骨科 · 本周文献汇编

Clinical guidelines consistently recommend low-impact physical activity (PA) for the management of hip or knee osteoarthritis (OA). This study aimed to determine the risk and mediators of joint replacement in people with hip or knee OA who participate in high-impact PA. We conducted a mediation analysis using data from the Good Life with osteoArthritis in Denmark (GLA:D) registry. Baseline PA was self-reported using the University of California, Los Angeles (UCLA) Activity Scale and categorised as high-impact, high-intensity, moderate-intensity or low-intensity. Outcomes were self-reported total hip replacement (THR) or total knee replacement (TKR) at 12 months. Candidate mediators measured at 3 months were joint pain intensity, functional capacity (30-second chair stand test) and fear of joint damage from PA. Among 5911 participants with hip OA (66.8 years, 69.5% women), 5.9% engaged in high-impact PA. Among 11 750 participants with knee OA (66.5 years, 72.7% women), 5.2% engaged in high-impact PA. High-impact PA was associated with 36-48% lower odds of THR and was not associated with altered risk of TKR. There was little evidence that pain intensity, functional capacity or fear of joint damage mediated these associations. However, a small indirect effect via functional capacity was observed, where a greater functional capacity was associated with a reduction in odds of TKR (OR 0.92, 95% CI 0.87 to 0.98). High-impact PA was associated with a substantially lower risk of THR, and did not increase TKR risk. Clinicians may consider recommending higher-impact activities for individuals with hip OA, and supporting continued participation in knee OA when symptoms, capacity and patient goals allow.

Extracellular matrix degradation is a fundamental pathological feature of osteoarthritis, while the roles of degraded matrix remain largely unknown. We previously showed that serum elastin fragments were a systemic aging driver. Here, we found that elastin fragments were upregulated in synovial fluid in dual-center osteoarthritis patients. Elastin fragments actively impaired joint tissue in mice and human explants. Mechanistically, a specific elastin motif containing Valine-Glycine-Valine-Alanine-Proline-Glycine (VGVAPG) oligopeptide (E-motif) promoted macrophage secretion of inflammatory factors via the neuraminidase-1, a component of the elastin receptor complex. These inflammatory factors, together with the E-motif, upregulated serum amyloid A3 protein in chondrocytes, accelerating cartilage degeneration. Therapeutically, both the myeloid-specific knockout of neutrophil elastase and the pharmacological inhibition using a clinically applied drug (sivelestat) alleviated joint degeneration in naturally aging mice partly by reducing elastin fragments levels. The pharmacological inhibitor exhibited 1-y systemic safety in dogs and alleviated osteoarthritis-like phenotypes in naturally aging dogs and human explants. Finally, several matrix fragments, including the fragments of type II collagen, fibronectin, hyaluronic acid, and aggrecan, were demonstrated to universally induce cartilage degeneration. Conclusively, this study identifies degraded matrix, especially elastin fragments, as one of the drivers of joint degeneration via pathological macrophage-chondrocyte crosstalk, suggesting elastase inhibitors as a potential therapeutic strategy for aging-related osteoarthritis.

Osteoarthritis (OA) is a highly heterogeneous disease that exhibits distinct clinical manifestations and pathological mechanisms in different joints, patients, and even at different disease stages for the same patient. Genetic and pathophysiological factors contribute to the heterogeneity of OA in clinical manifestations, treatment responses, and prognosis of patients. Despite efforts in developing disease-modifying OA drugs and treatment technologies, no current approach can efficiently delay OA progression, and results from clinical research are inconsistent due to the mismatch between treatment mechanisms and heterogeneous patient subtypes. Researchers utilize clinical data to classify OA into different phenotypes based on etiological factors, clinical symptoms, and imaging features, as well as endotypes based on biomarkers, molecular mechanisms, metabolism profiles, and omics analyses, but there is still a lack of unified standards. Therefore, a comprehensive understanding of the heterogeneity and classification of OA is crucial for stratified and personalized treatment. In this Review, we discuss the heterogeneity of OA, with an emphasis on heterogeneity in treatment responses. We provide a structured analysis of current studies of OA classification, offering new perspectives for future OA research and clinical practice.

Osteoarthritis (OA) is a common age-associated joint disorder driven not only by mechanical wear but also by progressive intracellular stress, metabolic imbalance, and chronic inflammation that culminate in cartilage degeneration and functional disability. Increasing evidence identifies mitochondrial dysfunction and endoplasmic reticulum stress (ERS) as central pathological hubs regulating chondrocyte survival, extracellular matrix (ECM) integrity, and inflammatory signaling. Mitochondrial impairment promotes excessive reactive oxygen species (ROS) generation, defective ATP production, disturbed mitochondrial dynamics, and inadequate mitophagy, collectively accelerating ECM catabolism and chondrocyte apoptosis. In parallel, ERS activates the unfolded protein response (UPR) to restore proteostasis through the PERK, IRE1α, and ATF6 pathways; however, sustained UPR activation shifts from adaptive signaling to maladaptive outcomes, amplifying inflammation, oxidative injury, and cell death in OA cartilage. Notably, emerging data highlight bidirectional crosstalk between mitochondria and ER, particularly via mitochondria-associated membranes (MAMs), as a key driver of Ca²⁺ dysregulation, inflammasome activation, and degenerative joint remodeling. Therapeutic strategies targeting these stress pathways including mitochondrial antioxidants, NAD⁺-boosting agents, mitophagy modulators, chemical chaperones, and selective UPR regulators have demonstrated potential to attenuate cartilage destruction and restore joint homeostasis. This review synthesizes current mechanistic insights into mitochondrial ERS signaling in OA and critically evaluates evolving disease-modifying interventions aimed at intracellular stress reprogramming. Finally, we discuss translational challenges and future directions for developing precision therapies that exploit organelle stress pathways to improve long-term joint health.

The development of osteoarthritis (OA) is accompanied by various metabolic disorders, highlighting the need for further investigation into metabolism-related pathogenesis and targeted therapeutic strategies. Herein, we found that linoleic acid (LA), the most abundant essential fatty acid in the diet, accumulates in the blood, synovial fluid, and cartilage tissue of elderly and OA individuals. Notably, LA not only induces ferroptosis in chondrocytes, but it also serves as a risk metabolite, driving OA onset and accelerating the progression of traumatic OA in male rat models. Mechanistically, LA can directly bind to iron-sulfur cluster assembly enzyme (ISCU) to induce its autophagic degradation and inhibit iron-sulfur cluster synthesis, which subsequently activates IRP1-mediated translational regulation to drive the ferroptosis process. Furthermore, upregulating or supplementing ISCU in cartilage tissue contributes to mitigating LA accumulation and trauma-induced OA progression, and this strategy can further enhance the therapeutic efficacy of moderate exercise in OA treatment by effectively inhibiting ferroptosis. Taken together, our findings identify LA as a key metabolite involved in the onset and progression of OA by driving ferroptosis and propose a targeted therapeutic strategy based on ISCU supplementation.

Overcoming short intra-articular retention and poor chondrocyte uptake of drugs remains a major challenge for osteoarthritis (OA) therapy. Thereby, we developed a tetrahedral DNA (TDN)-based nano-delivery system (TLM@CAP) via a two-step engineering strategy, involving the introduction of tunable numbers of specific DNA loops to significantly enhance metformin loading capacity, and conjugation with a chondrocyte-affinity peptide (CAP) to confer chondrocyte-targeting capability. The TLM@CAP complex demonstrated improved chondrocyte uptake, prolonged joint retention exceeding 72 h, and deep cartilage penetration. In vivo, TLM@CAP outperformed free metformin in restoring mitochondrial function, reducing cellular senescence, and rebalancing extracellular matrix metabolism via AMPK/mTOR pathway activation in senescent chondrocytes. In an OA rat model, intra-articular TLM@CAP administration effectively alleviated pain, improved gait, and protected against cartilage and subchondral bone destruction. This work not only presents a potent targeted therapeutic strategy for OA but also advances the rational design of TDN-based nanoplatforms for drug delivery.

