Acta biomaterialia最新文献

{"title":"Local Administration of Exendin-4 Ameliorates Wear-Particle-Induced Periprosthetic Osteolysis by Rebalancing Bone Remodeling.","authors":"Boyan Ma, Zhi Peng, Yixiao Pan, Zixiang Yi, Weiping Su","doi":"10.1016/j.actbio.2026.09.014","DOIUrl":"https://doi.org/10.1016/j.actbio.2026.09.014","url":null,"abstract":"<p><p>Periprosthetic osteolysis and aseptic loosening are the leading causes of total joint arthroplasty failure. Wear debris triggers chronic sterile inflammation, driving excessive osteoclast activation and insufficient osteoblastic bone formation. Drug-target Mendelian randomization showed that genetically predicted higher systemic expression of glucagon-like peptide-1 receptor (GLP-1R) is causally associated with a reduced risk of clinical revision arthroplasty. Histological analysis confirmed GLP-1R expression within osteolytic bone tissues. Whether local activation of GLP-1R could counter particle-induced osteolysis, however, remained untested. To address this, we evaluated the therapeutic potential of the GLP-1R agonist, Exendin-4, across animal models and in vitro assays. In a murine model of ultra-high-molecular-weight polyethylene (UHMWPE)-induced calvarial osteolysis, local Exendin-4 administration significantly mitigated bone resorption, suppressed osteoclastogenesis, and stimulated periprosthetic bone formation. Mechanistically, Exendin-4 shifted macrophages from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype, reducing osteolytic cytokines such as IL-6 and TNF-α; In vitro, it also acted directly on osteoclast precursors to suppress RANKL-driven osteoclastogenesis and rescued the osteogenic differentiation of bone marrow mesenchymal stem cells. These findings demonstrate that targeting GLP-1R signaling effectively restores the uncoupled bone homeostatic axis, offering a promising translational strategy for treating periprosthetic osteolysis. STATEMENT OF SIGNIFICANCE: Periprosthetic osteolysis (PPO) caused by wear debris is a major cause of joint replacement failure. While traditional treatments focus only on slowing down bone loss, strategies that can both stop bone destruction and promote bone healing are critically needed. In this study, we combined human genetic evidence with animal models to show that targeting the local GLP-1 receptor via Exendin-4 effectively treats PPO. Locally delivering Exendin-4 successfully switches pro-inflammatory M1 macrophages to an anti-inflammatory M2 phenotype and directly rescues the multi-stage bone formation process of stem cells under wear-particle stress, without causing systemic toxicity. This study provides a practical, biosafe strategy for reusing clinical metabolic drugs to balance bone remodeling and extend implant survival.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148898584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Digital Light Processing of Reactive Ceramic-Polymer Bone Scaffolds Enables In situ Hydroxyapatite Formation.","authors":"Roberto Fagotto-Clavijo, Irene Lodoso-Torrecilla, Anna Diez-Escudero, Maria-Pau Ginebra","doi":"10.1016/j.actbio.2026.09.013","DOIUrl":"https://doi.org/10.1016/j.actbio.2026.09.013","url":null,"abstract":"<p><p>The incorporation of calcium phosphates to additive manufacturing, particularly digital light processing (DLP), has gained increasing attention for the fabrication of bone tissue engineering scaffolds. DLP enables the production of patient-specific constructs with complex architectures and high spatial resolution. In this study, we develop photo-crosslinkable resin formulations based on poly(ethylene glycol) diacrylate (PEGDA) loaded with reactive α-tricalcium phosphate (α-TCP) particles for DLP printing. Using a liquid crystal display-based DLP (LCD-DLP) system, composite scaffolds were directly printed. High-resolution gyroid architectures containing 50 wt% α-TCP and a designed open porosity of 50% were successfully fabricated. The printed scaffolds exhibited controllable multiscale porosity and underwent an in situ hydrolysis reaction after printing, reaching more than 92% conversion of α-TCP to biomimetic calcium deficient hydroxyapatite (CDHA) composed of high-aspect-ratio nanocrystals. This