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Regulation of metabolic microenvironment with a nanocomposite hydrogel for improved bone fracture healing

Authors :
Kangkang Zha
Meijun Tan
Yiqiang Hu
Weixian Hu
Shengming Zhang
Yanzhi Zhao
Ze Lin
Wenqian Zhang
Hang Xue
Bobin Mi
Wu Zhou
Qian Feng
Faqi Cao
Guohui Liu
Source :
Bioactive Materials, Vol 37, Iss , Pp 424-438 (2024)
Publication Year :
2024
Publisher :
KeAi Communications Co., Ltd., 2024.

Abstract

Bone nonunion poses an urgent clinical challenge that needs to be addressed. Recent studies have revealed that the metabolic microenvironment plays a vital role in fracture healing. Macrophages and bone marrow-derived mesenchymal stromal cells (BMSCs) are important targets for therapeutic interventions in bone fractures. Itaconate is a TCA cycle metabolite that has emerged as a potent macrophage immunomodulator that limits the inflammatory response. During osteogenic differentiation, BMSCs tend to undergo aerobic glycolysis and metabolize glucose to lactate. Copper ion (Cu2+) is an essential trace element that participates in glucose metabolism and may stimulate glycolysis in BMSCs and promote osteogenesis. In this study, we develop a 4-octyl itaconate (4-OI)@Cu@Gel nanocomposite hydrogel that can effectively deliver and release 4-OI and Cu2+ to modulate the metabolic microenvironment and improve the functions of cells involved in the fracture healing process. The findings reveal that burst release of 4-OI reduces the inflammatory response, promotes M2 macrophage polarization, and alleviates oxidative stress, while sustained release of Cu2+ stimulates BMSC glycolysis and osteogenic differentiation and enhances endothelial cell angiogenesis. Consequently, the 4-OI@Cu@Gel system achieves rapid fracture healing in mice. Thus, this study proposes a promising regenerative strategy to expedite bone fracture healing through metabolic reprogramming of macrophages and BMSCs.

Details

Language :
English
ISSN :
2452199X
Volume :
37
Issue :
424-438
Database :
Directory of Open Access Journals
Journal :
Bioactive Materials
Publication Type :
Academic Journal
Accession number :
edsdoj.83d4cbc01a48fc8c9392ee749974cf
Document Type :
article
Full Text :
https://doi.org/10.1016/j.bioactmat.2024.03.025