups (RR: 0.88, 95% CI: 0.61-1.28). CPSP evidence was low certainty; opioid use was very low certainty. Network meta-analysis suggested that neuraxial techniques reduced the incidence of CPSP more effectively than peripheral techniques after thoracotomy (neuraxial RR: 0.64 95% CI: 0.49-0.83; peripheral RR: 0.84, 95% CI 0.73-0.96) and video-assisted thoracoscopic surgery (neuraxial RR: 0.60, 95% CI: 0.45-0.80; peripheral RR: 0.77, 95% CI: 0.63-0.94), compared with no block. Differences in effectiveness based on administration time point and method of administration varied by surgery type. Network meta-analysis evidence was low to very low certainty. Meta-regression showed no significant effect of surgery type, sex or baseline risk. Our findings indicate that regional anaesthesia reduces the incidence of CPSP for up to 12 months after surgery. The effectiveness of regional anaesthesia was influenced by the type of regional technique used, whereas the type of surgery, sex, or baseline risk did not have a significant impact.

As a key regulator of the immune system, regulatory T cells (Treg cells) suppress excessive immune responses and maintain self-tolerance through various immunosuppressive mechanisms, both contact-dependent and contact-independent. They have demonstrated significant therapeutic potential in immune-related diseases and some non-immune diseases. In this paper, we systematically review the induction strategies of Treg cells, covering various aspects including antigenic stimulation, cytokine modulation, metabolic pathways, epigenetic regulation, drug induction, and engineered technology. Although each strategy has its own advantages, no single approach can comprehensively address the complex issues surrounding Treg cell stability, target specificity, and large-scale production. Therefore, we propose that integrating multiple induction strategies during the Treg cell induction process is crucial for designing Treg cell therapies with superior functionality and broader applications, thereby overcoming the current limitations of Treg cell therapies. In addition, we introduce their therapeutic applications in immune diseases (such as autoimmune disease, organ transplantation, allergic asthma, and cancer) and non-immune diseases (such as insulin resistance, tissue repair, fibrotic diseases, and osteoporosis), and recent advancements. We also discuss current research bottlenecks of Treg cell-based therapeutic strategies and provide an outlook on their future development, aiming to deepen the understanding of Treg cells and promote the advancement of Treg cell-based cellular therapeutic strategies.

Cellulose microfibrils (CMFs) in wood macrofibrils are semi-crystalline including crystalline and disordered regions, yet the mechanical role of disordered cellulose remains elusive. Here, we employed reactive molecular dynamics simulations to systematically investigate the mechanical role of disordered cellulose by developing atomic models of softwood macrofibrils with varying cellulose crystallinity. Simulation results showed that there is a critical balance between the strength and toughness of macrofibrils governed by the cellulose crystallinity. Lowering cellulose crystallinity decreased the longitudinal modulus and tensile strength of macrofibrils but increased the ultimate strain. In contrast, toughness exhibited a non-monotonic dependence on crystallinity and reached a peak at approximately 90%. Hydrogen-bond analysis revealed that disordered cellulose mainly led to fewer hydrogen bonds within CMFs, thereby weakening the strength of macrofibrils. Fracture analysis further revealed that disordered regions acted as crack initiation points and energy dissipation regions, making macrofibrils exhibit more ductile behavior. In addition, a theoretical model based on mixture rule incorporating the effect of interphase was proposed to predict the longitudinal moduli of macrofibrils. These findings provide fundamental molecular insights into the structure-property relationships of macrofibrils in wood secondary cell walls and shed light on the design of wood-based materials with tailored mechanical properties.