phase transformation generated an entangled nanocrystalline network that increased the specific surface area and induced structural hardening, resulting in an interpenetrating polymer-ceramic composite architecture. As a consequence, the compressive strength of the scaffolds nearly doubled relative to the as-printed state while maintaining appreciable flexibility. Compared to conventional sintered calcium phosphate scaffolds, the reactive composite scaffolds exhibited markedly improved toughness and flexibility, with almost two-fold increase in strain energy density. Furthermore, the reactive scaffolds showed good cytocompatibility in vitro. These results demonstrate that combining DLP with reactive calcium phosphate-based resins enables the fabrication of mechanically resilient and biologically relevant bone scaffolds through a single-step printing process followed by low temperature in situ hardening. STATEMENT OF SIGNIFICANCE: Traditional 3D-printed bone scaffolds often rely on high-temperature sintering, producing brittle structures prone to failure. We introduce a reactive resin, combining poly(ethylene glycol) diacrylate and α-tricalcium phosphate, designed for Digital Light Processing (DLP). DLP offers significantly higher spatial resolution and architectural complexity than conventional micro-extrusion methods, allowing for more precise patient-specific geometries. Post-printing, an in situ reaction transforms the material into a toughened, interpenetrating polymer-ceramic network. This unique architecture doubles compressive strength and significantly enhances flexibility compared to traditional ceramics. By replacing fragile, sintered components with this resilient, nanocrystalline structure, our approach provides a robust, single-step pathway for creating mechanically durable, cytocompatible scaffolds essential for effective bone tissue engineering.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148898587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interleukin-4-Loaded Lipid Nanoparticles Reprogram Adipose Tissue Immunity and Promote Adipocyte Browning for the Treatment of Obesity.","authors":"Neda Mohaghegh, Narges Zargar Balajam, Nick Kraemer, Talia Marx, Shraddha Sawant, Gargi Y Digholkar, Aliesha O'Raw, Xiling Shen, Heemin Kang, Ryan M Pearson, Alireza Hassani Najafabadi","doi":"10.1016/j.actbio.2026.09.007","DOIUrl":"https://doi.org/10.1016/j.actbio.2026.09.007","url":null,"abstract":"<p><p>Obesity represents a global health crisis characterized by chronic adipose tissue (AT) inflammation (metaflammation) driven by pro-inflammatory M1 macrophage (MΦ) polarization, adipocyte hypertrophy, and impaired thermogenic capacity of white adipose tissue (WAT). While interleukin-4 (IL-4) potently induces M2 MΦ polarization, its clinical translation is limited by poor stability, rapid clearance, and off-target effects. Here, we engineered lipid nanoparticles (IL-4/LNP) via simple, robust thin-film hydration and extrusion to enable sustained IL-4 delivery to MΦs in inflamed AT. In vitro, IL-4/LNP achieved >70% encapsulation efficiency, a uniform ∼150 nm size, and superior M1 to M2 MΦ reprogramming compared with free IL-4, as evidenced by CD206 upregulation, reduced CD80/CD40 expression, and attenuated TNF-α/IL-6 secretion in LPS-stimulated MΦ. In adipocyte-mimicking cells (3T3-L1)-MΦ co-cultures representing white and brown adipose tissue (BAT), paracrine signaling from IL-4/LNP-polarized M2 MΦs drove a profound reduction in lipid droplets (LDs) and beiging, with decreased Feret diameter and integrated optical density. Using a high-fat diet-induced obese mouse model, localized inguinal/visceral AT injections blunted weight gain by ∼10%, induced multilocular beige-like adipocytes across depots, upregulated thermogenic genes (Ucp1 and Pgc1α), downregulated inflammatory markers (IL-6), and improved hepatic steatosis without systemic toxicity. These findings establish IL-4/LNP as a safe, multifunctional platform that links MΦ immunomodulation and adipose browning in obesity therapy. STATEMENT OF SIGNIFICANCE: This study establishes IL-4-loaded lipid nanoparticles (IL-4/LNPs) as a nanomedicine platform that targets the immunometabolic roots of