Pub Date : 2025-11-29DOI: 10.1016/j.bioactmat.2025.11.026
Liya Ma , Yelin Zhang , Zijun Song , Pinwen Wang , Lu Liang , Mingzhu Chen , Xianmin Liao , Songtao Yang , Jiangtian Hu , Kai Chen , Hefeng Yang
Small extracellular vesicles (sEVs) show therapeutic potential for periodontitis but functional components remain unclear, limiting clinical periodontal therapy application. Identifying key bioactive molecules and enhancing their functions via engineering strategies may overcome these limitations. By comparing the periodontal tropism of sEVs from different stem cells and conducting functional miRNA profiling, we identified miR-423–5p as a key component for periodontal ligament cell (PDLC) osteogenic differentiation by targeting PLCB1 (Phospholipase C Beta 1). We engineered miR-423-5p–enriched sEVs (sEVsmiR−423−5p) with miRNA loading levels up to 100,000-fold higher than those of native sEVs. Compared with unmodified sEVs, sEVsmiR−423−5p promoted the formation of Sfrp2+ osteogenic fibroblasts at periodontal defect sites, ultimately facilitating early osteogenesis and regeneration of a native-like cementum–PDL–alveolar bone complex. These findings establish miR-423–5p as a pivotal osteoinductive effector in sEVs and demonstrate that its targeted enrichment markedly amplifies the regenerative capacity of sEVs, laying the groundwork for personalized nanovesicle-based regenerative therapies.
{"title":"miR-423-5p-enriched small extracellular vesicles drive periodontal regeneration via Sfrp2+ cell expansion","authors":"Liya Ma , Yelin Zhang , Zijun Song , Pinwen Wang , Lu Liang , Mingzhu Chen , Xianmin Liao , Songtao Yang , Jiangtian Hu , Kai Chen , Hefeng Yang","doi":"10.1016/j.bioactmat.2025.11.026","DOIUrl":"10.1016/j.bioactmat.2025.11.026","url":null,"abstract":"<div><div>Small extracellular vesicles (sEVs) show therapeutic potential for periodontitis but functional components remain unclear, limiting clinical periodontal therapy application. Identifying key bioactive molecules and enhancing their functions via engineering strategies may overcome these limitations. By comparing the periodontal tropism of sEVs from different stem cells and conducting functional miRNA profiling, we identified miR-423–5p as a key component for periodontal ligament cell (PDLC) osteogenic differentiation by targeting <em>PLCB1</em> (Phospholipase C Beta 1). We engineered miR-423-5p–enriched sEVs (sEVs<sup>miR−423−5p</sup>) with miRNA loading levels up to 100,000-fold higher than those of native sEVs. Compared with unmodified sEVs, sEVs<sup>miR−423−5p</sup> promoted the formation of Sfrp2<sup>+</sup> osteogenic fibroblasts at periodontal defect sites, ultimately facilitating early osteogenesis and regeneration of a native-like cementum–PDL–alveolar bone complex. These findings establish miR-423–5p as a pivotal osteoinductive effector in sEVs and demonstrate that its targeted enrichment markedly amplifies the regenerative capacity of sEVs, laying the groundwork for personalized nanovesicle-based regenerative therapies.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"58 ","pages":"Pages 19-32"},"PeriodicalIF":18.0,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145623193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-28DOI: 10.1016/j.bioactmat.2025.10.028
Run Yang , Bowen Li , Yun Fu , Chenxu Shang , Guoqing Feng , Xuheng Chen , Huining He , Zhengmian Zhang , Yang Bai , Bin Zheng
The malate/aspartate shuttle is essential for maintaining mitochondrial membrane potential (MMP) and supporting tumor metabolism and survival. However, developing effective, controllable strategies to manipulate malate metabolism in vivo remains a challenge. Here, we report a sonogenically activated malate depletion modulator (MDM), GO/BCT:Mn, which integrates graphene oxide (GO) with Ca/Mn co-doped barium titanate (BCT:Mn) nanoparticles, enabling simultaneous metabolic and immune modulation under ultrasonic stimulation. Mechanistic studies reveal ultrasound triggers spatial charge separation in GO/BCT:Mn, generating reductive electrons and oxidative holes. Electrons drive the reduction of H+ to H2, lowering MMP and providing a gas therapy effect, whereas oxidative holes convert NADH to NAD+, suppressing malate synthesis and disrupting the malate/aspartate shuttle, thereby impairing mitochondrial integrity. These synergistic actions induce mitochondrial depolarization, autophagy, and apoptosis. In a murine colon cancer model, treatment with GO/BCT:Mn markedly suppressed tumor cell proliferation (Ki67) and angiogenesis (VEGF, CD31), while promoting apoptosis (TUNEL, Caspase-3). Transcriptomic and flow cytometry analyses further revealed activation of immune-related pathways, accompanied by increased infiltration of CD4+/CD8+ T cells and mature dendritic cells, indicating that metabolic perturbation synergistically enhances anti-tumor immunity. Collectively, this work establishes a precise ultrasound-responsive nanoplatform that couples redox-mediated metabolic disruption with immune activation, offering a promising strategy for integrated metabolism–immune cancer therapy.