Deep-sea mining in polymetallic nodule areas poses significant risks to the marine carbon sink. This study investigated the vertical distribution and three-dimensional fluorescence spectral characteristics of dissolved organic matter (DOM) in seawater and sediments within the Clarion-Clipperton Zone, as well as the sources and transformation pathways of DOM at the seawater-sediment interface and evaluated potential mining induced DOM release and impacts. Dissolved organic carbon (DOC) and the relative abundance of chromophoric dissolved organic matter (CDOM) decreased from the euphotic to aphotic layers but accumulated slightly in bottom waters, while DOC concentrations in porewater and CDOM abundance in sediments exceeded that in bottom water by orders of magnitude. Fluorescence analysis indicated that phytoplankton production and microbial reprocess dominated in the euphotic layer, whereas continuous microbial degradation and reworking on organic matter were the primary processes in the dysphotic, aphotic, bottom seawaters and sediments. However, the discontinuous CDOM profiles across the water column and sediment layers indicate a dominant origin from particulate organic matter reworked in situ by microbes. This is especially evident in the distinct discontinuity of CDOM signatures between the bottom seawater and surface sediment. Simulations estimated that mining disturbances could release 0.02-0.15 mg/L of sediment derived DOC into bottom water, where it was likely to persist in bottom water. It was suggested that deep-sea mining would induce a moderate and durable increase of DOM in the bottom water, by which substantially disrupting the organic matter distribution patterns of organic matter at the seawater-sediment interface.

Emerging evidence increasingly suggests a strong correlation linking the human gut microbiome and bone health, particularly in its ability to modulate bone metabolism and the genesis of bone disorders. It is essential to properly understand the mechanisms of the human microbiome to prevent and treat such bone complications. While several therapeutic and analytical techniques have been explored in the past, tissue engineering has recently gained prominence as a strategy that can take advantage of the microbiome's potential. Within this context, microbial exopolysaccharides represent a promising yet largely overlooked source of functional and structural polysaccharides. These natural polymers have significant potential offering meaningful advancements in creating effective materials for bone repair and regeneration. Their potential roles span from enhancing scaffold architecture and mechanical integrity to modulating immune response and promoting osteogenic activity. This review investigates the dynamic interplay between microbiome and bone health through exopolysaccharide-driven tissue engineering. The use of both gut-derived and non-gut microbial EPS in bone tissue engineering has been emphasized. Further EPS driven strategies and their potential for treating bone dysbiosis and contributing to the development of cell-free scaffolds for bone disorders like osteoporosis and osteoarthritis have been discussed.

Polyacrylamide (PAM) -based conductive hydrogels show immense promise for flexible wearable sensors and triboelectric nanogenerators (TENGs). However, integrating superior mechanical properties, strong adhesion, high conductivity, and fatigue resistance within a single system remains a formidable challenge. Herein, a triple-network hydrogel is synergistically constructed via hydrophobic interactions, Diels-Alder dynamic covalent bonds, and Fe3+ coordination. The hydrogel exhibits comprehensive performance: fracture stress of 1.42 MPa, strain of 718%, toughness of 4.94 MJ/m3, Young's modulus of 180.3 kPa, adhesion strength of 23.85 kPa to porcine skin, conductivity of 4.39 S/cm, and high sensitivity (gauge factor = 4.87, pressure sensitivity = 0.92 kPa-1). Benefiting from its rapid and stable signal response characteristics, this hydrogel holds significant potential for applications in human motion and subtle physiological signal monitoring. Moreover, the fabricated TENGs exhibit excellent energy harvesting capability. This work reports the design of multifunctional hydrogels featuring balanced mechanical, adhesive, and conductive properties to advance the development of flexible electronics and self-powered devices.

