骨科领域文献阅读汇编

Cartilage is susceptible to degeneration from injury, overuse, or age-related wear. Articular cartilage, the smooth hyaline cartilage covering the ends of bones in synovial joints, has limited intrinsic repair capacity because its avascular, aneural, and alymphatic matrix contains sparse, low-proliferative chondrocytes, allowing matrix damage to persist and drive joint dysfunction and osteoarthritis. Most therapies relieve symptoms without reliably restoring durable cartilage architecture. Recent advances in cell-based therapy, matrix-associated chondrocyte implantation, engineered scaffolds, controlled-release biologics, and quantitative clinical endpoints have shifted the field toward mechanism-based cartilage regeneration. In this feature review, we assess emerging clinical evidence across cell-based strategies, biomaterial- and scaffold-assisted repair, biologics, and combination approaches. We emphasize integrated, multimodal approaches and standardized outcome measures as essential for achieving durable cartilage repair and true disease modification.

To map current strategies for weight loss in hip and knee osteoarthritis (OA), with emphasis on the emerging role of glucagon-like peptide-1 receptor agonists (GLP-1-RAs) as tools in achieving weight loss and impacting symptoms, disease progression and perioperative outcomes in individuals with obesity. Scoping review conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) framework and methodological guidance from the Joanna Briggs Institute and Arksey and O'Malley. PubMed, Web of Science, Directory of Open Access Journals, Scopus, ProQuest Central (1 January 2010 to 18 August 2025). Included studies focused on adults (≥18 years) with obesity and hip or knee OA, examined weight-loss strategies (nutritional, physical activity, surgical or pharmacological) including GLP-1-RAs. Of 199 included studies, 36 (18.1%) directly assessed GLP-1-RAs and of these, 14/36 (38.9%) reported original data. Evidence was heavily skewed towards knee OA, with limited hip-specific data. Descriptive analysis revealed a narrow geographical distribution of studies and a rapidly increasing focus on GLP-1-RAs; most studies involving GLP-1-RAs (29/36, 80.6%) were published between 2024 and 2025 and were of a low level of evidence (19/36, 52.8% level 5). Randomised and cohort data in knee OA indicate that GLP-1-RAs are associated with substantial weight loss, with accompanying improvements in pain/function and reduced progression to arthroplasty. In contrast, evidence in hip OA is sparse with weaker associations. GLP-1-RAs represent a promising adjunct for managing individuals with OA complicated by obesity. Until further evidence emerges, GLP-1-RAs should be integrated into supervised, multimodal musculoskeletal care rather than used as standalone weight-loss agents.

Subchondral bone remodeling in the early stages of osteoarthritis (OA) is characterized by elevated bone turnover and is closely associated with osteocyte function within the subchondral bone. However, beyond the canonical role of gasdermin D (GSDMD) in mediating pyroptosis in immune cells, its function in osteocytes remains poorly understood. Accordingly, this study aimed to determine whether osteocyte-derived GSDMD regulates subchondral bone homeostasis or contributes to pathological remodeling during osteoarthritis progression. GSDMD expression was evident in osteocytes within the subchondral bone in both clinical and experimental models of OA, as well as in osteocytes co-cultured with stimulated chondrocytes, suggesting a potential role for osteocyte-derived GSDMD in the bone microenvironment. Remarkably, specific deletion of Gsdmd in osteocytes led to increased bone remodeling, which was accompanied by cartilage degeneration in an OA model, as well as bone loss in an osteoporosis model. Mechanistically, Gsdmd-deficient osteocytes displayed enhanced activation of CARD9/NF-κB signaling under inflammatory stimulation, leading to increased production of inflammatory mediators and osteoclastogenic factors that disrupted osteoblast-osteoclast coupling. These changes induced high-turnover subchondral bone remodeling, altered joint mechanical properties, and accelerated cartilage degeneration. Collectively, our findings identify osteocyte-derived GSDMD as an important regulator of subchondral bone remodeling and suggest that loss of this regulatory mechanism exacerbates OA progression. These results further indicate that therapeutic strategies targeting GSDMD should be approached with caution due to potential effects on bone remodeling and inflammatory signaling.

Osteoarthritis (OA) is a chronic disease that imposes a significant economic burden and deteriorates quality of life. Nevertheless, current therapeutic options for OA are limited to symptomatic remedies. As such, there is a high interest in novel methods for treating or preventing OA. One of the most promising medication modalities is through the clearance of cells that are cell cycle arrested but resistant to apoptosis, termed senescent cells. Additionally, these cells are also resistant to alternative programmed cell death modes, such as ferroptosis and pyroptosis. Senescent cells tend to accumulate with age due to increasing cellular and genetic damage. These cells can release inflammatory factors and signaling molecules termed senescence-associated secretory phenotype (SASP). In addition to triggering an inflammatory milieu in joints, SASP can also induce senescence in other cells through autocrine signaling. It has been shown via in vitro and in vivo tests that clearance of senescent cells through a class of drugs known as senolytics, or neutralization of SASP with senomorphics, can improve OA pathogenesis. Following these results, several clinical trials have been conducted to evaluate the efficacy of senotherapeutics against knee OA. Yet there remains a need for a comprehensive assessment of safety and optimization of senotherapeutic treatment regimens for knee OA. To this end, a better understanding of molecular mechanisms behind chondrocyte senescence and knee OA pathogenesis is necessary. Identification of novel compounds that can specifically target chondrocyte senescence pathways can assist in developing more effective therapies against OA.

An increase in the number of senescent cells with advancing age is a major predisposing factor for aging-related osteoarthritis (OA). However, effective intervention strategies targeting cellular senescence have yet to be developed. Increasing evidence suggests that rising epigenetic entropy, specifically the detachment of heterochromatin from the nuclear envelope, is a driver of cellular senescence. We sought to engineer an in situ structural restoration strategy that re-anchors unstable heterochromatin to the nuclear lamina of cells using bioorthogonal click chemistry. We developed a bioorthogonal reaction-driven chromatin architecture restoration system (BR-CARS) using azide-modified anti-LMNB1 and DBCO-conjugated anti-H3K9me3 antibodies. To enable cytosolic delivery, we established a freeze-thaw-facilitated liposomal encapsulation strategy. Crucially, the high molecular weight of these antibodies prevents them from crossing intact nuclear pore complexes of healthy cells, ensuring specificity for senescent cells in which the nuclear barrier is compromised. Efficacy and selectivity were evaluated in senescent chondrocytes and a rat OA model using confocal 3D reconstruction and multi-omics analyses. Our results confirmed that in vivo, BR-CARS was predominantly delivered to the superficial and upper-middle zones of the articular cartilage, where it preferentially infiltrated senescent chondrocyte nuclei compared with those of healthy controls. Upon nuclear entry, the components underwent a click reaction, tethering heterochromatin to the nuclear lamina. This forced approximation compacted the chromatin structure. Integrated ATAC-seq and RNA-seq analyses revealed that this structural restoration reduced chromatin accessibility at senescence-associated gene loci and repetitive elements, silencing their expression. This study pioneers an anti-senescence strategy based on structural epigenetic engineering that not only mechanically reverses cellular senescence but also achieves intrinsic selectivity by leveraging the biophysical defects of the senescent nucleus. This nuclear envelope pretargeting strategy emerges as a precise and safe preclinical candidate for OA treatment, with translational potential extending to a wider spectrum of age-associated pathologies.