{"title":"Sonogenic malate depleting modulator for tumor metabolic reprogramming and antitumor immune activation","authors":"Run Yang , Bowen Li , Yun Fu , Chenxu Shang , Guoqing Feng , Xuheng Chen , Huining He , Zhengmian Zhang , Yang Bai , Bin Zheng","doi":"10.1016/j.bioactmat.2025.10.028","DOIUrl":"10.1016/j.bioactmat.2025.10.028","url":null,"abstract":"<div><div>The malate/aspartate shuttle is essential for maintaining mitochondrial membrane potential (MMP) and supporting tumor metabolism and survival. However, developing effective, controllable strategies to manipulate malate metabolism in vivo remains a challenge. Here, we report a sonogenically activated malate depletion modulator (MDM), GO/BCT:Mn, which integrates graphene oxide (GO) with Ca/Mn co-doped barium titanate (BCT:Mn) nanoparticles, enabling simultaneous metabolic and immune modulation under ultrasonic stimulation. Mechanistic studies reveal ultrasound triggers spatial charge separation in GO/BCT:Mn, generating reductive electrons and oxidative holes. Electrons drive the reduction of H<sup>+</sup> to H<sub>2</sub>, lowering MMP and providing a gas therapy effect, whereas oxidative holes convert NADH to NAD<sup>+</sup>, suppressing malate synthesis and disrupting the malate/aspartate shuttle, thereby impairing mitochondrial integrity. These synergistic actions induce mitochondrial depolarization, autophagy, and apoptosis. In a murine colon cancer model, treatment with GO/BCT:Mn markedly suppressed tumor cell proliferation (Ki67) and angiogenesis (VEGF, CD31), while promoting apoptosis (TUNEL, Caspase-3). Transcriptomic and flow cytometry analyses further revealed activation of immune-related pathways, accompanied by increased infiltration of CD4<sup>+</sup>/CD8<sup>+</sup> T cells and mature dendritic cells, indicating that metabolic perturbation synergistically enhances anti-tumor immunity. Collectively, this work establishes a precise ultrasound-responsive nanoplatform that couples redox-mediated metabolic disruption with immune activation, offering a promising strategy for integrated metabolism–immune cancer therapy.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"56 ","pages":"Pages 682-702"},"PeriodicalIF":18.0,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145620755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-28DOI: 10.1016/j.bioactmat.2025.11.037
Gong Li , Birui Yang , Zhulian Li , Peiyang Gu , Yaping Zou , Yuxiang Wang , Yujiang Fan , Yong Sun
Dysregulated inflammatory microenvironment and insufficient recruitment of functional cells/factors at the early stage limit the efficacy of microfracture (MF) therapy. Here, we regulated the assembly structure of functional polycationic silk fibroin (CSF) with sulfhydryl-modified hyaluronan (HS) to fabricate a cartilage repair patch (ECSF-HS-H), which achieved rapid hemostasis, recruitment of reparative cells/factors, and inflammation regulation. Through non-covalent/covalent interactions and β-sheet transitions, the assembly structure of CSF was reconfigured to adapt to the cyclic mechanical properties required under articular stress conditions while preserving inherent rapid hemostatic ability, reduce the potential inhibitory effect of cationic charges on cell proliferation, and enhance chondrogenic differentiation of stem cells. In a rabbit MF model, ECSF-HS-H demonstrated accelerated coagulation, reduced early inflammation in synovial fluid, promoted M2 macrophage polarization, and improved hyaline cartilage regeneration. This strategy of functional structural regulation at the molecular level offers a novel approach for developing protein-based scaffolds to enhance MF procedures.