Chitosan, derived from crustacean and fungal chitin, is a versatile biopolymer with broad-spectrum antimicrobial activity governed by its molecular weight, degree of deacetylation, and crystallinity. Nanoscale derivatives, especially chitosan nanocrystals (ChNCs) and chitosan-based nanocomposites, exhibit enhanced efficacy through increased surface area, stronger electrostatic interactions, improved biofilm penetration, and metal-ion chelation. ChNCs also act synergistically with multiple antibiotic classes, restoring potency against multidrug-resistant pathogens, while chemical modification further expands their antimicrobial potential. Beyond antimicrobial use, chitosan and ChNCs are increasingly integrated into implantable devices, including orthopedic coatings, dental membranes, and guided bone regeneration scaffolds, where their bioactivity and degradability support osseointegration and localized therapeutic delivery. Although nanoforms may show higher cytotoxicity, they remain biocompatible within therapeutic ranges when properly engineered. Chitosan, ChNCs, and their nanocomposites/derivatives represent sustainable, modular platforms for next-generation antimicrobial and biomedical technologies. Emerging directions include green synthesis, metal-functionalized hybrids, and AI-assisted optimization to achieve predictable, tunable biological performance and accelerate clinical translation.

Gram-positive infections continue to pose a therapeutic challenge owing to their invasive nature (e.g., Staphylococcus aureus and Streptococcus pyogenes) and eradication difficulties (e.g., methicillin-resistant Staphylococcus aureus [MRSA] and vancomycin-resistant enterococci [VRE]). Long-acting lipoglycopeptides (laLGPs) present an effective and conveniently dosed option for the treatment of most invasive Gram-positive pathogens. Improved compliance monitoring associated with their infrequent intravenous dosing, that is not available to such degree with more frequently dosed antimicrobials outside of inpatient settings, is another benefit of laLGPs over more frequently dosed antimicrobials. In this article, we provide a narrative review, including the pharmacological characteristics of dalbavancin (DAL) and oritavancin (ORI), the only currently available laLGPs, as well as their approved and "off-label" use reported in the literature to date. We discuss their respective mechanism of action, caveats in compartments where they do not achieve sufficient concentrations (i.e., central nervous system [CNS]; potentially pneumonias with ORI), as well as their reported efficacy in individual organ systems as reported in literature. Lastly, we summarize insights about laLGP use in special populations and discuss the benefits of therapeutic drug monitoring of these agents, mainly in conditions requiring prolonged therapy (e.g., hardware-associated orthopedic infections).

Systemic antibiotics often fail to maintain bactericidal levels at bone and implant-associated infection sites, motivating local antibiotic application. Calcium sulfate (CaSO4) carriers are practical and promising in this application. However, the role of antibiotic-carrier interactions in controlling hydration, microstructure, and drug release remains poorly understood. Using in situ time‑resolved powder X-ray diffraction (XRD), we investigate the hydration of CaSO4 loaded with tobramycin, vancomycin and ceftriaxone. Vancomycin- and ceftriaxone-loaded matrices show hydration kinetics similar to unloaded CaSO4, even though the respective interaction mechanisms are different, whereas tobramycin strongly delays the process, reducing the transformation rate by one order of magnitude. Observed by Scanning Electron Microscopy (SEM), the antibiotics induce very different crystallite sizes and morphologies based on specific dissolution, nucleation and growth behaviors. X-ray computed tomography (XCT) reveals larger pore sizes in tobramycin- and ceftriaxone-containing systems due to limited water transport to the sites of crystal nucleation and growth. Related, non-transformed CaSO4 was partially found. These observations on a macroscale are the result of specific dominant molecular interactions: electrostatic adsorption with hydrogen-bonding in the CaSO4-Tobramycin system, hydrogen bonding for CaSO4-Vancomycin, and calcium complexation for CaSO4-Ceftriaxone. This molecular-level understanding of drug-carrier interactions is necessary to regulate hydration kinetics and microstructure, supporting optimization of local antibiotic delivery systems to improve infection management in orthopaedic and trauma surgery. STATEMENT OF SIGNIFICANCE: Periprosthetic joint infections and fracture-related infections are major complications in orthopaedics. Systemic antibiotic administration may fail to achieve sufficient drug concentration at the infection site and expose patients to systemic toxicity. Local administration overcomes these limitations by delivering high levels of drugs directly to the infection site. CaSO4 is in use as drug carrier but its interaction with specific antibiotics is not fully understood. Our multiscale analytical approach using a combination of dynamic XRD studies and X-ray imaging methods for antibiotic-loading into CaSO4 for tobramycin, vancomycin and ceftriaxone allows us to discover the connection between molecular interactions, macroscopic morphological behavior and loading kinetics. This would enable us to design optimized antibiotic release for local drug administration.

