Macrophage metabolic reprogramming-based diabetic infected bone defect/bone reconstruction though multi-function silk...

Area of Science:

• Biomaterials Science
• Immunology
• Regenerative Medicine

Background:

• Diabetic infected bone defects (DIBD) present significant clinical challenges due to impaired immune metabolism, leading to persistent infections and delayed bone regeneration.
• Immune metabolism plays a critical role in regulating immunological processes and tissue repair.
• Current treatments for DIBD often struggle to address both infection and compromised healing.

Purpose of the Study:

• To develop a macrophage metabolic reprogramming hydrogel for treating DIBD.
• To investigate the potential of M2 Macrophage-derived Exosomes (M2-Exo) integrated into a silk fibroin/poly-l-lysine hydrogel (Silk-6/ε-PL@Exo) for modulating immune responses and promoting bone regeneration.
• To evaluate the efficacy of the Silk-6/ε-PL@Exo hydrogel in controlling infection and accelerating bone healing in a DIBD rat model.

Main Methods:

• Fabrication of a degradable hydrogel (Silk-6/ε-PL@Exo) by combining modified silk fibroin, poly-l-lysine, and M2-Exosomes.
• Assessment of the hydrogel's broad-spectrum antibacterial activity against Gram-positive and Gram-negative bacteria.
• In vitro investigation of M2-Exo release and its effects on M1 macrophage polarization, hexokinase II (HK2) activity, NF-κB pathway, and glycolysis.
• In vivo evaluation of the hydrogel's performance in a rat model of DIBD, assessing infection control, immune balance, and bone defect healing.

Main Results:

• The Silk-6/ε-PL@Exo hydrogel demonstrated broad-spectrum antibacterial properties.
• M2-Exo released from the hydrogel successfully targeted M1 macrophages, modulating HK2 activity and the NF-κB pathway.
• The hydrogel treatment alleviated lactate accumulation and normalized glycolysis, promoting a shift from M1 to M2 macrophage polarization.
• In vivo studies showed that the Silk-6/ε-PL@Exo hydrogel effectively controlled infection, balanced immune responses, and accelerated bone defect healing in rats.

Conclusions:

• The developed Silk-6/ε-PL@Exo hydrogel is a promising multifunctional biomaterial for treating DIBD.
• Macrophage metabolic reprogramming via M2-Exo release is a viable strategy for enhancing bone regeneration in infected defects.
• This study highlights the critical role of metabolic reprogramming in addressing the complexities of DIBD treatment.