Pub Date : 2024-10-23DOI: 10.1016/j.bioactmat.2024.10.016
Jialin Chen , Renwang Sheng , Qingyun Mo , Ludvig J. Backman , Zhiyuan Lu , Qiuzi Long , Zhixuan Chen , Zhicheng Cao , Yanan Zhang , Chuanquan Liu , Haotian Zheng , Yu Qi , Mumin Cao , Yunfeng Rui , Wei Zhang
Tendon repair remains challenging due to its poor intrinsic healing capacity, and stem cell therapy has emerged as a promising strategy to promote tendon regeneration. Nevertheless, the inflammatory environment following acute tendon injuries disrupts stem cell differentiation, leading to unsatisfied outcomes. Our study recognized the critical role of NF-κB signaling in activating inflammation and suppressing tenogenic differentiation of stem cells after acute tendon injury via multiomics analysis. TPCA-1, a selective inhibitor of IKKβ/NF-κB signaling, efficiently restored the impaired tenogenesis of stem cells in the inflammatory environment. By developing a microsphere-incorporated hydrogel system for stem cell delivery and controlled release of TPCA-1, we successfully engineered a pro-tenogenic niche to initiate tenogenesis for tendon regeneration. Collectively, we recognize NF-κB signaling as a critical target to tailor a pro-tenogenic niche and propose the combined delivery of stem cells and TPCA-1 as a potential strategy for acute tendon injuries.
{"title":"Controlled TPCA-1 delivery engineers a pro-tenogenic niche to initiate tendon regeneration by targeting IKKβ/NF-κB signaling","authors":"Jialin Chen , Renwang Sheng , Qingyun Mo , Ludvig J. Backman , Zhiyuan Lu , Qiuzi Long , Zhixuan Chen , Zhicheng Cao , Yanan Zhang , Chuanquan Liu , Haotian Zheng , Yu Qi , Mumin Cao , Yunfeng Rui , Wei Zhang","doi":"10.1016/j.bioactmat.2024.10.016","DOIUrl":"10.1016/j.bioactmat.2024.10.016","url":null,"abstract":"<div><div>Tendon repair remains challenging due to its poor intrinsic healing capacity, and stem cell therapy has emerged as a promising strategy to promote tendon regeneration. Nevertheless, the inflammatory environment following acute tendon injuries disrupts stem cell differentiation, leading to unsatisfied outcomes. Our study recognized the critical role of NF-κB signaling in activating inflammation and suppressing tenogenic differentiation of stem cells after acute tendon injury via multiomics analysis. TPCA-1, a selective inhibitor of IKKβ/NF-κB signaling, efficiently restored the impaired tenogenesis of stem cells in the inflammatory environment. By developing a microsphere-incorporated hydrogel system for stem cell delivery and controlled release of TPCA-1, we successfully engineered a pro-tenogenic niche to initiate tenogenesis for tendon regeneration. Collectively, we recognize NF-κB signaling as a critical target to tailor a pro-tenogenic niche and propose the combined delivery of stem cells and TPCA-1 as a potential strategy for acute tendon injuries.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"44 ","pages":"Pages 319-338"},"PeriodicalIF":18.0,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142532334","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 : 2024-10-22DOI: 10.1016/j.bioactmat.2024.10.015
Zilin Tan , Liangjie Tian , Yang Luo , Kexin Ai , Xuehua Zhang , Haitao Yuan , Jinfan Zhou , Guangyao Ye , Shuofei Yang , Ming Zhong , Gaohua Li , Yanan Wang
Colorectal cancer (CRC) recurrence post-surgery remains a major challenge. While Chimeric Antigen Receptor (CAR)-engineered natural killer (NK) cells hold immense therapeutic potential, their intratumoral infiltration ability remains limited, hampering efficacy. Building upon prior research suggesting that chemokines like C-X-C motif chemokine ligand 9 (CXCL9) and C-X-C motif chemokine ligand 10 (CXCL10) recruit CAR-NK cells, we hypothesized that tumor cell m6A methylation, regulated by Methyltransferase-like 3 (METTL3), influences chemokine secretion. This study aims to elucidate the underlying mechanisms and improve METTL3 inhibition efficiency. We designed an adhesive hemostasis hydrogel loaded with STM2457, a METTL3 inhibitor, aimed at sustained release in the acidic tumor microenvironment. In vitro, the hydrogel promoted CAR-NK cell recruitment and tumor killing via sustained METTL3 inhibition. The hydrogel's Schiff base bonds further enabled intestinal adhesion and hemostasis in an incomplete tumor resection model of CRC. Combining the hydrogel with CAR-NK cell therapy significantly reduced CRC recurrence in vivo. Overall, our study reveals the crucial role of METTL3 in CRC recurrence and proposes a promising, multimodal strategy using STM2457-loaded hydrogel and CAR-NK cells for enhanced therapeutic efficacy.