Delayed and nonhealing fractures, affecting 5 to 10% of cases, are associated with prolonged disability and diminished quality of life. Although acute inflammation is required to initiate repair, persistent mechanical instability can sustain maladaptive immune and fibrotic responses that impede regeneration. Existing animal models do not adequately recapitulate mechanical instability, the principal driver of hypertrophic nonunion in clinical settings, thereby limiting translational relevance. We developed a murine model of delayed fracture healing using tunable intramedullary fixation to impose controlled interfragmentary strain. High-strain conditions (low-stiffness nail, 15 to 30% strain) produced enlarged calluses characterized by delayed ossification, increased fibrotic tissue (3.3-fold, P = 0.0147), and reduced biomechanical integrity (1.6-fold decrease in stiffness, P = 0.024) relative to low-strain controls (high-stiffness nail, <5% strain). Spatial transcriptomic analysis identified persistent fibrotic niches in high-strain calluses enriched with fibroblast-associated genes (e.g., Pdgfrb and Lgals3) and dysregulated macrophage-fibroblast signaling (Spp1 and Mmp9). Systemically, high-strain fractures were associated with distinct immune signatures in which CD206+ macrophages and CD25+ regulatory T cells predicted healing outcomes (R = 0.72, P = 0.004), suggesting early immune polarization as a determinant of repair trajectory. Elevated CD8+ T cell responses were observed, consistent with a sustained inflammatory state associated with impaired healing. These findings identify mechanical instability as a driver of pathological immune-stromal interactions and establish a preclinical platform for investigating mechanobiology-informed therapeutic strategies. This work supports a conceptual framework in which hypertrophic nonunion is understood as a disorder arising from dysregulated interactions between mechanical cues and immune responses.

Bone regeneration is a complex, tightly regulated process involving coordinated interactions of immune and stromal cells. Early phases of healing rely on the timely clearance of debris, a task primarily carried out by macrophages and osteoclasts. However, the sequence of events leading to the presence of osteoclasts at the fracture site and how this is shaped by local tissue microenvironments remains poorly understood, particularly at single-cell and spatial resolution. Using single-cell RNA sequencing and multi-epitope ligand cartography, we mapped the spatial organization of distinct cell compartments engaged in early fracture healing in both young and aged female mice at the start of healing. Surprisingly, we found that young mice exhibited an increased presence of activated osteoclasts at day 7, concentrated within the cortical niche. This compartment was also characterized by a spatially restricted immune response with a selective accumulation of distinct macrophage types jointly interacting with neutrophils and stromal cells. This raised the possibility that local cell organization influences osteoclast precursor differentiation. We identified a fracture-associated Spp1hi macrophage subset enriched at the cortex, which represented a transitional monocyte-derived state that expressed early osteoclast differentiation transcripts and gave rise to osteoclasts ex vivo. Neutrophils preceded fracture-associated Spp1hi macrophage accumulation and may promote their recruitment through chemotactic signaling. This coordination was less pronounced in aged mice despite preserved transcriptional states. In parallel, stromal cells in young animals displayed higher expression of essential niche factors, further supporting local osteoclastogenesis at the cortex. Together, our findings identify a distinct macrophage state that contains cells with osteoclast differentiation potential and reveal early, cortex-specific niche activity supporting osteoclastogenesis. This provides a new framework for understanding the initiation of spatial immune-stromal interactions for the early stages of regeneration.