Osteoarthritis (OA) is a prevalent degenerative joint disease, with postmenopausal women being disproportionately affected. Early pathological alterations in subchondral bone remodeling are increasingly recognized as pivotal precursors to articular cartilage degeneration. However, the precise mechanisms by which estrogen deficiency drives this deleterious bone-to-cartilage crosstalk remain poorly understood. This study aimed to elucidate the role of osteoblast-derived Connective Tissue Growth Factor (CTGF) in mediating bone-to-cartilage crosstalk under estrogen-deficient conditions and to delineate the underlying molecular signaling pathways. To simulate postmenopausal conditions, we established an estrogen-deficient OA model via bilateral ovariectomy (OVX-OA). Integrated bioinformatic strategies were utilized to screen for potential protein contributors of the osteoblast-chondrocyte interaction and identify candidate upstream transcription factors. Cartilage degeneration was assessed via Safranin O staining and qRT-PCR. The expression of CTGF, EGFR, NF-κB, and cartilage matrix markers was quantified by immunohistochemistry (IHC), qRT-PCR, and western blotting. Immunoprecipitation-mass spectrometry (IP-MS) was employed to characterize the molecular interactome of the identified mediators. We identified CTGF as the key contributor of OVX-osteoblast-induced chondrocyte dysfunction. CTGF knockdown in OVX-osteoblasts reversed the detrimental effects of osteoblasts on chondrocytes. CTGF was found to form a complex with EGFR, activating the EGFR/NF-κB pathway and promoting OA development. Treatment with the CTGF-neutralizing antibody neutralized excessive CTGF activity, significantly attenuating subchondral bone remodeling and alleviating cartilage degeneration. Abnormally increased CTGF contributes to detrimental bone-to-cartilage crosstalk following estrogen loss by activating the EGFR/NF-κB axis in chondrocytes. These results delineate CTGF as a critical pathological nexus, the pharmacological sequestration of which may yield potent therapeutic avenues for attenuating estrogen deficiency-induced OA.

Beyond their conventional role as passive transdermal delivery vehicles, microneedle (MN) platforms now function as active bio-interfaces capable of modulating therapeutic responses in both localized and systemic diseases. This review summarizes recent advances in MN technology, focusing on the transition from traditional matrix-controlled delivery to bioactive microneedles. Although localized applications at barrier surfaces, such as treating cutaneous disorders and mucosal lesions, remain a fundamental focus, this review emphasizes the application of MNs in complex chronic metabolic diseases (e.g., diabetes), oncology (e.g., melanoma and glioblastoma), and deep-tissue degenerative diseases of the cardiovascular, nervous, and musculoskeletal systems. Integrating stimuli-responsive materials, including metal-organic frameworks (MOFs), aggregation-induced emission luminogens (AIEgens), and smart hydrogels, with external physical stimuli enables autonomous, closed-loop interventions, thereby advancing personalized systemic therapy. Furthermore, we summarize recent progress in applying MNs to non-traditional sites and deep-tissue repair. Finally, rather than focusing solely on phenotypic efficacy, we discuss key translational challenges, including manufacturing scalability, biosafety, and regulatory pathways, to guide future clinical translation.

Artificial prosthetic manufacturing is moving toward patient-specific design and production, and zirconia-based three-dimensional printing is emerging as a promising approach because of its mechanical properties and biocompatibility. Yet the step from laboratory development to clinical use is still limited by the gap between laboratory-scale process optimization and clinically relevant validation of performance, reproducibility, and long-term reliability. This review provides an application-oriented overview of zirconia-based photopolymerization additive manufacturing for dental, orthopedic, and scaffold applications, discussing relevant functional requirements alongside key processing parameters, postprocessing steps, and quality-critical variables. We outline major bottlenecks, such as optical scattering and slurry rheology during fabrication, as well as defects and dimensional deviations introduced during debinding and sintering, and we discuss recent performance-oriented strategies, including triply periodic minimal surface (TPMS) architectures and functionally graded additive manufacturing (FGAM) routes. Finally, we highlight the critical requirements for clinical translation, including qualification-ready process control, lot-to-lot manufacturing consistency, and robust durability validation under clinically relevant conditions. Taken together, these aspects establish a process-defect-performance relationship, where photopolymerization parameters govern defect evolution during debinding and sintering and, ultimately, determine the mechanical reliability and clinical performance of zirconia-based prostheses. Addressing these challenges will be essential for bridging the gap between laboratory-scale demonstrations and the scalable production of patient-specific zirconia prostheses.

MXenes combine rich surface chemistry, mechanical strength, and high conductivity for a multitude of emerging applications. Predictive modeling supports accelerated materials designs and has been limited by the absence of validated and transferable force fields. Here, we introduce an interpretable, reactive INTERFACE force field (IFF and IFF-R) for Ti3C2Tx MXenes that is trained based on chemical knowledge and achieves quantitative agreement with experiments across lattice parameters (<0.5%), density (<0.2%), liquid contact angles, Raman spectra, and the in-plane elastic modulus (∼320 GPa). The models cover surface terminations from hydroxyl (-OH) to fluorine (-F) groups and are extensible to other chemistries. We introduce pH-resolved surface chemistry and identify dopamine adsorption mechanisms at MXene-aqueous interfaces supported by QCM-D and UV-Vis experiments. The data reveal coplanar and perpendicular binding modes and concentration-dependent multilayer assembly. We predict previously inaccessible properties, including termination-dependent cleavage energies, interlayer shear moduli and dynamic shear failure, nanoindentation and brittle fracture, anisotropic in-plane and out-of-plane thermal conductivities, including the role of defects. Agreement with available experimental data is consistently close and exceeds DFT accuracy across the benchmark properties examined. The IFF/IFF-R model is compatible with CHARMM, AMBER, OPLS, and CVFF force fields for simulations of MXenes with diverse surface terminations, electrolyte interfaces, biointerfaces, and polymer composites without additional parameters. Parameter sets, 3D models, and analysis scripts are provided for community use. The validated, reactive, and transferable IFF framework facilitates predictive design of MXene-based films, membranes, sensing interfaces, and composites.

