Pub Date : 2025-11-25DOI: 10.1016/j.bioactmat.2025.11.020
Xihua Liu , Shuangjian Li , Guodong Wu , Wenzhe Jia , Yiguo Zhao , Yapeng Fang , Yiping Cao
Oral delivery of biologics presents a formidable challenge: achieving high bioavailability without compromising gastrointestinal barrier integrity or clinical scalability—a trilemma that remains unaddressed by existing chemical permeation enhancers, ligand-modified nanoparticles, or exosome platforms. Here, we repurpose β-lactoglobulin (BLG) nanofibrils that resolve this challenge through a unique “enhance-degrade-restore” mechanism. In vivo, these nanofibrils enable oral insulin bioavailability reaching 10.2–12.3 %, and long-term safety studies confirm the absence of intestinal damage. Mechanistic studies reveal that the nanofibrils facilitate Ca2+ influx-induced calpain activation to enhance paracellular permeability, followed by protease-mediated degradation that ensures timely restoration of barrier integrity. Moreover, nanofibrils maintain full adjuvant activity when integrated into commercial milk products, highlighting their formulation flexibility and robustness. This work introduces a sustainable “waste-to-nanomedicine” strategy that unites high-efficiency peptide delivery with environmentally responsible nanomaterial design.
{"title":"Food-derived β-lactoglobulin nanofibrils: An efficacy, safe, and scalable solution to overcome oral insulin delivery challenges","authors":"Xihua Liu , Shuangjian Li , Guodong Wu , Wenzhe Jia , Yiguo Zhao , Yapeng Fang , Yiping Cao","doi":"10.1016/j.bioactmat.2025.11.020","DOIUrl":"10.1016/j.bioactmat.2025.11.020","url":null,"abstract":"<div><div>Oral delivery of biologics presents a formidable challenge: achieving high bioavailability without compromising gastrointestinal barrier integrity or clinical scalability—a trilemma that remains unaddressed by existing chemical permeation enhancers, ligand-modified nanoparticles, or exosome platforms. Here, we repurpose β-lactoglobulin (BLG) nanofibrils that resolve this challenge through a unique “enhance-degrade-restore” mechanism. In vivo, these nanofibrils enable oral insulin bioavailability reaching 10.2–12.3 %, and long-term safety studies confirm the absence of intestinal damage. Mechanistic studies reveal that the nanofibrils facilitate Ca<sup>2+</sup> influx-induced calpain activation to enhance paracellular permeability, followed by protease-mediated degradation that ensures timely restoration of barrier integrity. Moreover, nanofibrils maintain full adjuvant activity when integrated into commercial milk products, highlighting their formulation flexibility and robustness. This work introduces a sustainable “waste-to-nanomedicine” strategy that unites high-efficiency peptide delivery with environmentally responsible nanomaterial design.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"57 ","pages":"Pages 646-659"},"PeriodicalIF":18.0,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145621132","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 : 2025-11-21DOI: 10.1016/j.bioactmat.2025.11.021
Jiamei Zhang , Wenbi Wu , Ya Ren , Xide Dai , Shuwei Ye , Wei Zhao , Haofan Liu , Liming He , Boya Li , Li Zhang , Xia Luo , Wentao Li , Xue Zhang , Shuai Yang , Maling Gou
Platelets show great promise for nerve repair due to their abundant release of growth factors. However, they often suffer from rapid activation-induced burst release of the cargo, making it challenging to develop long-acting platelet preparation. Here, we show a biosynthetic nerve conduit containing platelets with prolonged survival for peripheral nerve repair. This conduit was rapidly fabricated using a customized 3D printer by coating a platelet-loaded Pluronic F127 diacrylate hydrogel onto an electrospinning polycaprolactone conduit. The hydrogel can protect the platelets from stress-induced activation during deformation through its nanocolloid-based energy-dissipative centers, achieving a platelet survival rate of 34.7 % after 600 compression cycles. Platelets survived in this hydrogel for over 2 weeks, enabling the sustained release of bioactive cargo such as NGF and VEGF for more than 20 days. This conduit also had good mechanical properties, including compression and stretch resistance, to support surgical suturing and structural stability in vivo. Twelve weeks post-implantation, this conduit efficiently promoted nerve repair with functional outcomes by providing a growth factor-rich microenvironment, demonstrating potential clinical application.
