Bioactive Materials (Jul 2024)

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

  • 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

Journal volume & issue
Vol. 37
pp. 424 – 438

Abstract

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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.

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