{"title":"Hyaluronan regulates the assembly structure and biofunction of polycationic silk fibroin to boost microfracture","authors":"Gong Li , Birui Yang , Zhulian Li , Peiyang Gu , Yaping Zou , Yuxiang Wang , Yujiang Fan , Yong Sun","doi":"10.1016/j.bioactmat.2025.11.037","DOIUrl":"10.1016/j.bioactmat.2025.11.037","url":null,"abstract":"<div><div>Dysregulated inflammatory microenvironment and insufficient recruitment of functional cells/factors at the early stage limit the efficacy of microfracture (MF) therapy. Here, we regulated the assembly structure of functional polycationic silk fibroin (CSF) with sulfhydryl-modified hyaluronan (HS) to fabricate a cartilage repair patch (ECSF-HS-H), which achieved rapid hemostasis, recruitment of reparative cells/factors, and inflammation regulation. Through non-covalent/covalent interactions and β-sheet transitions, the assembly structure of CSF was reconfigured to adapt to the cyclic mechanical properties required under articular stress conditions while preserving inherent rapid hemostatic ability, reduce the potential inhibitory effect of cationic charges on cell proliferation, and enhance chondrogenic differentiation of stem cells. In a rabbit MF model, ECSF-HS-H demonstrated accelerated coagulation, reduced early inflammation in synovial fluid, promoted M2 macrophage polarization, and improved hyaline cartilage regeneration. This strategy of functional structural regulation at the molecular level offers a novel approach for developing protein-based scaffolds to enhance MF procedures.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"57 ","pages":"Pages 754-767"},"PeriodicalIF":18.0,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145621135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-27DOI: 10.1016/j.bioactmat.2025.10.017
Jichun Yang , Qianqian Wu , Yunqian Fu , Xiaohui Chen , Hengyi Chen , Yuhan Wang , Xiang Wu , Xin Cui , Sitong Wang , Yao Luo , Yufang Zhang , Yican Li , Yan Zhao , Zhixin Cha , Linke Shi , Xianlong Jiao , Fang Li , Yang Luo
Lung cancer's metastatic propensity and recurrence prevalence necessitate innovative immunotherapy strategies beyond conventional single-mode regulation. We engineered low-capacity turmeric-derived extracellular vesicles (TEVs) that integrated with zeolitic imidazolate framework-8 (ZIF-8) to construct an “all-in-one” nanoagent, addressing both high drug loading nanocarriers production and immunologically cold tumor challenges. The system co-delivered chlorin e6 (Ce6) and PD-L1 siRNA, while exploited TEVs' inherent curcumin for Wnt/β-catenin pathway inhibition. Ce6-mediated photodynamic therapy (PDT) induced immunogenic cell death (ICD), releasing damage associated molecular patterns (DAMPs) to activate antigen-presenting cells (APCs). Compared with control groups, artificial intelligence model confirmed the role of curcumin in enhancing immune infiltration by 6.1-fold. PD-L1 siRNA synergistically downregulates the checkpoint expression with a 66 % reduction in vivo to prevent the immune escape. This coordinated strategy achieved full-cycle immunomodulation: (1) ICD initiated antigens release, (2) Wnt/β-catenin pathway inhibition drived T cell infiltration, and (3) PD-L1 blockade receded the immune escape. In vivo results demonstrated that 64 % primary tumor suppression and 81 % metastasis reduction versus monotherapy groups. The ZIF-8@TEV hybrid platform exhibited 12.8 % payload loading efficiency, surpassing liposomal carriers by 4.7-fold. This study established a scalable nanoengineering approach to transform immunosuppressive tumors into immunotherapy-responsive targets through a full-cycle immune coordination.
{"title":"Turmeric extracellular vesicles-derived “all-in-one” nanoagent enables full-cycle synergistic immunomodulation of lung cancer","authors":"Jichun Yang , Qianqian Wu , Yunqian Fu , Xiaohui Chen , Hengyi Chen , Yuhan Wang , Xiang Wu , Xin Cui , Sitong Wang , Yao Luo , Yufang Zhang , Yican Li , Yan Zhao , Zhixin Cha , Linke Shi , Xianlong Jiao , Fang Li , Yang Luo","doi":"10.1016/j.bioactmat.2025.10.017","DOIUrl":"10.1016/j.bioactmat.2025.10.017","url":null,"abstract":"<div><div>Lung cancer's metastatic propensity and recurrence prevalence necessitate innovative immunotherapy strategies beyond conventional single-mode regulation. We engineered low-capacity turmeric-derived extracellular vesicles (TEVs) that integrated with zeolitic imidazolate framework-8 (ZIF-8) to construct an “all-in-one” nanoagent, addressing both high drug loading nanocarriers production and immunologically cold tumor challenges. The system co-delivered chlorin e6 (Ce6) and PD-L1 siRNA, while exploited TEVs' inherent curcumin for Wnt/β-catenin pathway inhibition. Ce6-mediated photodynamic therapy (PDT) induced immunogenic cell death (ICD), releasing damage associated molecular patterns (DAMPs) to activate antigen-presenting cells (APCs). Compared with control groups, artificial intelligence model confirmed the role of curcumin in enhancing immune infiltration by 6.1-fold. PD-L1 siRNA synergistically downregulates the checkpoint expression with a 66 % reduction <em>in vivo</em> to prevent the immune escape. This coordinated strategy achieved full-cycle immunomodulation: (1) ICD initiated antigens release, (2) Wnt/β-catenin pathway inhibition drived T cell infiltration, and (3) PD-L1 blockade receded the immune escape. <em>In vivo</em> results demonstrated that 64 % primary tumor suppression and 81 % metastasis reduction versus monotherapy groups. The ZIF-8@TEV hybrid platform exhibited 12.8 % payload loading efficiency, surpassing liposomal carriers by 4.7-fold. This study established a scalable nanoengineering approach to transform immunosuppressive tumors into immunotherapy-responsive targets through a full-cycle immune coordination.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"56 ","pages":"Pages 666-681"},"PeriodicalIF":18.0,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145620756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-27DOI: 10.1016/j.bioactmat.2025.11.024
