Wireless Magnetoelectric Stimulation Platform Orchestrating Multicellular Coupling in Complex Neurovascularized Tissue Regeneration.

Bone regeneration is a well-orchestrated biological process involving coordinate efforts of multiple cells, cytokines, and signals, among which nerves play a dominant role in regulating osteogenesis. Draw inspiration from the inherent electroactive features of bone and nerve, bioelectric implant providing wireless delivery of electrical stimulation (ES), is an emerging alternative to conventional invasive electrode-based therapy. Herein, we develop a lead-free magnetoelectric (ME) core-shell MnFe2O4@Ba0.85Ca0.15Zr0.1Ti0.9O3 (MFO@BCZT) nanoheterostructure-integrated biodegradable 3D-printed hydrogel implant providing high-performance wireless ES for neurovascularized bone regeneration. Under low-intensity magnetic field stimulation (20 mT, 50 Hz), the strain generated by the magnetostriction of MFO core is directly transmitted into BCZT piezoelectric shell to generate electrical signals. Thus, 3D-printed ME implants activate multiple neurogenesis- and osteogenesis-related signals including calcium ion-mediated CaMKII/CREB and CaMKKβ/AMPK/Nrf2 pathway, as well as other pro-regenerative pathways including PI3K-AKT and TGF-β signaling. The implants recreate electrophysiological microenvironments of bone defect in vivo, thereby inducing early neuroangiogenesis and recruiting endogenous stem cells, resulting in 3.1-fold and 4.6-fold increase in innervation and bone formation, respectively. Beyond bone repair, this magnetically driven electrical stimulation strategy establishes a ME-multicellular coupling platform for minimally invasive complex tissue regenerative therapies. Furthermore, the stimuli-responsive 3D-printed ME hydrogel implant establishes a versatile foundation for multifunctional wireless bioelectronic interfaces, allowing a single system to integrate therapeutic and neuroelectronic functions with potential applications in treating traumatic brain injury and neurological disorders, as well as in next-generation brain-machine interfaces.