{"title":"Bioprinting of live platelet-loaded nerve conduit using energy-dissipative hydrogel","authors":"Jiamei Zhang , Wenbi Wu , Ya Ren , Xide Dai , Shuwei Ye , Wei Zhao , Haofan Liu , Liming He , Boya Li , Li Zhang , Xia Luo , Wentao Li , Xue Zhang , Shuai Yang , Maling Gou","doi":"10.1016/j.bioactmat.2025.11.021","DOIUrl":"10.1016/j.bioactmat.2025.11.021","url":null,"abstract":"<div><div>Platelets show great promise for nerve repair due to their abundant release of growth factors. However, they often suffer from rapid activation-induced burst release of the cargo, making it challenging to develop long-acting platelet preparation. Here, we show a biosynthetic nerve conduit containing platelets with prolonged survival for peripheral nerve repair. This conduit was rapidly fabricated using a customized 3D printer by coating a platelet-loaded Pluronic F127 diacrylate hydrogel onto an electrospinning polycaprolactone conduit. The hydrogel can protect the platelets from stress-induced activation during deformation through its nanocolloid-based energy-dissipative centers, achieving a platelet survival rate of 34.7 % after 600 compression cycles. Platelets survived in this hydrogel for over 2 weeks, enabling the sustained release of bioactive cargo such as NGF and VEGF for more than 20 days. This conduit also had good mechanical properties, including compression and stretch resistance, to support surgical suturing and structural stability <em>in vivo</em>. Twelve weeks post-implantation, this conduit efficiently promoted nerve repair with functional outcomes by providing a growth factor-rich microenvironment, demonstrating potential clinical application.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"57 ","pages":"Pages 616-631"},"PeriodicalIF":18.0,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145576897","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 : 2025-11-21DOI: 10.1016/j.bioactmat.2025.10.007
Feng Tian , Yue Kong , Qinghua Liu , Shuoji Zhu , Xu Guo , YanLin Su , Bingyang Yu , Chao Zhang , Dongzhen Zhu , Zhao Li , Wei Song , Yi Kong , Xiangye Yin , Yuyan Huang , Yaxin Tan , Mengde Zhang , Jinpeng Du , Liting Liang , Jianjun Li , Ping Zhu , Sha Huang
Chronic diabetic wounds remain a major clinical challenge due to impaired angiogenesis and dysregulated immune homeostasis. While mesenchymal stem cell (MSC) therapy holds promise, poor survival and inconsistent paracrine function limit efficacy. Herein, we present a novel biohybrid strategy that synergistically combines microbe-mimetic preconditioning of MSCs with bacterial cell wall components (peptidoglycan, PGN and lipoteichoic acid, LTA) and their sustained delivery within a gelatin methacryloyl (GelMA) hydrogel (plMSC-GelMA) to overcome these limitations. We demonstrate that dual PGN/LTA priming uniquely activates MSCs via Toll-like receptor 2 (TLR2), triggering the PI3K/Akt pathway and profoundly enhancing their pro-angiogenic (e.g., VEGF) and immunomodulatory (e.g., IL-10, TGF-β) secretome, promoting endothelial cell function and M2 macrophage polarization in vitro. Encapsulation within biocompatible GelMA hydrogel ensured prolonged viability and localized release of these potent factors. In both acute and diabetic murine wound models, plMSC-GelMA significantly accelerated wound closure, surpassing unprimed MSC-GelMA or GelMA alone. This was driven by enhanced neovascularization (CD31+/α-SMA+) and a shift towards pro-healing M2 macrophages. Mechanistic studies confirmed the pivotal role of the TLR2-PI3K/Akt axis, as genetic (siRNA) or pharmacological (LY294002) inhibition abolished the enhanced therapeutic benefits of plMSCs. This study uncovers a microbiota-inspired priming strategy that reprograms MSC paracrine function and establishes a translational biohybrid platform (plMSC-GelMA). By harnessing microbial cues and biomaterial engineering, we offer a promising solution for enhancing stem cell therapy in refractory diabetic wound healing.