Osteoarthritis (OA) is a multifactorial joint disease propelled by interrelated pathological processes including synovial inflammation, failure of joint lubrication, and impaired cartilage regeneration. Hydrogel microspheres have demonstrated potential in the treatment of OA. However, previous studies primarily concentrated on the functionalization of hydrogel microspheres, while overlooking the influence of size effects on OA repair. Considering the intricate multicellular characteristic of the joint microenvironment, the regulatory function of particle size on biological responses differs, thus making a quantitative design strategy necessary. Here, we present a size-engineered and machine learning (ML)-guided strategy for OA therapy based on cooperatively engineered multi-size HA hydrogel microspheres. We further elucidate the relationships between microsphere size and their corresponding biological functions. In vitro and in vivo results revealed clear functional specialization: small microspheres enhanced interfacial lubrication, medium-sized microspheres exhibited optimal immunomodulatory activity, and large microspheres preferentially supported chondrocyte proliferation and extracellular matrix (ECM) production. To quantitatively optimize their cooperative effects, a deep kernel learning Gaussian process (DKL-GP) model was employed for Bayesian optimization of microsphere composition. The ML-optimized formulation significantly outperformed uniform-ratio mixtures and single-size controls in vivo, promoting cartilage protection and favorable immune microenvironment remodeling. Collectively, this work establishes a size-engineered hydrogel microsphere platform for OA therapy and introduces a generalizable paradigm for designing injectable biomaterials tailored to multiscale degenerative diseases.

Spinal diseases are common and widely impactful health issues in modern society. With the advancement of computer vision and medical image analysis, image-based automatic recognition and classification of spinal diseases have become research hotspots. However, existing methods often show limited performance in recognizing spinal diseases from complex or low-quality X-ray images. Their performance is easily affected by noise and exposure variations, leading to the extraction of pseudo-features unrelated to the disease. In addition, discrepancies among data sources and imaging conditions result in poor model generalization, making it difficult to adapt to cross-domain variations in clinical applications. To address these challenges, this study proposes an Information Bottleneck-based Optimal Transport Network (IBOTSpine) for automated diagnosis of spinal diseases. The IBOTSpine model introduces an information bottleneck-constrained feature extraction module that effectively captures disease-relevant structural information while suppressing irrelevant noise. Moreover, by incorporating an optimal transport mechanism, the model learns domain-invariant features, thereby reducing the distribution discrepancy between training and testing data and enhancing robustness and generalization across multi-source datasets. Specifically, the model employs a Swin Transformer as the backbone network and jointly optimizes the information bottleneck and optimal transport losses to achieve synergistic improvement in feature extraction, domain adaptation, and classification performance. Experimental results on real spinal X-ray dataset demonstrate that the proposed model outperforms existing methods in classification accuracy, generalization capability, and feature discriminability, validating its effectiveness and application potential in intelligent spinal image diagnosis.

Spinal aging is a progressive degenerative process involving structural and functional decline of the spine as a whole and of its individual components, ultimately contributing to the development of degenerative spinal diseases (DSDs). Previous studies have largely focused on local spinal tissues or the intervertebral disc (IVD). However, recent advances in geroscience indicate that spinal degeneration is not an isolated local event, but is influenced by systemic aging through a multi-organ aging network. Accordingly, this review proposes a "from local to systemic" framework to better understand the mechanisms underlying spinal aging. At the local level, spinal aging follows heterogeneous trajectories, with intervertebral disc degeneration (IVDD) often serving as a central process. Different DSDs share common pathological mechanisms, and their anatomical proximity allows them to interact biomechanically. Therefore, the spine should be regarded as an integrated organ system within systemic aging. Based on this concept, we propose that vertebral osteoporosis and paraspinal muscle degeneration should also be incorporated into the framework of spinal aging and DSDs. At the systemic level, immunosenescence, skeletal muscle aging, neural and vascular aging, digestive system aging, endocrine system aging, and nutrient-sensing dysregulation may collectively affect the spine through circulating inflammatory factors, senescence-associated secretory phenotypes, metabolic mediators, endocrine signals, and mechanical loading, thereby influencing the susceptibility, progression, clinical phenotypes, and treatment responses of DSDs. We further discuss clinical translation in spinal aging, including anatomical barriers to drug delivery and emerging strategies to overcome them, and summarize therapeutic approaches based on multi-organ aging. Ultimately, this review emphasizes that future DSD treatment should achieve more precise stratification, move beyond lesion-centered local interventions, and incorporate systemic anti-aging strategies to optimize long-term clinical outcomes in patients with DSDs.

Intervertebral disc degeneration, the leading cause of chronic low back pain, remains incurable with traditional conservative therapies limited to symptomatic alleviation. We present an ECM-mimetic injectable hydrogel (HPTC) synthesized via dynamic crosslinking of hyaluronic acid-phenylboronic acid (HA-PBA) and tannic acid-cerium(III) metal-polyphenol networks (TA-Ce³⁺ MPNs), which faithfully recapitulates native nucleus pulposus ECM to enable functional tissue regeneration. In vitro, HPTC presented broad-spectrum reactive oxygen species scavenging and downregulated pro-inflammatory cytokine expression (TNF-α, IL-1β, IL-6), while upregulating anti-inflammatory markers (IL-4, IL-10). Crucially, Ce³⁺ effectively reduced dissolved oxygen levels (to 105% vs. 115% in control at 15 min), thereby promoting HIF-1α signal expression and mitigating nucleus pulposus cells senescence under H₂O₂-induced oxidative stress. In rat and rabbit intervertebral disc degeneration models, a single, minimally invasive injection of the ECM-mimetic HPTC hydrogel preserved the disc height index and magnetic resonance imaging signal intensity, enhanced aggrecan and collagen II deposition, suppressed inflammatory mediators, and elevated HIF-1α while reducing p21 expression in situ. Transcriptomic analysis further implicated HIF-1α pathways in ECM regeneration. All these findings demonstrate that the HPTC hydrogel leverages metal-polyphenol chemistry within an ECM-inspired framework to synergistically modulate oxygen homeostasis, oxidative stress, and inflammation, offering a bifunctional and biomimetic platform for disc regeneration.

Intervertebral disc degeneration (IVDD) is a primary cause of chronic low back pain. Although inflammation is a prominent feature of degenerating discs, anti-inflammatory therapies often provide limited and transient benefit, suggesting that disc degeneration is maintained by a more stable tissue-level program. We therefore hypothesized that IVDD is sustained by a fibrosis-inflammation-coupled cell state, and that effective intervention requires both disrupting fibrotic signaling and overcoming the delivery barriers imposed by the disc's avascular, ECM-dense environment. To test this, we integrated clinical stratification, single-cell transcriptomics, and mechanical modeling to identify pathogenic nucleus pulposus (NP) cell states. Single-cell mapping revealed an expanded fibrosis-inflammation-coupled NP subpopulation in degenerated discs, characterized by the concurrent activation of ECM remodeling and inflammatory programs. Mechanical stress locked NP cells in this state, inducing persistent inflammation even after stimulus removal, suggesting that fibrosis is an upstream driver. We developed a platelet-derived growth factor receptor α (PDGFRα)-targeted NP membrane vesicle (NMV)-coated nanotherapeutic (NMV@PC) with a dual antifibrotic drug system. This therapy effectively suppressed profibrotic pathways, targeted fibrotic NP cells, and restored disc height and hydration in a lumbar spine instability model. NMV@PC reduced collagen deposition, inflammatory mediators, and pain-related behaviors, reprogramming degenerated discs toward a homeostatic state and overcoming structural delivery barriers.

Long-duration spaceflight elicits spinal impairments, including bone loss and intervertebral disc degeneration (IVDD). As the connective hub of the entire spine, the intervertebral disc (IVD) plays a pivotal role in maintaining spinal stability. However, the molecular mechanisms through which space microgravity mediates IVDD remain elusive, and the core spinal component responsible for mechanical load-bearing and the maintenance of spinal mechanical homeostasis has not been identified. Herein, we identified for the first time that space microgravity induces nucleus pulposus (NP) degeneration via PIEZO1. Analysis of samples from patients with IVDD indicates downregulated PIEZO1 expression in NP cells. Specific Piezo1 deficiency in NP cells not only disrupts the extracellular matrix (ECM) metabolism of NP but also impairs the homeostasis of the annulus fibrosus and cartilage endplate. Mechanistically, Piezo1 deficiency drives NP cell apoptosis and alters their secretory profile by activating the AMP-activated protein kinase (AMPK) signaling pathway, thereby mediating functional spinal unit (FSU) dysfunction through paracrine regulation. Targeted delivery of AMPK inhibitors to NP tissue markedly mitigates the progression of IVDD induced by mechanical instability. Together, our findings uncover the central role of the NP in mechanical response and its paracrine function within the FSU for the first time, providing a potential therapeutic strategy for IVDD treatment and astronaut spinal protection.

