Pub Date : 2025-03-26DOI: 10.1016/j.biomaterials.2025.123296
Yi Huang , Ali Osouli , Hui Li , Megan Dudaney , Jessica Pham , Valeria Mancino , Taranatee Khan , Baishali Chaudhuri , Nuria M. Pastor-Soler , Kenneth R. Hallows , Eun Ji Chung
Chronic kidney disease (CKD) is a widespread health concern, impacting approximately 600 million individuals worldwide and marked by a progressive decline in kidney function. A common form of CKD is autosomal dominant polycystic kidney disease (ADPKD), which is the most inherited genetic kidney disease and affects greater than 12.5 million individuals globally. Given that there are over 400 pathogenic PKD1/PKD2 mutations in patients with ADPKD, relying solely on small molecule drugs targeting a single signaling pathway has not been effective in treating ADPKD. Urinary extracellular vesicles (uEVs) are naturally released by cells from the kidneys and the urinary tract, and uEVs isolated from non-disease sources have been reported to carry functional polycystin-1 (PC1) and polycystin-2 (PC2), the respective products of PKD1 and PKD2 genes that are mutated in ADPKD. uEVs from non-disease sources, as a result, have the potential to provide a direct solution to the root of the disease by delivering functional proteins that are mutated in ADPKD. To test our hypothesis, we first isolated uEVs from healthy mice urine and conducted a comprehensive characterization of uEVs. Then, PC1 levels and EV markers CD63 and TSG101 of uEVs were confirmed via ELISA and Western blot. Following characterization of uEVs, the in vitro cellular uptake, inhibition of cyst growth, and gene rescue ability of uEVs were demonstrated in kidney cells. Next, upon administration of uEVs in vivo, uEVs showed bioavailability and accumulation in the kidneys. Lastly, uEV treatment in ADPKD mice (Pkd1fl/fl;Pax8-rtTA;Tet-O-Cre) showed smaller kidney size, lower cyst index, and enhanced PC1 levels without affecting safety despite repeated treatment. In summary, we demonstrate the potential of uEVs as natural nanoparticles to deliver protein and gene therapies for the treatment of chronic and genetic kidney diseases such as ADPKD.
{"title":"Therapeutic potential of urinary extracellular vesicles in delivering functional proteins and modulating gene expression for genetic kidney disease","authors":"Yi Huang , Ali Osouli , Hui Li , Megan Dudaney , Jessica Pham , Valeria Mancino , Taranatee Khan , Baishali Chaudhuri , Nuria M. Pastor-Soler , Kenneth R. Hallows , Eun Ji Chung","doi":"10.1016/j.biomaterials.2025.123296","DOIUrl":"10.1016/j.biomaterials.2025.123296","url":null,"abstract":"<div><div>Chronic kidney disease (CKD) is a widespread health concern, impacting approximately 600 million individuals worldwide and marked by a progressive decline in kidney function. A common form of CKD is autosomal dominant polycystic kidney disease (ADPKD), which is the most inherited genetic kidney disease and affects greater than 12.5 million individuals globally. Given that there are over 400 pathogenic <em>PKD1/PKD2</em> mutations in patients with ADPKD, relying solely on small molecule drugs targeting a single signaling pathway has not been effective in treating ADPKD. Urinary extracellular vesicles (uEVs) are naturally released by cells from the kidneys and the urinary tract, and uEVs isolated from non-disease sources have been reported to carry functional polycystin-1 (PC1) and polycystin-2 (PC2), the respective products of <em>PKD1</em> and <em>PKD2</em> genes that are mutated in ADPKD. uEVs from non-disease sources, as a result, have the potential to provide a direct solution to the root of the disease by delivering functional proteins that are mutated in ADPKD. To test our hypothesis, we first isolated uEVs from healthy mice urine and conducted a comprehensive characterization of uEVs. Then, PC1 levels and EV markers CD63 and TSG101 of uEVs were confirmed via ELISA and Western blot. Following characterization of uEVs, the <em>in vitro</em> cellular uptake, inhibition of cyst growth, and gene rescue ability of uEVs were demonstrated in kidney cells. Next, upon administration of uEVs <em>in vivo</em>, uEVs showed bioavailability and accumulation in the kidneys. Lastly, uEV treatment in ADPKD mice (<em>Pkd1</em><sup><em>fl/fl</em></sup><em>;Pax8-rtTA;Tet-O-Cre</em>) showed smaller kidney size, lower cyst index, and enhanced PC1 levels without affecting safety despite repeated treatment. In summary, we demonstrate the potential of uEVs as natural nanoparticles to deliver protein and gene therapies for the treatment of chronic and genetic kidney diseases such as ADPKD.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"321 ","pages":"Article 123296"},"PeriodicalIF":12.8,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143734543","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}
Although recent therapeutic developments have greatly improved the outcomes of patients with cancer, it remains on ongoing problem, particularly in relation to acquired drug resistance. Vascular disrupting agents (VDAs) directly damage tumor blood vessels, thus promoting drug efficacy and reducing the development of drug resistance; however, their low molecular weight and resulting lack of selectivity for tumor endothelial cells (TECs) lead to side effects that can hinder their practical use. Here, we report a novel tumor vascular disrupting therapy using nucleic acid-loaded lipid nanoparticles (LNPs). We prepared two LNPs: a small interfering RNA (siRNA) against Fas ligand (FasL)-loaded cyclic RGD modified LNP (cRGD-LNP) to knock down FasL in TECs and a stimulator of interferon genes (STING) agonist-loaded LNP to induce systemic type I interferon (IFN) production. The combination therapy disrupted the tumor vasculature and induced broad tumor cell apoptosis within 48 h, leading to rapid and strong therapeutic effects in various tumor models. T cells were not involved in these antitumor effects. Furthermore, the combination therapy demonstrated a significantly superior therapeutic efficacy compared with conventional anti-angiogenic agents and VDAs. RNA sequencing analysis suggested that reduced collagen levels may have been responsible for TEC apoptosis. These findings demonstrated a potential therapeutic method for targeting the tumor vasculature, which may contribute to the development of a new class of anti-cancer drugs.