Symptom evolution in degenerative cervical myelopathy (DCM) is traditionally characterized by severity of neurological deficit. A recent expert consensus challenged this view, proposing that DCM fluctuates across neurological, functional and health-related quality of life measures. We examined whether joint changes across these three domains define distinct recovery patterns in a clinic-based cohort of adult patients with DCM. Cohorts analysed were the Cervical Spondylotic Myelopathy-North America (CSM-NA, 2005-2007, N = 278), CSM-International (CSM-I, 2007-2011, N = 479) and the CSM-PROTECT Trial (2012-2017, N = 290). All participants were symptomatic adult DCM patients who underwent surgical treatment and completed at least three longitudinal assessments. Bayesian consensus clustering (BCC) was used to simultaneously model one-year changes in the modified Japanese Orthopaedic Association (mJOA), Neck Disability Index (NDI), and health-related quality of life (SF-36 Score). The optimal number of trajectory clusters was selected using maximum mean adjusted adherence. Multivariable logistic regression examined association between trajectory classes and achievement of minimal clinically important difference (MCID) across outcomes with internal validation performed using 100 bootstrap resamples. The final analytical cohort consisted of 1047 patients diagnosed with DCM. The mean age was 56.8 years, and 60.7% were male. The mean symptom duration was 29.8 months, and most patients exhibited involvement of two spinal levels. Joint modelling of multiple longitudinal outcomes resulted in three distinct patient groups. Trajectory 1 (n = 177, 17%) was characterised by minimal postoperative improvement with persistently low neurological function and health-related quality-of-life scores. Trajectory 2 (n = 524, 50%) demonstrated the greatest reductions in neck pain disability. Trajectory 3 (n = 346, 33%) exhibited global recovery, with substantial improvements across neurological, functional, and quality-of-life domains. Trajectory 3 patients had markedly higher odds of achieving MCID in neurological function (odds ratio [OR] 10.90, 95% CI 6.15-19.32), physical quality of life (OR 7.32, 95% CI 3.53-15.22), and disability (OR 3.02, 95% CI 1.85-4.93) compared to patients in Trajectory 1. BCC-derived models reduced clustering uncertainty and improved model discrimination beyond conventional outcome predictors. Predictors of global recovery included an anterior surgical approach (OR 3.55, 95% CI 1.21-10.37) and higher baseline frailty (OR 1.42, 95% CI 1.14-1.76). We provide evidence that outcomes in DCM follow three distinct, multidimensional trajectories that are not captured by neurological severity alone. Simultaneous assessment of neurological, functional, and health-related quality-of-life outcomes is both valid and informative, enabling phenotypic stratification and improved longitudinal prognostication in DCM. External validation of these recovery phenotypes in independent DCM cohorts is warranted. None.

Opioids exert important negative effects on respiration, evident across a range of behaviours. The present study evaluated whether fentanyl administration decreases diaphragm muscle forces across levels of inspiratory loading in adult patients undergoing elective knee arthroplasty surgery. Adult patients undergoing elective knee arthroplasty with no pulmonary pathology were randomly assigned to a fentanyl dose (25, 50, or 100 μg) in a double-blind, single-institution clinical trial. Ultrasound-based shear wave elastography was used to measure diaphragm Young's modulus (E). The primary outcome was change in the difference in E achieved across levels of inspiratory loading (E range) before randomisation and 10 min post-fentanyl (ΔE range) as a measure of fentanyl-induced changes in diaphragm force-generating capacity. Sixty-nine patients (average age 69 yr) were randomised, with final data analysis in 22, 22, and 19 patients from the 25, 50, and 100 μg groups, respectively. The ΔE range was compared across dose groups using analysis of covariance, with the pretreatment E range included as the covariate. The estimated treatment effect (95% confidence interval) for 50 μg vs 25 μg, and for 100 μg vs 25 μg was -0.7 (-9.5, 8.1) and -5.3 (-14.1, 3.6), respectively. There was no statistically significant effect of fentanyl on ΔE range (P=0.432). Fentanyl did not reduce the E range generated by the diaphragm muscle during inspiratory pressure-threshold loading, possibly reflecting relatively low levels of inspiratory loading or the presence of a fentanyl effect even at the lowest dose used (25 μg) in this older patient population. NCT05856136.