obesity by reprogramming adipose tissue macrophages and promoting white fat browning. IL-4/LNPs are produced by a simple, scalable thin-film hydration-extrusion method, yielding ∼150 nm particles with ∼73% encapsulation, suitable for local adipose delivery. In vitro, the NPs outperform free IL-4 by enhancing M2 polarization, driving paracrine adipocyte remodeling, and reducing lipid burden in 3T3-L1 co-cultures. In high-fat diet-obese mice, depot-specific IL-4/LNP injections limit weight gain, induce adipocyte beiging, improve hepatic steatosis, and reduce systemic inflammation without detectable toxicity, supporting IL-4/LNPs as a translatable cytokine nanotherapy for metaflammatory obesity.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Applications and Challenges of Stage-Specific Microenvironment-Responsive Hydrogels for Myocardial Infarction.","authors":"Jiahao Hu, Yue Wang, Boya Yan, Yuling Zhao, Zeqi Chen, Li Yang, Yunbing Wang","doi":"10.1016/j.actbio.2026.09.009","DOIUrl":"https://doi.org/10.1016/j.actbio.2026.09.009","url":null,"abstract":"<p><p>Myocardial infarction (MI) progresses through a series of distinct pathological stages, from acute ischemia and reperfusion injury to chronic inflammation, fibrotic proliferation, and ventricular remodeling, each characterized by a unique combination of microenvironmental cues and therapeutic demands. Traditional injectable hydrogels, designed primarily as passive mechanical fillers, largely fail to adapt to these stage-specific needs: their fixed degradation, mechanics, and drug release profiles cannot match the dynamic post-MI milieu. Microenvironment-responsive hydrogels, by sensing signals such as reactive oxygen species (ROS), pH changes, and matrix metalloproteinases (MMPs), offer a means to align hydrogel behavior more closely with pathological progression. While existing reviews have catalogued these systems by their response mechanisms, this review takes a pathology-driven perspective. We first analyze the evolving microenvironmental characteristics and repair requirements across the major phases of MI. Then, rather than organizing the discussion by stimulus type, we examine how hydrogel properties, including responsiveness, mechanical support, electrical conductivity, and degradation, can be rationally combined with appropriate delivery formats (injectable hydrogels, cardiac patches, and composite constructs) and clinical workflows to address phase-specific therapeutic objectives. Finally, we identify bottlenecks that currently prevent these materials from reaching clinical application and outline practical strategies for overcoming them. By linking material design directly to stage-specific pathology, this review aims to offer a more clinically relevant framework for developing next-generation responsive hydrogels for MI repair. STATEMENT OF SIGNIFICANCE: Myocardial infarction (MI) is a leading cause of heart failure. Revascularization improves survival, yet reperfusion injury and remodeling drive long-term mortality. Traditional injectable hydrogels are passive fillers that cannot adapt to the post-infarction microenvironment. Most reviews classify responsive hydrogels by chemical trigger, separating material design from clinical pathology. We take a different view, linking hydrogel design to the four phases of MI healing. For each phase we identify the microenvironmental signals, then show how reactive oxygen species (ROS), pH and matrix metalloproteinase (MMP) responsiveness, mechanics, conductivity, and degradation can be combined for stage-specific therapy. We also examine how injectable hydrogels, epicardial patches, and composite constructs integrate with percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) workflows. This pathology-matched framework highlights translational bottlenecks and strategies to bridge materials science and clinical application.