{"title":"Preventing postsurgical colorectal cancer relapse: A hemostatic hydrogel loaded with METTL3 inhibitor for CAR-NK cell therapy","authors":"Zilin Tan , Liangjie Tian , Yang Luo , Kexin Ai , Xuehua Zhang , Haitao Yuan , Jinfan Zhou , Guangyao Ye , Shuofei Yang , Ming Zhong , Gaohua Li , Yanan Wang","doi":"10.1016/j.bioactmat.2024.10.015","DOIUrl":"10.1016/j.bioactmat.2024.10.015","url":null,"abstract":"<div><div>Colorectal cancer (CRC) recurrence post-surgery remains a major challenge. While Chimeric Antigen Receptor (CAR)-engineered natural killer (NK) cells hold immense therapeutic potential, their intratumoral infiltration ability remains limited, hampering efficacy. Building upon prior research suggesting that chemokines like C-X-C motif chemokine ligand 9 (CXCL9) and C-X-C motif chemokine ligand 10 (CXCL10) recruit CAR-NK cells, we hypothesized that tumor cell m6A methylation, regulated by Methyltransferase-like 3 (METTL3), influences chemokine secretion. This study aims to elucidate the underlying mechanisms and improve METTL3 inhibition efficiency. We designed an adhesive hemostasis hydrogel loaded with STM2457, a METTL3 inhibitor, aimed at sustained release in the acidic tumor microenvironment. In vitro, the hydrogel promoted CAR-NK cell recruitment and tumor killing via sustained METTL3 inhibition. The hydrogel's Schiff base bonds further enabled intestinal adhesion and hemostasis in an incomplete tumor resection model of CRC. Combining the hydrogel with CAR-NK cell therapy significantly reduced CRC recurrence in vivo. Overall, our study reveals the crucial role of METTL3 in CRC recurrence and proposes a promising, multimodal strategy using STM2457-loaded hydrogel and CAR-NK cells for enhanced therapeutic efficacy.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"44 ","pages":"Pages 236-255"},"PeriodicalIF":18.0,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142532281","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 : 2024-10-21DOI: 10.1016/j.bioactmat.2024.09.015
A.M. Rich , W. Rubin , S. Rickli , T. Akhmetshina , J. Cossu , L. Berger , M. Magno , K.M. Nuss , B. Schaller , J.F. Löffler
Biodegradable magnesium is a highly desired material for fracture fixation implants because of its good mechanical properties and ability to completely dissolve in the body over time, eliminating the need for a secondary surgery to remove the implant. Despite extensive research on these materials, there remains a dearth of information regarding critical factors that affect implant performance in clinical applications, such as the in vivo pH and mechanical loading conditions. We developed a measurement system with implantable strain, temperature, pH and motion sensors to characterize magnesium and titanium plates, fixating bilateral zygomatic arch osteotomies in three Swiss alpine sheep for eight weeks. pH 1–2 mm above titanium plates was 6.6 ± 0.4, while for magnesium plates it was slightly elevated to 7.4 ± 0.8. Strains on magnesium plates were higher than on titanium plates, possibly due to the lower Young's modulus of magnesium. One magnesium plate experienced excessive loading, which led to plate failure within 31 h. This is, to our knowledge, the first in vivo strain, temperature, and pH data recorded for magnesium implants used for fracture fixation. These results provide insight into magnesium degradation and its influence on the in vivo environment, and may help to improve material and implant design for future clinical applications.