Yogendra Pratap Singh , Joseph Christakiran Moses , Myoung Hwan Kim , Deepak Gupta , Vaibhav Pal , Irem Derman Deniz , Ethan Michael Gerhard , Ibrahim T. Ozbolat
The field of biofabrication is rapidly evolving, yet it faces persistent challenges, including long manufacturing latency, slow throughput, issues with reproducibility, and scalability limitations. High-throughput biofabrication (HTBF) has emerged as a powerful strategy which is presented here to address these gaps through a structured, three-tier framework. Tier 1 encompasses core HTBF methods, such as multi-modal bioprinting and robotic bioassembly, which enable the rapid fabrication of large, physiologically relevant tissue constructs. Tier 2 comprises assisting platforms, including microfluidics and microphysiological bioreactors, which provide perfusion, mechanical conditioning, multiplexable sensing, and process parallelization. Tier 3 represents HTBF outcomes, including organoids, organ-on-a-chip systems, and engineered tissue grafts that deliver clinically and pharmacologically relevant insights. These advancements enable the development of in-vitro models that streamline drug testing, making it more cost-effective and efficient, while enhancing the accuracy and reliability of preclinical drug evaluation. This review defines HTBF by outlining its core characteristics and framework, presenting insights into recent technological advancements and their applications in regenerative medicine and drug discovery. Additionally, it addresses the regulatory and clinical translation challenges that must be resolved to facilitate the adoption of HTBF in personalized healthcare.
{"title":"Three-tier framework for high-throughput biofabrication: Integrating 3D bioprinting, assistive platforms, and translational opportunities","authors":"Yogendra Pratap Singh , Joseph Christakiran Moses , Myoung Hwan Kim , Deepak Gupta , Vaibhav Pal , Irem Derman Deniz , Ethan Michael Gerhard , Ibrahim T. Ozbolat","doi":"10.1016/j.bioactmat.2025.11.024","DOIUrl":"10.1016/j.bioactmat.2025.11.024","url":null,"abstract":"<div><div>The field of biofabrication is rapidly evolving, yet it faces persistent challenges, including long manufacturing latency, slow throughput, issues with reproducibility, and scalability limitations. High-throughput biofabrication (HTBF) has emerged as a powerful strategy which is presented here to address these gaps through a structured, three-tier framework. Tier 1 encompasses core HTBF methods, such as multi-modal bioprinting and robotic bioassembly, which enable the rapid fabrication of large, physiologically relevant tissue constructs. Tier 2 comprises assisting platforms, including microfluidics and microphysiological bioreactors, which provide perfusion, mechanical conditioning, multiplexable sensing, and process parallelization. Tier 3 represents HTBF outcomes, including organoids, organ-on-a-chip systems, and engineered tissue grafts that deliver clinically and pharmacologically relevant insights. These advancements enable the development of in-vitro models that streamline drug testing, making it more cost-effective and efficient, while enhancing the accuracy and reliability of preclinical drug evaluation. This review defines HTBF by outlining its core characteristics and framework, presenting insights into recent technological advancements and their applications in regenerative medicine and drug discovery. Additionally, it addresses the regulatory and clinical translation challenges that must be resolved to facilitate the adoption of HTBF in personalized healthcare.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"57 ","pages":"Pages 726-753"},"PeriodicalIF":18.0,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145621134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-26DOI: 10.1016/j.bioactmat.2025.11.027
Hongjuan Zhao , Di Meng , Yajing Wang , Yinke Wang , Qing Li , Yuxin Guo , Qingling Song , Lei Wang
The multidimensional complexity between metabolism and inflammation within the obese tumor microenvironment (OTME) poses substantial barriers to postsurgical immunotherapy and wound management. Herein, we engineered a multifunctional hydrogel (Lipo/CXB@Hydrogel) through covalent conjugation of dopamine-crosslinked oxidized hyaluronic acid and a ROS-sensitive linker, co-delivering the non-steroidal anti-inflammatory drug celecoxib (CXB) and the lipid metabolism modulator Lipofermata (Lipo) to facilitate T cell immunotherapy and wound healing. The unique multi-dynamic-bond crosslinked structure endows the hydrogel with excellent self-healing, tissue adhesiveness and mechanical properties. The implanted Lipo/CXB@Hydrogel degrades and releases CXB to suppress hyperinflammation and enhance intratumoral cytotoxic T lymphocyte (CTL) infiltration, while Lipo inhibits the predatory uptake of fatty acids by tumor cells in the OTME for competing metabolic resources of intratumoral infiltrated CTLs. Importantly, such a cascaded immunological effect of Lipo/CXB@Hydrogel treatment amplifies CTL proliferation and activity specifically through targeting the arachidonic acid (AA)/COX-2/PGE2 signaling axis, a central hub linking lipid metabolism and inflammation, initiating a long-lasting immune response to suppress colorectal tumor postsurgical recurrence and metastasis in obesity contexts. Moreover, the hydrogel can easily repeatedly close the reopened wounds and promote skin regeneration. Thus, this multifunctional hydrogel may provide a promising strategy for postsurgical obese tumor immunotherapy and wound closure.