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Electroactive fibrous scaffolds for tendon repair: From bioelectric microenvironment engineering to motion-driven and remotely activated stimulation.","authors":"Jiamin Peng, Shasha Wang, Xuanming Zhang, Fujun Wang, Lu Wang, Jifu Mao","doi":"10.1016/j.actbio.2026.09.010","DOIUrl":"https://doi.org/10.1016/j.actbio.2026.09.010","url":null,"abstract":"<p><p>Tendon injuries rank among the most prevalent musculoskeletal disorders. Their clinical treatment remains challenging due to the inherently poor self-healing capacity and highly ordered hierarchical architecture of native tendon tissues. In recent years, electroactive fiber-based biomaterials have attracted growing attention in the field of tendon regeneration, attributed to their unique capability to mimic the fibrous microstructure of natural tissues while providing therapeutic electrical stimulation throughout tissue repair. In this review, recent advances in electroactive fibrous scaffolds for tendon repair are summarized, with particular focus on their biological functions and regenerative potential. First, the review introduces the bioelectrical microenvironment of native tendon tissues and explains its importance in tissue remodeling and healing. Then, the fundamental design strategies of biomimetic fibrous scaffolds are discussed, including fiber architecture, mechanical characteristics, and commonly used fabrication techniques. Different categories of electroactive material systems and electrically assisted repair approaches are then presented, including conductive scaffolds for wired electrical stimulation, piezoelectric scaffolds that generate electrical signals through physiological-motion-driven stimulation, and externally activated systems such as ultrasound (US) or magnetic fields (MF). Recent progress in intelligent electrotherapeutic platforms that integrate sensing, stimulation, and adaptive regulation into one integrated system is also outlined. Finally, current challenges associated with the clinical translation of electroactive fibrous scaffolds are analyzed, and prospective research directions in this field are proposed. STATEMENT OF SIGNIFICANCE: Electroactive fibrous scaffolds provide a unique opportunity to reconstruct both the anisotropic architecture and the bioelectrical microenvironment of injured tendon. However, fibrous scaffold design, electroactive materials, and electrical stimulation have largely been reviewed as separate topics. This review integrates these areas from a fiber-centered perspective and establishes a structure-property-stimulation-regeneration framework linking fiber alignment, hierarchical assembly, and functional-component distribution with mechanical behavior, electrical transduction, and tendon-regenerative responses. Conductive, motion-driven piezoelectric, remotely activated, and monitoring-enabled systems are critically compared within this framework. By defining how electroactive functions can be engineered through fibrous architecture, this review provides design principles for advancing passive tendon scaffolds toward programmable regenerative biointerfaces.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Bioactive Polyurethane Adhesive Delivers Interfacial Mechano-Biochemical Cues for Meniscus Tear Repair.","authors":"Xiaolong Yang, Lin Yang, Shiji Gao, Yi Zhou, Zhe Xu, Junqiao Li, Jiehua Li, Hong Tan, Feng Luo, Weili Fu","doi":"10.1016/j.actbio.2026.09.004","DOIUrl":"https://doi.org/10.1016/j.actbio.2026.09.004","url":null,"abstract":"<p><p>Meniscus repair is often limited by poor intrinsic healing, an adverse oxidative-inflammatory microenvironment, and insufficient mechanical continuity across the tear interface. Here, we engineered a solvent-free injectable polyurethane adhesive (PUA) loaded with connective tissue growth factor (PUA@CTGF) for meniscus tear repair that combines rapid wet interfacial stabilization, compliant defect filling, and prolonged CTGF release. The adhesive showed rapid in situ curing, high apparent initial wet lap-shear strength, and stable short-cycle compressive behavior in a 100-cycle loading-unloading test. In vitro, PUA@CTGF reduced oxidative stress-associated mitochondrial injury, modulated macrophage-associated inflammatory markers toward a more repair-supportive profile, promoted meniscal cell migration, and enhanced fibrochondrogenic matrix synthesis when combined with cyclic tensile stimulation. In a rabbit outer-vascular-zone meniscus tear model, PUA@CTGF improved repair-region