Treating bone defects becomes particularly challenging when drug-resistant bacteria take hold. Standard antibiotics often fail to clear these infections completely, and the resulting inflammatory environment actively blocks new bone formation. To tackle this problem, we developed a sulfonated-PEEK scaffold called SPMiL that carries two distinct payloads: the human derived antimicrobial peptide LL37 and mitochondria-rich vesicles (EV-Mito). We generated these vesicles from ectomesenchymal stem cells (EMSCs) lacking Opa1, a key regulator of mitochondrial dynamics. Knocking out this gene substantially boosts vesicle production, solving the supply limitations that have hampered previous attempts to use EV-Mito therapeutically. In tests using MRSA-infected rat calvarial defects, SPMiL released LL37 continuously to eliminate the resistant bacteria while simultaneously transferring functional mitochondria into recipient cells. These transplanted organelles promoted osteogenic differentiation and suppressed osteoclast activity through metabolic reprogramming, antioxidant effects, and restoration of mitochondrial membrane potential. This work demonstrates that combining antibacterial defense with mitochondrial transfer offers a viable approach for treating infected bone defects that resist conventional treatment.

MRSA associated infections in skeletal and soft tissues remain formidable clinical issues with limited treatments, due to antibiotic resistance, biofilm formation and pathological hypoxia. Herein, yolk-shell nanoplatform (BMP@M) is developed for targeted mild photothermal-triggered cascade gas therapy against MRSA infections. BMP@M features a polydopamine photothermal yolk and mesoporous MnO2 shell loaded with NO donor (BNN6), enabling spatially separated heat generation and cascade NO release via gradual photothermal conduction. Macrophages are preactivated with MRSA membrane vesicles (MVs) to obtain engineered macrophage MVs with elevated Toll-like receptor 2, endowing BMP@M with MRSA-specific targeting and infectious lesion-targeting ability. The photothermal effect of BMP@M further promotes injectable thermosensitive chitosan to form tissue repair matrix (BMP@M/C). The synergistic photothermal-gas therapy effectively eradicates MRSA and disrupts biofilms. Moreover, the MnO2 shell in situ decomposes pathological H2O2 into O2, alleviating hypoxia. The coordinated release of NO and O2 restores mitochondrial function, scavenges ROS, suppresses NF-κB/NLRP3 inflammatory axis, and drives M2 polarization. In models of MRSA-induced osteomyelitis and full-thickness skin defects, BMP@M/C achieves effective infection control, anti-inflammatory, osteogenesis and angiogenesis effects. This study offers a combined antibacterial, immunomodulatory, and regenerative approach for infected tissue repair.

Bacterial infection is now a significant obstacle to the effective repair and regeneration of both soft tissues and bone in clinical settings. Managing infected sites is challenging due to multiple antimicrobial resistance, abnormal inflammatory responses, and an excessive inflammatory microenvironment. To meet the complex healing needs following soft tissue or bone, an immunomodulatory thermosensitive hydrogel was designed and synthesized. The composite hydrogel (CQDs@UPDA@gel) combines carbon quantum dots (CQDs) as the second near-infrared window (NIR-II) photothermal agents (PTAs) and ultrasmall polydopamine nanoparticles (UPDA NPs) as reactive oxygen species (ROS) scavengers and immunomodulators, embedded within a chitosan matrix coordinated with Cu2+ that enhances the good swelling performance and stable rheological properties of the hydrogel. This synergistic approach simultaneously inhibits bacterial infection and alters the immunosuppressive microenvironment, thereby promoting coordinated soft tissue or bone regeneration. In vivo studies have shown that the hydrogel can encourage the regeneration of soft tissue or bone under NIR-II laser irradiation for the treatment of infectious wounds, subcutaneous abscesses, and infectious bone defects in the maxillofacial region. Overall, this project offers a general strategy for creating multifunctional hydrogels that both eradicate pathogens and modulate the immune microenvironment to support the repair of complex soft tissue or bone infections.

To describe the epidemiology of injuries and illnesses at the Paris 2024 Paralympic Games. Injuries and illnesses were recorded daily via a web-based injury and illness surveillance system and local organising committee medical facilities. Adjusted incidences (injuries/illnesses per 1000 athlete days; 95% CIs), injury prevalence (IP; %) and injury burden (days lost per 1000 athlete days; 95% CIs) are reported. In total, 4450 athletes (1978 female; 2472 male) from 163 National Paralympic Committees were monitored prospectively during the 14-day Games period (62300 athlete days). A total of 535 injuries (IP=10.9%) were reported in 485 athletes, with an incidence of 8.6 (7.9-9.4). Taekwondo (27.3 (20.7-35.8)), football 5-a-side (22.3 (14.4-37.7)) and sitting volleyball (19.9 (14.8-26.7)) showed higher incidences of injury compared to other sports (p<0.001). Injury burden was 8.5 (6.5-11.1) and 19.1% of injuries resulting in time loss from training/competition. The highest burden was observed in taekwondo (64.3 (35.9-115.2)) and football 5-a-side (23.4 (6.2-88.3)). A total of 520 illnesses were reported in 467 athletes (IP=10.5%), with an incidence of 8.3 (7.6-9.1). Illness incidence for female athletes (10.6 (9.4-11.9)) was higher than recorded for male athletes (6.6 (5.7-7.5)); p<0.001 and higher in triathlon (18.2 (12.6-26.7)) compared to other sports (p<0.05). The incidence and burden of injury in taekwondo and football 5-a-side were significantly higher compared with other sports at the Paris 2024 Paralympic Games. The highest incidence of illness was observed in triathlon and female athletes had a higher illness incidence than male athletes.

To evaluate whether biomarkers of systemic inflammation and alterations in redox homeostasis, which we refer to as oxidative stress, associate with musculoskeletal injury (MSKI) during US Army Basic Combat Training (BCT) and to characterise longitudinal changes in these biomarkers throughout BCT. This prospective observational study included 206 Army trainees (51% female) undergoing BCT. Blood samples were collected and analysed for high-sensitivity C reactive protein (hsCRP), free oxygen radical test (FORT), free oxygen radical defence (FORD) and Oxidative Stress Index (OSI=FORT/FORD). Injuries were identified using the International Classification of Diseases, Tenth Revision (ICD-10) codes. Mixed-effects logistic regression models assessed associations between biomarker levels and injury diagnosis over three timeframes (0-7 days before draw, 1-7 days following draw and 8-14 days following draw). Models included both chronic (between-person) and acute (within-person) biomarker components. Inflammation and oxidative stress biomarker associations with MSKI were strongest in the 0-7 days before and 0-7 days after injury diagnosis. Acute elevation in hsCRP (OR=1.41, 95% CI 1.03 to 1.93, p=0.034) was associated with 41% higher odds of injury diagnosis within the next 7 days. Chronically high hsCRP and OSI were also associated with increased MSKI risk (OR 2.27, 95% CI 1.22 to 4.19, p=0.01 and OR=1.72, 95% CI 1.01 to 2.92, p=0.046, respectively). Elevated hsCRP and OSI were temporally associated with MSKI diagnoses during BCT, with the strongest associations in the week surrounding diagnosis. These associative findings may reflect heightened physiological stress and early injury-related tissue stress and repair responses.

The mechanisms underlying exercise rehabilitation-induced tendon-bone healing remain unclear. Using a mouse model of anterior cruciate ligament reconstruction, we found that low-intensity mechanical stimulation promoted macrophage M2 polarization, phagocytosis, and efferocytosis at the tendon-bone interface via acyl-CoA synthetase long-chain family member 4 (ACSL4)-mediated lipid metabolism reprogramming. Acsl4 silencing reduced fatty acid oxidation and efferocytosis, impairing exercise rehabilitation-induced tendon-bone healing. Notably, the CCL9-CCR1 axis contributed to bone marrow stromal cell homing following macrophage efferocytosis. In addition, engineered CCL9-expressing exosomes accelerated tendon-bone repair.