Glucagon is used to treat severe hypoglycaemia in patients with diabetes, and PTH(1-34), an N-terminal fragment of parathyroid hormone, is used to treat osteoporosis. Each peptide activates a cognate G-protein-coupled receptor (GPCR). High-resolution structures of peptide-receptor complexes show that glucagon and PTH(1-34) are fully α-helical in the bound state. Here we describe a design strategy that destabilizes the helical conformation of glucagon or PTH(1-34) but nevertheless delivers potent agonists of each receptor. Replacement of multiple L-α-amino-acid residues with D-α-amino-acid residues, at selected positions, generates heterochiral analogues of both glucagon and PTH(1-34) that approach the all-L peptide in receptor activation potency (cAMP production). The heterochiral agonists are biased away from β-arrestin recruitment relative to the all-L peptide. The glucagon analogues are also biased away from receptor internalization relative to glucagon itself. These unanticipated findings for two dissimilar class B1 GPCRs raise the prospect that heterochiral design will be impactful for other members of this receptor family, which includes multiple therapeutic targets.

Estrogen receptor-positive (ER+) breast cancer exhibits a marked propensity for skeletal metastasis; however, the molecular drivers of bone colonization remain incompletely defined. We investigated the tumor suppressor neurofibromin (NF1), a dual repressor for RAS and ER signaling, whose inactivation promotes endocrine therapy (ET) resistance and is associated with inferior relapse-free survival. NF1 copy number loss was detected in 62% of ER+ patients who subsequently developed metastases and was associated with an increased likelihood of bone metastases at initial diagnosis. In mouse xenograft models, NF1-depleted ER+ breast cancer cells demonstrated enhanced dissemination to skeletal sites following surgical resection of primary tumors. Furthermore, after intra-iliac injection, NF1-depleted cells generated significantly greater tumor burden in bone. Transcriptomic profiling revealed enrichment of bone-related gene signatures in NF1-depleted ER+ breast cancer cells, which more potently induced osteoclast differentiation and bone loss in co-culture systems. In parallel, low NF1 expression correlated with repressed T cell functional states in primary breast tumors and bone metastases. Consistent with these clinical observations, NF1-depleted ER+ breast cancer cells more effectively inhibited proliferation, interferon-γ secretion, and cytotoxicity of human primary CD8+ T cells. Collectively, these findings identify NF1 inactivation as a key driver of bone metastasis in a substantial subset of ER+ breast cancers. By amplifying the osteolytic "vicious cycle" and promoting immune evasion, NF1 loss remodels the microenvironment to favor tumor expansion. These results further suggest that NF1 loss functionally links therapy resistance with increased skeletal metastatic potential.

Tendinopathy is a prevalent degenerative condition driven by complex metabolic dysregulation, yet its inherent metabolic heterogeneity remains poorly characterized, hindering targeted therapeutic development. To address this, we performed systematic multi-omics profiling of human rotator cuff tendinopathy (n = 192). Unsupervised clustering based on the activity of 149 metabolic pathways, validated by pseudotargeted metabolomics, revealed three distinct metabolic-pathway-based classifications (MPCs): MPC-G (glycolytic), with upregulated carbohydrate and glycan metabolism; MPC-F (fatty acid oxidative), exhibiting elevated fatty acid oxidation and amino acid metabolism; and MPC-I (imbalanced), showing dysregulated metabolite homeostasis alongside moderate glycolysis increase and fatty acid oxidation decrease. Single-cell RNA sequencing identified classification-specific pathogenic cell populations. Mechanistically, hypoxia-induced glycolytic reprogramming via HIF-1α led to lactate accumulation, which in turn stabilized HIF-1α, forming a feed-forward loop that promoted the formation of chondro-modulatory tenocytes and drove MPC-G pathogenesis. Genetic inhibition of HIF-1α and direct targeting of lactate both attenuated disease progression, validating the critical role of this axis. Notably, we identified and validated the clinical drug temsirolimus as an effective agent specifically against MPC-G in experimental models. Collectively, our study delineates the metabolic heterogeneity of tendinopathy and establishes a classification framework that enables precision medicine strategies tailored to distinct metabolic profiles.