{"title":"A multifunctional hydrogel for obesity-associated tumor immunotherapy and postsurgical wound healing promotion","authors":"Hongjuan Zhao , Di Meng , Yajing Wang , Yinke Wang , Qing Li , Yuxin Guo , Qingling Song , Lei Wang","doi":"10.1016/j.bioactmat.2025.11.027","DOIUrl":"10.1016/j.bioactmat.2025.11.027","url":null,"abstract":"<div><div>The multidimensional complexity between metabolism and inflammation within the obese tumor microenvironment (OTME) poses substantial barriers to postsurgical immunotherapy and wound management. Herein, we engineered a multifunctional hydrogel (Lipo/CXB@Hydrogel) through covalent conjugation of dopamine-crosslinked oxidized hyaluronic acid and a ROS-sensitive linker, co-delivering the non-steroidal anti-inflammatory drug celecoxib (CXB) and the lipid metabolism modulator Lipofermata (Lipo) to facilitate T cell immunotherapy and wound healing. The unique multi-dynamic-bond crosslinked structure endows the hydrogel with excellent self-healing, tissue adhesiveness and mechanical properties. The implanted Lipo/CXB@Hydrogel degrades and releases CXB to suppress hyperinflammation and enhance intratumoral cytotoxic T lymphocyte (CTL) infiltration, while Lipo inhibits the predatory uptake of fatty acids by tumor cells in the OTME for competing metabolic resources of intratumoral infiltrated CTLs. Importantly, such a cascaded immunological effect of Lipo/CXB@Hydrogel treatment amplifies CTL proliferation and activity specifically through targeting the arachidonic acid (AA)/COX-2/PGE2 signaling axis, a central hub linking lipid metabolism and inflammation, initiating a long-lasting immune response to suppress colorectal tumor postsurgical recurrence and metastasis in obesity contexts. Moreover, the hydrogel can easily repeatedly close the reopened wounds and promote skin regeneration. Thus, this multifunctional hydrogel may provide a promising strategy for postsurgical obese tumor immunotherapy and wound closure.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"57 ","pages":"Pages 710-725"},"PeriodicalIF":18.0,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145621133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-26DOI: 10.1016/j.bioactmat.2025.11.012
Ziyang Dong , Chenyuan Gao , Xinguang Wang , Ti Zhang , Xiao Geng , Jiazheng Chen , Junhao Feng , Yuhang Zheng , Yipu Zhang , Zhencan Han , Hao Wang , Ji Tan , Xianming Zhang , Yang Li , Zijian Li , Chongbin Wei , Qing Cai , Hua Tian
Total knee arthroplasty (TKA) remains the gold-standard treatment for end-stage osteoarthritis, yet persistent challenges in prosthetic material performance limit its long-term clinical efficacy. CoCrMo alloy is commonly used material of femoral component in TKA due to its excellent mechanical durability. However, two critical limitations persist: (1) substantial elastic modulus mismatch inducing stress-shielding effects, and (2) bioinert surface impairing osseointegration. To address these dual challenges, we developed a synergistic surface engineering strategy combining 3D-printed porous architecture with Mg2+ functionalization via plasma immersion ion implantation (PIII). The porous structure significantly reduced the elastic modulus and achieve biomimetic mechanical compatibility. Mg2+-implanted scaffolds (CoCrMo-Mg) demonstrated multifunctional bioactivity through synergistic physicochemical interactions. Surface topography modification via 3D printing generated micro-scale features that enhanced osteoblast adhesion through mechanotransduction pathways, while the release of Mg2+ exerted immunomodulatory, pro-angiogenic and osteogenic effects. Mg2+-mediated downregulation of pro-inflammatory cytokines, established an anti-inflammatory microenvironment conducive to bone regeneration, while Mg2+ stimulation promoted substantial neovascularization - collectively creating an osteogenic niche favoring coupled angiogenesis-osteogenesis process. These findings were further validated in vivo, where the CoCrMo-Mg scaffolds showed improved anti-inflammation, neovascularization and bone ingrowth capacities, along with favorable biomechanical integration. Overall, this dual-modality approach combining structural optimization with bioactive ion engineering establishes a paradigm for developing mechanically compliant and biologically active orthopedic implants, with particular translational relevance for cementless TKA applications.