Traumatic brain injury often accelerates fracture repair, but the neural circuits linking brain state to bone healing remain unclear. Here we show that, in male mice, a hippocampal-cortical circuit linking the dentate gyrus (DG) and the retrosplenial granular cortex (RSGc) regulates repair after bone injury. Skeletal injury increased activity-associated labeling in both regions. Inhibiting excitatory neurons in the DG or RSGc, or suppressing neuronal populations associated with the DG-RSGc pathway, accelerated repair, whereas activating DG or RSGc excitatory neurons delayed healing. RSGc activation counteracted the pro-healing effect of DG inhibition, supporting DG-RSGc circuit dependence under the tested conditions. Inhibitory circuit manipulations were associated with increased circulating neuropeptide Y, macrophage IDO1 induction at the repair site, and elevated L-kynurenine, which promoted osteogenic differentiation. Pharmacological blockade and rescue experiments support an NPY-IDO1-kynurenine effector arm linking central circuit state to peripheral bone repair.

Bone healing is orchestrated by multiple cell populations, including those that normally do not produce bone but acquire osteoprogenitor capabilities following injury. Muscle-resident fibroadipogenic progenitors (FAPs) and superficial periosteal cells are among such cells, however their physiologic significance in bone healing and the mechanisms regulating their differentiation are unclear. Here, using the new tamoxifen-inducible Clec3b.CreERT2 allele, we show that both of these populations can be traced and manipulated in a mouse model. Clec3b+ cells are completely absent in marrow and bone-lining surfaces and can differentiate to multiple cell types including osteoblasts during fracture repair and BMP2-induced heterotopic ossification. Orthotopic transplantation assays indicate that Clec3b+ FAPs rather than Clec3b+ periosteal cells are mobilized to become osteoblasts in these conditions. Further, Clec3b+ cells appear functionally distinct from periosteal skeletal progenitors as they exhibit remarkably low chondrogenesis during fracture healing; however, they can form cartilage during heterotopic ossification of muscle and ex vivo culture. Inhibition of WNT-signaling or depletion of Clec3b+ cells reduce mineralization during both processes. These data show that extra-skeletal cells that normally do not produce bone, FAPs in particular, are recruited to help repair bone fractures, and could represent a novel target for therapies aimed to enhance fracture healing.

Osteoporosis, a prevalent age-related disease, is characterized by impaired bone formation and an increased risk of fractures. Current anabolic treatments primarily rely on biologics, which are costly and require inconvenient administration. Identifying regulators of osteoblastogenesis that are amenable to small-molecule targeting is essential for developing more accessible therapies. Through an unbiased kinome-wide RNAi screen in primary murine calvarial osteoblasts, we identified the AXL receptor tyrosine kinase (Axl) as a negative regulator of osteoblast differentiation. Axl is most highly expressed in undifferentiated and early differentiated osteoblasts, with a rapid decline in expression during osteoblast maturation. siRNA-mediated knockdown of Axl or pharmacological inhibition with the small molecule BGB324 significantly enhanced osteoblast differentiation and mineralization in vitro. In mice, BGB324 treatment significantly increased bone mass by promoting bone formation. Mechanistically, Axl knockdown or inhibition upregulated interferon-stimulated gene 15 (Isg15), while Isg15 knockdown impaired osteoblast differentiation and enhanced Erk phosphorylation, leading to increased expression of osteoblast-specific genes. Consistently, double knockdown experiments demonstrated that simultaneous loss of Axl with either Isg15 or Mapk1, but not other interferon-related genes, reversed the Axl knockdown-induced increase in osteoblast differentiation, reinforcing their mechanistic involvement. Collectively, our study identifies Axl as a promising therapeutic target for osteoporosis and other bone-related disorders.

Aging of the skeleton is a hallmark of organismal decline and underlies prevalent age-related disorders such as osteoporosis and osteoarthritis. Bone marrow-derived mesenchymal stem cells (BMSCs), the primary source of osteoblasts, undergo profound functional deterioration during senescence, leading to an imbalance between bone formation and resorption. This review systematically summarizes the key features of BMSC senescence, including impaired proliferation and differentiation, epigenetic dysregulation, and the acquisition of a pro-inflammatory senescence-associated secretory phenotype (SASP). We highlight recent advances in understanding how epigenetic mechanisms (DNA methylation, histone modifications, RNA methylation, and non-coding RNAs) orchestrate BMSC aging. In addition, we discuss the intricate crosstalk between senescent BMSCs and the bone microenvironment, emphasizing their contribution to age-related bone diseases. Finally, we propose future research directions, including the integration of multi‑omics, single-cell technologies, and targeted epigenetic interventions, as well as emerging therapeutic strategies such as senolytics, metabolic modulators, and extracellular vesicle-based approaches. A deeper understanding of BMSC aging will facilitate the development of novel treatments to preserve bone health and combat aging-related skeletal disorders.

The repair of critical-size bone defects remains clinically challenging, largely owing to the limited homing and osteogenic capacity of endogenous bone marrow mesenchymal stem cells (BMSCs). To address this, we developed a cell-free strategy that combines a decellularized fish scale (DC-FS) scaffold with stem cell sheet-derived extracellular vesicles (CS-EVs). This design leverages the scale's innate microgrooved topography for directional cell guidance while loading CS-EVs to provide sustained pro-osteogenic cues. The resulting CS-EVs/DC-FS composite retained the intrinsic micro/nanoarchitecture and mineralized composition of the biological scaffold and permitted controlled EVs release. The scaffold promoted directional migration, adhesion, and osteogenic differentiation of BMSCs in vitro, upregulating key markers including RUNX2, OPN, and BMP2. Mechanistically, EV-derived miRNAs, notably miR-146a-5p, were associated with activation of the Sirt1/Wnt/β-catenin signaling pathway. In a rat critical-size calvarial defect model, CS-EVs/DC-FS accelerated bone deposition, improved trabecular microstructure, and enhanced overall regeneration quality. This study establishes a topography-guided and EV-mediated strategy for bone regeneration, offering an integrated nature-derived solution for reconstructing challenging maxillofacial and orthopedic bone defects.

To compare the effects of different physical therapy interventions and identify the most effective intervention on pain, function, quality of life (QoL) and adverse events (AEs) in adults with rotator cuff (RC) tendinopathy. Systematic review and network meta-analysis (NMA) of randomised clinical trials (RCTs). Seven databases and two trial registries were searched up to March 2024. RCTs comparing physical therapy interventions to any other physical therapy intervention, sham, placebo, waiting list or no treatment on pain, function, QoL and AEs in adults with RC tendinopathy. A frequentist NMA using a random-effects model was performed. Risk of bias and certainty of the evidence were assessed using the revised Cochrane risk-of-bias tool and the Grading of Recommendations, Assessment, Development and Evaluation approach, respectively. 89 RCTs (5532 participants) were included. Exercises targeting the shoulder muscles may reduce pain (standardised mean difference (SMD) -0.79, 95% CI -1.33 to -0.26) and improve function (SMD 0.74, 95% CI 0.34 to 1.14) compared with no treatment but the evidence is very uncertain. Exercises targeting shoulder and scapular muscles in addition to percutaneous electrolysis (SMD -1.58, 95% CI -2.68 to -0.48) and to trigger point dry needling (SMD 3.10, 95% CI 1.99 to 4.22) seem to be the most effective interventions on pain and function at the end of treatment, respectively. Most of the interventions identified may not be superior to isolated shoulder exercises alone, which might be considered a reasonable first-line approach, but the evidence is very uncertain and most interventions are informed by limited data. High-quality research is needed to improve evidence of physical therapy interventions in adults with RC tendinopathy. CRD42024527176.

Chordoma is a rare malignant bone tumor with high local recurrence, metastatic spread in 40% to 60% of patients over the disease course, and significant morbidity. Because of its rarity, anatomical complexity, and prolonged natural history, high-quality evidence to guide management is limited. International consensus guidelines for localized chordoma were first published in 2015; however, advances in pathology, imaging, surgery, radiotherapy, and supportive care since then necessitate updated multidisciplinary recommendations. To update and expand the 2015 consensus recommendations on the diagnosis, treatment, and follow-up of pediatric and adult patients with primary, localized chordoma. In June 2025, a meeting of the Global Chordoma Consensus Group was held in Milan, Italy, that included experts from all relevant specialties as well as patient representatives. A comprehensive literature review guided structured discussions on the management of primary localized disease. Levels of evidence and grades of recommendation were assigned. A total of 305 articles were included in the literature review. Management strategies were stratified by anatomical site (skull base, mobile spine, and sacrum). The central principal of care was treatment at experienced, multidisciplinary centers, with maximally safe surgery followed by high-dose, highly conformal radiotherapy. Guidance was provided on diagnosis, surgical approaches, and radiotherapy planning for each anatomical site. Systemic therapy options; long-term, risk-adapted follow-up; and supportive, palliative, and rehabilitative care were also addressed. This global consensus statement provided updated multidisciplinary guidance for the management of primary, localized chordoma. It aimed to harmonize clinical practice, support shared decision-making, and identify priorities for future collaborative research in this rare and challenging disease.

