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

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.

The morphology of the Cu COF and hydrogels was observed via TEM and SEM (LIBRA 200 CS, Carl Zeiss Co., Germany).

The compressive mechanical characteristics of the blank gel and 4-OI@Cu@Gel (3 mm thick) were detected using a MACH-1 Micromechanical System (Biomomentum, Inc., Canada). The compressive strength was calculated by using the following equation: F = P/A, where F refers to the compressive strength, P refers to the maximum load, A refers to the cross-section of the area.