Injectable hydrogels offer a promising strategy for treating intervertebral disc degeneration (IVDD), a leading cause of chronic low back pain. However, effective intradiscal diffusion and timely in situ gelation remain challenging within the confined high-pressure nucleus pulposus. Inspired by the temporal regulation of blood coagulation, we developed a biomimetic dual-network hydrogel (named HAD-HPTC) that achieves time-programmed diffusion and delayed solidification to enhance delivery and retention. Upon injection, an initial physical network, formed through dynamic hydrogen bonding and coordination between hyaluronic acid-phenylboronic acid (HA-PBA) and tannic acid-cerium metal polyphenol networks (TA-Ce MPNs), enables fluid-like diffusion and conformal defect filling, analogous to initial blood infiltration in wounds. Subsequently, a second chemical network gradually forms via thiol-Michael addition between hyaluronic acid acrylate (HA-AA) and dithiothreitol (DTT) under physiological conditions, achieving stable in situ gelation reminiscent of fibrin formation. This temporally programmed structure provides delayed gelation and improved diffusion, while integrated TA-Ce MPNs confer antioxidant, anti-inflammatory, and anti-senescence functions. Furthermore, in vivo studies in rat and rabbit models demonstrated superior disc height preservation, extracellular matrix restoration, and inflammation suppression compared to conventional preformed hydrogels. These findings establish blood-coagulation-inspired, time-programmed hydrogels as a promising platform for minimally invasive intervertebral disc regeneration.

Ligamentum flavum hypertrophy (LFH) is a major cause of lumbar spinal stenosis, which can lead to progressive lower back pain and impaired nerve function, resulting in a significant global disease burden. At present, the pathological mechanism of LFH has not been fully elucidated, and effective treatment methods are lacking. Piezo1 is a channel activated by mechanical stress. It is activated under mechanical stress and participates in various physiological and pathological processes related to oxidative stress, including inflammation, fibrosis, ferroptosis, vascular remodeling and pyrolysis. However, its role in the development of LFH is still unclear. In this review, we examined the role of Piezo1 in oxidative stress, inflammation, fibrosis, ferroptosis, vascular remodeling, cell pyroptosis, as well as its potential connection with LFH. These findings provide new ideas for the treatment of the LFH.

Persistent neuroinflammation is a hallmark of central nervous system (CNS) injury, driving neuronal loss and functional deficits. While microglial lipid metabolic reprogramming, particularly lipid droplet accumulation, has been implicated in chronic inflammation, the underlying mechanisms remain poorly understood. Using single-cell transcriptomics, we identified a previously defined lipid droplet-accumulating microglia (LDAM) subpopulation in spinal cord injury (SCI), characterized by elevated PLIN2 expression. Genetic deletion of Plin2 markedly reduced lipid droplet burden, attenuated neuroinflammation, and promoted neuronal survival and functional recovery in vivo. Mechanistically, PLIN2 interacts with the mitochondrial outer membrane protein PGAM5 to regulate lipid droplet-mitochondria contacts. This interaction inverts canonical metabolic flux by redirecting fatty acids from mitochondria back to lipid droplets, thereby suppressing β-oxidation and inducing mitochondrial dysfunction, which subsequently triggers STING-dependent inflammation. Notably, the PLIN2 220-392 domain is essential for PGAM5 binding and contact formation; disrupting this interaction attenuates STING signaling and enhances neuroprotection and functional recovery in vivo. Our findings identify the PLIN2-PGAM5 as a critical metabolic-immune pathway and suggest that targeting organelle-contact-mediated metabolic reprogramming represents a potential therapeutic strategy for CNS injury.

To quantify the excess risk of any fractures, major osteoporotic fractures (MOF), and hip fractures in type 1 diabetes (T1D) by age, stages of diabetic kidney disease (DKD), and sex, and to evaluate risk factors for fractures. The study included 5,035 individuals from the Finnish Diabetic Nephropathy Study (FinnDiane) and 12,286 control individuals without diabetes. We assessed the standardized incidence ratios (SIRs) for fractures in individuals with T1D compared with control individuals. Cox regression analyses were conducted in individuals with T1D to identify potential factors associated with fractures. SIR for any fracture was 2.15 (95% CI 2.06-2.25), 2.60 (2.41-2.79) for MOF, and 5.24 (4.55-6.02) for hip fracture. SIR of hip fracture was the highest in those aged 40-49 years, 8.13 (5.75-11.2). All age-groups after 10-19 years had excess fracture risk. The SIR of any fracture increased with the DKD stages; 2.54 (2.36-2.72) in individuals without albuminuria, 3.47 (3.02-3.98), in those with moderate albuminuria, 3.73 (3.27-4.25) in those with severe albuminuria, and 5.08 (4.16-6.16) in those with kidney failure. SIRs for MOF were 2.62 (2.34-2.93) in those without albuminuria, 3.84 (3.10-4.71) in those with moderate albuminuria, 4.53 (3.72-5.48) in those with severe albuminuria, and 5.85 (4.38-7.68) in those with kidney failure. Hypoglycemic coma episodes (hazard ratio 1.04 [1.01-1.07]) and HbA1c (1.11 [1.06-1.15]) were associated with risk of any fracture, and episodes of diabetic ketoacidosis were associated with risk of MOF (1.18 [1.11-1.25]) in T1D. Findings suggest that fracture risk assessment may need to be considered earlier than currently recommended, especially among individuals with DKD.

Mechanical signals are essential for bone homeostasis and regeneration. Reduced mechanical stimulation, such as that occurring during fractures, paralysis, or aging, leads to bone loss and impaired osseous repair. However, effective clinical strategies that restore osteogenesis by reactivating mechanotransduction remain limited. In this study, we investigated downstream pathways of mechanotransduction that regulate osteogenesis to identify potential therapeutic targets for bone regeneration. Our results show that mechanical stimulation enhances glycolysis in mesenchymal stem cells (MSCs), and the resulting lactate promotes osteogenic differentiation via histone lactylation. High substrate stiffness or pharmacological activation with rotenone increased glycolytic activity, whereas decreased stiffness suppressed it. Importantly, enhancing glycolysis with rotenone partially restored osteogenic capacity in MSCs under reduced mechanical input, as reflected by improved mineralized nodule formation and osteogenic marker expression. To translate these findings into a therapeutic strategy, we developed an inflammation-responsive hydrogel encapsulating rotenone, designed to release the drug in response to elevated matrix metalloproteinase (MMP) and lipase activity during inflammation. In a rat periodontal bone defect model characterized by insufficient chewing force stimulation, this hydrogel significantly enhanced bone regeneration by promoting MSC-mediated osteogenesis, thereby partially bypassing the requirement for direct mechanical stimulation. Collectively, these findings identify a "mechanics-glycolysis-histone lactylation" axis that regulates MSC osteogenesis and bone regeneration. By targeting a downstream metabolic effector of mechanotransduction, the rotenone-loaded hydrogel provides a potential strategy for enhancing osteogenesis and promoting bone defect repair under conditions of insufficient mechanical stimulation. STATEMENT OF SIGNIFICANCE: Insufficient mechanical stimuli during periodontitis, trauma or ageing undermine the osteogenic programme of mesenchymal stem cells, yet no clinical strategy reinstates this lost mechanotransduction. We reveal that the downstream axis that mechanical cue is transduced to promote osteogenesis: mechanical stimulation activates glycolysis to enhance the production of lactate, which enters the nucleus, installs histone lactylation and switches on osteogenic genes. By packaging the glycolytic activator rotenone into an MMP/lipase-responsive hydrogel, we stimulated this metabolic signal at the defect site and achieved significant periodontal bone regeneration in rats despite abolished chewing forces. The work converts an insight into targeting the "mechanics-glycolysis-histone lactylation" axis to rescues bone healing when mechanical loading is compromised.