Sleep disturbances are highly prevalent among individuals with chronic non-cancer pain and are associated with worse pain severity and poorer prognosis. The comparative trade-offs between the effectiveness and safety of available pharmacotherapies for sleep outcomes in this population remain poorly defined. Ninety-eight RCTs involving 28,920 participants (mean age 53.2 years, 71.2% female) were included. Moderate-certainty evidence demonstrated that melatonin significantly improved sleep quality compared with placebo (standardized mean difference [SMD] = -0.60, 95%CI: -0.98, -0.22). Ten agents (e.g., amitriptyline, oxycodone, gabapentin, pregabalin, duloxetine) also showed statistically significant improvements in subjective sleep quality (SMD = -0.24 to -1.07), but most effects were supported by low-certainty evidence and were accompanied by an increased risk of adverse events (odds ratio [OR] = 1.90 to 37.00). Conversely, melatonin was not associated with an increased risk (OR = 0.88, 95%CI: 0.19, 3.94). Our findings indicate that melatonin shows promise as a safe, adjunctive option for improving sleep quality in this population, but larger, condition-specific trials are warranted to confirm these effects. Other pharmacological agents are limited by lower-certainty and unfavorable safety profiles. These results should be interpreted cautiously given limited direct comparisons, heterogeneous chronic pain populations, the high proportion of trials at high risk of bias, and the predominance of subjective sleep outcomes.

Provide an updated comparison of the prevalence of mild or more severe depressive symptoms between high-performance athletes and non-athletes. Comparative OR meta-analysis. PubMed (Medline), PsycINFO (Ebsco), Scopus (Elsevier) and SportDiscus (Ebsco). We conducted hand searches of reference lists of relevant papers. Studies were included that were published in full in English; compared high-performance athletes and non-athletes; used a validated measure of depressive symptoms; and provided the prevalence of individuals who indicated at least mild depressive symptoms. 1834 records were screened, 58 reviewed for eligibility, and five studies were included and added to five studies from our previous meta-analysis. Collectively, 10 studies reporting data on 2430 high-performance athletes and 2725 non-athletes were evaluated. A risk of bias in prevalence studies assessment demonstrated an agreement between the two evaluating authors that was considered substantial or strong with a kappa statistic of 0.75. There was no significant difference in depressive symptom prevalence between high-performance athletes and non-athletes (OR=1.016, 95% CI=0.815 to 1.267, p=0.888). Male high-performance athletes (n=1708) were no more likely than male non-athletes (n=1556) to report mild or more severe depressive symptoms (OR=0.936, 95% CI=0.710 to 1.235, p=0.641). Female high-performance athletes (n=722) were no more likely than female non-athletes (n=1157) to report mild or more severe depressive symptoms (OR=1.031, 95% CI=0.818 to 1.299, p=0.796). Male high-performance athletes (n=1019) were 47% less likely to report mild or more severe depressive symptoms than female high-performance athletes (n=722) (OR=0.527, 95% CI=0.418 to 0.664, p<0.001). Male non-athletes (n=955) were 33% less likely to report mild or more severe depressive symptoms than female non-athletes (n=1157) (OR=0.666, 95% CI=0.447 to 0.992, p=0.045). This meta-analysis found no significant difference in depressive symptom prevalence between high-performance athletes and non-athletes. However, both female high-performance athletes and non-athletes report a greater prevalence of depressive symptoms than their male counterparts.

Frailty is a multifactorial geriatric condition linked to increased mortality and adverse health outcomes and is associated with gut microbiome features that differ from those observed in healthy ageing. We analyze gut metagenomic profiles in relation to estimated frailty severity and frailty-related clinical outcomes assessed with an internally developed and validated Frailty Mortality Index (FMI) in the SUPERB cohort, comprising 2,081 Swedish women aged 75-80 years. The FMI is a composite measure that integrates functional, physiological and psychological dimensions associated with frailty and mortality risk, and shows stronger associations with mortality compared to the Charlson Comorbidity Index in the SUPERB cohort. The FMI is inversely associated with microbial diversity, gene richness, and predicted functional capacity, which are linked to physical function, mortality and fall-related injuries. A total of 404 bacterial species are significantly associated with FMI, and most show concordant associations in a Chinese cohort of 1,448 older adults. Here we show microbial signatures linked to frailty and mortality across different continents.

We sought to generate recommendations for the tennis community regarding the provision of mental healthcare and the promotion of mental wellness among elite tennis athletes, including junior tennis athletes. Recommendations were generated using a multimethod approach that included an in-person summit held during the 2022 US Open Tennis Championships in New York, New York, USA, and an asynchronous Delphi consensus process. Participants (n=83) were purposively selected to ensure diverse representation from all seven governing bodies of tennis and the broader tennis ecosystem, including: current and former elite adult and junior players, coaches, sport administrators, parents, physiotherapists, athletic trainers, physicians (sports medicine, psychiatry, neurology), other licensed mental health providers, epidemiologists and other academic subject matter experts. The summit included expert presentations and cross-organisation group discussion, which were used to generate provisional consensus statements. Statements were rated anonymously and refined iteratively based on synthesis of open-ended feedback until predetermined numeric thresholds were reached. The summit also included discussion of implementation challenges and priorities. As a result of this process, 2 foundational principles and 25 actionable recommendations were adopted, covering 5 domains: (1) standards of care, (2) education, (3) media and social media, (4) safeguarding and (5) research. The foundational principles emphasised that mental health must be prioritised by tennis governing bodies and that these bodies should collaborate across the tennis ecosystem. This output is a starting point for coordinated mental health efforts in tennis. More broadly, this pragmatic process is a replicable model for cross-organisational collaboration in other high-performance sports.

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.

A discredited trial has fractured trust in one landmark result-the first randomized evidence on checkpoint inhibitor dosing timing-but not the broader hypothesis it was meant to prove: that circadian biology shapes immunotherapy efficacy. Researchers on both sides of the debate are now recalculating what the surviving evidence can actually support.

Acute myeloid leukaemia (AML) is an aggressive blood cancer characterized by the unregulated proliferation of immature myeloblasts. Gene mutations have been shown to have a large effect on pathogenesis, inter-tumour heterogeneity and clinical outcomes in AML1-8; however, the role of epigenetic alterations in these respects has been investigated less extensively. Here we use ATAC-seq (assay for transposase-accessible chromatin with sequencing) in a cohort of 1,563 individuals with a recent diagnosis of AML (the 'eCHROMA' cohort) to show that AML can be classified into 16 subgroups on the basis of chromatin accessibility profiles. Multiomics analyses of gene mutations, the transcriptome, DNA methylation and histone marks show that these ATAC subgroups exhibit distinct driver mutations, differentiation states, gene expression, DNA methylation and super-enhancer profiles, and are also associated with clinical outcomes. These findings were validated in independent cohorts. Single-cell ATAC sequencing reveals that all leukaemic cells in each subgroup share a common chromatin accessibility profile, which suggests that subgroup-specific epigenomic fingerprints underlie the ATAC-based classification. Mechanistically, the subgroups have distinct gene-regulatory networks that are driven by the activities of key transcription factors in haematopoiesis, and in which subgroup-specific super-enhancers have a pivotal role. Multiomics single-cell analysis further reveals deregulated trajectories of differentiation coupled with chromatin accessibility and gene expression. Notably, ATAC subgroups have an independent prognostic effect, compared with genomic classification, and are associated with particular drug sensitivities. In summary, ATAC-based chromatin profiling, combined with multiomics data, provides insights into AML pathogenesis beyond genomics and constitutes a valuable resource for AML research.