continuity, matrix deposition, and tensile properties and attenuated early joint degenerative changes relative to untreated, suture, fibrin, and PUA controls, although native meniscal tensile properties were not fully restored during the 12-week observation period. Transcriptomic profiling identified mechanotransduction-related signatures, while inhibitor-supported in vitro analyses showed that GsMTx4 attenuated dynamic-loading-induced Ca²⁺ and YAP responses, supporting a GsMTx4-sensitive mechanotransduction response. These findings support PUA@CTGF as a bioactive polyurethane adhesive platform for wet, mechanically active meniscal repair interfaces. STATEMENT OF SIGNIFICANCE: Meniscus tears are difficult to heal because the injured interface is wet, mechanically active, and biologically hostile. This study introduces a solvent-free injectable polyurethane adhesive that rapidly stabilizes wet meniscal tears while providing localized delivery of connective tissue growth factor. By combining catechol-assisted wet adhesion, compliant defect filling, short-cycle energy dissipation, reactive oxygen species buffering, and prolonged CTGF release, the adhesive provides interfacial stabilization and microenvironmental regulation. In vitro and rabbit studies showed enhanced cell migration and matrix-associated responses, improved repair-region continuity and tensile properties, and attenuation of early joint degenerative changes. This work advances biomaterial design by integrating wet interfacial stabilization with localized biochemical delivery for the repair of mechanically active, load-bearing soft-tissue interfaces.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microneedle patch integrated with hydroxyapatite nanoparticles and abemaciclib for treatment of meningioma.","authors":"Haibo Teng, Qingqing Ren, Cong Feng, Haibo Tao, Yuyi Wang, Hao Shi, Xin Qiao, Zhiyong Liu, Ouying Yan, Hongxu Chen, Xiangdong Zhu, Kai Zhang, Xiangfeng Li, Xingdong Zhang, Jianguo Xu","doi":"10.1016/j.actbio.2026.09.012","DOIUrl":"https://doi.org/10.1016/j.actbio.2026.09.012","url":null,"abstract":"<p><p>Surgery remains the primary treatment for meningiomas, with radiotherapy used for high-grade tumors, residual disease, and recurrences. However, many high-risk meningiomas progress despite resection or radiotherapy, and effective pharmacological therapies remain lacking. Here, we explored a local microneedle-mediated delivery strategy using gelatin methacryloyl hydrogels (Gel-MA) to co-deliver hydroxyapatite nanoparticles (n-HA) and the selective CDK4/6 inhibitor abemaciclib in meningioma cell-line models. n-HA and abemaciclib were associated with reduced proliferation, increased apoptosis-related signals, and cell-cycle inhibition in the tested models. Exploratory RNA sequencing suggested that n-HA treatment was associated with transcriptional changes related to cellular stress, calcium homeostasis, apoptosis, endocytosis, and immune-related pathways; these findings should be interpreted as hypothesis-generating rather than definitive mechanistic evidence. In an orthotopic xenograft model, local microneedle delivery of n-HA and abemaciclib suppressed tumor progression and was associated with treatment-related histological changes. Overall, this study provides proof-of-concept evidence that a biodegradable microneedle platform may enable local combination therapy for residual, recurrent, or incompletely resectable meningiomas. STATEMENT OF SIGNIFICANCE: Hydroxyapatite nanoparticles (n-HA), a bone-like material, suppress meningioma cell growth while stimulating anti-tumor immune responses, suggesting a therapeutic role beyond structural biomaterials. We further show that n-HA synergizes with abemaciclib to enhance tumor inhibition and immunity. To deliver this combination precisely to the tumor site, we develop GelMA microneedle patches that enable localized and controlled release, reducing reliance on systemic dosing. In animal models, microneedles loaded with n-HA and abemaciclib produce marked anti-tumor effects. Finally, incorporating β-cyclodextrin improves abemaciclib bioavailability, strengthening local therapy. Together, this work introduces an immunoactive biomaterial-drug microneedle strategy with potential for safer, more effective meningioma treatment.