{"title":"Development of an implantable sensor system for in vivo strain, temperature, and pH monitoring: comparative evaluation of titanium and resorbable magnesium plates","authors":"A.M. Rich , W. Rubin , S. Rickli , T. Akhmetshina , J. Cossu , L. Berger , M. Magno , K.M. Nuss , B. Schaller , J.F. Löffler","doi":"10.1016/j.bioactmat.2024.09.015","DOIUrl":"10.1016/j.bioactmat.2024.09.015","url":null,"abstract":"<div><div>Biodegradable magnesium is a highly desired material for fracture fixation implants because of its good mechanical properties and ability to completely dissolve in the body over time, eliminating the need for a secondary surgery to remove the implant. Despite extensive research on these materials, there remains a dearth of information regarding critical factors that affect implant performance in clinical applications, such as the <em>in vivo</em> pH and mechanical loading conditions. We developed a measurement system with implantable strain, temperature, pH and motion sensors to characterize magnesium and titanium plates, fixating bilateral zygomatic arch osteotomies in three Swiss alpine sheep for eight weeks. pH 1–2 mm above titanium plates was 6.6 ± 0.4, while for magnesium plates it was slightly elevated to 7.4 ± 0.8. Strains on magnesium plates were higher than on titanium plates, possibly due to the lower Young's modulus of magnesium. One magnesium plate experienced excessive loading, which led to plate failure within 31 h. This is, to our knowledge, the first <em>in vivo</em> strain, temperature, and pH data recorded for magnesium implants used for fracture fixation. These results provide insight into magnesium degradation and its influence on the <em>in vivo</em> environment, and may help to improve material and implant design for future clinical applications.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"43 ","pages":"Pages 603-618"},"PeriodicalIF":18.0,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142535291","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 : 2024-10-19DOI: 10.1016/j.bioactmat.2024.10.011
Rui Sun , Man Wang , Tianjiao Zeng , Huajian Chen , Toru Yoshitomi , Masaki Takeguchi , Naoki Kawazoe , Yingnan Yang , Guoping Chen
Combining hyperthermia and chemotherapy for maximum anticancer efficacy remains a challenge because drug-tolerant cancer cells often evade this synergistic treatment due to drug resistance and asynchronous drug release. In this study, multifunctional scaffolds were designed to efficiently treat drug-tolerant breast cancer by improving the sensitization of breast cancer cells and synchronizing anticancer drug release with magnetic hyperthermia. The scaffolds contained microRNA-encapsulated matrix metalloproteinase-cleavable liposomes, doxorubicin-encapsulated thermoresponsive liposomes and Fe3O4 nanoparticles. The scaffolds could release microRNA specifically to improve the sensitization of breast cancer cells to anticancer drugs. The scaffolds also showed excellent hyperthermia effects under alternating magnetic field irradiation. Moreover, doxorubicin release was synchronized with magnetic hyperthermia. In vitro and in vivo studies demonstrated that the scaffolds effectively reduced drug resistance and eliminated doxorubicin-tolerant MDA-MB-231 cells through the synergistic effect of magnetic hyperthermia and sensitizing chemotherapy. Additionally, the scaffolds could support the proliferation and adipogenic differentiation of stem cells for adipose tissue regeneration after killing cancer cells at a late therapeutic stage. These composite scaffolds offer an innovative strategy for treating breast cancer, with synergistic anticancer effects and regenerative functions.
{"title":"Scaffolds functionalized with matrix metalloproteinase-responsive release of miRNA for synergistic magnetic hyperthermia and sensitizing chemotherapy of drug-tolerant breast cancer","authors":"Rui Sun , Man Wang , Tianjiao Zeng , Huajian Chen , Toru Yoshitomi , Masaki Takeguchi , Naoki Kawazoe , Yingnan Yang , Guoping Chen","doi":"10.1016/j.bioactmat.2024.10.011","DOIUrl":"10.1016/j.bioactmat.2024.10.011","url":null,"abstract":"<div><div>Combining hyperthermia and chemotherapy for maximum anticancer efficacy remains a challenge because drug-tolerant cancer cells often evade this synergistic treatment due to drug resistance and asynchronous drug release. In this study, multifunctional scaffolds were designed to efficiently treat drug-tolerant breast cancer by improving the sensitization of breast cancer cells and synchronizing anticancer drug release with magnetic hyperthermia. The scaffolds contained microRNA-encapsulated matrix metalloproteinase-cleavable liposomes, doxorubicin-encapsulated thermoresponsive liposomes and Fe<sub>3</sub>O<sub>4</sub> nanoparticles. The scaffolds could release microRNA specifically to improve the sensitization of breast cancer cells to anticancer drugs. The scaffolds also showed excellent hyperthermia effects under alternating magnetic field irradiation. Moreover, doxorubicin release was synchronized with magnetic hyperthermia. <em>In vitro</em> and <em>in vivo</em> studies demonstrated that the scaffolds effectively reduced drug resistance and eliminated doxorubicin-tolerant MDA-MB-231 cells through the synergistic effect of magnetic hyperthermia and sensitizing chemotherapy. Additionally, the scaffolds could support the proliferation and adipogenic differentiation of stem cells for adipose tissue regeneration after killing cancer cells at a late therapeutic stage. These composite scaffolds offer an innovative strategy for treating breast cancer, with synergistic anticancer effects and regenerative functions.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"44 ","pages":"Pages 205-219"},"PeriodicalIF":18.0,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142532279","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 : 2024-10-19DOI: 10.1016/j.bioactmat.2024.10.013