{"title":"TLR2-PI3K/Akt mediated microbe-mimetic priming boosts the therapeutic paracrine function of GelMA-Encapsulated MSCs for diabetic wound regeneration","authors":"Feng Tian , Yue Kong , Qinghua Liu , Shuoji Zhu , Xu Guo , YanLin Su , Bingyang Yu , Chao Zhang , Dongzhen Zhu , Zhao Li , Wei Song , Yi Kong , Xiangye Yin , Yuyan Huang , Yaxin Tan , Mengde Zhang , Jinpeng Du , Liting Liang , Jianjun Li , Ping Zhu , Sha Huang","doi":"10.1016/j.bioactmat.2025.10.007","DOIUrl":"10.1016/j.bioactmat.2025.10.007","url":null,"abstract":"<div><div>Chronic diabetic wounds remain a major clinical challenge due to impaired angiogenesis and dysregulated immune homeostasis. While mesenchymal stem cell (MSC) therapy holds promise, poor survival and inconsistent paracrine function limit efficacy. Herein, we present a novel biohybrid strategy that synergistically combines microbe-mimetic preconditioning of MSCs with bacterial cell wall components (peptidoglycan, PGN and lipoteichoic acid, LTA) and their sustained delivery within a gelatin methacryloyl (GelMA) hydrogel (plMSC-GelMA) to overcome these limitations. We demonstrate that dual PGN/LTA priming uniquely activates MSCs via Toll-like receptor 2 (TLR2), triggering the PI3K/Akt pathway and profoundly enhancing their pro-angiogenic (e.g., VEGF) and immunomodulatory (e.g., IL-10, TGF-β) secretome, promoting endothelial cell function and M2 macrophage polarization in vitro. Encapsulation within biocompatible GelMA hydrogel ensured prolonged viability and localized release of these potent factors. In both acute and diabetic murine wound models, plMSC-GelMA significantly accelerated wound closure, surpassing unprimed MSC-GelMA or GelMA alone. This was driven by enhanced neovascularization (CD31+/α-SMA+) and a shift towards pro-healing M2 macrophages. Mechanistic studies confirmed the pivotal role of the TLR2-PI3K/Akt axis, as genetic (siRNA) or pharmacological (LY294002) inhibition abolished the enhanced therapeutic benefits of plMSCs. This study uncovers a microbiota-inspired priming strategy that reprograms MSC paracrine function and establishes a translational biohybrid platform (plMSC-GelMA). By harnessing microbial cues and biomaterial engineering, we offer a promising solution for enhancing stem cell therapy in refractory diabetic wound healing.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"57 ","pages":"Pages 601-615"},"PeriodicalIF":18.0,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145576911","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 : 2025-11-20DOI: 10.1016/j.bioactmat.2025.10.040
Wei Chen , Zhe Yi , Xinran Wang , Shuai Wang , Weichen Wang , Aijie Zhang , Fei Liu , Rui Shi , Yudong Zheng , Bo Liu
Neuromodulatory signals play a critical role in initiating early vascularized bone regeneration following bone injury. Despite advancements in bone tissue engineering centered on mesenchymal stem cell regulation, the pivotal contributions of early innervation and late mechanical transduction in bone regeneration and remodeling are frequently overlooked. Nerve growth factor (NGF) facilitates neuronal axon regeneration in the initial stage of bone injury, while Yoda1, acting as a chemical agonist, triggers Piezo1-mediated mechanical transduction signals crucial for the mid-to-late stages of bone remodeling. This study developed a composite sequential delivery system utilizing GelMA hydrogel and PLA microspheres to enable the rapid release of NGF and delayed release of Yoda1, mimicking and expediting the natural bone repair process. The system was found to stimulate the migration and maturation of RSC96 and induce neuronal-like differentiation of PC-12, subsequently enhancing osteogenesis and angiogenesis within a neuromodulatory microenvironment. Notably, early neurovascularization and collagen fiber deposition were observed in a subcutaneous implantation model. Further investigations in a femur defect model confirmed that the rapid release of NGF initiates early neuro-vascular-osteogenic coupling, while sustained Yoda1 release in the mid-to-late phases activates and maintains bone regeneration and remodeling effects. In summary, this study underscores the critical roles of early innervation and late-stage mechanical transduction in bone regeneration, offering an innovative and precise therapeutic approach for bone defects.