{"title":"Selective vascular disrupting therapy by lipid nanoparticle-mediated Fas ligand silencing and stimulation of STING","authors":"Rikito Endo , Tomoki Ueda , Takumi Nagaoki , Yusuke Sato , Nako Maishi , Kyoko Hida , Hideyoshi Harashima , Takashi Nakamura","doi":"10.1016/j.biomaterials.2025.123297","DOIUrl":"10.1016/j.biomaterials.2025.123297","url":null,"abstract":"<div><div>Although recent therapeutic developments have greatly improved the outcomes of patients with cancer, it remains on ongoing problem, particularly in relation to acquired drug resistance. Vascular disrupting agents (VDAs) directly damage tumor blood vessels, thus promoting drug efficacy and reducing the development of drug resistance; however, their low molecular weight and resulting lack of selectivity for tumor endothelial cells (TECs) lead to side effects that can hinder their practical use. Here, we report a novel tumor vascular disrupting therapy using nucleic acid-loaded lipid nanoparticles (LNPs). We prepared two LNPs: a small interfering RNA (siRNA) against Fas ligand (FasL)-loaded cyclic RGD modified LNP (cRGD-LNP) to knock down FasL in TECs and a stimulator of interferon genes (STING) agonist-loaded LNP to induce systemic type I interferon (IFN) production. The combination therapy disrupted the tumor vasculature and induced broad tumor cell apoptosis within 48 h, leading to rapid and strong therapeutic effects in various tumor models. T cells were not involved in these antitumor effects. Furthermore, the combination therapy demonstrated a significantly superior therapeutic efficacy compared with conventional anti-angiogenic agents and VDAs. RNA sequencing analysis suggested that reduced collagen levels may have been responsible for TEC apoptosis. These findings demonstrated a potential therapeutic method for targeting the tumor vasculature, which may contribute to the development of a new class of anti-cancer drugs.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"321 ","pages":"Article 123297"},"PeriodicalIF":12.8,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143734542","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 : 2025-03-26DOI: 10.1016/j.biomaterials.2025.123292
Xingyue Fan , Yue Sun , Jiaqi Fu , Hui Cao , Shiyi Liao , Cheng Zhang , Shuangyan Huan , Guosheng Song
Diabetic liver injury has emerged as a significant complication associated with diabetes, warranting increased attention. The generation of hydrogen peroxide (H2O2) due to oxidative stress plays a critical role in the onset and progression of this condition. Despite this, there is a scarcity of probes capable of non-invasively, accurately, and reliably visualizing H2O2 levels in deep-seated liver in diabetes-induced liver injury. In this study, we introduce a novel H2O2-responsive magnetic probe (H2O2-RMP), designed for the sensitive imaging of H2O2 in the liver injury caused by diabetes. H2O2-RMP is synthesized through the co-precipitation of a H2O2-responsive amphiphilic polymer, manganese(III) porphyrin (Mn-porphyrin), and iron oxide nanoparticles. When exposed to H2O2, the released iron oxide nanoparticles aggregate, resulting in an increased T2-weighted MR signal intensity. H2O2-RMP not only demonstrates a wide dynamic response range (initial r2 = 9.87 mM-1s-1, Δr2 = 7.69 mM-1s-1), but also exhibits superior selectivity for H2O2 compared to other reactive oxygen species. Importantly, H2O2-RMP exhibits high sensitivity, with a detection limit for hydrogen peroxide as low as 0.56 μM. Moreover, H2O2-RMP has been effectively applied for real-time imaging of H2O2 levels in the livers of diabetic model mice with varying degrees of severity, highlighting its potential for visual diagnosis and monitoring the progression of diabetic liver injury.