Junlin Chen , Qingtao Li , Haofei Li , Chuhan Lv , Hongbo Yu , Qi Feng , Hua Dong
Articular cartilage repair and regeneration is still a significant challenge despite years of research. Although microfracture techniques are commonly used in clinical practice, the newborn cartilage is usually fibrocartilage rather than hyaline cartilage, which is mainly attributed to the inadequate microenvironment for effectively recruiting, anchoring, and inducing bone marrow mesenchymal stem cells (BMSCs) to differentiate into hyaline cartilage. This paper introduces a novel cartilage acellular matrix (CACM) microgel assembly with excellent microporosity, injectability, tissue adhesion, BMSCs recruitment and chondrogenic differentiation capabilities to improve the microfracture-based articular cartilage regeneration. Specifically, the sustained release of simvastatin (SIM) from the SIM@CACM microgel assembly efficiently recruits BMSCs in the early stage of cartilage regeneration, while the abundant interconnected micropores and high specific area assure the quick adhesion, proliferation and infiltration of BMSCs. Additionally, the active factors within the CACM matrix, appropriate mechanical properties of the microgel assembly, and excellent tissue adhesion provide a conductive environment for the continuous chondrogenic differentiation of BMSCs into hyaline cartilage. Owing to the synergistic effect of the above-mentioned factors, good articular cartilage repair and regeneration is achieved.
{"title":"Injectable acellular matrix microgel assembly with stem cell recruitment and chondrogenic differentiation functions promotes microfracture-based articular cartilage regeneration","authors":"Junlin Chen , Qingtao Li , Haofei Li , Chuhan Lv , Hongbo Yu , Qi Feng , Hua Dong","doi":"10.1016/j.bioactmat.2024.10.013","DOIUrl":"10.1016/j.bioactmat.2024.10.013","url":null,"abstract":"<div><div>Articular cartilage repair and regeneration is still a significant challenge despite years of research. Although microfracture techniques are commonly used in clinical practice, the newborn cartilage is usually fibrocartilage rather than hyaline cartilage, which is mainly attributed to the inadequate microenvironment for effectively recruiting, anchoring, and inducing bone marrow mesenchymal stem cells (BMSCs) to differentiate into hyaline cartilage. This paper introduces a novel cartilage acellular matrix (CACM) microgel assembly with excellent microporosity, injectability, tissue adhesion, BMSCs recruitment and chondrogenic differentiation capabilities to improve the microfracture-based articular cartilage regeneration. Specifically, the sustained release of simvastatin (SIM) from the SIM@CACM microgel assembly efficiently recruits BMSCs in the early stage of cartilage regeneration, while the abundant interconnected micropores and high specific area assure the quick adhesion, proliferation and infiltration of BMSCs. Additionally, the active factors within the CACM matrix, appropriate mechanical properties of the microgel assembly, and excellent tissue adhesion provide a conductive environment for the continuous chondrogenic differentiation of BMSCs into hyaline cartilage. Owing to the synergistic effect of the above-mentioned factors, good articular cartilage repair and regeneration is achieved.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"44 ","pages":"Pages 220-235"},"PeriodicalIF":18.0,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142532280","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 : 2024-10-18DOI: 10.1016/j.bioactmat.2024.10.010
Intan Rosalina Suhito , Christina Sunil , Andy Tay
Animal models have been extensively used as a gold standard in various biological research, including immunological studies. Despite high availability and ease of handling procedure, they inadequately represent complex interactions and unique cellular properties in humans due to inter-species genetic and microenvironmental differences which have resulted in clinical-stage failures. Organoid technology has gained enormous attention as they provide sophisticated insights about tissue architecture and functionality in miniaturized organs. In this review, we describe the use of organoid system to overcome limitations in animal-based investigations, such as physiological mismatch with humans, costly, time-consuming, and low throughput screening. Immune organoids are one of the specific advancements in organogenesis ex vivo, which can reflect human adaptive immunity with more physiologically relevant aspects. We discuss how immune organoids are established from patient-derived lymphoid tissues, as well as their characteristics and functional features to understand immune mechanisms and responses. Also, some bioengineering perspectives are considered for any potential progress of immuno-engineered organoids.