Neddylation regulates diverse cellular processes, yet its role in osteoclast-mediated bone resorption is poorly understood. Here, we identify NAE1 (NEDD8 activating enzyme E1 subunit 1)-mediated neddylation as a critical regulator of postmenopausal osteoporosis and osteoclast differentiation through two distinct regulatory mechanisms. Pharmacological inhibition of Nae1 or myeloid-specific genetic ablation of Nae1 attenuated osteoclastogenesis in vitro and ameliorated ovariectomy (OVX)-induced osteoporosis in vivo without impairing osteoblast function. Mechanistically, Nae1 depletion disrupted intracellular iron metabolism, thereby suppressing ferritinophagy initiation in osteoclast precursors. Concurrently, integrated transcriptomics and affinity purification-mass spectrometry revealed ACSL3 as a direct neddylation substrate. Nae1-mediated neddylation modulates monounsaturated fatty acid (MUFA) biosynthesis, regulating the sensitivity of bone marrow-derived macrophages (BMDMs) to ferroptosis. This dual regulatory mechanism coordinately governs ferritinophagy initiation in iron metabolism and the sensitivity to ferroptosis mediated by ACSL3 neddylation, thereby critically influencing osteoclastogenesis. Clinically, serum MUFA levels positively correlated with bone mineral density (r = 0.329, p < 0.05). These findings support MLN4924, a clinical-stage NAE inhibitor, as a potential therapeutic strategy for osteoporosis and define an Nae1-ACSL3-MUFA-ferroptosis axis regulating osteoclast metabolism.Abbreviations: 4-HNE: 4-hydroxynonenal; ACP5/TRAP: acid phosphatase, tartrate resistant; ACSL3: acyl-CoA synthetase long chain family member 3; ACSL4: acyl-CoA synthetase long chain family member 4; BGLAP/OCN: bone gamma-carboxyglutamate protein; BMD: bone mineral density; BMDMs: bone marrow-derived macrophages; BV/TV: bone volume per total volume; CHX: cycloheximide; cKO: conditional knockout; co-IP: co-immunoprecipitation; CTSK: cathepsin K; DFO: deferoxamine; MDS: myelodysplastic syndrome; MUFA: monounsaturated fatty acid; NAE1: NEDD8 activating enzyme E1 subunit 1; NCOA4: nuclear receptor coactivator 4; NEDD8: NEDD8 ubiquitin like modifier; NFE2L2: NFE2 like bZIP transcription factor 2; NFATC1: nuclear factor of activated T cells 1; OC: osteoclast; OVX: ovariectomy; PUFA: polyunsaturated fatty acid; ROS: reactive oxygen species; RUNX2: RUNX family transcription factor 2; SLC40A1: solute carrier family 40 member 1; SLC7A11: solute carrier family 7 member 11; Tb.N: trabecular number; Tb.Sp: trabecular separation; Tb.Th: trabecular thickness; TFRC: transferrin receptor; TNFSF11/RANKL: TNF superfamily member 11; UBE2M: ubiquitin conjugating enzyme E2 M.

Notch signaling is an emerging regulator of liposarcoma (LPS), but its role in mediating communication with the tumor microenvironment (TME) is unclear. Here, we investigate how Notch activation (NICD overexpression) alters the proteomes of LPS-derived extracellular vesicles (EVs). We used quantitative mass spectrometry to profile the EV proteome in multiple contexts: cultured LPS cells, LPS tumor, circulating EVs of LPS-bearing mice, and human LPS samples. We found that Notch signaling increases the secretion of EV proteins that favor tumor progression and metastasis but suppresses immune responses in murine LPS cells. Overlapping murine and human LPS data identifies 18 proteins that are increased in LPS EVs of both species, including endotrophin as a biomarker of LPS. Functional analysis supports a role of LPS EVs in regulating gene expression and behaviors of endothelial cells in TME. Together, these data demonstrate that in addition to its known function in driving tumorigenesis, Notch signaling also regulates TME through EV secretion.

TIGIT (T cell immunoreceptor with Ig and ITIM domains) has emerged as a key exhaustion marker of intratumoral natural killer (NK) cells, but results from clinical trials with TIGIT blockade have been largely negative. Recent data have suggested that a subset of TIGIT-expressing NK cells can show increased functionality. We hypothesized that there are differences in function between peripheral and intratumoral TIGIT-expressing NK cells in patients with sarcoma and preclinical sarcoma models, which undermine the efficacy of systemic TIGIT blockade. We sought to investigate differences in TIGIT+ NK cells using systemic versus intratumoral TIGIT-blocking strategies. Peripheral and intratumoral NK cells were analyzed from human patients and mice with osteosarcoma (OSA) and soft tissue sarcoma (STS). NK phenotype and function were evaluated using flow cytometry, immunohistochemistry, live-cell imaging, and RNA sequencing. Mouse antimouse-IgG1 TIGIT blockade was delivered systemically or intratumorally in flank models of OSA (K7M2) and STS (MCA-205). Clinical and genomic data were evaluated using Caris CODEai. Expression of the TIGIT ligand CD155 on myeloid and tumor cells was evaluated as a marker of TIGIT function. Using multiple readouts, TIGIT+ NK cells from the spleen of tumor-bearing mice or peripheral blood of patients with STS and OSA showed increased functionality compared with TIGIT- NK, while TIGIT+ NK cells from the sarcoma tumor microenvironment (TME) of mice and humans were dysfunctional, with upregulated senescence and inhibitory gene pathways. Systemic TIGIT blockade reinvigorated intratumoral NK cell function but inhibited peripheral NK cells, while intratumoral administration of TIGIT blockade significantly delayed tumor growth and prolonged survival with partial reversal of NK dysfunction in the TME. Clinical and genomic data demonstrated that more NK cell infiltration in human STS was prognostic of improved overall survival only when intratumoral CD155 expression was low, indicating that elevated CD155 expression is correlated with greater NK cell dysfunction. We identified a cross-species role of TIGIT expression dependent on location, where peripheral TIGIT+ NK cells showed evidence of enhanced functionality, while intratumoral TIGIT+ NK cells were dysfunctional. These differences impacted antitumor effects of TIGIT blockade, suggesting that intratumoral delivery of TIGIT blockade may be a novel translational strategy in high-risk bone and soft tissue sarcomas.

