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Abstract
The alterations in glucose metabolism flux induced by mitochondrial function changes are crucial for regulating bone immune homeostasis. The restoration of mitochondrial homeostasis, serving as a pivotal rheostat for balancing glucose metabolism in immune cells, can effectively mitigate inflammation and initiate osteogenesis. Herein, an ion-activated mitochondrial rheostat fiber-microsphere polymerization system (FM@CeZnHA) was innovatively constructed. Physical-chemical and molecular biological methods confirmed that CeZnHA, characterized by a rapid degradation rate, releases Ce/Zn ions that restore mitochondrial metabolic homeostasis and M1/M2 balance of macrophages through swift redox reactions. This process reduces the glycolysis level of macrophages by down-regulating the NF-κB p65 signaling pathway, enhances their mitochondrial metabolic dependence, alleviates excessive early inflammatory responses, and promptly initiates osteogenesis. The FM network provided a stable platform for macrophage glycolytic transformation and simulated extracellular matrix microenvironment, continuously restoring mitochondrial homeostasis and accelerating ossification center formation through the release of metal ions from the internal CeZnHA for efficient bone immune cascade reactions. This strategy of bone immunity mediated by the restoration of macrophage mitochondrial metabolic function and glucose metabolic flux homeostasis opens up a new approach to treating bone defects.
| Original language | English |
|---|---|
| Pages (from-to) | 399-417 |
| Number of pages | 19 |
| Journal | Bioactive materials |
| Volume | 49 |
| Early online date | 15 Mar 2025 |
| DOIs | |
| Publication status | Published - Jun 2025 |
| MoE publication type | A1 Journal article-refereed |
Funding
In this study, inspired by macrophage metabolic reprogramming characteristics and mitochondrial regulation strategies, mitochondrial rheostats fiber microsphere scaffolds that can restore macrophage mitochondrial function and glucose metabolism fluxes were innovatively constructed by guiding the polymerization of short fibers and hydrogel microspheres (Scheme 1). CeZnHA dynamically removed ROS from macrophage mitochondria through a REDOX process, thereby restoring functional homeostasis. The fiber network (FM) mimicked the extracellular matrix microenvironment of cancellous bone, providing cell growth space and mechanical support for the injury site. FM also provided a stable platform for regulating macrophage function, and the hydrogel microspheres inside it continuously release metal ions to restore the mitochondrial metabolism and M1/M2 balance of macrophages under oxidative stress, accelerating the formation of ossification centers and realizing highly efficient osteoimmunological cascade reactions. Firstly, the physicochemical properties of the mitochondrial varactors were investigated, and secondly, their ability to target macrophage mitochondria and scavenge ROS was verified, and the mechanism of regulating macrophage mitochondrial metabolism was explored. Next, the immune-osteogenic effects following the regulation of macrophage mitochondrial metabolism were evaluated. Finally, a rat femoral condylar defect model was constructed and implanted with mitochondrial rheostat scaffolds. Both the early immune response and the later osteogenic ability at the defect site were investigated. Mitochondrial rheostats, constructed from short fibers and microspheres, which restore mitochondrial function and regulate macrophage glucose metabolism, offer new strategies for repairing various tissue injuries.Pengzhen Zhuang and Yu Chen contributed equally to this work. This work was supported by the Program of Shanghai Academic/Technology Research Leader (22XD1422600), the Research Fellow (Grant No.353146), Research Project (347897), Solution for Health Profile (336355), InFLAMES Flagship (337531) grants and Printed Intelligence Infrastructure\" (PII-FIRI) from Research Council of Finland. This study is part of the activities of the \u00C5bo Akademi University Foundation (S\u00C5A) funded Center of Excellence in Research \u201CMaterials-driven solutions for combating antimicrobial resistance (MADNESS)\u201D at \u00C5AU. Pengzhen Zhuang and Yu Chen contributed equally to this work. This work was supported by the Program of Shanghai Academic/Technology Research Leader (22XD1422600), the Research Fellow (Grant No.353146), Project (347897), Solution for Health Profile (336355), InFLAMES Flagship (337531) grants from Academy of Finland; Finland China Food and Health International Pilot Project funded by the Finnish Ministry of Education and Culture.
Keywords
- Glucose metabolism
- Mitochondrial metabolic homeostasis
- Mitochondrial rheostat
- Short fibers
- Hydrogel microspheres
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MADNESS: Centre of Excellence in Materials-driven solutions for combatting antimicrobial resistance
Rosenholm, J. (Principal Investigator), Porres Paltor, I. (Co-Principal Investigator), Bansal, K. (Coordinator), Lafond, S. (Co-Principal Investigator), Uppstu, P. (Co-Principal Investigator), Viitala, T. (Co-Principal Investigator), Wang, X. (Co-Principal Investigator), Wilen, C.-E. (Co-Principal Investigator), Xu, C. (Co-Principal Investigator), Zhang, H. (Co-Principal Investigator), Lu, Z. (Co-Investigator), Verma, J. (Co-Investigator), Kumar, V. (Co-Investigator), Frejborg, F. (Co-Investigator), Wang, S. (Co-Investigator), Ran, M. (Co-Investigator), Ma, X. (Co-Investigator), Yang, W. (Co-Investigator), Liang, S. (Co-Investigator), Zhang, Y. (Co-Investigator), Fan, L. (Co-Investigator), Chen, Y. (Co-Investigator), Wang, L. (Co-Investigator), Zhuang, P. (Co-Investigator), Rajan Prakash, D. (Co-Investigator), Howaili, F. (Co-Investigator), Gulshan, R. (Co-Investigator), Yadav, D. (Co-Investigator), Pathak, C. (Co-Investigator), Mustafa, R. (Co-Investigator), Rostami, L. (Co-Investigator), Jafari Dargahlou, M. (Co-Investigator), Nygård, A. (Co-Investigator) & Manasut, P. (Co-Investigator)
01/01/24 → 31/12/28
Project: Foundation
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Targeted Delivery of CRISPR/Cas9 for Advanced Liver Cancer Therapy Through c-Myc Knockout
Zhang, H. (Principal Investigator)
01/09/22 → 31/08/24
Project: Research Council of Finland/Other Research Councils