{"title":"Magnesium ion implantation enhances the osseointegration and vascularization of 3D-Printed CoCrMo alloy scaffolds for load-bearing orthopedic applications","authors":"Ziyang Dong , Chenyuan Gao , Xinguang Wang , Ti Zhang , Xiao Geng , Jiazheng Chen , Junhao Feng , Yuhang Zheng , Yipu Zhang , Zhencan Han , Hao Wang , Ji Tan , Xianming Zhang , Yang Li , Zijian Li , Chongbin Wei , Qing Cai , Hua Tian","doi":"10.1016/j.bioactmat.2025.11.012","DOIUrl":"10.1016/j.bioactmat.2025.11.012","url":null,"abstract":"<div><div>Total knee arthroplasty (TKA) remains the gold-standard treatment for end-stage osteoarthritis, yet persistent challenges in prosthetic material performance limit its long-term clinical efficacy. CoCrMo alloy is commonly used material of femoral component in TKA due to its excellent mechanical durability. However, two critical limitations persist: (1) substantial elastic modulus mismatch inducing stress-shielding effects, and (2) bioinert surface impairing osseointegration. To address these dual challenges, we developed a synergistic surface engineering strategy combining 3D-printed porous architecture with Mg<sup>2+</sup> functionalization <em>via</em> plasma immersion ion implantation (PIII). The porous structure significantly reduced the elastic modulus and achieve biomimetic mechanical compatibility. Mg<sup>2+</sup>-implanted scaffolds (CoCrMo-Mg) demonstrated multifunctional bioactivity through synergistic physicochemical interactions. Surface topography modification <em>via</em> 3D printing generated micro-scale features that enhanced osteoblast adhesion through mechanotransduction pathways, while the release of Mg<sup>2+</sup> exerted immunomodulatory, pro-angiogenic and osteogenic effects. Mg<sup>2+</sup>-mediated downregulation of pro-inflammatory cytokines, established an anti-inflammatory microenvironment conducive to bone regeneration, while Mg<sup>2+</sup> stimulation promoted substantial neovascularization - collectively creating an osteogenic niche favoring coupled angiogenesis-osteogenesis process. These findings were further validated <em>in vivo</em>, where the CoCrMo-Mg scaffolds showed improved anti-inflammation, neovascularization and bone ingrowth capacities, along with favorable biomechanical integration. Overall, this dual-modality approach combining structural optimization with bioactive ion engineering establishes a paradigm for developing mechanically compliant and biologically active orthopedic implants, with particular translational relevance for cementless TKA applications.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"57 ","pages":"Pages 676-693"},"PeriodicalIF":18.0,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145621170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-26DOI: 10.1016/j.bioactmat.2025.11.022
Shiqi Wang , Jiaqi Wang , Mingyu Li , Dinghui Gao , Xin Yu , Penglong Zhao , Huan Dou , Chengchen Guo , Siming Yuan
Achieving rapid hemostasis, infection control, and tissue regeneration remains a central challenge in acute wound management, particularly under emergency and battlefield conditions. Current hemostatic materials often suffer from delayed coagulation, low bioactivity, and potential immunogenicity, limiting their use in critical care. Here, we present a chemically engineered charged silk-based hydrogel (SAMA) that integrates ultrafast gelation, intrinsic antibacterial activity, and programmable biological function. SAMA is synthesized via dual side-chain modification of silk fibroin with methacrylate (MA) for photo-crosslinking and dimethylamino groups (DMA) for surface charge tuning. The hydrogels enable photo-triggered crosslinking within 8 s under 405 nm light, while offering programmable surface charge and aqueous stability. The positively charged SAMA-5.0(+) hydrogel markedly enhances coagulation and platelet activation, as evidenced by reduced blood loss, shortened clotting time, and elevated CD62P+/PAC-1+ platelet populations. The hydrogels exhibit over 95 % antibacterial efficacy against Staphylococcus aureus and Escherichia coli, while maintaining excellent cytocompatibility, hemocompatibility, and promoting favorable responses in endothelial and immune cells. Mechanistically, SAMA(+) induces macrophage polarization toward the anti-inflammatory M2 phenotype, suppressing IL-6-mediated inflammation and facilitating angiogenesis and collagen remodeling. Controlled release assays demonstrate first-order kinetics for both the model protein (BSA) and ropivacaine, enabling sustained and timely delivery under neutral and mildly acidic wound environments. These findings position charged SAMA hydrogels as a clinically translatable solution for acute wound care, integrating rapid sealing, antimicrobial protection, immune regulation, and tissue repair into a low-cost platform suitable for wound and emergency applications.