{"title":"Composite hydrogel-microsphere delivery system promotes early nerve-mediated bone regeneration and late-stage mechanotransduction-driven bone remodeling via sequential release of NGF and Yoda1","authors":"Wei Chen , Zhe Yi , Xinran Wang , Shuai Wang , Weichen Wang , Aijie Zhang , Fei Liu , Rui Shi , Yudong Zheng , Bo Liu","doi":"10.1016/j.bioactmat.2025.10.040","DOIUrl":"10.1016/j.bioactmat.2025.10.040","url":null,"abstract":"<div><div>Neuromodulatory signals play a critical role in initiating early vascularized bone regeneration following bone injury. Despite advancements in bone tissue engineering centered on mesenchymal stem cell regulation, the pivotal contributions of early innervation and late mechanical transduction in bone regeneration and remodeling are frequently overlooked. Nerve growth factor (NGF) facilitates neuronal axon regeneration in the initial stage of bone injury, while Yoda1, acting as a chemical agonist, triggers Piezo1-mediated mechanical transduction signals crucial for the mid-to-late stages of bone remodeling. This study developed a composite sequential delivery system utilizing GelMA hydrogel and PLA microspheres to enable the rapid release of NGF and delayed release of Yoda1, mimicking and expediting the natural bone repair process. The system was found to stimulate the migration and maturation of RSC96 and induce neuronal-like differentiation of PC-12, subsequently enhancing osteogenesis and angiogenesis within a neuromodulatory microenvironment. Notably, early neurovascularization and collagen fiber deposition were observed in a subcutaneous implantation model. Further investigations in a femur defect model confirmed that the rapid release of NGF initiates early neuro-vascular-osteogenic coupling, while sustained Yoda1 release in the mid-to-late phases activates and maintains bone regeneration and remodeling effects. In summary, this study underscores the critical roles of early innervation and late-stage mechanical transduction in bone regeneration, offering an innovative and precise therapeutic approach for bone defects.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"57 ","pages":"Pages 531-550"},"PeriodicalIF":18.0,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145576906","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 : 2025-11-20DOI: 10.1016/j.bioactmat.2025.11.015
Daniela Lopes , Joana Lopes , Luigia Serpico , Hélder A. Santos , Ana Cláudia Paiva-Santos
In the intricate tapestry of life, subcellular structures stand out as the fundamental building blocks that orchestrate the complexities of cellular function. Collectively, they govern the course of events at the subcellular level and cooperate to maintain cellular physiological functions and homeostasis and they are present in all eukaryotic cells, from the unicellular organisms to the more complex ones. Herein, we aim to explore the cutting-edge, bioinspired brunch of nanotechnology focused on the fabrication of biomimetic nanoparticles consisting of a synthetic core coated with the natural membranes deriving from membrane-bound subcellular organelles. Beyond the well-grounded biomedical evidence on the use of membranes derived from cells, exosomes and bacteria, recent insights have unlocked the potential of the nanosystems mimicking the subcellular intricacy for subcellular-oriented medicine. Despite the recent promising results, several challenges remain in the translation of this technology to the clinical settings. The current lack of standardization, challenging industrial scale-up, immunological concerns, as well as demanding regulatory considerations still remains aspects to be analyzed and discussed, in order to fill the current gap between the research and the clinical application.