{"title":"MRI-responsive nanoprobes for visualizing hydrogen peroxide in diabetic liver injury","authors":"Xingyue Fan , Yue Sun , Jiaqi Fu , Hui Cao , Shiyi Liao , Cheng Zhang , Shuangyan Huan , Guosheng Song","doi":"10.1016/j.biomaterials.2025.123292","DOIUrl":"10.1016/j.biomaterials.2025.123292","url":null,"abstract":"<div><div>Diabetic liver injury has emerged as a significant complication associated with diabetes, warranting increased attention. The generation of hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) due to oxidative stress plays a critical role in the onset and progression of this condition. Despite this, there is a scarcity of probes capable of non-invasively, accurately, and reliably visualizing H<sub>2</sub>O<sub>2</sub> levels in deep-seated liver in diabetes-induced liver injury. In this study, we introduce a novel H<sub>2</sub>O<sub>2</sub>-responsive magnetic probe (H<sub>2</sub>O<sub>2</sub>-RMP), designed for the sensitive imaging of H<sub>2</sub>O<sub>2</sub> in the liver injury caused by diabetes. H<sub>2</sub>O<sub>2</sub>-RMP is synthesized through the co-precipitation of a H<sub>2</sub>O<sub>2</sub>-responsive amphiphilic polymer, manganese(III) porphyrin (Mn-porphyrin), and iron oxide nanoparticles. When exposed to H<sub>2</sub>O<sub>2</sub>, the released iron oxide nanoparticles aggregate, resulting in an increased T<sub>2</sub>-weighted MR signal intensity. H<sub>2</sub>O<sub>2</sub>-RMP not only demonstrates a wide dynamic response range (initial r<sub>2</sub> = 9.87 mM<sup>-</sup><sup>1</sup>s<sup>-</sup><sup>1</sup>, Δr<sub>2</sub> = 7.69 mM<sup>-</sup><sup>1</sup>s<sup>-</sup><sup>1</sup>), but also exhibits superior selectivity for H<sub>2</sub>O<sub>2</sub> compared to other reactive oxygen species. Importantly, H<sub>2</sub>O<sub>2</sub>-RMP exhibits high sensitivity, with a detection limit for hydrogen peroxide as low as 0.56 μM. Moreover, H<sub>2</sub>O<sub>2</sub>-RMP has been effectively applied for real-time imaging of H<sub>2</sub>O<sub>2</sub> levels in the livers of diabetic model mice with varying degrees of severity, highlighting its potential for visual diagnosis and monitoring the progression of diabetic liver injury.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"321 ","pages":"Article 123292"},"PeriodicalIF":12.8,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143738403","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 : 2025-03-25DOI: 10.1016/j.biomaterials.2025.123289
Lingbing Yang , Pu Wang , Yilin Zhang , Jin Zhou , Xuewei Bi , Zhiyong Qian , Sen Hou , Linhao Li , Yubo Fan
Tension-free synthetic meshes are the clinical standard for hernia repair, but they often trigger immune response-mediated complications such as severe foreign-body reactions (FBR), visceral adhesions, and fibrotic healing, increasing the risk of recurrence. Herein, we developed a hybrid cell membrane coating for macroscale mesh fibers that acts as an immune orchestrator, capable of balancing immune responses with tissue regeneration. Cell membranes derived from red blood cells (RBCs) and platelets (PLTs) were covalently bonded to fiber surfaces using functionalized-liposomes and click chemistry. The fusion of clickable liposomes with cell membranes significantly improved coating efficiency, coverage uniformity, and in vivo stability. Histological and flow cytometric analyses of subcutaneous implantation in rats and mice demonstrated significant biofunctional heterogeneity among various cell membrane coatings in FBR. Specifically, the RBC-PLT-liposome hybrid cell membrane coating markedly mitigated FBR, facilitated host cell infiltration, and promoted M2-type macrophage polarization. Importantly, experimental results of abdominal wall defect repairs in rats indicate that the hybrid cell membrane coating effectively prevented visceral adhesions, promoted muscle regenerative healing, and enhanced the recruitment of Pax7+/MyoD+ muscle satellite cells. Our findings suggest that the clickable hybrid cell membrane coating offers a promising approach to enhance clinical outcomes of hernia mesh in abdominal wall reconstruction.
{"title":"Hybrid cell membrane coating orchestrates foreign-body reactions, anti-adhesion, and pro-regeneration in abdominal wall reconstruction","authors":"Lingbing Yang , Pu Wang , Yilin Zhang , Jin Zhou , Xuewei Bi , Zhiyong Qian , Sen Hou , Linhao Li , Yubo Fan","doi":"10.1016/j.biomaterials.2025.123289","DOIUrl":"10.1016/j.biomaterials.2025.123289","url":null,"abstract":"<div><div>Tension-free synthetic meshes are the clinical standard for hernia repair, but they often trigger immune response-mediated complications such as severe foreign-body reactions (FBR), visceral adhesions, and fibrotic healing, increasing the risk of recurrence. Herein, we developed a hybrid cell membrane coating for macroscale mesh fibers that acts as an immune orchestrator, capable of balancing immune responses with tissue regeneration. Cell membranes derived from red blood cells (RBCs) and platelets (PLTs) were covalently bonded to fiber surfaces using functionalized-liposomes and click chemistry. The fusion of clickable liposomes with cell membranes significantly improved coating efficiency, coverage uniformity, and <em>in vivo</em> stability. Histological and flow cytometric analyses of subcutaneous implantation in rats and mice demonstrated significant biofunctional heterogeneity among various cell membrane coatings in FBR. Specifically, the RBC-PLT-liposome hybrid cell membrane coating markedly mitigated FBR, facilitated host cell infiltration, and promoted M2-type macrophage polarization. Importantly, experimental results of abdominal wall defect repairs in rats indicate that the hybrid cell membrane coating effectively prevented visceral adhesions, promoted muscle regenerative healing, and enhanced the recruitment of Pax7<sup>+</sup>/MyoD<sup>+</sup> muscle satellite cells. Our findings suggest that the clickable hybrid cell membrane coating offers a promising approach to enhance clinical outcomes of hernia mesh in abdominal wall reconstruction.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"321 ","pages":"Article 123289"},"PeriodicalIF":12.8,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143715733","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 : 2025-03-24DOI: 10.1016/j.biomaterials.2025.123287
