Gradient Nanoaggregation in a Magnetically Actuated Scaffold for Multiscale Immunoregulation and Microenvironment Remodeling Accelerates Nerve and Muscle Repair

Biophysical cues are important additive considerations in smart degradable implants apart from chemical modification in tissue engineering. Similar with electrical and ultrasonic stimulation, intrinsic magnetic actuation in integrated implants of iron oxide nanoparticles and topological structures affects cell fate decision to enhance tissue injury repair. It also saves the trouble of carrying an external stimulator to better suit clinical and daily use. In this study, a gradient magnetized iron oxide nanoparticle scaffold (GIONS) is designed using 3D multilayered method. It has a high magnetic saturation with nanoaggregation of iron oxide nanoparticles and is featured with evenly distributed micropores and multilayer structure to realize moderate elasticity and mechanical stability. GIONS facilitates directed growth and protuberance extension of neurons and immunoregulates pro-regenerative polarization of macrophages. In a rat nerve defect injury model, GIONS successfully improves remyelination and axon sprouting in the regenerated region, and activates reparative microenvironment by stimulating neurogenesis, angiogenesis and reducing muscle atrophy. It further facilitates glial cell activation and macrophage immunoregulation in vivo by mechanochemical signaling to significantly accelerate the repair of different severed tissues. Consequently, this smart implant increases nerve conducting velocity and locomotor function and contributes to multifunctional regeneration of severe tissue injury.