{"title":"Harnessing nature's blueprint: Unlocking the potential of subcellular structure membrane-coated nanosystems for precision medicine","authors":"Daniela Lopes , Joana Lopes , Luigia Serpico , Hélder A. Santos , Ana Cláudia Paiva-Santos","doi":"10.1016/j.bioactmat.2025.11.015","DOIUrl":"10.1016/j.bioactmat.2025.11.015","url":null,"abstract":"<div><div>In the intricate tapestry of life, subcellular structures stand out as the fundamental building blocks that orchestrate the complexities of cellular function. Collectively, they govern the course of events at the subcellular level and cooperate to maintain cellular physiological functions and homeostasis and they are present in all eukaryotic cells, from the unicellular organisms to the more complex ones. Herein, we aim to explore the cutting-edge, bioinspired brunch of nanotechnology focused on the fabrication of biomimetic nanoparticles consisting of a synthetic core coated with the natural membranes deriving from membrane-bound subcellular organelles. Beyond the well-grounded biomedical evidence on the use of membranes derived from cells, exosomes and bacteria, recent insights have unlocked the potential of the nanosystems mimicking the subcellular intricacy for subcellular-oriented medicine. Despite the recent promising results, several challenges remain in the translation of this technology to the clinical settings. The current lack of standardization, challenging industrial scale-up, immunological concerns, as well as demanding regulatory considerations still remains aspects to be analyzed and discussed, in order to fill the current gap between the research and the clinical application.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"57 ","pages":"Pages 551-577"},"PeriodicalIF":18.0,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145576912","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 : 2025-11-20DOI: 10.1016/j.bioactmat.2025.11.009
Meiqi Jin , Miao Xia , Tianlin Wang , Yanan Zhao , Dali Xu , Linxuan Wu , Taotao Liu , Tianqi Li , Dake Xu , Huazhe Yang , Xiaoqian Xu
The complex bone repair microenvironment remains a significant challenge in orthopedics. As pivotal regulators, bioactive metal ions can promote osseointegration by coordinating the bone immune microenvironment. To address this, we engineered Zn2+/Ce3+ double-doped whitlockite nanoparticles (Zn2+/Ce3+-WH) via a biomimetic GelMA template (GM&Zn2+/Ce3+-WH). These biomimetic GM&Zn2+/Ce3+-WH hydrogel scaffolds exhibit excellent antioxidant, significantly activated anti-inflammatory macrophage phenotypes and inhibited osteoclastogenesis. The resulting immune microenvironment favorably promoted osteogenic differentiation in vitro and facilitated implant-to-bone osteointegration in vivo. Additionally, the scaffolds demonstrated potential for post-operative anti-infection activity. Notably, GM&Zn2+/Ce3+-WH exhibited excellent overall performance. In summary, the natural bone-like Zn2+/Ce3+ co-doping strategy endows GM&Zn2+/Ce3+-WH with immunomodulatory, bacteriostatic, and osseointegrative properties, offering a distinctive and promising approach to re-establishing an immunoregulated osteogenic microenvironment for bone regeneration.
{"title":"Immune regulative GelMA&Zn2+/Ce3+-whitlockite scaffolds with continuous ions release for bone regeneration","authors":"Meiqi Jin , Miao Xia , Tianlin Wang , Yanan Zhao , Dali Xu , Linxuan Wu , Taotao Liu , Tianqi Li , Dake Xu , Huazhe Yang , Xiaoqian Xu","doi":"10.1016/j.bioactmat.2025.11.009","DOIUrl":"10.1016/j.bioactmat.2025.11.009","url":null,"abstract":"<div><div>The complex bone repair microenvironment remains a significant challenge in orthopedics. As pivotal regulators, bioactive metal ions can promote osseointegration by coordinating the bone immune microenvironment. To address this, we engineered Zn<sup>2+</sup>/Ce<sup>3+</sup> double-doped whitlockite nanoparticles (Zn<sup>2+</sup>/Ce<sup>3+</sup>-WH) via a biomimetic GelMA template (GM&Zn<sup>2+</sup>/Ce<sup>3+</sup>-WH). These biomimetic GM&Zn<sup>2+</sup>/Ce<sup>3+</sup>-WH hydrogel scaffolds exhibit excellent antioxidant, significantly activated anti-inflammatory macrophage phenotypes and inhibited osteoclastogenesis. The resulting immune microenvironment favorably promoted osteogenic differentiation <em>in vitro</em> and facilitated implant-to-bone osteointegration <em>in vivo</em>. Additionally, the scaffolds demonstrated potential for post-operative anti-infection activity. Notably, GM&Zn<sup>2+</sup>/Ce<sup>3+</sup>-WH exhibited excellent overall performance. In summary, the natural bone-like Zn<sup>2+</sup>/Ce<sup>3+</sup> co-doping strategy endows GM&Zn<sup>2+</sup>/Ce<sup>3+</sup>-WH with immunomodulatory, bacteriostatic, and osseointegrative properties, offering a distinctive and promising approach to re-establishing an immunoregulated osteogenic microenvironment for bone regeneration.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"57 ","pages":"Pages 578-600"},"PeriodicalIF":18.0,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145576910","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 : 2025-11-19DOI: 10.1016/j.bioactmat.2025.11.018
Yue Yuan , Zishuo Hou , Miaomiao Chen , Jingwei Yu , Minghao Zhou , Jiaxin Kang , Tengjiao Wang , Peng Li , Hongbo Wei
The weaker soft tissue integration around implants compared to natural teeth poses a substantial challenge to the long-term success of implants. To enhance soft tissue integration, we develop an on-demand and long-lasting H2-releasing implant to achieve precise sequential regulation of the soft tissue integration through immunomodulation and pro-remodeling coupling. In the inflammatory phase, the system on-demand releases H2 responded to the local mild acidic microenvironment, which eliminates 73.6 % reactive oxygen species to induce M2 macrophage polarization, thereby establishing a pro-remodeling microenvironment. During the subsequent remodeling phase, the implant sustains release H2 based on the hierarchical nanostructure, effectively promoting collagen fiber formation and angiogenesis. Surprisingly, we propose that H2 can coordinately activate MAPK signaling in both gingival fibroblasts and vascular endothelial cells, coupled with stimulating pro-angiogenic paracrine of gingival fibroblasts. This implant achieves the on-demand transition of H2 release kinetics that matches the temporal progression of soft tissue integration, implying great potential of enhancing soft tissue integration.