{"title":"Engineering human immune organoids for translational immunology","authors":"Intan Rosalina Suhito , Christina Sunil , Andy Tay","doi":"10.1016/j.bioactmat.2024.10.010","DOIUrl":"10.1016/j.bioactmat.2024.10.010","url":null,"abstract":"<div><div>Animal models have been extensively used as a gold standard in various biological research, including immunological studies. Despite high availability and ease of handling procedure, they inadequately represent complex interactions and unique cellular properties in humans due to inter-species genetic and microenvironmental differences which have resulted in clinical-stage failures. Organoid technology has gained enormous attention as they provide sophisticated insights about tissue architecture and functionality in miniaturized organs. In this review, we describe the use of organoid system to overcome limitations in animal-based investigations, such as physiological mismatch with humans, costly, time-consuming, and low throughput screening. Immune organoids are one of the specific advancements in organogenesis <em>ex vivo</em>, which can reflect human adaptive immunity with more physiologically relevant aspects. We discuss how immune organoids are established from patient-derived lymphoid tissues, as well as their characteristics and functional features to understand immune mechanisms and responses. Also, some bioengineering perspectives are considered for any potential progress of immuno-engineered organoids.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"44 ","pages":"Pages 164-183"},"PeriodicalIF":18.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142446327","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 : 2024-10-18DOI: 10.1016/j.bioactmat.2024.10.009
Mengke Fan , Youliang Ren , Yanbin Zhu , Hao Zhang , Shuaijie Li , Chunyu Liu , Hongzhi Lv , Lei Chu , Zhiyong Hou , Yingze Zhang , Haobo Pan , Xu Cui , Wei Chen
Bone infection is a catastrophe in clinical orthopedics. Despite being the standard therapy for osteomyelitis, antibiotic-loaded polymethyl methacrylate (PMMA) cement has low efficiency against bacteria in biofilms. Furthermore, high-dose antibiotic-loaded implants carry risks of bacterial resistance, tissue toxicity, and impairment of local tissue healing. By incorporating borosilicate bioactive glass (BSG) into low-dose gentamicin sulfate (GS)-loaded PMMA cement, an intelligent strategy that synergistically eradicates bacteria and sequentially promotes osseointegration, was devised. Results showed that BSG did not compromises the handling properties of the cement, but actually endowed it with an ionic and alkaline microenvironment, thereby damaging the integrity of bacterial cell walls and membranes, inhibiting ATP synthesis by disrupting the respiratory chain in cell membranes and glycogen metabolism, and elevating reactive oxygen species (ROS) levels by weakening antioxidant components (peroxisomes and carotenoids). These antibacterial characteristics of BSG synergistically reinforced the effectiveness of GS, which was far below the actual clinical dosage, achieving efficient bacterial killing and biofilm clearance by binding to the 30S subunit of ribosomes. Furthermore, the released GS and the ionic and alkaline microenvironment from the implants fostered the osteogenic activity of hBMSCs in vitro and coordinately enhanced osseointegration in vivo. Collectively, this study underscores that BSG incorporation offers a promising strategy for reducing antibiotic dosage while simultaneously enhancing the antibacterial activity and osteogenesis of implants. This approach holds potential for resolving the conflict between bacterial resistance and bone infection.
