Remote-Controlled Magnetic Stimulation of Cell-Based Bioengineered Tissues for In Situ Bone Regeneration

The native cell microenvironment activates signaling pathways through mechanotransduction mechanisms, influencing cells' physiological and functional outcomes. Magnetic fields are explored to manipulate these environments, and magnetic nanoparticles (MNPs) are highlighted as nano-instructive agents capable of activating key signaling pathways, presenting exciting possibilities in tissue engineering. Still, the ability to precisely control the assembly and differentiation of stem cells within a dynamically responsive microenvironment, crucial for effective tissue regeneration, remains unexplored. This study showcases a novel method wherein MNPs facilitate the precise assembly of magnetically responsive cells into complex 3D tissue structures upon internalization and exposure to temporally defined cyclic magnetic fields. By remotely stimulating these constructs, it is demonstrated for the first time the possibility of remote-controlled modulation of stem cell fate in vivo without biochemical supplementation. Notably, this approach led to ectopic bone formation, highlighting the ability of magnetic actuation to drive osteogenesis in non-bone environments. MNP-driven mechanical stimulation of implanted tissues functions as a bioresponsive system guiding osteogenic differentiation of human adipose-derived stem cells. The in vivo model further illustrates accelerated construct integration, enhanced osteogenic differentiation, and minimal local inflammation, underscoring the potential of this less invasive, remotely controllable platform to advance regenerative strategies for bone engineering.