{"title":"Sequential hydrogen-release implant for promoting the soft tissue integration through immunomodulatory and pro-remodeling coupling","authors":"Yue Yuan , Zishuo Hou , Miaomiao Chen , Jingwei Yu , Minghao Zhou , Jiaxin Kang , Tengjiao Wang , Peng Li , Hongbo Wei","doi":"10.1016/j.bioactmat.2025.11.018","DOIUrl":"10.1016/j.bioactmat.2025.11.018","url":null,"abstract":"<div><div>The weaker soft tissue integration around implants compared to natural teeth poses a substantial challenge to the long-term success of implants. To enhance soft tissue integration, we develop an on-demand and long-lasting H<sub>2</sub>-releasing implant to achieve precise sequential regulation of the soft tissue integration through immunomodulation and pro-remodeling coupling. In the inflammatory phase, the system on-demand releases H<sub>2</sub> responded to the local mild acidic microenvironment, which eliminates 73.6 % reactive oxygen species to induce M2 macrophage polarization, thereby establishing a pro-remodeling microenvironment. During the subsequent remodeling phase, the implant sustains release H<sub>2</sub> based on the hierarchical nanostructure, effectively promoting collagen fiber formation and angiogenesis. Surprisingly, we propose that H<sub>2</sub> can coordinately activate MAPK signaling in both gingival fibroblasts and vascular endothelial cells, coupled with stimulating pro-angiogenic paracrine of gingival fibroblasts. This implant achieves the on-demand transition of H<sub>2</sub> release kinetics that matches the temporal progression of soft tissue integration, implying great potential of enhancing soft tissue integration.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"57 ","pages":"Pages 514-530"},"PeriodicalIF":18.0,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145576905","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 : 2025-11-19DOI: 10.1016/j.bioactmat.2025.11.014
Liuxin Zhang , Jindong Tan , Bo Liao , Mengya Huang , Rui Huang , Xinyu Zhang , Xu He , Xinhe Li , Xiaoqian Ding , Anan Jiang , Zijie Wang , Wang Han , Xiaoyu Han , Dingqun Bai
Impaired functional regeneration following tendon-to-bone interface (TBI) injury is a major challenge in sports medicine. The rigidity and limited efficacy of existing rehabilitation strategies remain significant constraints. Physical modalities, leveraging advantages such as non-invasiveness, spatiotemporal controllability, and low immunogenicity, offer effective intervention options for the long-term management of TBI healing. However, conventional physical modalities struggle to address the complex pathological microenvironment involved in TBI healing. In contrast, therapeutic strategies utilizing physical energy-responsive biomaterials enable programmable, precise, and dynamic regulation, potentially integrating these advantages while overcoming inherent limitations, thereby opening new and effective therapeutic avenues for TBI healing. This review systematically examines the benefits, current applications, and shortcomings of physical modalities for TBI injuries, with particular focus on parameter-response relationships and underlying biological effector mechanisms. Furthermore, it summarizes the design strategies and application progress of energy-responsive biomaterials in TBI healing and discusses future directions and promising prospects, aiming to address the core therapeutic challenges in achieving robust TBI healing.