{"title":"Rapidly photocrosslinkable charged silk-based hydrogel for emergency hemostasis and multifunctional wound therapy","authors":"Shiqi Wang , Jiaqi Wang , Mingyu Li , Dinghui Gao , Xin Yu , Penglong Zhao , Huan Dou , Chengchen Guo , Siming Yuan","doi":"10.1016/j.bioactmat.2025.11.022","DOIUrl":"10.1016/j.bioactmat.2025.11.022","url":null,"abstract":"<div><div>Achieving rapid hemostasis, infection control, and tissue regeneration remains a central challenge in acute wound management, particularly under emergency and battlefield conditions. Current hemostatic materials often suffer from delayed coagulation, low bioactivity, and potential immunogenicity, limiting their use in critical care. Here, we present a chemically engineered charged silk-based hydrogel (SAMA) that integrates ultrafast gelation, intrinsic antibacterial activity, and programmable biological function. SAMA is synthesized via dual side-chain modification of silk fibroin with methacrylate (MA) for photo-crosslinking and dimethylamino groups (DMA) for surface charge tuning. The hydrogels enable photo-triggered crosslinking within 8 s under 405 nm light, while offering programmable surface charge and aqueous stability. The positively charged SAMA-5.0(+) hydrogel markedly enhances coagulation and platelet activation, as evidenced by reduced blood loss, shortened clotting time, and elevated CD62P<sup>+</sup>/PAC-1<sup>+</sup> platelet populations. The hydrogels exhibit over 95 % antibacterial efficacy against <em>Staphylococcus aureus</em> and <em>Escherichia coli</em>, while maintaining excellent cytocompatibility, hemocompatibility, and promoting favorable responses in endothelial and immune cells. Mechanistically, SAMA(+) induces macrophage polarization toward the anti-inflammatory M2 phenotype, suppressing IL-6-mediated inflammation and facilitating angiogenesis and collagen remodeling. Controlled release assays demonstrate first-order kinetics for both the model protein (BSA) and ropivacaine, enabling sustained and timely delivery under neutral and mildly acidic wound environments. These findings position charged SAMA hydrogels as a clinically translatable solution for acute wound care, integrating rapid sealing, antimicrobial protection, immune regulation, and tissue repair into a low-cost platform suitable for wound and emergency applications.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"57 ","pages":"Pages 694-709"},"PeriodicalIF":18.0,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145621169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Current bone adhesives typically lack adequate mechanical strength, long-term stability, or biocompatibility. To address these limitations, we designed a new adhesion strategy using a solid-state hydroxyapatite (HAp) adhesive in combination with bone surface demineralization.
Methods
Solid-state HAp adhesives were synthesized via wet chemical precipitation and heat treatment. Cortical bone specimens were partially demineralized with phosphoric acid (H3PO4) or ethylenediaminetetraacetic acid (EDTA), and characterized using scanning electron microscopy (SEM) and attenuated total reflectance–Fourier transform infrared spectroscopy (ATR-FTIR). Shear adhesion strength of HAp to demineralized bone was measured over time. In vivo fixation was assessed in rats using micro-computed tomography and histology. Statistical analysis used Tukey-Kramer tests after normality and variance checks.
Results
Although the HAp adhesive failed to adhere to non-demineralized bone, effective adhesion was achieved on the surface-demineralized bone tissue. Shear adhesion strength was significantly higher in EDTA-treated samples (238.4 kPa at 10 h) compared to H3PO4-treated samples (102.9 kPa at 1 h), with performance correlating with demineralization depth. ATR-FTIR and SEM analyses revealed that EDTA preserved collagen's triple-helix structure and free water content, both enhancing adhesion. Animal experiments confirmed stable fixation of HAp adhesive to demineralized bone tissue.
Conclusions
Surface demineralization enabled strong adhesion of the solid-state HAp adhesive to bone by exposing collagen swollen with water. Adhesion strength was influenced by structural changes in the demineralized layer, and the adhesive provided stable in vivo fixation, supporting its potential for bone-anchored biomedical applications.
{"title":"Robust adhesion between solid-state hydroxyapatite and bone tissue through surface demineralization","authors":"Shichao Xie , Masahiro Okada , Haruyuki Aoyagi , Akihisa Otaka , Xiaofeng Yang , Takayoshi Nakano , Takuya Matsumoto","doi":"10.1016/j.bioactmat.2025.11.030","DOIUrl":"10.1016/j.bioactmat.2025.11.030","url":null,"abstract":"<div><h3>Objective</h3><div>Current bone adhesives typically lack adequate mechanical strength, long-term stability, or biocompatibility. To address these limitations, we designed a new adhesion strategy using a solid-state hydroxyapatite (HAp) adhesive in combination with bone surface demineralization.</div></div><div><h3>Methods</h3><div>Solid-state HAp adhesives were synthesized via wet chemical precipitation and heat treatment. Cortical bone specimens were partially demineralized with phosphoric acid (H<sub>3</sub>PO<sub>4</sub>) or ethylenediaminetetraacetic acid (EDTA), and characterized using scanning electron microscopy (SEM) and attenuated total reflectance–Fourier transform infrared spectroscopy (ATR-FTIR). Shear adhesion strength of HAp to demineralized bone was measured over time. <em>In vivo</em> fixation was assessed in rats using micro-computed tomography and histology. Statistical analysis used Tukey-Kramer tests after normality and variance checks.