Chromosome copy number variations are poorly understood drivers of human malignancies. -7/del(7q) is common in acute myeloid leukemia, confers a poor prognosis, and is thought to harbor several tumor suppressors. Previously, we identified the histone methyltransferase KMT2C as a tumor suppressor in this region. Here, through a differentiation CRISPR screen in hematopoietic stem and progenitor cells, we find that the mitochondrial iron transporter ABCB8 is essential for their differentiation. ABCB8 deficiency accelerates leukemogenesis in vivo and disrupts iron homeostasis, reducing cytoplasmic iron availability and impairing iron-dependent enzymes, including the histone demethylase KDM6A. Consequently, ABCB8 loss elevates H3K27me3 levels, repressing differentiation genes in an iron- and KDM6A-dependent manner. Notably, ABCB8 and KMT2C, neighboring genes on 7q, cooperatively regulate H3K27me3 to suppress leukemogenesis. Our findings reveal ABCB8 as a tumor suppressor in -7/del(7q) acute myeloid leukemia and uncover an epigenetic collaboration between neighboring tumor suppressors, driven by iron-mediated chromatin remodeling.

Human aging is characterized by complex structural and functional decline, but quantifying its heterogeneity and assessing biological age remain challenges. We present the mCAS (multicentric Chinese aging standardized cohort) developed from 2,019 Chinese individuals aged 18-91 years. Integrating high-dimensional clinical, physiological, and molecular-level data, we constructed a three-tiered aging framework: the core capacity clock (CC-clock) to quantify clinical physiological decline, the multimodal clock (MM-clock) with extensive parameter coverage and enhanced predictive precision, and organ-associated aging clocks. Cross-layer analysis demonstrates that plasma protein clocks not only capture chronological age but also serve as efficient proxies for systemic physiological capacity. Leveraging this framework for discovery, we identified the age-dependent accumulation of coagulation factors as a driver of multi-organ senescence and systemic inflammatory activation. This study provides a foundational framework that bridges molecular signatures with functional decline, identifies new biomarkers for aging assessment, and reveals a novel translational driver of aging.

Ice shelves buttress the flow of the Antarctic ice sheet, but this stabilizing effect weakens as fractures form, reducing ice viscosity and accelerating ice discharge toward the ocean. Here, we incorporate physically consistent damage mechanics into an ice-sheet model and apply it across the Amundsen Sea Embayment, the largest current contributor to Antarctic mass loss. Simulations reproduce key satellite-derived damage patterns under present-day conditions. Projections to 2300 show that allowing damage to evolve strongly amplifies future ice loss, increasing sea-level contributions by up to a factor of [Formula: see text]4.5. Even when damage is held fixed at its present-day extent, projected contributions increase by 50 to 130[Formula: see text], indicating that existing fractures already commit the system to enhanced ice loss. Basal crevasses dominate this response, accounting for [Formula: see text]90% of damage-induced amplification. Healing mechanisms substantially moderate damage, as neglecting gravitational crevasse closure and compressive healing overestimates ice loss by almost 50%. Together, these results suggest that fracture-driven weakening substantially alters Antarctic ice-sheet dynamics and should be represented in projections of future sea-level rise.

Melatonin (Mel) exerts antioxidant and anti-ferroptosis effects not only via the canonical receptors Mt1/Mt2 but also via metabotropic glutamate receptor 1 (mGluR1)/glutamate-mediated signaling. Nevertheless, the regulatory mechanism by which Mel modulates mGluR1/glutamate signaling in retinal ischemia-reperfusion (I/R) injury and its downstream effects on ferroptosis and oxidative stress remain poorly understood. Here, bulk RNA sequencing identified that the Mel receptors Mt1/Mt2 and ferroptosis/iron-redox regulators (Gpx4, Fth1, and xCT) were significantly downregulated after retinal I/R. Mel improved retinal structural and visual function, visual-guidance behavior, and electrophysiological responses following I/R while concurrently reducing ferroptotic and inflammatory injury markers. These benefits were largely abolished by Mel membrane receptor antagonists. Mechanistically, Mel upregulated Homer1a in vivo and in vitro in a receptor-dependent manner. Conditional deletion of Homer1a in transgenic mice, as well as Homer1a knockdown in retinal ganglion cells (RGCs), abolished the protective effects of Mel on visual function, along with its anti-ferroptotic and anti-inflammatory activities. Molecular docking and immunoprecipitation assays demonstrated that Mel restored the interaction between Homer1a and mGluR1 and activated the xCT/GSH/Gpx4 antioxidant axis. Pharmacologic inhibition of xCT with the buthionine sulfoximine (BSO) simulation pr genetic interference with xCT expression counteracted the protective effects of Mel. Mel also enhanced Nrf2-mediated transcriptional expression of cCT in a Homer1a/mGluR1-dependent manner. Collectively, our results define a Mel-Homer1a/mGluR1-Nrf2/xCT signaling cascade that promotes RGCs survival after I/R by suppressing ferroptosis/iron-redox reactions, thereby providing a potential translatable strategy for receptor-targeted intervention in I/R-related retinal damage.

The kinetics of a Knoevenagel condensation between vanillin and barbituric acid has recently provided insight into the differences between mechanical and traditional solution-based synthetic methods. The solution-based reaction follows first-order reaction kinetics, while mechanochemical reaction kinetics follow a sigmoid pattern, with a rapid acceleration of reactivity following a slow induction period. Previous works theorize the source of the reaction acceleration to be either particle fracture evolution or changes to the reactant's rheological properties. Here, we examined the reaction kinetics in stainless steel, Teflon, zirconia, and aluminum reaction vessels using different milling frequencies to determine the role of reagent mechanics under varying mechanical environments. Reaction vessels with interchangeable midsections and end-caps of different materials were used to discern the role of jar/ball material surface energy and localized shear vs normal loading forces on the reaction kinetics. The kinetics remained sigmoidal regardless of milling jar/ball materials, milling frequency, and observed rheological changes. Based on a kinetic energy model, the reaction is consistent with a force-accelerated autocatalytic process. High mixing in a low-force environment (Teflon) resulted in conversion ∼8x higher than high-force environments (stainless steel), which also showed more ready formation of solid volumes of product that were not free-flowing, reducing yields, suggesting that optimizing interfacial adhesion, impact force, and the relative amounts of shear vs normal forces yields significant rate improvements. Previously reported "cohesive states" likely arise from conditions of shear flow in reaction systems, making the methods introduced here broadly applicable to a host of mechanochemically accelerated chemical systems.

High temperature Nb-Si based alloys face a critical challenge: achieving adequate room-temperature fracture toughness ( > 18 MPa·m1/2) for processing while maintaining high-temperature strength, properties that typically compete with each other. Here, we overcome this inherent trade-off through machine learning-guided alloy design, employing a three-step feature screening strategy to identify 6 key descriptors from 200 initial features. SHAP analysis reveals how melting enthalpy and atomic radius mismatch control property outcomes, enabling targeted multi-objective optimization via NSGA-II algorithm. The optimized Nb-12.26Si-21.35Ti-1.98Al-1.96Cr-0.51Hf-4.34Zr-4.35 V alloy achieves an as-cast fracture toughness of 18.92 MPa·m1/2 while maintaining 322 MPa strength at 1250 °C, surpassing all reported as-cast Nb-Si alloys. Microstructural analysis shows that the superior properties originate from the dispersed distribution of nanoscale γ'-Nb5Si3 phase and crack deflection at phase boundaries with 67.6% lattice mismatch. Our results demonstrate that combining machine learning techniques with mechanistic understanding can accelerate the discovery of high temperature materials.

Skin-integrated flexible electronics are rapidly advancing from short-term use to continuous, long-term wear to meet the demands of health monitoring, wound healing, and skin disease treatment. While three-dimensionally (3D) architected devices offer sensing capabilities and outstanding mechanical performances, the development of a conformal interface between these 3D electronic devices and skin for long-term comfortable wear remains challenging due to their geometric complexity and mechanical fragility. Here, we introduce a multifunctional porous interface that bridges 3D flexible electronics with skin through engineered microporous networks. Such a porous design enhances elastic stretchability and electrical reliability while providing moisture permeability, thermal buffering, impact mitigation, and drug delivery capability. Stiffness reduction and localized pore-wall-shell buckling synergistically underpin the outstanding mechanical resilience under large deformations. The proposed multifunctional porous interface allows development of a 3D closed-loop wound administration patch capable of multimodal sensing and on-demand therapy, markedly accelerating scald wound healing in vivo.