{"title":"From physical modalities to energy-responsive biomaterials: Current strategies and challenges in tendon-to-bone healing","authors":"Liuxin Zhang , Jindong Tan , Bo Liao , Mengya Huang , Rui Huang , Xinyu Zhang , Xu He , Xinhe Li , Xiaoqian Ding , Anan Jiang , Zijie Wang , Wang Han , Xiaoyu Han , Dingqun Bai","doi":"10.1016/j.bioactmat.2025.11.014","DOIUrl":"10.1016/j.bioactmat.2025.11.014","url":null,"abstract":"<div><div>Impaired functional regeneration following tendon-to-bone interface (TBI) injury is a major challenge in sports medicine. The rigidity and limited efficacy of existing rehabilitation strategies remain significant constraints. Physical modalities, leveraging advantages such as non-invasiveness, spatiotemporal controllability, and low immunogenicity, offer effective intervention options for the long-term management of TBI healing. However, conventional physical modalities struggle to address the complex pathological microenvironment involved in TBI healing. In contrast, therapeutic strategies utilizing physical energy-responsive biomaterials enable programmable, precise, and dynamic regulation, potentially integrating these advantages while overcoming inherent limitations, thereby opening new and effective therapeutic avenues for TBI healing. This review systematically examines the benefits, current applications, and shortcomings of physical modalities for TBI injuries, with particular focus on parameter-response relationships and underlying biological effector mechanisms. Furthermore, it summarizes the design strategies and application progress of energy-responsive biomaterials in TBI healing and discusses future directions and promising prospects, aiming to address the core therapeutic challenges in achieving robust TBI healing.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"57 ","pages":"Pages 474-513"},"PeriodicalIF":18.0,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145576898","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 : 2025-11-18DOI: 10.1016/j.bioactmat.2025.11.019
Shiyuan Song , Wen Zhang , Hongmei Zhuang , Wei Wei , Shuyu Cheng , Dan Qiao , Yin Xiao , Yangheng Zhang , Fuhua Yan
Oral and maxillofacial bone defects are prevalent and challenging to treat, often leading to significant complications such as infection and impaired healing. Enhancing the antibacterial and osteoimmunomodulatory properties of bone graft materials represents a promising approach to improve regenerative outcomes. In this study, we developed a hydroxyapatite scaffold coated with a biofilm of the probiotic Akkermansia muciniphila (Akk-HA), engineered to simultaneously combat infection and modulate the immune environment. Akk-HA exhibited vigorous anti-adhesive activity against pathogenic bacteria and attenuated inflammatory responses by suppressing proinflammatory cytokine secretion while promoting the release of proregenerative mediators from macrophages. Mechanistic studies revealed that Akk-HA activated the PI3K/AKT signalling pathway, leading to the upregulation of interleukin-10 (IL-10), in turn enhancing the osteogenic differentiation of periodontal ligament cells (PDLCs). In a murine model of infected periodontal bone defects, Akk-HA demonstrated significant antibacterial and immunomodulatory effects, resulting in markedly improved bone regeneration. These findings highlight the therapeutic potential of probiotic-functionalized bone grafts as a dual-action strategy for managing infected bone defects in the oral and maxillofacial regions.