Conduct a comprehensive scoping review of sport science and medicine (SSM) research in highly trained, elite and world-class female athletes. Scoping review. PubMed (MEDLINE, EBSCOhost), Scopus, SPORTDiscus (EBSCOhost), Web of Science and base-search (grey literature). Peer-reviewed and grey literature informing the health and performance of highly trained, elite and/or world-class female athletes (>16 years of age), with mixed-group studies retained when data were reported separately. Sports that require physical exertion or highly skilled movements were included. The search was restricted to English with no date limits. 3,867 (1970-2025) records including 3,250 (84%) original studies reporting 4,374,571 participants [31% female (n=1,368,170)] were reviewed. 3,221 (99%) studies included athletes [world class, n=433 (13%); elite, n=1,873 (58%); highly trained, n=1,302 (40%)] across 102 different sport disciplines from 74 different countries. 135 (4%) studies included athletes with disabilities, 58 (2%) retired and 37 (1%) masters athletes. Physiology (n=1,059 studies, 33%), performance analysis (n=947, 29%) and injury (n=820, 25%) were the most common SSM general themes; equipment (n=84, 3%), law (n=17, 1%) and business (n=8, 0%) were least common. Health-related SSM themes included musculoskeletal (n=364, 22%), mental (n=243, 15%) and cardiovascular (n=183, 11%) health; pelvic floor (n=26, 2%), breast health (n=11, 1%) and (peri-)menopause (n=2, 0%) were least common. Research in high-performing female athletes is increasing, however persistent gaps remain in participant representation, geographical coverage and health-related themes. Targeted, co-created and multidisciplinary research approaches are needed to improve equity, relevance and impact in female athlete health and performance.

Virtual care is increasingly used for preoperative assessment. We aimed to estimate the noninferiority of virtual vs in-person anaesthesiology consultations with respect to 90-day morbidity and mortality in at-risk adults having noncardiac surgery. We conducted a retrospective observational comparative effectiveness study using a target trial emulation framework. Eligible participants were aged ≥40 yr, with an ASA physical status ≥3, having elective, noncardiac, non-orthopaedic, moderate- to high-risk surgery, and attended a preoperative anaesthesiology consultation in Ontario, Canada, between October 2020 and March 2022. Exposures were receipt of virtual vs in-person preoperative anaesthesiology consultation in the 60 days preceding surgery. The primary outcome was 90-day major morbidity or mortality (noninferiority margin of upper 95% confidence interval [CI] <1.10 on relative scale). Secondary outcomes included 90-day mortality, length of hospital stay, costs of care, and days alive and at home within 90 days (DAH90). Travel-attributable carbon emissions were also estimated. Analyses used instrumental variable and propensity score methods. Among 17 027 patients, 8399 (49.3%) received a virtual consultation. The primary outcome occurred in 2212 (26.3%) virtual consult patients and 2147 (24.9%) of 8628 in-person consult patients. Primary outcome noninferiority was inconclusive based on both instrumental variable (adjusted odds ratio [adj-OR] 1.02, 95% CI 0.92-1.13) and propensity-score adjusted (adj-OR 0.99, 95% CI 0.89-1.101) analyses. Noninferiority was observed for length of hospital stay, costs of care, and DAH90. In-person care was associated with an estimated increase of 8618 (SD 17 200) g CO2 per visit. Before moderate-to-high-risk noncardiac, non-orthopaedic elective surgery, the noninferiority of virtual vs in-person anaesthesiology consultation for major morbidity or mortality was inconclusive. Virtual care was noninferior for several secondary outcomes and associated with reduced carbon emissions. Further research is required to refine triage models and increase certainty regarding morbidity.

Cancer management remains fragmented across its continuum, from late-stage diagnosis and salvage therapies to non-personalized surveillance. Here, we present Oncoformer, a unified multimodal transformer model trained on the China Oncology Multimodal Prediction and Surveillance Study (COMPASS) cohort (3.67 million individuals, 17.7 million clinical visits) and validated on independent external cohorts, including the UK Biobank. Oncoformer integrates longitudinal electronic health records with chest X-ray imaging to address multiple clinical tasks: pan-cancer diagnosis (area under the receiver operating characteristic curve [AUROC] = 0.956), future cancer prediction up to 1 year before diagnosis (AUROC = 0.869), tumor stage inference (mean AUROC > 0.90), patient-specific treatment-response forecasting, and recurrence-free survival stratification across ten cancer types (all p < 0.01). Staging predictions were independently validated against postoperative pathological endpoints and shown to converge on core cancer genomic pathways. By translating routine clinical data into a dynamic view of cancer evolution, Oncoformer provides a framework for risk-informed cancer prediction and treatment stratification using routine clinical data.

Foot ulceration is a common complication of diabetes and is associated with high mortality and costs. The quality of evidence to inform clinical practice is limited, partly because clinical studies do not consistently report baseline participant characteristics. This study aimed to develop a core descriptor set (CDS), a minimum set of descriptors to be measured in all studies evaluating interventions for people with diabetes-related foot ulceration. A longlist of descriptors was generated through a systematic review of studies assessing interventions for diabetes-related foot ulcers, pre-registered with PROSPERO (CRD42019128250). The identified descriptors were then ranked based on perceived importance by healthcare professionals from different fields and geographical locations using a nine-point Likert scale in the first round of a Delphi survey. Using standardised criteria, descriptors without consensus were re-ranked in round two. Critical descriptors and those without consensus after the Delphi process were discussed in the consensus meeting to finalise the CDS. The systematic review yielded 95 candidate descriptors. The two Delphi rounds were completed by 102 and 69 healthcare professionals, respectively. The Delphi process identified 34 critically important descriptors and 13 descriptors without consensus, which were discussed in the consensus meeting. The ratified CDS included 28 descriptors across nine domains: demographic variables; individual factors; ulcer characteristics; limb characteristics; ongoing medical interventions; previous surgical interventions; medication history; biochemical measurements; and quality of life/function/symptoms. This CDS reflects characteristics important to health professionals and researchers when reporting clinical studies on diabetes-related foot ulceration. Its use will aid the reporting of future studies.