{"title":"Borosilicate bioactive glass synergizing low-dose antibiotic loaded implants to combat bacteria through ATP disruption and oxidative stress to sequentially achieve osseointegration","authors":"Mengke Fan , Youliang Ren , Yanbin Zhu , Hao Zhang , Shuaijie Li , Chunyu Liu , Hongzhi Lv , Lei Chu , Zhiyong Hou , Yingze Zhang , Haobo Pan , Xu Cui , Wei Chen","doi":"10.1016/j.bioactmat.2024.10.009","DOIUrl":"10.1016/j.bioactmat.2024.10.009","url":null,"abstract":"<div><div>Bone infection is a catastrophe in clinical orthopedics. Despite being the standard therapy for osteomyelitis, antibiotic-loaded polymethyl methacrylate (PMMA) cement has low efficiency against bacteria in biofilms. Furthermore, high-dose antibiotic-loaded implants carry risks of bacterial resistance, tissue toxicity, and impairment of local tissue healing. By incorporating borosilicate bioactive glass (BSG) into low-dose gentamicin sulfate (GS)-loaded PMMA cement, an intelligent strategy that synergistically eradicates bacteria and sequentially promotes osseointegration, was devised. Results showed that BSG did not compromises the handling properties of the cement, but actually endowed it with an ionic and alkaline microenvironment, thereby damaging the integrity of bacterial cell walls and membranes, inhibiting ATP synthesis by disrupting the respiratory chain in cell membranes and glycogen metabolism, and elevating reactive oxygen species (ROS) levels by weakening antioxidant components (peroxisomes and carotenoids). These antibacterial characteristics of BSG synergistically reinforced the effectiveness of GS, which was far below the actual clinical dosage, achieving efficient bacterial killing and biofilm clearance by binding to the 30S subunit of ribosomes. Furthermore, the released GS and the ionic and alkaline microenvironment from the implants fostered the osteogenic activity of hBMSCs <em>in vitro</em> and coordinately enhanced osseointegration <em>in vivo</em>. Collectively, this study underscores that BSG incorporation offers a promising strategy for reducing antibiotic dosage while simultaneously enhancing the antibacterial activity and osteogenesis of implants. This approach holds potential for resolving the conflict between bacterial resistance and bone infection.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"44 ","pages":"Pages 184-204"},"PeriodicalIF":18.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142533126","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 : 2024-10-17DOI: 10.1016/j.bioactmat.2024.10.007
Alexandra N. Borelli , Courtney L. Schultze , Mark W. Young , Bruce E. Kirkpatrick , Kristi S. Anseth
Cell interactions with the extracellular matrix (ECM) influence intracellular signaling pathways related to proliferation, differentiation, and secretion, amongst other functions. Herein, bone-marrow derived mesenchymal stromal cells (MSCs) are encapsulated in a hydrazone crosslinked hyaluronic acid (HA) hydrogel, and the extent of stress relaxation is controlled by systemic introduction of irreversible triazole crosslinks. MSCs form elongated multicellular structures within hydrogels containing RGD peptide and formulated with elastic composition slightly higher than the hydrogel percolation threshold (12 % triazole, 88 % hydrazone). A scaling analysis is presented ( ∼Nα) to quantify cell-material interactions within these structures with the scaling exponent (α) describing either elongated (0.66) or globular (0.33) structures. Cellular interactions with the material were controlled through peptides to present integrin binding ECM cues (RGD) or cadherin binding cell-cell cues (HAVDI) and MSCs were observed to form highly elongated structures in RGD containing hydrogels (), whereases collapsed structures were observed within HAVDI containing hydrogels (). Finally, cytokine secretion was investigated, and a global increase in secreted cytokines was observed for collapsed structures compared to elongated. Taken together, this study presents a novel method to characterize cellular interactions within a stress relaxing hydrogel where altered cluster morphology imparts changes to cluster secretory profiles.
{"title":"Ligand presentation controls collective MSC response to matrix stress relaxation in hybrid PEG-HA hydrogels","authors":"Alexandra N. Borelli , Courtney L. Schultze , Mark W. Young , Bruce E. Kirkpatrick , Kristi S. Anseth","doi":"10.1016/j.bioactmat.2024.10.007","DOIUrl":"10.1016/j.bioactmat.2024.10.007","url":null,"abstract":"<div><div>Cell interactions with the extracellular matrix (ECM) influence intracellular signaling pathways related to proliferation, differentiation, and secretion, amongst other functions. Herein, bone-marrow derived mesenchymal stromal cells (MSCs) are encapsulated in a hydrazone crosslinked hyaluronic acid (HA) hydrogel, and the extent of stress relaxation is controlled by systemic introduction of irreversible triazole crosslinks. MSCs form elongated multicellular structures within hydrogels containing RGD peptide and formulated with elastic composition slightly higher than the hydrogel percolation threshold (12 % triazole, 88 % hydrazone). A scaling analysis is presented (<span><math><mrow><msup><mrow><mo><</mo><msup><msub><mi>R</mi><mrow><mi>g</mi><mspace></mspace><mtext>Structure</mtext></mrow></msub><mn>2</mn></msup><mo>></mo></mrow><mfrac><mn>1</mn><mn>2</mn></mfrac></msup></mrow></math></span> ∼N<sup>α</sup>) to quantify cell-material interactions within these structures with the scaling exponent (α) describing either elongated (0.66) or globular (0.33) structures. Cellular interactions with the material were controlled through peptides to present integrin binding ECM cues (RGD) or cadherin binding cell-cell cues (HAVDI) and MSCs were observed to form highly elongated structures in RGD containing hydrogels (<span><math><mrow><mi>α</mi><mo>=</mo><mn>0.56</mn><mo>±</mo><mn>0.05</mn></mrow></math></span>), whereases collapsed structures were observed within HAVDI containing hydrogels (<span><math><mrow><mi>α</mi><mo>=</mo><mn>0.39</mn><mspace></mspace><mo>±</mo><mspace></mspace><mn>0.04</mn></mrow></math></span>). Finally, cytokine secretion was investigated, and a global increase in secreted cytokines was observed for collapsed structures compared to elongated. Taken together, this study presents a novel method to characterize cellular interactions within a stress relaxing hydrogel where altered cluster morphology imparts changes to cluster secretory profiles.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"44 ","pages":"Pages 152-163"},"PeriodicalIF":18.0,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142446326","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}
