MFO@BCZT- and metformin-integrated biomimetic hydrogel for magnetoelectric stimulation-induced neurogenesis and neuroprotection in synergistically promoting brain tissue repair

Abstract

After injuries, the repair of brain tissue is hindered by poor neuronal regeneration and severe neuroinflammation. Although magnetoelectric (ME) stimulation has emerged as a promising wireless strategy to promote axonal growth, its efficacy is strictly dependent on the ME coupling efficiency of the materials used. Furthermore, while microglia-mediated inflammation remains a critical barrier to neurogenesis, integrating neuroprotective strategies to modulate this inhibitory environment with ME stimulation strategies has seldom been explored. Herein, we developed a multi-functional biomimetic hydrogel platform combining neuro-protective and neuro-inductive properties simultaneously. This platform is composed of collagen/oxidized hyaluronic acid-metformin hydrogel matrix with encapsulated biocompatible core-shell ME nanoparticles (NPs), MnFe2O4@Ba0.85Ca0.15Ti0.9Zr0.1O3 (MFO@BCZT), with a high ME coefficient. We confirmed that the metformin in the hydrogel effectively inhibited lipopolysaccharide (LPS)-induced M1 polarization of BV2 microglia, providing neuroprotection. Concurrently, under pulsed magnetic field stimulation, the embedded MFO@BCZT NPs generated local electrical signals, significantly promoting neuronal differentiation of neural stem cells (NSCs). In a rat traumatic brain injury (TBI) model, this synergistic system alleviated neuroinflammation, recruited endogenous NSCs, and promoted their neuronal differentiation and maturation within the lesion. This led to enhanced axonal regeneration, remyelination, synaptic reconstruction, and ultimately, improved cognitive function recovery. Overall, this work presents a promising strategy that combines ME stimulation-driven neuroinduction with metformin-mediated neuroprotection for effective brain tissue repair, shedding light on innovative strategies for biomaterial design and the treatment of central nervous system injuries.