Fuel-maintenance coupling reprograms mitochondrial homeostasis to enable peripheral nerve regeneration.

Area of Science:

• Biomaterials Science
• Regenerative Medicine
• Neuroscience

Background:

• Peripheral nerve regeneration is hindered by metabolic issues like mitochondrial dysfunction.
• Current nerve guidance conduits lack metabolic support, failing to address energy deficits.
• Mitochondrial homeostasis is a critical, yet underexplored, target for nerve repair.

Purpose of the Study:

• To develop a metabolically active nerve guidance conduit to overcome regeneration bottlenecks.
• To engineer a biomimetic conduit combining fuel provision and mitochondrial quality control.
• To investigate the conduit's efficacy in promoting peripheral nerve regeneration and functional recovery.

Main Methods:

• Engineered a polycaprolactone (PCL) sheath nerve guidance conduit filled with a Magnolol-loaded chitosan-lipoic acid hydrogel (LA-CS@Mag).
• Utilized α-lipoic acid as metabolic fuel and Magnolol for mitophagy.
• Evaluated *in vitro* effects on Schwann cells and *in vivo* performance in a rat sciatic nerve defect model.

Main Results:

• LA-CS@Mag *in vitro* protected Schwann cells, restored mitochondrial function, and enhanced ATP production.
• The conduit modulated macrophage polarization towards a reparative M2 phenotype.
• *In vivo*, the conduit promoted axonal regeneration, remyelination, prevented muscle atrophy, and restored function.

Conclusions:

• Mitochondrial homeostasis is a viable therapeutic target for peripheral nerve repair.
• The developed nerve guidance conduit offers a metabolically instructive strategy for enhanced nerve regeneration.
• This approach represents a significant advancement towards next-generation nerve repair technologies.