The healing of diabetic skin wounds is a complex process significantly affected by the hyperglycemic environment. In this context, glucose oxidase (GOx), by catalyzing glucose to produce gluconic acid and hydrogen peroxide, not only modulates the hyperglycemic microenvironment but also possesses antibacterial and oxygen-supplying functions, thereby demonstrating immense potential in the treatment of diabetic wounds. Despite the growing interest in GOx-based therapeutic strategies in recent years, a systematic summary and review of these efforts have been lacking. To address this gap, this review article outlines the advancements in the application of GOx and GOx-like nanozymes in the treatment of diabetic wounds, including reaction mechanisms, the selection of carrier materials, and synergistic therapeutic strategies such as multi-enzyme combinations, microneedle structures, and gas therapy. Finally, the article looks forward to the application prospects of GOx in aiding the healing of diabetic wounds and the challenges faced in translating these innovations to clinical practice. We sincerely hope that this review can provide readers with a comprehensive understanding of GOx-based diabetic treatment strategies, facilitate the rigorous construction of more robust multifunctional therapeutic systems, and ultimately benefit patients with diabetic wounds.
{"title":"Glucose oxidase: An emerging multidimensional treatment option for diabetic wound healing","authors":"Yuheng Liao , Zhenhe Zhang , Yanzhi Zhao , Shengming Zhang , Kangkang Zha, Lizhi Ouyang, Weixian Hu, Wu Zhou, Yun Sun, Guohui Liu","doi":"10.1016/j.bioactmat.2024.10.006","DOIUrl":"10.1016/j.bioactmat.2024.10.006","url":null,"abstract":"<div><div>The healing of diabetic skin wounds is a complex process significantly affected by the hyperglycemic environment. In this context, glucose oxidase (GOx), by catalyzing glucose to produce gluconic acid and hydrogen peroxide, not only modulates the hyperglycemic microenvironment but also possesses antibacterial and oxygen-supplying functions, thereby demonstrating immense potential in the treatment of diabetic wounds. Despite the growing interest in GOx-based therapeutic strategies in recent years, a systematic summary and review of these efforts have been lacking. To address this gap, this review article outlines the advancements in the application of GOx and GOx-like nanozymes in the treatment of diabetic wounds, including reaction mechanisms, the selection of carrier materials, and synergistic therapeutic strategies such as multi-enzyme combinations, microneedle structures, and gas therapy. Finally, the article looks forward to the application prospects of GOx in aiding the healing of diabetic wounds and the challenges faced in translating these innovations to clinical practice. We sincerely hope that this review can provide readers with a comprehensive understanding of GOx-based diabetic treatment strategies, facilitate the rigorous construction of more robust multifunctional therapeutic systems, and ultimately benefit patients with diabetic wounds.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"44 ","pages":"Pages 131-151"},"PeriodicalIF":18.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142438162","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}
Bacterial wound infections are a growing challenge in healthcare, posing severe risks like systemic infection, organ failure, and sepsis, with projections predicting over 10 million deaths annually by 2050. Antibacterial hydrogels, with adaptable extracellular matrix-like features, are emerging as promising solutions for treating infectious wounds. However, the antibacterial properties of most of these hydrogels are largely attributed to extrinsic agents, and their mechanisms of action remain poorly understood. Herein we introduce for the first time, modified imidazolidinyl urea (IU) as the polymeric backbone for developing tissue-like antibacterial hydrogels. As-designed hydrogels behave tissue-like mechanical features, outstanding antifreeze behavior, and rapid self-healing capabilities. Molecular dynamics (MD) simulation and density functional theory (DFT) calculation were employed to well-understand the extent of H-bonding and metal-ligand coordination to finetune hydrogels’ properties. In vitro studies suggest good biocompatibility of hydrogels against mouse fibroblasts & human skin, lung, and red blood cells, with potential wound healing capacity. Additionally, the hydrogels exhibit good 3D printability and remarkable antibacterial activity, attributed to concentration dependent ROS generation, oxidative stress induction, and subsequent disruption of bacterial membrane. On top of that, in vitro biofilm studies confirmed that developed hydrogels are effective in preventing biofilm formation. Therefore, these tissue-mimetic hydrogels present a promising and effective platform for accelerating wound healing while simultaneously controlling bacterial infections, offering hope for the future of wound care.