</div></div><div><h3>Results</h3><div>Although the HAp adhesive failed to adhere to non-demineralized bone, effective adhesion was achieved on the surface-demineralized bone tissue. Shear adhesion strength was significantly higher in EDTA-treated samples (238.4 kPa at 10 h) compared to H<sub>3</sub>PO<sub>4</sub>-treated samples (102.9 kPa at 1 h), with performance correlating with demineralization depth. ATR-FTIR and SEM analyses revealed that EDTA preserved collagen's triple-helix structure and free water content, both enhancing adhesion. Animal experiments confirmed stable fixation of HAp adhesive to demineralized bone tissue.</div></div><div><h3>Conclusions</h3><div>Surface demineralization enabled strong adhesion of the solid-state HAp adhesive to bone by exposing collagen swollen with water. Adhesion strength was influenced by structural changes in the demineralized layer, and the adhesive provided stable <em>in vivo</em> fixation, supporting its potential for bone-anchored biomedical applications.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"57 ","pages":"Pages 632-645"},"PeriodicalIF":18.0,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145621131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-25DOI: 10.1016/j.bioactmat.2025.11.023
Yang Huang , Yan Wang , Guoyu Yang , Yunsheng Jiang , Menglong Sun , Shidi Cheng , Ling Zhong , Xiangling Pu , Bin Yang , Jiajia Chen , Zhiyu Chen , Chenwen Li , Liu Yang , Cheng Chen , Jianxiang Zhang
Osteoarthritis (OA), a debilitating degenerative joint disease driven by chronic inflammation and cartilage degradation, remains inadequately addressed by current therapies. While mesenchymal stem cells (MSCs) offer regenerative potential, their clinical efficacy is hindered by poor survival, transient retention, and pathological joint microenvironments. Here, we present a bioengineered hydrogel-based stem cell niche (PPT hydrogel) that dynamically coordinates microenvironmental reprogramming and MSC functional redirection to achieve sustained OA treatment. The PPT platform integrates intrinsic antioxidative and anti-inflammatory properties to neutralize OA-associated oxidative stress and inflammation while enhancing bone marrow MSCs (BMSCs) survival via Hedgehog signaling activation, overcoming limitations of conventional cell delivery. By incorporating a pro-differentiation agent, PPT hydrogel steers BMSCs toward stable hyaline cartilage regeneration, suppressing the formation of fibrotic and hypertrophic cartilage even under inflammatory conditions. Furthermore, PPT amplifies BMSCs paracrine signaling to restore redox homeostasis and autophagy flux in resident chondrocytes through FOXO1-dependent mechanisms, establishing a self-reinforcing therapeutic loop. The modular amphiphilic design enables spatiotemporal co-delivery of diverse therapeutics, synergistically regulating stem cell behavior and host tissue responses. Through bridging stem cell-chondrocyte crosstalk, this multifaceted PPT hydrogel represents a transformative paradigm for precision regenerative medicine, offering a universally adaptable platform to address complex inflammatory and degenerative diseases beyond OA.
{"title":"Modular hydrogel niche orchestrates microenvironment detoxification and stem cell redirecting toward precision osteoarthritis therapy","authors":"Yang Huang , Yan Wang , Guoyu Yang , Yunsheng Jiang , Menglong Sun , Shidi Cheng , Ling Zhong , Xiangling Pu , Bin Yang , Jiajia Chen , Zhiyu Chen , Chenwen Li , Liu Yang , Cheng Chen , Jianxiang Zhang","doi":"10.1016/j.bioactmat.2025.11.023","DOIUrl":"10.1016/j.bioactmat.2025.11.023","url":null,"abstract":"<div><div>Osteoarthritis (OA), a debilitating degenerative joint disease driven by chronic inflammation and cartilage degradation, remains inadequately addressed by current therapies. While mesenchymal stem cells (MSCs) offer regenerative potential, their clinical efficacy is hindered by poor survival, transient retention, and pathological joint microenvironments. Here, we present a bioengineered hydrogel-based stem cell niche (PPT hydrogel) that dynamically coordinates microenvironmental reprogramming and MSC functional redirection to achieve sustained OA treatment. The PPT platform integrates intrinsic antioxidative and anti-inflammatory properties to neutralize OA-associated oxidative stress and inflammation while enhancing bone marrow MSCs (BMSCs) survival via Hedgehog signaling activation, overcoming limitations of conventional cell delivery. By incorporating a pro-differentiation agent, PPT hydrogel steers BMSCs toward stable hyaline cartilage regeneration, suppressing the formation of fibrotic and hypertrophic cartilage even under inflammatory conditions. Furthermore, PPT amplifies BMSCs paracrine signaling to restore redox homeostasis and autophagy flux in resident chondrocytes through FOXO1-dependent mechanisms, establishing a self-reinforcing therapeutic loop. The modular amphiphilic design enables spatiotemporal co-delivery of diverse therapeutics, synergistically regulating stem cell behavior and host tissue responses. Through bridging stem cell-chondrocyte crosstalk, this multifaceted PPT hydrogel represents a transformative paradigm for precision regenerative medicine, offering a universally adaptable platform to address complex inflammatory and degenerative diseases beyond OA.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"57 ","pages":"Pages 660-675"},"PeriodicalIF":18.0,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145621130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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