Yinjing Shen , Nuo Yu , Wenjing Zhao , Shining Niu , Pu Qiu , Haiyan Zeng , Zhigang Chen , Wei Men , Dong Xie
Immunotherapy is a powerful weapon for inhibiting tumor metastasis, while its efficacy is significantly compromised in immunosuppressive tumor microenvironment (TME). To reverse TME, this work has developed biomimetic nanoframeworks with calcium overload and photo-sonosensitization capacity to activate multiple immunities for metastasis inhibition. The biomimetic nanoframeworks were prepared by the assembly of Ca2+ ions and Protoporphyrin IX (PpIX) into nanoframeworks (Ca-PpIX), and the encapsulation of M1 macrophage membrane (Ca-PpIX@M). They exhibit pH-dependent Ca2+ ions release, 1O2 generation and photothermal conversion under external near-infrared light and ultrasound stimuli. The Ca2+-overload and elevated 1O2 cause oxidative stress within cells, leading to efficient mitochondrial dysfunction. Successively, the mitochondrial dysfunction induces a reduction in adenosine triphosphate (ATP) levels to inhibit the HSP90 expression, improving photothermal ablation's efficacy. The photo-sonosensitization has the ability to repolarize macrophages with the ratio of M1/M2 macrophage increasing from 0.25 to 2.45, which is better than monoactivation. Importantly, the Ca-PpIX@M also can induce the process of immunogenic cell death, resulting in the maturation of dendritic cells (30.2 %) and activation of cytotoxic (12.4 %) and helper T cells (19.7 %), thereby enhancing antitumor immunity in vivo. As a result, tumor growth and metastasis have been significantly inhibited. This work offers insights into developing biomimetic nanoframeworks to reverse TME for activating multiple immunity.
{"title":"M1-macrophage membrane-camouflaged nanoframeworks activate multiple immunity via calcium overload and photo-sonosensitization","authors":"Yinjing Shen , Nuo Yu , Wenjing Zhao , Shining Niu , Pu Qiu , Haiyan Zeng , Zhigang Chen , Wei Men , Dong Xie","doi":"10.1016/j.biomaterials.2025.123287","DOIUrl":"10.1016/j.biomaterials.2025.123287","url":null,"abstract":"<div><div>Immunotherapy is a powerful weapon for inhibiting tumor metastasis, while its efficacy is significantly compromised in immunosuppressive tumor microenvironment (TME). To reverse TME, this work has developed biomimetic nanoframeworks with calcium overload and photo-sonosensitization capacity to activate multiple immunities for metastasis inhibition. The biomimetic nanoframeworks were prepared by the assembly of Ca<sup>2+</sup> ions and Protoporphyrin IX (PpIX) into nanoframeworks (Ca-PpIX), and the encapsulation of M1 macrophage membrane (Ca-PpIX@M). They exhibit pH-dependent Ca<sup>2+</sup> ions release, <sup>1</sup>O<sub>2</sub> generation and photothermal conversion under external near-infrared light and ultrasound stimuli. The Ca<sup>2+</sup>-overload and elevated <sup>1</sup>O<sub>2</sub> cause oxidative stress within cells, leading to efficient mitochondrial dysfunction. Successively, the mitochondrial dysfunction induces a reduction in adenosine triphosphate (ATP) levels to inhibit the HSP90 expression, improving photothermal ablation's efficacy. The photo-sonosensitization has the ability to repolarize macrophages with the ratio of M1/M2 macrophage increasing from 0.25 to 2.45, which is better than monoactivation. Importantly, the Ca-PpIX@M also can induce the process of immunogenic cell death, resulting in the maturation of dendritic cells (30.2 %) and activation of cytotoxic (12.4 %) and helper T cells (19.7 %), thereby enhancing antitumor immunity <em>in vivo</em>. As a result, tumor growth and metastasis have been significantly inhibited. This work offers insights into developing biomimetic nanoframeworks to reverse TME for activating multiple immunity.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"320 ","pages":"Article 123287"},"PeriodicalIF":12.8,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143715334","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 : 2025-03-24DOI: 10.1016/j.biomaterials.2025.123288
Shuncheng Yao , Xi Cui , Chao Zhang , Wenguo Cui , Zhou Li
There is a growing recognition that force-electric conversion biomaterials and devices can convert mechanical energy into electrical energy without an external power source, thus potentially revolutionizing the use of electrical stimulation in the biomedical field. Based on this, this review explores the application of force-electric biomaterials and devices in the field of regenerative medicine. The article focuses on piezoelectric biomaterials, piezoelectric devices and triboelectric devices, detailing their categorization, mechanisms of electrical generation and methods of improving electrical output performance. Subsequently, different sources of driving force for electroactive biomaterials and devices are explored. Finally, the biological applications of force-electric biomaterials and devices in regenerative medicine are presented, including tissue regeneration, functional modulation of organisms, and electrical stimulation therapy. The aim of this review is to emphasize the role of electrical stimulation generated by force-electric conversion biomaterials and devices on the regulation of bioactive molecules, ion channels and information transfer in living systems, and thus affects the metabolic processes of organisms. In the future, physiological modulation of electrical stimulation based on force-electric conversion is expected to bring important scientific advances in the field of regenerative medicine.