Roman concrete structures have remained serviceable for nearly two millennia and are widely regarded as outstanding examples of durable ancient engineering. Existing literature attributes Roman concrete longevity to the pozzolanic reaction that occurs between reactive volcanic ashes and lime. While the pozzolanic reaction is of fundamental importance, we argue that carbonation over a long period of time also substantially enhances the durability and potential self-healing properties of concrete. To validate this claim, a comprehensive analysis of the concrete used in a latrine included in the Canopus western substructures, in Hadrian's Villa (Roman imperial residence, Tivoli, Italy, 2nd century AD), is performed using multiscale spectroscopic and tomographic approaches to uncover the mechanisms behind the resilience of these enduring structures. Microstructural evidence reveals that volcanic lava composed of leucite, analcime, and ferrian diopside was combined by the Romans with lime at a water-to-binder ratio of ~0.4 to 0.45 to mix the concrete. Calcite cementation in pore spaces and fractures served as the primary binding mineral phase, while the formation of a relatively minor amount of calcium-aluminum-silicate-hydrate precipitated around and between lava fragments to further enhance the integrity of concrete. Conversely, unhydrated calcium oxide reacted with atmospheric carbon dioxide and moisture to form volumetrically dominant calcite cements, creating the primary driver to reinforce structural strength and occlude porosity. This radiaxial fibrous calcite has the potential to mitigate environmental and mechanical stresses in modern concrete infrastructure and advance the development of sustainable and resilient construction materials in the future.

Fracture mechanics models suggest that aseismic slip may either lag behind or outpace the fluid pressure front, depending on injection conditions and the fault's initial stress state. However, direct experimental validation of these predictions has been lacking. Here, we report laboratory experiments on granite samples under upper crustal stress conditions, where we simultaneously tracked the propagation of fluid pressure and aseismic slip during fluid injection. We show that aseismic slip lags the pressure front at low injection rates and low initial stress but rapidly outpaces it under high-rate injection or near-failure initial stress conditions. The transition is governed by a dimensionless loading parameter that integrates injection rate, fault strength, and initial shear stress. Our results provide direct support for fracture mechanics models of fluid-induced aseismic slip and suggest that in critically stressed crustal faults, rupture propagation may commonly outpace fluid diffusion.

Establishment of the blood-brain barrier (BBB) and blood-cerebrospinal fluid (CSF) barrier requires precise coordination between diverse cell types to protect and nourish the brain. Here, we identify developmentally programmed p21+ senescent cells that exhibit divergent senescence-associated features across these two brain interfaces in mice. In the choroid plexus (ChP), epithelial cells adopt a lifelong, non-inflammatory senescent state associated with CSF production and blood-CSF barrier integrity. In contrast, vascular endothelial cells and brain-resident macrophages transiently exhibit pro-inflammatory senescence profiles during brain vascularization, with reciprocal signaling linked to angiogenic patterning and extracellular matrix assembly. The ablation of p21+ cells during mid-gestation disrupts brain vascular patterning and ChP integrity, which results in hemorrhage, impaired CSF production, and ventricular collapse. These findings indicate that embryonic senescent cells adopt divergent transient and long-lived states that support brain-barrier formation and homeostasis, thus reframing the prevailing view of persistent senescence beyond solely a pathological state.

The global quest for a sustainable energy matrix is fundamentally a crisis of material constraints where success relies on structural control at the atomic scale. Herein, we report a universal, physical protocol: cyclic rapid annealing and cooling (CRAC) that simultaneously orchestrates phase-engineering and dimensional reduction. By subjecting bulk TMDs (MoS2, MoSe2, and CoSe2) to extreme, repetitive cryo-thermal shocks, we induce a controlled structural fracturing that yields zero-dimensional (0D) nanoparticles with locked metastable phases (1T/cubic) through rapid kinetic quenching. Comprehensive characterization reveals a profound alteration of the materials' physical landscape: X-ray diffraction and spectroscopic analyses confirm a dominant metallic phase concentration, while electron microscopy unveils sub-10 nm nanoclusters with an abundance of exposed edge sites. Consequently, these CRAC-engineered 0D TMDs exhibit exceptional electrocatalytic performance, delivering very low overpotentials and robust kinetics for the hydrogen and oxygen evolution reactions (HER/OER), high-efficiency oxygen reduction reaction (ORR) pathways, and superior rate capability in super capacitive energy storage. This electrocatalytic prowess originates from the dual-modulation technique. By bridging the gap between materials engineering and electrochemistry, this work provides a universal and scalable blueprint for sculpting earth-abundant materials into high-performance catalysts, establishing a new frontier in the design of noble-metal-free energy technologies.

Hypertrophic scarring remains a challenging clinical problem because of its multifactorial pathology involving reduced apoptosis, excessive collagen deposition, aberrant fibroblast migration, and sustained inflammation. Here, we report Cuprorivaite as a multifunctional biomaterial for hypertrophic scar modulation with intrinsic photothermal enhancement. Through sustained multi-ion release, Cuprorivaite enables concomitant modulation of key scar-associated cellular processes, including apoptosis, collagen deposition, migration, and inflammatory responses. In addition to ionic regulation, the material exhibits an intrinsic photothermal response under near-infrared irradiation, which further enhances ion-mediated cellular modulation without introducing additional photothermal agents. In vitro and in vivo evaluations demonstrate effective attenuation of hypertrophic scarring, evidenced by reduced collagen accumulation, increased apoptotic activity, and improved scar architecture. Transcriptomic analysis coupled with functional validation further identifies representative regulatory factors, including H3C14 and SOX9, associated with the combined material response, providing mechanistic insight at the level of cellular regulation. Together, these findings highlight Cuprorivaite as a multifunctional material integrating ionic regulation and intrinsic photothermal enhancement for hypertrophic scar modulation.

Nanoconfinement is known to alter polymer mechanics, yet how it couples with interfacial interactions to govern stiffness and fracture in polymer-graphene layered nanocomposites remains fundamentally elusive. This work provides a mechanistic decoupling of these effects by investigating well-defined polycarbonate-graphene heterostructures across a range of polymer thicknesses (hp). Using in situ MEMS tensile testing integrated with Raman spectroscopy, we demonstrate that geometric confinement significantly strengthens the interfacial anchoring. As the polymer thickness approaches molecular length scales (hp < 2Rg), the PC chains undergo a critical conformational transition from random coils to flattened, interface-parallel configurations. This molecular ordering drives a shift in the deformation mechanism from bulk-like chain slippage to interface-governed bond stretching. Consequently, we observe an anomalous modulus stiffening that significantly exceeds the theoretical upper bounds of classical mixture rules, accompanied by a concurrent ductile-to-brittle fracture transition. Enhanced Raman strain sensitivity and spatially distributed graphene lattice degradation provide direct evidence of highly efficient stress transfer under strong confinement. Our findings reveal that the synergistic coupling of geometric and interfacial constraints dictates the mechanical landscape of polymer-graphene heterostructures, offering essential guidelines for engineering high-performance layered nanocomposites.

Recent advances in mechanochemistry have shown that the deliberate incorporation of mechanically weak bonds, specifically scissile mechanophores, can improve the fracture resistance of polymer networks. In pendant cross-linked elastomers (e.g., side-chain cross-linked or vulcanized elastomers), bifunctional mechanophores incorporated into cross-links produce substantial toughening. By contrast, utilizing the same motifs for toughening in end-linked or step-growth networks, which are ubiquitous in industrial thermosets, has remained a challenge. Here, by establishing a topological correspondence between pendant cross-linked and end-linked architectures, we identify a design strategy that enables bifunctional scissile motifs to successfully toughen end-linked networks. We validate this approach using model thermoset polyurethanes and show that the resulting mechanophore-driven toughening is substantial, yielding a 16-fold enhancement in tensile toughness and an 8-fold enhancement in tearing energy. We further show that this strategy can be combined with conventional polyurethane toughening approaches to produce materials with outstanding properties. More broadly, this work establishes strand continuity as a mechanochemical design principle for fracture resistant materials across diverse polymer architectures.