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"3D Printed Zinc Oxide-Tricalcium Phosphate Scaffolds with Quercetin for Bone Tissue Repair.","authors":"Priya Kushram, Susmita Bose","doi":"10.1016/j.actbio.2026.09.011","DOIUrl":"https://doi.org/10.1016/j.actbio.2026.09.011","url":null,"abstract":"<p><p>Successful bone repair requires coordinated regulation of osteogenesis, osteoclast activity, and angiogenesis, yet most bone graft materials address only one or two of these processes. Here, 3D-printed β-tricalcium phosphate scaffolds doped with zinc oxide (ZnO-TCP) and loaded with quercetin (Que) are developed to provide a multifunctional platform for regenerating critical-size defects. ZnO doping enhances densification and mechanical strength, while Zn²⁺ and Que together regulate bone remodeling by suppressing osteoclast activity and promoting osteogenic and angiogenic signaling. In vitro, the combined ZnO-TCP-Que scaffolds significantly reduce Tartrate-Resistant Acid Phosphatase (TRAP) activity, upregulate osteogenic and angiogenic genes, and maintain cytocompatibility. In a rat distal femur model, ZnO-TCP-Que scaffolds increase bone formation by ∼1.5-fold and enhance vascularization by ∼1.8-fold compared to TCP controls. These findings show that co-delivery of Zn²⁺ and Que creates a microenvironment that promotes bone formation, limits resorption, and supports vascular ingrowth. This approach provides a multifunctional ceramic scaffold that can coordinate bone formation, resorption, and vascularization in complex bone defects. STATEMENT OF SIGNIFICANCE: Repairing large bone defects requires coordinated regulation of bone formation, vascularization, and resorption. Most existing biomaterials address only one or two of these processes. Here, we develop a 3D-printed tricalcium phosphate scaffold doped with zinc and loaded with quercetin to simultaneously target these pathways. Zinc improves mechanical strength and supports osteogenic activity, while quercetin provides controlled release and modulates cellular responses. The scaffold reduces osteoclast activity while promoting osteoblast function and endothelial cell behavior. In a rat model, it increased new bone formation by ∼1.5-fold and vascularization by ∼1.8-fold. This work presents a multifunctional approach for designing biomaterials that better support coordinated bone regeneration.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transient Calcium Signaling Reprograms YAP Mechanosensitivity through Actin Remodeling.","authors":"Julian M Jimenez, Badri Narayanan Narasimhan, Zihou Ye, Kun-Che Peng, Stephanie I Fraley","doi":"10.1016/j.actbio.2026.09.002","DOIUrl":"https://doi.org/10.1016/j.actbio.2026.09.002","url":null,"abstract":"&lt;p&gt;&lt;p&gt;YAP is a central regulator of cell fate, proliferation, and tissue homeostasis that integrates physical cues from the extracellular matrix (ECM). While stiff environments canonically drive YAP nuclear localization and soft environments promote cytoplasmic sequestration, the logic by which cells integrate mechanical inputs with transient biochemical signals remains poorly defined. Here, we examine how intracellular calcium transients interact with substrate compliance to regulate YAP dynamics and transcriptional outputs across epithelial, myoblast, and fibroblast lineages. Using collagen-coated polyacrylamide hydrogels with tunable mechanics, we show that substrate compliance shapes the kinetics of calcium signaling, calcium-mediated actin remodeling, and YAP nuclear shuttling. We demonstrate that calcium signaling can transiently relax baseline mechanical constraints on YAP activity, triggering nuclear translocation and transcriptional activation even on compliant or non-adhesive substrates where YAP is classically suppressed. We identify substrate compliance as a biophysical regulator that filters the transduction of calcium transients into gene-specific programs. Targets such as CYR61 are induced across all mechanical contexts tested, whereas targets like CTGF and AREG require permissive mechanical conditions. These results suggest a preliminary model in which