{"title":"Force-electric biomaterials and devices for regenerative medicine","authors":"Shuncheng Yao , Xi Cui , Chao Zhang , Wenguo Cui , Zhou Li","doi":"10.1016/j.biomaterials.2025.123288","DOIUrl":"10.1016/j.biomaterials.2025.123288","url":null,"abstract":"<div><div>There is a growing recognition that force-electric conversion biomaterials and devices can convert mechanical energy into electrical energy without an external power source, thus potentially revolutionizing the use of electrical stimulation in the biomedical field. Based on this, this review explores the application of force-electric biomaterials and devices in the field of regenerative medicine. The article focuses on piezoelectric biomaterials, piezoelectric devices and triboelectric devices, detailing their categorization, mechanisms of electrical generation and methods of improving electrical output performance. Subsequently, different sources of driving force for electroactive biomaterials and devices are explored. Finally, the biological applications of force-electric biomaterials and devices in regenerative medicine are presented, including tissue regeneration, functional modulation of organisms, and electrical stimulation therapy. The aim of this review is to emphasize the role of electrical stimulation generated by force-electric conversion biomaterials and devices on the regulation of bioactive molecules, ion channels and information transfer in living systems, and thus affects the metabolic processes of organisms. In the future, physiological modulation of electrical stimulation based on force-electric conversion is expected to bring important scientific advances in the field of regenerative medicine.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"320 ","pages":"Article 123288"},"PeriodicalIF":12.8,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143697420","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 : 2025-03-22DOI: 10.1016/j.biomaterials.2025.123270
Bruno Ladeira , Maria Gomes , Kongchang Wei , Catarina Custódio , João Mano
Recapitulating the biophysical and biochemical complexity of the extracellular matrix (ECM) remains a major challenge in tissue engineering. Hydrogels derived from decellularized ECM provide a unique opportunity to replicate the architecture and bioactivity of native ECM, however, they exhibit limited long-term stability and mechanical integrity. In turn, materials assembled through supramolecular interactions have achieved considerable success in replicating the dynamic biophysical properties of the ECM. Here, we merge both methodologies by promoting the supramolecular assembly of decellularized human amniotic membrane (hAM), mediated by host-guest interactions between hAM proteins and acryloyl-β-cyclodextrin (AcβCD). Photopolymerization of the cyclodextrins results in the formation of soft hydrogels that exhibit tunable stress relaxation and strain-stiffening. Disaggregation of bulk hydrogels yields an injectable granular material that self-reconstitutes into shape-adaptable bulk hydrogels, supporting cell delivery and promoting neovascularization. Additionally, cells encapsulated within bulk hydrogels sense and respond to the biophysical properties of the surrounding matrix, as early cell spreading is favored in hydrogels that exhibit greater susceptibility to applied stress, evidencing proper cell-matrix interplay. Thus, this system is shown to be a promising substitute for native ECM in tissue repair and modelling.
{"title":"Supramolecular assembly of multi-purpose tissue engineering platforms from human extracellular matrix","authors":"Bruno Ladeira , Maria Gomes , Kongchang Wei , Catarina Custódio , João Mano","doi":"10.1016/j.biomaterials.2025.123270","DOIUrl":"10.1016/j.biomaterials.2025.123270","url":null,"abstract":"<div><div>Recapitulating the biophysical and biochemical complexity of the extracellular matrix (ECM) remains a major challenge in tissue engineering. Hydrogels derived from decellularized ECM provide a unique opportunity to replicate the architecture and bioactivity of native ECM, however, they exhibit limited long-term stability and mechanical integrity. In turn, materials assembled through supramolecular interactions have achieved considerable success in replicating the dynamic biophysical properties of the ECM. Here, we merge both methodologies by promoting the supramolecular assembly of decellularized human amniotic membrane (hAM), mediated by host-guest interactions between hAM proteins and acryloyl-β-cyclodextrin (AcβCD). Photopolymerization of the cyclodextrins results in the formation of soft hydrogels that exhibit tunable stress relaxation and strain-stiffening. Disaggregation of bulk hydrogels yields an injectable granular material that self-reconstitutes into shape-adaptable bulk hydrogels, supporting cell delivery and promoting neovascularization. Additionally, cells encapsulated within bulk hydrogels sense and respond to the biophysical properties of the surrounding matrix, as early cell spreading is favored in hydrogels that exhibit greater susceptibility to applied stress, evidencing proper cell-matrix interplay. Thus, this system is shown to be a promising substitute for native ECM in tissue repair and modelling.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"320 ","pages":"Article 123270"},"PeriodicalIF":12.8,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143682859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-21DOI: 10.1016/j.biomaterials.2025.123285
Yang Yang , Qianrui Zeng , Chaoyue Zhao , Jie Shi , Wanmeng Wang , Yunkai Liang , Changyi Li , Qingxin Guan , Bo Chen , Wei Li
Oxidative stress at bone defect sites mediates inflammation and even osteoblast apoptosis, severely hindering the repair process. While current antioxidant bone tissue engineering (BTE) scaffolds lack broad-spectrum reactive oxygen species (ROS) scavenging capability and structure-activity elucidation. Herein, we report a three-dimensional nitrogen-doped carbon antioxidant nanozyme (ZIFC) derived from metal-organic frameworks, which exhibits cascading superoxide dismutase- and catalase-like activities, along with the ability to scavenge other harmful free radicals. Through the experimental studies and theoretical calculations, we reveal that the catalase-like activity arises from the synergistic catalytic interaction between graphitized pyridinic nitrogen and its adjacent carbon atom. Moreover, hybrid double network hydrogel integrated with ZIFC is utilized to construct composite scaffold (Gel/ZIFC) by 3D printing. In vivo transcriptome analysis confirms that Gel/ZIFC can rapidly activate antioxidant defense system and suppress local inflammation under oxidative stress microenvironment, thereby protecting cells from oxidative damage. Subsequently, owing to the unique osteoinductive property of carbon nanomaterials and the osteoconductive property of 3D-printed scaffold, Gel/ZIFC composite scaffold exhibits desirable bone repair efficacy. The elucidation of structure-activity relationship and therapeutic mechanism provides new insights and guidance for devising antioxidant BTE scaffolds, and demonstrates their feasibility for clinical application.