Rheumatoid arthritis (RA) exhibits clinical and biological heterogeneity, with synovial tissue stratified into histological pathotypes: lympho-myeloid, diffuse-myeloid, and pauci-immune fibroid. Although genome-wide association studies (GWAS) have uncovered RA risk loci, how genetic risk relates to synovial immunopathology remains unclear. To better understand how genetic predisposition may shape divergent early disease mechanisms, we characterised the expression patterns of GWAS-identified RA susceptibility genes and related rheumatic diseases across the synovial pathotypes. Synovial RNA sequencing of patients with early RA (Pathobiology of Early Arthritis Cohort [PEAC] [N = 87] and Flinders [N = 18]) was used for differential gene expression between pathotypes, and pathway enrichment analyses were performed using GWAS-identified susceptibility genes for RA, osteoarthritis (OA), ankylosing spondylitis, psoriatic arthritis, and systemic lupus erythematosus. RA susceptibility gene expression in synovial tissue separated patients by pathotype and correlated with markers of disease activity. RA susceptibility genes were significantly enriched among genes upregulated in lympho-myeloid synovium and linked to lymphocyte activation and differentiation pathways. In contrast, OA susceptibility genes were upregulated in diffuse-myeloid and fibroid synovium. Both patterns were most pronounced in anticitrullinated protein antibody (ACPA)-positive and directionally consistent in ACPA-negative patients. Expression of RA susceptibility genes is not evenly distributed across synovial pathotypes but is strongly biased towards the lympho-myeloid pathotype, indicating that current GWAS signals preferentially capture immune-driven disease mechanisms. Enrichment of OA susceptibility genes in diffuse-myeloid and fibroid pathotypes, even among ACPA-positive patients, suggests shared biological features between autoimmune and noninflammatory degenerative joint diseases in certain RA subtypes. Synovial pathotype stratification is therefore essential for interpreting genetic risk and understanding disease heterogeneity.

The emergence of AI technology has sparked curiosity regarding the capabilities of large language models (LLMs) in the field of medicine. Minimal research exists regarding the proficiency of various AI models in ethics scenarios, specifically in specialty-based scenarios. This study aimed to compare the performance of GPT-4o and Claude Sonnet 4 on ethics questions with that of medical students and orthopedic residents. A total of 200 ethical or legal scenario questions were randomly selected from question banks targeted for third- and fourth-year medical students (UWorld, AMBOSS) and orthopedic residents (OrthoBullets). Questions at the medical student level were exclusively text-based, while resident-level questions included text-based questions accompanied by images. Each question was entered identically into each AI model 3 separate times. If answers varied between trials, the answer provided most frequently by the model was used as the selected answer. GPT-4o correctly answered 140 (70%) of 200 questions, which was similar to the average human test taker score of 71% (~142/200 questions). Claude correctly answered 180 (89%) questions, a score greater than that of human test takers and significantly better than GPT-4o (P<.001). Claude scored significantly higher than GPT-4o in almost all question categories. GPT-4o provided different responses to identically worded trials for 27 (21%) of 130 general questions and 3 (4%) of 70 orthopedic questions (P=.002), while Claude did not have a significant difference in variability between these 2 groups (general: 16/130, 12% vs orthopedic: 3/70, 4%; P=.06). GPT-4o selected the incorrect response for 60 (30%) total questions and chose the incorrect response most commonly selected by humans significantly more frequently on UWorld interpersonal-specific questions (30/40, 75%) than on UWorld all social sciences (27/40, 68%; P=.03). Claude showed no significant difference in the rate of most common incorrect response selection between question categories. These results suggest that GPT-4o can potentially answer both general and specialty-specific ethical questions with similar proficiency to sample groups of both medical students and orthopedic residents, while Claude AI performs significantly better than both humans and GPT-4o. Variables such as AI model framework and training data may drive the observed difference in performance, but the exact cause cannot be definitively isolated without intentional testing. Therefore, further research is needed to ensure safety by minimizing output variability before integrating AI as a patient-facing resource.

Guidelines recommend routine preoperative frailty assessment; however, existing data suggest that adherence is low. The ability with which patients can evaluate their frailty before surgery is unknown. Our objective was to evaluate the agreement of patient self-reporting of frailty compared with trained assessors using the Clinical Frailty Scale (CFS). This was a sub study of a multicentre prospective cohort study of people ≥65 yr of age having elective noncardiac surgery. Preoperatively, patients and trained assessors independently rated patient frailty using the CFS. Agreement between raters on the ordinal scale was estimated using weighted kappa. We evaluated agreement after dichotomising scores (CFS≥4) using Cohen's kappa. We also described the discriminative ability of self-reported and assessor-reported CFS scores in predicting the occurrence of death or new disability 90 days after surgery. There were 531 participants with both self-reported and assessor-reported CFS. Agreement was moderate (weighted kappa=0.58 [95% confidence interval, CI 0.53-0.63], Cohen's kappa=0.61 [95% CI 0.54-0.68]). Assessor-rated scores were systematically higher than self-rated scores by a mean of 0.45 points (95% CI 0.39-0.52; P<0.001). When predicting death or new disability, paired receiver operating characteristic curve analysis revealed no difference in discriminative capability of self-rated or assessor-rated CFS assessment (c-statistic difference 0.010 [95% CI -0.072 to 0.092; P=0.81]). Patients self-report their frailty status using the CFS with moderate agreement to a trained frailty assessor. Self-reported and assessor-rated scores had similar predictive capability for postoperative death or new disability.

Thrombosis drives myocardial infarction, acute ischemic stroke and pulmonary embolism, yet more than half of patients undergoing mechanical thrombectomy fail to achieve functional independence, and residual thrombus is detected in up to 91% of cases after catheter-directed thrombolysis. These persistent clinical failures reflect a fundamental gap: thrombus removal is not merely dissolution or extraction, but a multiphysics process governed by the fracture, deformation and fragmentation of a highly anisotropic composite material whose mechanical behavior remains poorly understood and insufficiently predicted. In this review, we examine physics-based and data-driven numerical models of thrombus mechanics, fracture, and fragmentation from a failure-oriented perspective and assess their potential clinical impact. A thrombus is a hierarchically organized composite in which a fibrin network scaffold, functionally differentiated platelet subpopulations and red blood cells interact across scales spanning six orders of magnitude, thus residual thrombus and fragment migration emerge as the fundamental challenges shared by all recanalization strategies from pharmacological thrombolysis to mechanical thrombectomy. We survey six major computational paradigms, including continuum-based approaches, lattice Boltzmann method, particle-based mesoscopic simulation, discrete fiber network models, multiscale coupling frameworks and artificial intelligence/machine learning-assisted methods, and trace the field's evolution over four decades from reaction kinetics to multiphysics fracture coupling. Finally, we delineate critical gaps in current simulation frameworks and argue that AI-driven surrogate models, physics-informed digital twins and generative virtual patient cohorts could transform thrombus simulation from a predominantly academic endeavor into a clinically actionable platform for real-time decision support. STATEMENT OF SIGNIFICANCE: Blood clots cause heart attacks, strokes, and pulmonary embolism, yet current treatments fail to fully remove clots in over half of cases. A key reason is that we still cannot predict how clots break apart during treatment. This review is the first to systematically examine thrombus simulation from a mechanical failure perspective, synthesizing six computational paradigms-from continuum mechanics to artificial intelligence-and tracing their four-decade evolution from modeling how clots form to predicting how they fail. By establishing residual thrombus and fragment migration as the shared unresolved challenges across all treatment strategies, we identify critical modeling gaps and propose AI-driven translational pathways, including digital twins and virtual patient cohorts, that could transform clot simulation into a real-time clinical decision-support tool.