The "2026 Guidelines for Adult Stroke Rehabilitation and Recovery" replaces the 2016 "Guidelines for Adult Stroke Rehabilitation and Recovery." This updated guideline is intended to provide a comprehensive, up-to-date, evidence-based set of recommendations. The intended audience includes physicians, allied health professionals, and caregivers. A comprehensive search for literature published since the 2016 guideline, derived from research involving human participants, published in English, and indexed in MEDLINE, PubMed, Cochrane Library, and other selected databases relevant to this guideline, was conducted between June and October 2025. Other documents on related subject matter previously published by the American Heart Association were also reviewed. This guideline provides recommendations based on the most current evidence available for stroke rehabilitation and recovery. Key updates include new and revised recommendations across the stroke recovery continuum, including the assessment and treatment of medical comorbidities, fracture risk, fall prevention, technology-enabled rehabilitation, caregiver support, participation, and safe return to work and driving. Although this guideline reflects significant advances, it also highlights gaps in knowledge and underscores the urgent need for continued research to further refine and improve treatment strategies.

We evaluated whether combined general and regional anaesthesia (GA+RA) was associated with improvements in activities of daily living compared with GA alone in adult patients having major orthopaedic surgery. This target trial emulation used data from the Japanese Diagnosis Procedure Combination system (April 1, 2016-December 31, 2023) for patients undergoing major orthopaedic surgery. The primary outcome was discharge-anchored functional change, defined as the difference in the Barthel Index scores between admission and discharge, among admissions with observed and comparable discharge Barthel Index scores. We conducted stabilised inverse probability of treatment weighting using preoperative covariates, and weighted linear regression models were fitted. Secondary outcomes included in-hospital mortality and postoperative length of stay. Missing data were handled using multiple imputations, and sensitivity analyses (inverse probability of censoring weighting, subgroup analyses, and complete case analysis) were performed. A total of 244 212 patients received GA+RA (peripheral nerve block: 183 564; epidural anaesthesia: 60 648) and 435 462 patients received GA alone. After propensity score weighting, GA+RA yielded a higher change in Barthel Index scores (mean difference 0.73, 95% confidence interval [CI] 0.57-0.88, P<0.001), shorter postoperative length of stay (-1.40 days, 95% CI -1.45 to -1.35, P<0.001) and lower in-hospital mortality (hazard ratio 0.85, 95% CI 0.76-0.96, P=0.006). Sensitivity analyses yielded directionally consistent findings. Combined general and regional anaesthesia was associated clinically with modest improvements in discharge-anchored functional change, postoperative stay and in-hospital mortality. Residual confounding and heterogeneity of regional anaesthesia techniques warrant cautious interpretation and prospective confirmation.

Ecnoglutide is a cyclic adenosine monophosphate (cAMP)-biased glucagon-like peptide-1 (GLP-1) receptor agonist being developed by Sciwind Biosciences for the treatment of type 2 diabetes mellitus (T2DM) and for use in long-term weight management. In January 2026, subcutaneous ecnoglutide received its first approval, in China, for use in glycaemic control in adults with T2DM. Subsequently, in March 2026, ecnoglutide received approval in China for use (in combination with diet control and increased physical activity) in long-term weight management in adults with obesity or with overweight with one or more weight-related comorbidity. Ecnoglutide is also under clinical evaluation for use in adolescents with obesity, and in adults with obesity and obstructive sleep apnoea and adults with obesity and knee osteoarthritis. An oral tablet formulation of ecnoglutide is in clinical development. This article summarises the milestones in the development of ecnoglutide leading to these first approvals for T2DM and long-term weight management.