{"title":"Metal-free antioxidant nanozyme incorporating bioactive hydrogel as an antioxidant scaffold for accelerating bone reconstruction","authors":"Yang Yang , Qianrui Zeng , Chaoyue Zhao , Jie Shi , Wanmeng Wang , Yunkai Liang , Changyi Li , Qingxin Guan , Bo Chen , Wei Li","doi":"10.1016/j.biomaterials.2025.123285","DOIUrl":"10.1016/j.biomaterials.2025.123285","url":null,"abstract":"<div><div>Oxidative stress at bone defect sites mediates inflammation and even osteoblast apoptosis, severely hindering the repair process. While current antioxidant bone tissue engineering (BTE) scaffolds lack broad-spectrum reactive oxygen species (ROS) scavenging capability and structure-activity elucidation. Herein, we report a three-dimensional nitrogen-doped carbon antioxidant nanozyme (ZIFC) derived from metal-organic frameworks, which exhibits cascading superoxide dismutase- and catalase-like activities, along with the ability to scavenge other harmful free radicals. Through the experimental studies and theoretical calculations, we reveal that the catalase-like activity arises from the synergistic catalytic interaction between graphitized pyridinic nitrogen and its adjacent carbon atom. Moreover, hybrid double network hydrogel integrated with ZIFC is utilized to construct composite scaffold (Gel/ZIFC) by 3D printing. <em>In vivo</em> transcriptome analysis confirms that Gel/ZIFC can rapidly activate antioxidant defense system and suppress local inflammation under oxidative stress microenvironment, thereby protecting cells from oxidative damage. Subsequently, owing to the unique osteoinductive property of carbon nanomaterials and the osteoconductive property of 3D-printed scaffold, Gel/ZIFC composite scaffold exhibits desirable bone repair efficacy. The elucidation of structure-activity relationship and therapeutic mechanism provides new insights and guidance for devising antioxidant BTE scaffolds, and demonstrates their feasibility for clinical application.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"320 ","pages":"Article 123285"},"PeriodicalIF":12.8,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143682951","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 : 2025-03-21DOI: 10.1016/j.biomaterials.2025.123286
Lingyun Li , Zhongyun Lan , Huarui Qiao , Xiangjing Meng , Ziyang Shi , Wanting Zhang , Yi'ang Wang , Zengchao Sun , Qianqian Cui , Lu Wang , Siyu Zhou , Fangzheng Hu , Daizhou Zhang , Yuanyuan Dai , Hao Chen , Yong Geng
Esophageal cancer (EC) is one of the most common causes of cancer-related mortality due in part to challenges in early diagnosis. Biomarker identification is crucial for improved early screening and treatment strategies for patients. Firstly, we employed serum proteomics techniques to screen for potential biomarkers in 15 early-stage EC patients and 5 healthy individuals. Among the differentially expressed proteins, FGL1 emerged as a promising candidate (AUC = 0.974) for early detection of EC. Subsequently, we developed NanoBiT-conjugated dual nanobodies (NBNB) sensors for robust and quantitative signal detection in fetal bovine serum (FBS) in 30 min or less, with a limit of detection (LoD) of 11.38 pM. In a case–control study recruiting 96 EC patients and 99 control samples, testing serum samples with the developed NBNB sensors revealed significantly elevated serum level of FGL1 in all-stage EC patients (AUC = 0.7880) and early-stage EC patients (AUC = 0.8286). Additionally, the combined diagnostic performance of FGL1 and CEA in EC samples is notably enhanced (AUC = 0.8847). These findings propose FGL1 as a novel and promising target for the early-stage EC diagnosis and treatment selection. Furthermore, we applied the assay to patients across six types of cancer, suggesting FGL1 as a potential pan-cancer marker. This study introduces a rapid, easy-to-use, cost-effective, reliable, universal, and high-throughput alternative to meet the growing demand for cancer biomarker testing in both academic and clinical settings.