{"title":"Dual functional properties of a probiotic biofilm-decorated bone substitute to combat infection and promote osteoimmunomodulation","authors":"Shiyuan Song , Wen Zhang , Hongmei Zhuang , Wei Wei , Shuyu Cheng , Dan Qiao , Yin Xiao , Yangheng Zhang , Fuhua Yan","doi":"10.1016/j.bioactmat.2025.11.019","DOIUrl":"10.1016/j.bioactmat.2025.11.019","url":null,"abstract":"<div><div>Oral and maxillofacial bone defects are prevalent and challenging to treat, often leading to significant complications such as infection and impaired healing. Enhancing the antibacterial and osteoimmunomodulatory properties of bone graft materials represents a promising approach to improve regenerative outcomes. In this study, we developed a hydroxyapatite scaffold coated with a biofilm of the probiotic <em>Akkermansia muciniphila</em> (<em>Akk</em>-HA), engineered to simultaneously combat infection and modulate the immune environment. <em>Akk</em>-HA exhibited vigorous anti-adhesive activity against pathogenic bacteria and attenuated inflammatory responses by suppressing proinflammatory cytokine secretion while promoting the release of proregenerative mediators from macrophages. Mechanistic studies revealed that <em>Akk</em>-HA activated the PI3K/AKT signalling pathway, leading to the upregulation of interleukin-10 (IL-10), in turn enhancing the osteogenic differentiation of periodontal ligament cells (PDLCs). In a murine model of infected periodontal bone defects, <em>Akk</em>-HA demonstrated significant antibacterial and immunomodulatory effects, resulting in markedly improved bone regeneration. These findings highlight the therapeutic potential of probiotic-functionalized bone grafts as a dual-action strategy for managing infected bone defects in the oral and maxillofacial regions.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"57 ","pages":"Pages 457-473"},"PeriodicalIF":18.0,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145576908","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 : 2025-11-17DOI: 10.1016/j.bioactmat.2025.11.017
Pengqi Wan , Ting Hua , Xingjun Zhao , Mingxiao Deng , Li Chen , Chunsheng Xiao , Xuesi Chen
Tertiary alkylamines serve as privileged structural motifs ubiquitously distributed across natural products, pharmaceutical agents, and bioactive molecules. However, their application in the design of antibacterial polymers has not been extensively explored. Here, a series of cationic polyaspartamides (PASP-n) with different tertiary alkylamine pendants were synthesized and screened for combatting methicillin-resistant Staphylococcus aureus (MRSA) induced infections. Among all the synthesized PASP-n, the polymer bearing N, N-dibutylamine groups (PASP-4) exhibited the best antibacterial activity and the highest selectivity (>640 and > 160 for S. aureus and E. coli, respectively). The mechanistic study revealed that, due to the relative longer alkyl chain, PASP-4 could effectively bind with bacteria-specific anionic phosphatidylglycerol (POPG), thereby destroying the integrity of the bacterial membrane and resulting in the leakage of cytoplasmic components (e.g., ATP, DNA, and K+). Owing to this membrane disrupting ability, PASP-4 showed rapid bacterial killing kinetics without developing bacteria resistance after repeated treatments over 28 generations. Furthermore, PASP-4 demonstrated significant therapeutic potential in both local and systemic MRSA infections. Overall, this study proposes a viable strategy for the rational design of antibacterial polymers based on tertiary alkylamine structures.
{"title":"Tertiary alkylamine-functionalized polyaspartamides with potent antibacterial activity","authors":"Pengqi Wan , Ting Hua , Xingjun Zhao , Mingxiao Deng , Li Chen , Chunsheng Xiao , Xuesi Chen","doi":"10.1016/j.bioactmat.2025.11.017","DOIUrl":"10.1016/j.bioactmat.2025.11.017","url":null,"abstract":"<div><div>Tertiary alkylamines serve as privileged structural motifs ubiquitously distributed across natural products, pharmaceutical agents, and bioactive molecules. However, their application in the design of antibacterial polymers has not been extensively explored. Here, a series of cationic polyaspartamides (PASP-n) with different tertiary alkylamine pendants were synthesized and screened for combatting methicillin-resistant <em>Staphylococcus aureus</em> (MRSA) induced infections. Among all the synthesized PASP-n, the polymer bearing <em>N</em>, <em>N</em>-dibutylamine groups (PASP-4) exhibited the best antibacterial activity and the highest selectivity (>640 and > 160 for <em>S. aureus</em> and <em>E. coli</em>, respectively). The mechanistic study revealed that, due to the relative longer alkyl chain, PASP-4 could effectively bind with bacteria-specific anionic phosphatidylglycerol (POPG), thereby destroying the integrity of the bacterial membrane and resulting in the leakage of cytoplasmic components (<em>e.g.</em>, ATP, DNA, and K<sup>+</sup>). Owing to this membrane disrupting ability, PASP-4 showed rapid bacterial killing kinetics without developing bacteria resistance after repeated treatments over 28 generations. Furthermore, PASP-4 demonstrated significant therapeutic potential in both local and systemic MRSA infections. Overall, this study proposes a viable strategy for the rational design of antibacterial polymers based on tertiary alkylamine structures.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"57 ","pages":"Pages 445-456"},"PeriodicalIF":18.0,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145576907","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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