Dry eye disease (DED) is a prevalent ocular surface disorder driven by a self-perpetuating cycle of oxidative stress and inflammation, for which current therapies face limitations in bioavailability, retention, and multimechanistic action. To address this, we developed a core-shell structured BPNS@Gel platform, integrating a functionalized black phosphorus nanosheet (f-BPNS) core with a thermoresponsive hydrogel shell. The f-BPNS core (3-5 nm thick) was surface-modified with thiol groups and hyaluronic acid for mucoadhesion and corneal targeting, retaining superior multienzyme-mimetic activities (SOD: 5120 U/mg, CAT: 385 U/mg, GPx: 240 U/mg). The shell, composed of Pluronic F127/N-isopropylacrylamide/chitosan, exhibited thermoresponsiveness (sol-gel transition at 37 °C, gelation time: 45 ± 3 s) and smart ROS/pH sensitivity (68.3% BPNS release under 100 μM H2O2). In vitro, BPNS@Gel demonstrated excellent biocompatibility (>90% cell viability at f-BPNS ≤ 50 μg/mL), targeted corneal epithelial uptake, and multimechanistic action: it scavenged reactive oxygen species, reprogrammed macrophages from a pro-inflammatory M1 (CD86+: 69.6% → 28.3%) to an anti-inflammatory M2 phenotype (CD206+: 18.7% → 42.5%), and promoted corneal epithelial repair (89.3% thickness recovery) and goblet cell regeneration (85.6% density restoration). In a benzalkonium chloride-induced DED mouse model, BPNS@Gel significantly improved tear secretion (78.5% increase), tear film stability (tear breakup time: 8.5 s), and corneal integrity (65.2% reduction in fluorescein staining scores), with excellent long-term biocompatibility. This core-shell design exemplifies a paradigm shift in DED therapy, combining smart responsiveness, targeted delivery, and multimechanistic synergy. This work establishes a paradigm for smart, multitarget nanomedicines to restore ocular surface homeostasis, offering a promising clinical strategy for DED and related inflammatory ocular surface diseases.

Overcoming the inherent strength-toughness trade-off remains a persistent challenge for bioinspired structural materials. Here we develop a high-performance topologically interlocking-like cellulose (TICell) via sacrificial oligomer templating followed by post-cross-linking. Calcium phosphate oligomeric clusters (CPOs) are introduced as transient inorganic templates to confine space within a regenerated cellulose network. Subsequent citric-acid treatment removes the templates while simultaneously covalently cross-linking cellulose, effectively "locking in" a topologically constrained architecture after demineralization. Multiscale characterization shows that the cellulose crystalline framework is largely retained, yet the nanoscale organization reorganizes qualitatively into a continuous, percolated network composed of puzzle-like interlocking modules. This interlocked topology reshapes damage evolution: catastrophic crack run-away is suppressed and energy is dissipated progressively through crack deflection and stepwise advance. As a result, TICell exhibits a strength of 226 MPa and a fracture toughness of 7.0 kJ m-2, representing several-fold improvements over biological materials and conventional polymers. These findings suggest a sustainable route to damage-tolerant, biobased structural materials in which mechanical performance is governed primarily by topology, rather than by crystallinity or composition alone.

Inorganic semiconductors are essential for modern electronics, but their inherent brittleness restricts their applications in flexible and wearable devices. This issue is particularly acute in low-symmetry structures, where the lack of slip systems further suppresses plastic deformation. Here, we reveal an intrinsic toughening mechanism in monoclinic GaTe using in situ SEM microfracture experiments. In contrast to the catastrophic brittle cleavage along the interlayer direction, cross-layer crack propagation undergoes continuous deflection, generating a highly tortuous crack path that enhances the mean fracture toughness by ∼60%. Combining high-resolution imaging with atomic simulations, we identify stress-triggered monoclinic-to-trigonal phase transitions at deflection points, which effectively impede and redirect crack propagation. The toughening mechanism is further validated in a flexible GaTe photodetector, which retains an excellent photoresponse and mechanical durability over tens of thousands of bending cycles. These findings lay a solid foundation for nanodevice applications in which both mechanical robustness and functional stability are required.

Nanoimprint lithography (NIL) is a key enabler for next-generation nanomanufacturing, yet its industrial scalability remains constrained by persistent challenges at the mold-resist interface, including mold fracture, structural deformation, and inefficient demolding. These limitations arise from the lack of coordinated control over adhesion, friction, and stress evolution during imprinting. Guided by simulation-based insights that identify tunable interfacial layers as a critical lever, we employ conformal molecular/atomic layer deposition (MLD/ALD) as a rational strategy to actively regulate these coupled interactions. Here we systematically investigate MLD/ALD-grown graphene, Al2O3, and polyurea as model interfacial layers for NIL molds. By integrating molecular dynamics simulations, finite element modeling, atomic force microscopy (AFM), and experimental imprinting, we establish quantitative links between coating chemistry, interfacial energetics, stress evolution, and pattern fidelity. Among the materials studied, graphene exhibits the most favorable balance of properties, reducing peak imprint-induced mechanical stress to ∼20% of that of bare silicon while maintaining ultralow surface energy (≤0.13 J m-2) and friction coefficient (≤0.1), thereby minimizing structural deformation during imprinting. We further identify coating-dependent thresholds in adhesion, friction, and elastic modulus that define a practical design window for high-performance NIL molds. This work introduces a unified and predictive framework for active interfacial control via ALD coatings in NIL, providing actionable guidelines for coating selection and establishing a pathway toward durable molds, efficient demolding, and reproducible, high-precision nanoscale pattern transfer.

Mesenchymal stem cells (MSCs) are widely used for tissue repair and regeneration, but prolonged in vitro expansion induces senescence and limits their therapeutic efficacy. Given the key role of mitochondria in cellular senescence and metabolic regulation, mitochondrial transfer may offer a promising strategy for ameliorating senescence-associated phenotypes. However, conventional mitochondrial transfer methods, such as coculture and microinjection, are limited by poor quantitative control, low throughput, and potential cell damage. Here, an inertial-focusing-assisted droplet microfluidic platform was developed for high-throughput, high-efficiency, and quantitative control of mitochondrial transfer at the single-cell level. The platform achieved 29.2% single-cell droplets and 1.3% multicell droplets, with a transfer efficiency of up to 56% at a droplet generation rate exceeding 4000 Hz. Using this platform, the transfer of 19 mitochondria from young adipose-derived MSCs (ADSCs) to senescent ADSCs enhanced proliferation capacity and metabolic activities, reduced senescence-associated markers, and transformed the senescent phenotype into a young MSC-like phenotype. The developed technique provides a cell therapy strategy for mitochondrial-related diseases.

Conventional sulfur vulcanization provides practical cross-linking for unsaturated rubbers but struggles to simultaneously improve tear resistance, impact durability, processing stability, and aging performance through a simple and scalable strategy. Herein, we report a calix[6]arene-mediated inverse vulcanization approach to engineer mechanically interlocked polysulfide cross-linkers for natural rubber/carbon black (NR/CB) composites. Two macrocyclic systems were designed to clarify the role of the interface integration. Tert-butylcalix[6]arene (TBC6), lacking polymerizable groups, forms polyrotaxane structures that operate primarily at the rubber-filler interface, enhancing bound rubber formation and enabling interfacial sliding. In contrast, allyl-functionalized calix[6]arene (ATBC6) covalently incorporates into the vulcanized network, constructing slidable cross-links within the bulk while simultaneously strengthening rubber-filler interfacial coupling. This coordinated network interface architecture promotes efficient stress transfer and suppresses crack propagation. The ATBC6-based composite exhibits a 140% increase in tear strength and a 340% enhancement in fracture toughness relative to those of conventional vulcanizates, accompanied by pronounced strain-rate hardening and improved energy absorption. Additionally, stable polysulfide linkages and phenolic units impart enhanced thermo-oxidative aging resistance. This scalable interface engineering strategy offers a practical pathway toward high-performance elastomer composites.

Biomaterials are evolving from passive scaffolds to responsive platforms, yet most lack true feedback regulation. A shift toward adaptive biomaterial systems that integrate sensing, computational processing, and dynamic actuation directly within a macromolecular network could transform these multifunctional biomaterials into precision platforms capable of regulating biological processes in real time.

Retinoids comprise vitamin A and its structurally related natural and synthetic derivatives. Retinoid dynamics involves multiple retinoid forms, carrier proteins, and enzymes that orchestrate the absorption, transport, storage and biotransformation of dietary vitamin A. Beyond their canonical metabolic functions, metabolites and proteins involved in retinoid metabolism also play distinct roles in signal transduction and transcriptome reprogramming, broadening the mechanisms that influence immune cell fate decisions. Age‑related changes in retinoid bioavailability and signaling intensity alter immune cell polarization and function, thereby contributing to the pathogenesis of chronic inflammation in neurodegenerative diseases, cardiovascular diseases, osteoarthritis, and other age-related diseases. In this review, we focus on age-related alterations in the retinoid metabolic pathway and their impact on inflammation and the progression of age-related diseases. This review highlights the pivotal role of retinoid metabolism in anti-ageing interventions and considers future directions and challenges in this field.