{"title":"Design of NanoBiT-Nanobody-based FGL1 biosensors for early assisted diagnosis of esophageal cancer","authors":"Lingyun Li , Zhongyun Lan , Huarui Qiao , Xiangjing Meng , Ziyang Shi , Wanting Zhang , Yi'ang Wang , Zengchao Sun , Qianqian Cui , Lu Wang , Siyu Zhou , Fangzheng Hu , Daizhou Zhang , Yuanyuan Dai , Hao Chen , Yong Geng","doi":"10.1016/j.biomaterials.2025.123286","DOIUrl":"10.1016/j.biomaterials.2025.123286","url":null,"abstract":"<div><div>Esophageal cancer (EC) is one of the most common causes of cancer-related mortality due in part to challenges in early diagnosis. Biomarker identification is crucial for improved early screening and treatment strategies for patients. Firstly, we employed serum proteomics techniques to screen for potential biomarkers in 15 early-stage EC patients and 5 healthy individuals. Among the differentially expressed proteins, FGL1 emerged as a promising candidate (AUC = 0.974) for early detection of EC. Subsequently, we developed NanoBiT-conjugated dual nanobodies (NBNB) sensors for robust and quantitative signal detection in fetal bovine serum (FBS) in 30 min or less, with a limit of detection (LoD) of 11.38 pM. In a case–control study recruiting 96 EC patients and 99 control samples, testing serum samples with the developed NBNB sensors revealed significantly elevated serum level of FGL1 in all-stage EC patients (AUC = 0.7880) and early-stage EC patients (AUC = 0.8286). Additionally, the combined diagnostic performance of FGL1 and CEA in EC samples is notably enhanced (AUC = 0.8847). These findings propose FGL1 as a novel and promising target for the early-stage EC diagnosis and treatment selection. Furthermore, we applied the assay to patients across six types of cancer, suggesting FGL1 as a potential pan-cancer marker. This study introduces a rapid, easy-to-use, cost-effective, reliable, universal, and high-throughput alternative to meet the growing demand for cancer biomarker testing in both academic and clinical settings.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"320 ","pages":"Article 123286"},"PeriodicalIF":12.8,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143697425","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 : 2025-03-21DOI: 10.1016/j.biomaterials.2025.123283
Jiajia Lu , Jiao Cai , Zhibin Zhou , Jun Ma , Tianyu Han , Nan Lu , Lei Zhu
<div><h3>Objective</h3><div>This study investigates the role of Gelatin-Catalase (Gel@CAT)-L hydrogel in mediating reactive oxygen species (ROS) production and maintaining mitochondrial homeostasis through SIRT3-mediated unfolded protein response (UPR<sup>mt</sup>), while exploring its involvement in the molecular mechanism of osteoarthritis (OA).</div></div><div><h3>Methods</h3><div>Self-assembled Gel@CAT-L hydrogels were fabricated and characterized using transmission electron microscopy, mechanical testing, external release property evaluation, and oxygen production measurement. Biocompatibility was assessed via live/dead cell staining and CCK8 assays. An OA mouse model was established using destabilization of the medial meniscus (DMM) surgery. X-ray and micro-CT imaging were employed to evaluate the structural integrity of the mouse knee joints, while histological staining was used to assess cartilage degeneration. Immunohistochemistry was performed to analyze the expression of proteins including Col2a1, Aggrecan, MMP13, ADAMTS5, SIRT3, PINK1, and Parkin. Multi-omics analyses—encompassing high-throughput sequencing, proteomics, and metabolomics—were conducted to identify key genes and metabolic pathways targeted by Gel@CAT-L hydrogel intervention in OA. Immunofluorescence techniques were utilized to measure ROS levels, mitochondrial membrane potential, and the expression of SIRT3, PINK1, Parkin, LYSO, LC3B, Col2a1, and MMP13 in primary mouse chondrocytes and mouse knee joints. Flow cytometry was applied to quantify ROS-positive cells. RT-qPCR analysis was conducted to determine mRNA levels of Aggrecan, Col2a1, ADAMTS5, MMP13, SIRT3, mtDNA, HSP60, LONP1, CLPP, and Atf5 in primary mouse chondrocytes, mouse knee joints, and human knee joints. Western blotting was performed to measure protein expression levels of SIRT3, HSP60, LONP1, CLPP, and Atf5 in both primary mouse chondrocytes and mouse knee joints. Additionally, 20 samples each from the control (CON) and OA groups were collected for analysis. Hematoxylin and eosin staining was used to evaluate cartilage degeneration in human knee joints. The Mankin histological scoring system quantified the degree of cartilage degradation, while immunofluorescence analyzed SIRT3 protein expression in human knee joints.</div></div><div><h3>Results</h3><div><em>In vitro</em> experiments demonstrated that self-assembled Gel@CAT-L hydrogels exhibited excellent biodegradability and oxygen-releasing capabilities, providing a stable three-dimensional environment conducive to cell viability and proliferation while reducing ROS levels. Multi-omics analysis identified SIRT3 as a key regulatory gene in mitigating OA and revealed its central role in the UPR<sup>mt</sup> pathway. Furthermore, Gel@CAT-L was confirmed to regulate mitochondrial homeostasis. Both <em>in vitro</em> experiments and <em>in vivo</em> mouse model studies confirmed that Gel@CAT-L significantly reduced ROS levels and regulated mitochondrial autop