Chronic diabetic wounds are characterized by persistent inflammation, impaired angiogenesis, and disrupted intercellular communication, including altered macrophage-endothelial interactions. In this study, we develop macrophage membrane-camouflaged, didymin (DM)-loaded metal-organic framework microneedles (Mac@DM-MOF MNs), a biomimetic nanozyme platform designed to selectively restore this intercellular communication and re-establish a pro-regenerative microenvironment. RNA-seq and mechanistic analyses identify activation of the SPP1-ApoE signaling axis, an unrecognized pathway linking M2 polarization to endothelial activation, as a central mechanism by which Mac@DM-MOF MNs synchronize inflammation resolution and angiogenesis. Nanozyme-mediated ROS scavenging relieves redox stress, while DM promotes macrophage polarizationtoward the reparative M2 state. M2-derived SPP1 subsequently interacts with endothelial ApoE, thereby promoting endothelial sprouting, and restoring vascular functionality. In diabetic mouse and Bama mini pig models, Mac@DM-MOF MNs attenuate inflammation, rescue angiogenic deficits, and markedly accelerate wound closure. Importantly, vascular restoration further reinforces M2 polarization, forming a self-sustaining pro-healing feedback loop. Our findings define macrophage-endothelial coupling as a pivotal regulatory mechanism in diabetic wound repair and introduce a synergistic nanomedicine-based strategy that concurrently resolves chronic inflammation and restores angiogenesis.

Neurons depend on the ubiquitin system to maintain proteostasis, which plays crucial roles in processes of neuronal death and axon regeneration after injuries and diseases. Developing druggable targets within the ubiquitin system that simultaneously support neuroprotection and axon regeneration has been considered an attractive therapeutic strategy. To systematically identify druggable molecules within the ubiquitin signaling pathway and evaluate their efficacy in neuroprotection. To this end, we screened 181 ubiquitination-related small-molecule compounds for neuroprotective effects by performing excitotoxic interventions in HT22 cell lines and mouse primary neurons. Subsequently, using a mouse optic nerve crush model, we demonstrated the neuroprotective effect of BC1618 through RGC survival and axon regeneration. To investigate the mechanism, we employed LC-MS, co-IP, and RNA-seq to delineate the BC1618-FBXO48-SERBP1 regulatory axis and its downstream regulation of mRNA expression. To further evaluate the translational potential of BC1618, we assessed cell survival rates and behavioral impairments using both MPTP-induced mouse Parkinson's disease model and MPP+-induced apoptosis model of iPSC-derived dopaminergic neurons. We identified BC1618 as an effective neuroprotectant that prevented glutamate-induced excitotoxicity in vitro and enhanced neurite outgrowth in immature neurons. Additionally, we showed its effectiveness in an optic nerve crush model, where BC1618 supported RGC survival and encouraged axon regeneration. Mechanistically, BC1618 inhibited FBXO48-mediated K63-linked ubiquitination of SERBP1 at K52, which protected SERBP1 from autophagic degradation. Our findings established SERBP1 as a key regulator that coordinates downstream mRNA expression to mediate neuroprotection. Notably, our results demonstrated that BC1618 mitigated MPTP-induced degeneration of dopaminergic neurons and motor deficits, while also exhibiting robust neuroprotective effects in MPP+-stimulated human-derived dopaminergic neurons. These findings highlight that targeting FBXO48 with BC1618 promotes axon regeneration and alleviates symptoms of Parkinson's disease by reducing the degradation of SERBP1, revealing a novel therapeutic target for clinical translation.

Severe burn wounds with excessive exudation and high infection risk disrupt all four healing phases, requiring antibacterial, exudate-managing, and phase-specific strategies to drive wound contraction and tissue regeneration. Herein, we develop a spatially programmed hydrogel dressing (SPHD) via confined layer-by-layer photopolymerization, with Ga3+ and Fe3+ ions layer-specifically immobilized to enable chelation- and spatially guided programmable release with phase-matched kinetics. Abundant hydrophilic groups and dynamic catechol-boronate ester network render the hydrogel high swelling capacity, resilience, self-healing, and strong tissue adhesion. Its pH/temperature dual responsiveness enables adaptation to wound microenvironmental changes through reversible metal coordination and polymer conformational transitions. Hierarchically designed layers yield release kinetics aligned with healing phases, the inner layer rapidly releases Ga3+ within 16 h to suppress infection during the inflammatory phase, whereas the outer layer sustains Fe3+ release over 96 h, activating prolyl hydroxylase and promoting collagen synthesis and angiogenesis in the proliferative phase. Molecular dynamics simulations elucidate ion-specific diffusion barriers and mechanisms underlying phase-matched release. In murine deep second-degree burn model, SPHD accelerates wound closure to 96% in 12 days, enhancing epidermal barrier recovery and neovascularization. This work defines a paradigm for programmable wound management, offering a versatile platform extendable to regenerative medicine.

3D printing is reshaping ophthalmic biomaterials, tissue models, implants, biosensors, and drug-delivery systems, but its clinical value depends on matching each printing strategy to ocular-specific requirements rather than on printing capability alone. This review classifies ophthalmic 3D printing into extrusion-based, inkjet-based, electric field-assisted, and light-assisted approaches, while clarifying the boundary between acellular material inks and cell-laden bioinks. We summarize how ink formulation, spatial resolution, optical transparency, mechanical stiffness, degradation, sterilization, immune response, and regulatory classification influence applications in corneal, conjunctival, lens, retinal, orbital, sensing, and drug-delivery contexts. We further discuss hybrid printing and artificial intelligence (AI)-assisted process control as emerging strategies that may improve patient-specific design, reproducibility, and quality assurance. By emphasizing current limitations, clinical translation barriers, and actionable priorities, this review aims to provide a balanced roadmap from basic ophthalmic 3D-printing research toward clinically meaningful transformation. STATEMENT OF SIGNIFICANCE: Ophthalmic diseases affect millions worldwide, yet traditional treatments like eye drops suffer from poor efficacy due to the eye's complex biological barriers. Three-dimensional (3D) printing offers a revolutionary solution by enabling the creation of customized, structurally precise biomaterials. This review provides a comprehensive overview of how advanced 3D printing technologies are being used to engineer delicate eye tissues (cornea, conjunctiva, and retina) and develop novel drug delivery systems (microneedles and smart contact lenses). Furthermore, we introduce the concept of 'dynamic bioprinting,' highlighting how smart materials can adapt to the ocular microenvironment over time. This work bridges the gap between biomaterial structure-function design and clinical ophthalmology, providing a roadmap for future personalized vision therapies.