the mechanical state of the cell tunes the activation barrier for YAP-dependent transcription, enabling context-dependent responses to universal biochemical triggers. We show that destabilizing the F-actin cytoskeleton by promoting depolymerization or sequestering actin monomers results in attenuation of the calcium-mediated YAP activity, while stabilizing F-actin results in amplification YAP activity in response to calcium stimulation. This work reveals a fundamental mechanism by which transient signals integrate with matrix mechanics to produce distinct YAP-dependent outcomes, suggesting new strategies for controlling cell fate in regenerative medicine and engineered tissues. STATEMENT OF SIGNIFICANCE: Although YAP regulation by steady-state mechanical cues is well established, how these cues interact with dynamic biochemical signals such as calcium transients to control gene-specific transcription remains unclear. We show that intracellular calcium transients act as rapid, tunable inputs that promote YAP nuclear localization and target gene expression, even on soft substrates that normally suppress YAP activity. Low-threshold gene targets are activated broadly, whereas high-threshold targets require stiffer environments, positioning substrate mechanics as a biophysical gate that shapes the magnitude, kinetics, and gene specificity of calcium-mediated YAP responses. These findings provide insights into how cells integrate transient calcium signals with steady-state matrix mechanics to regulate proliferation, differentiation, and tissue behavior, and provide a framework for guiding","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Zirconium Metal-Organic Framework-Based Composite Drug Delivery System for Precise Drug Release and Synergistic Modulation of the Tumor Microenvironment in Liver Cancer Therapy.","authors":"Yujia Han, Haixiang Zeng, Jing Xu, Hongyan Hao, Hongxia Li, Xiaohui Niu, Yan Li, Xiaoyu Liu, Deyi Zhang, Li Chen, Dongqiang Zhang, Kunjie Wang","doi":"10.1016/j.actbio.2026.09.006","DOIUrl":"https://doi.org/10.1016/j.actbio.2026.09.006","url":null,"abstract":"<p><p>Zirconium-based metal-organic framework (MOF-808) materials were selected as drug delivery carriers, with 5-fluorouracil (5-Flu) as the model drug. MOF-808@5-Flu drug-loaded carriers were designed and prepared at different ratios. The drug release behavior of the MOF-808@5-Flu nanocomposite was investigated under different pH conditions (7.4/6.5/5.0). The results showed that when the mass ratio of MOF-808 to 5-Flu was 1:0.25, the material released 55.56% of the drug within 50 hours at pH 5.0, compared with 47.85% and 48.00% at pH 7.4 and 6.5, respectively. The drug release behavior was well fitted by the Higuchi model the Higuchi model. Cell and animal experiments demonstrated that MOF-808@5-Flu exhibited good biocompatibility and significantly inhibited the growth of Hepa1-6 cells, indicating its potential as a targeted nanocarrier to enhance therapeutic efficacy. Studies indicate that MOF-808@5-Flu induces cancer cell death through the apoptotic pathway. The catalytic activity of Zr⁴⁺ acted synergistically with the pharmacological effects of 5-Flu, generated a large amount of reactive oxygen species (ROS), significantly reducing tumor cell viability. Theoretical calculations indicated that MOF-808@5-Flu exhibits synergistic effects through multiple interactions, including π-π stacking, electrostatic attraction, and hydrophobic interactions. This results further highlights the advantages of MOF-808@5-Flu as a drug delivery platform. In summary, MOF-808@5-Flu shows great potential as a targeted nanocarrier for anticancer drug delivery. STATEMENT OF SIGNIFICANCE: Developed MOF-808@5-Flu nanocarriers with strong potential for targeted anticancer drug delivery. Achieved pH-responsive 5-Flu release, with the highest release rate of 55.56% at pH 5.0 within 50 h. Confirmed that the drug release profile follows the Higuchi model. Demonstrated good biocompatibility and effective inhibition of Hepa1-6 tumor cell growth. Revealed a \"carrier-drug\" synergistic mechanism driven by Zr⁴⁺ catalysis and multiple intermolecular interactions.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}