本研究探讨了明胶-催化酶（Gel@CAT）-L 水凝胶在通过 SIRT3 介导的未折叠蛋白反应（UPRmt）介导活性氧（ROS）产生和维持线粒体稳态中的作用，同时探讨了其参与骨关节炎（OA）的分子机制。生物相容性通过活/死细胞染色和 CCK8 试验进行评估。通过内侧半月板失稳（DMM）手术建立了 OA 小鼠模型。X射线和显微CT成像用于评估小鼠膝关节的结构完整性，组织学染色用于评估软骨退化。免疫组化分析了Col2a1、Aggrecan、MMP13、ADAMTS5、SIRT3、PINK1和Parkin等蛋白质的表达。多组学分析包括高通量测序、蛋白质组学和代谢组学，旨在确定 Gel@CAT-L 水凝胶干预 OA 所针对的关键基因和代谢通路。利用免疫荧光技术测量小鼠原代软骨细胞和小鼠膝关节中的 ROS 水平、线粒体膜电位以及 SIRT3、PINK1、Parkin、LYSO、LC3B、Col2a1 和 MMP13 的表达。流式细胞术用于量化 ROS 阳性细胞。通过 RT-qPCR 分析，确定原代小鼠软骨细胞、小鼠膝关节和人类膝关节中 Aggrecan、Col2a1、ADAMTS5、MMP13、SIRT3、mtDNA、HSP60、LONP1、CLPP 和 Atf5 的 mRNA 水平。用 Western 印迹法测定原代小鼠软骨细胞和小鼠膝关节中 SIRT3、HSP60、LONP1、CLPP 和 Atf5 的蛋白表达水平。此外，还收集了对照组（CON）和 OA 组各 20 个样本进行分析。采用苏木精和伊红染色法评估人体膝关节软骨退化情况。结果体外实验表明，自组装的 Gel@CAT-L 水凝胶具有良好的生物降解性和释氧能力，能提供稳定的三维环境，有利于细胞存活和增殖，同时降低 ROS 水平。多组学分析发现 SIRT3 是减轻 OA 的关键调控基因，并揭示了它在 UPRmt 通路中的核心作用。此外，Gel@CAT-L 被证实能调节线粒体的平衡。体外实验和体内小鼠模型研究均证实，Gel@CAT-L 能显著降低 ROS 水平，并通过激活 SIRT3 介导的 UPRmt 通路调节线粒体自噬，从而改善 OA 的病理状态。结论 Gel@CAT-L 水凝胶可激活 SIRT3 介导的 UPRmt，从而调节 ROS 和线粒体稳态，为 OA 提供潜在的治疗益处。
{"title":"Gel@CAT-L hydrogel mediates mitochondrial unfolded protein response to regulate reactive oxygen species and mitochondrial homeostasis in osteoarthritis","authors":"Jiajia Lu , Jiao Cai , Zhibin Zhou , Jun Ma , Tianyu Han , Nan Lu , Lei Zhu","doi":"10.1016/j.biomaterials.2025.123283","DOIUrl":"10.1016/j.biomaterials.2025.123283","url":null,"abstract":"<div><h3>Objective</h3><div>This study investigates the role of Gelatin-Catalase (Gel@CAT)-L hydrogel in mediating reactive oxygen species (ROS) production and maintaining mitochondrial homeostasis through SIRT3-mediated unfolded protein response (UPR<sup>mt</sup>), while exploring its involvement in the molecular mechanism of osteoarthritis (OA).</div></div><div><h3>Methods</h3><div>Self-assembled Gel@CAT-L hydrogels were fabricated and characterized using transmission electron microscopy, mechanical testing, external release property evaluation, and oxygen production measurement. Biocompatibility was assessed via live/dead cell staining and CCK8 assays. An OA mouse model was established using destabilization of the medial meniscus (DMM) surgery. X-ray and micro-CT imaging were employed to evaluate the structural integrity of the mouse knee joints, while histological staining was used to assess cartilage degeneration. Immunohistochemistry was performed to analyze the expression of proteins including Col2a1, Aggrecan, MMP13, ADAMTS5, SIRT3, PINK1, and Parkin. Multi-omics analyses—encompassing high-throughput sequencing, proteomics, and metabolomics—were conducted to identify key genes and metabolic pathways targeted by Gel@CAT-L hydrogel intervention in OA. Immunofluorescence techniques were utilized to measure ROS levels, mitochondrial membrane potential, and the expression of SIRT3, PINK1, Parkin, LYSO, LC3B, Col2a1, and MMP13 in primary mouse chondrocytes and mouse knee joints. Flow cytometry was applied to quantify ROS-positive cells. RT-qPCR analysis was conducted to determine mRNA levels of Aggrecan, Col2a1, ADAMTS5, MMP13, SIRT3, mtDNA, HSP60, LONP1, CLPP, and Atf5 in primary mouse chondrocytes, mouse knee joints, and human knee joints. Western blotting was performed to measure protein expression levels of SIRT3, HSP60, LONP1, CLPP, and Atf5 in both primary mouse chondrocytes and mouse knee joints. Additionally, 20 samples each from the control (CON) and OA groups were collected for analysis. Hematoxylin and eosin staining was used to evaluate cartilage degeneration in human knee joints. The Mankin histological scoring system quantified the degree of cartilage degradation, while immunofluorescence analyzed SIRT3 protein expression in human knee joints.</div></div><div><h3>Results</h3><div><em>In vitro</em> experiments demonstrated that self-assembled Gel@CAT-L hydrogels exhibited excellent biodegradability and oxygen-releasing capabilities, providing a stable three-dimensional environment conducive to cell viability and proliferation while reducing ROS levels. Multi-omics analysis identified SIRT3 as a key regulatory gene in mitigating OA and revealed its central role in the UPR<sup>mt</sup> pathway. Furthermore, Gel@CAT-L was confirmed to regulate mitochondrial homeostasis. Both <em>in vitro</em> experiments and <em>in vivo</em> mouse model studies confirmed that Gel@CAT-L significantly reduced ROS levels and regulated mitochondrial autop","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"321 ","pages":"Article 123283"},"PeriodicalIF":12.8,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143823849","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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