Temporomandibular disorders (TMD) pain is the most common orofacial pain with limited effective treatments. Here, we observed elevated lysophosphatidic acid (LPA), a bioactive lipid, in blood, trigeminal ganglion (TG), and peri-temporomandibular joint (TMJ) tissues in mouse models of TMD-like pain induced by TMJ inflammation or masseter muscle injury. Notably, LPA levels were also elevated in TMD patients' blood and positively correlated with their pain intensity. LPA receptors (LPAR) 1 and 3 were expressed in mouse and human TG neurons and upregulated in TMD-like pain models. Inhibition or knockout of LPAR1 or LPAR3 attenuated TMD-like pain, while LPA injection into the TMJ or masseter muscle evoked pain. Furthermore, we demonstrated that LPA/LPAR signaling upregulates and sensitizes PIEZO2, a mechanosensitive ion channel, in TG neurons via extracellular signal-regulated kinase (ERK). Specific deletion or inhibition of PIEZO2 and suppression of ERK activation in TG neurons mitigated TMD-like pain. These findings suggest that LPA/LPAR signaling drives TMD-like pain via PIEZO2, offering potential therapeutic targets.

Crevassing critically controls glacier stability. Crevasses can penetrate deep into a glacier or ice shelf, promoting calving, ice avalanches, and even sudden catastrophic ice shelf collapse. Yet quantifying subsurface fracture damage remains largely unquantified. Here, we show how distributed acoustic sensing technology can quantify subsurface fracture damage in unprecedented detail at an alpine glacier. We first demonstrate that seismic anisotropy can quantify fracture extent. We also study crevasse icequake failure mechanisms, which fail predominantly via tensile opening. Icequake-derived crevasse opening is consistent with anisotropy-derived estimates (∼8% of total ice volume), suggesting that damage is dominated by fracture rather than melt. These results establish a scalable approach for monitoring subsurface ice damage that complements existing satellite surface observations. Applications range from monitoring the stability of alpine glaciers that pose a risk to alpine communities to providing foundations for assessing subsurface fracture extent at globally pertinent ice sheets and ice shelves.

Coal mining substantially alters watershed hydrology processes, yet quantitatively disentangling the dominant mechanisms within hydrological models remains challenging. Here, an enhanced Spatiotemporal Variable Source Mixed Runoff model, termed E-SVSMR, was developed to explicitly represent two key mining-induced perturbations: enhanced slope infiltration caused by mining fractures, parameterized through a soil-fissure dual-permeability system with an equivalent saturated hydraulic conductivity, and riverbed leakage, characterized by a nonlinear discharge-dependent function. The physical framework was initially validated at the hillslope scale via high-fidelity 3D variably-saturated flow modeling (COMSOL) in the Wujiayao catchment (78.7 km²). The physical basis of the framework was first evaluated at the hillslope scale in the Wujiayao catchment using high-resolution three-dimensional variably saturated flow simulations. Results demonstrate that goaf-induced fractures form preferential flow pathways and increase effective infiltration by approximately one order of magnitude. When upscaled to the Luzhuang catchment, the E-SVSMR markedly improved runoff simulation, increasing the Nash-Sutcliffe efficiency from 0.41 in the traditional SVSMR to 0.89. Continuous simulations from 1996 to 2009 indicated a cumulative mining-induced runoff loss of 1.73 × 10⁸ m³. Mechanistic decomposition of a representative storm event further suggested that enhanced slope infiltration accounted for approximately 70% of the runoff reduction, whereas riverbed leakage contributed the remaining 30%. Application to the independent Lingshi catchment further demonstrated the transferability of the model. By correcting the systematic post-1994 runoff overestimation in the baseline model, the E-SVSMR increased the Nash-Sutcliffe efficiency from -2.27 to 0.88, and successfully captured the timing and magnitude of mining-driven hydrological disturbances. Overall, the E-SVSMR provides a physically interpretable and transferable modeling framework for diagnosing mining impacts on runoff generation, with implications for flood forecasting and water-resource management in mining-affected catchments.

Osteonecrosis of the femoral head (ONFH) is a debilitating condition caused by compromised local blood supply to the femoral head, which leads to bone tissue death. The primary therapeutic goals are to restore blood perfusion and reconstruct the damaged bone structure. In this study, we present an advanced three dimensional printed multifunctional composite scaffold that integrates structural biomimicry, sustained drug release, and microenvironment regulation to enable the sequentially coordinated augmentation of ONFH repair. The scaffold features Voronoi-designed porous titanium alloy biomimetic trabeculae that provide robust mechanical support, combined with a gelatin methacryloyl and silk fibroin hydrogel-liposome dual-release system. This design ensures mechanical stability, bioactive functionality, and sustained delivery of tetramethylpyrazine. In vitro assessments demonstrate its excellent biocompatibility, promoting osteogenic differentiation and angiogenic tube formation. In vivo studies using a rat ONFH model reveal significantly increased new bone volume and density, accompanied by enhanced angiogenesis and bone repair. Thus, this scaffold presents a promising strategy for the early treatment of hip-preserving ONFH.

Stress-induced fractures are recognized as a primary cause of degradation in a wide range of positive electrode active materials during battery operation. However, the state-of-the-art mechanistic understanding and strategy development often overlook the brittle nature of these materials, as well as the dynamic and localized characteristics of mechanical stress during the charge and discharge cycles of the cell. Here we present a shape-memory polymer nanocoating method using initiated chemical vapour deposition to dynamically delocalize concentrated stresses in various positive electrode active materials, including Ni-rich layered oxides with different Ni contents and LiFePO4. Fracture simulations and surface-to-bulk physicochemical characterizations collectively show that the balanced stiffness and deformability of the shape-memory polymer nanocoating on the positive electrode material effectively mitigate stress gradients and the consequent surface reconstruction, chemical heterogeneity and intergranular cracking during battery operation. In particular, when a polymeric nanocoated nickel-rich layered oxide positive electrode active material (90 at% of Ni) is tested in non-aqueous lithium metal coin cell configuration at 25 °C, the cells can be consistently charged and discharged over long cycles at moderate (for example, 1,000 cycles at 400 mA g-1) and high (for example, 500 cycles at 1 A g-1) specific currents.

Tissue engineering (TE) remains a cornerstone of regenerative medicine, aiming to bypass the limitation of organ transplantation through the fabrication of functional tissue substitutes. Traditionally, TE has followed two primary paradigms: the top-down approach, utilising single cells seeded on a scaffold, and the bottom-up approach, employing cell spheroids as building blocks. While top-down offers architectural and structural control, bottom-up promotes self-assembly, native-like extracellular matrix deposition, and intercellular signalling. However, modern techniques increasingly blur this dichotomy, creating a spectrum of cell-based fabrication approaches. This review evaluates the diverse approaches across four major tissue classes: epithelial (pancreas as an example), connective (cartilage), muscle (heart), and nervous (brain) tissues. For each tissue, we examine notable studies to evaluate how different assembly methods recapitulate native tissue properties. By reviewing case studies across diverse tissue types, we highlight the relative strengths and limitations of various fabrication strategies. Although this review is limited by a selective cross-section of literature within a rapidly advancing technological landscape, it provides critical insights into optimising next-generation tissue constructs. In conclusion, we posit that there is no universal fabrication strategy; rather, the future of the field depends on tailoring approaches along this single-cell-to-spheroid spectrum based on the specific architectural and functional demands of the target tissue.

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.