细菌伤口感染是医疗保健领域面临的一个日益严峻的挑战，它带来了全身感染、器官衰竭和败血症等严重风险，预计到 2050 年，每年死亡人数将超过 1000 万。抗菌水凝胶具有类似细胞外基质的适应性，正在成为治疗感染性伤口的理想解决方案。然而，大多数此类水凝胶的抗菌特性主要归因于外在因子，其作用机制仍然鲜为人知。在此，我们首次引入改性咪唑烷基脲（IU）作为聚合物骨架，用于开发类组织抗菌水凝胶。所设计的水凝胶具有类似组织的机械特性、出色的抗冻性和快速自愈合能力。研究人员利用分子动力学（MD）模拟和密度泛函理论（DFT）计算，深入了解了 H 键和金属配体的配位程度，从而对水凝胶的性能进行了微调。体外研究表明，水凝胶对小鼠成纤维细胞、人类皮肤、肺部和红细胞具有良好的生物相容性，并具有潜在的伤口愈合能力。此外，水凝胶还具有良好的三维打印性和显著的抗菌活性，这归功于浓度依赖性 ROS 生成、氧化应激诱导以及随后的细菌膜破坏。此外，体外生物膜研究证实，开发的水凝胶能有效防止生物膜的形成。因此，这些仿组织水凝胶为加速伤口愈合同时控制细菌感染提供了一个前景广阔的有效平台，为未来的伤口护理带来了希望。
{"title":"On-demand imidazolidinyl urea-based tissue-like, self-healable, and antibacterial hydrogels for infectious wound care","authors":"Qi Wu , Krishanu Ghosal , Nadine Kana'an , Shounak Roy , Nagham Rashed , Ranabir Majumder , Mahitosh Mandal , Liang Gao , Shady Farah","doi":"10.1016/j.bioactmat.2024.10.003","DOIUrl":"10.1016/j.bioactmat.2024.10.003","url":null,"abstract":"<div><div>Bacterial wound infections are a growing challenge in healthcare, posing severe risks like systemic infection, organ failure, and sepsis, with projections predicting over 10 million deaths annually by 2050. Antibacterial hydrogels, with adaptable extracellular matrix-like features, are emerging as promising solutions for treating infectious wounds. However, the antibacterial properties of most of these hydrogels are largely attributed to extrinsic agents, and their mechanisms of action remain poorly understood. Herein we introduce for the first time, modified imidazolidinyl urea (IU) as the polymeric backbone for developing tissue-like antibacterial hydrogels. As-designed hydrogels behave tissue-like mechanical features, outstanding antifreeze behavior, and rapid self-healing capabilities. Molecular dynamics (MD) simulation and density functional theory (DFT) calculation were employed to well-understand the extent of H-bonding and metal-ligand coordination to finetune hydrogels’ properties. <em>In vitro</em> studies suggest good biocompatibility of hydrogels against mouse fibroblasts & human skin, lung, and red blood cells, with potential wound healing capacity. Additionally, the hydrogels exhibit good 3D printability and remarkable antibacterial activity, attributed to concentration dependent ROS generation, oxidative stress induction, and subsequent disruption of bacterial membrane. On top of that, <em>in vitro</em> biofilm studies confirmed that developed hydrogels are effective in preventing biofilm formation. Therefore, these tissue-mimetic hydrogels present a promising and effective platform for accelerating wound healing while simultaneously controlling bacterial infections, offering hope for the future of wound care.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"44 ","pages":"Pages 116-130"},"PeriodicalIF":18.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142438163","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}
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