3D Gradient and Linearly Aligned Magnetic Microcapsules in Nerve Guidance Conduits with Remotely Spatiotemporally Controlled Release to Enhance Peripheral Nerve Repair

Although numerous strategies have been implemented to develop nerve guidance conduits (NGCs) to treat peripheral nerve injury (PNI), functionalization of an NGC to make it remotely controllable for providing spatiotemporal modulation on in situ nerve tissues remains a challenge. In this study, a gelatin/silk (GS) hydrogel was used to develop an NGC based on its self-owned reversible thermoresponsive sol-to-gel phase transformation ability that permitted rapid three-dimensional (3D) micropatterning of the incorporated nerve growth factor (NGF)-loaded magnetic poly(lactic-co-glycolic acid) (PLGA) microcapsules (called NGF@MPs) via multiple magnetic guidance. The thermally controllable viscosity of GS enabled the rapid formation of a 3D gradient and linearly aligned distribution of NGF@MPs, leading to magnetically controlled 3D gradient release of NGF to enhance topographical nerve guidance and wound healing in PNIs. Particularly, the as-formed micropatterned hydrogel, called NGF@MPs-GS, showed corrugation topography with a pattern height H of 15 mu m, which resulted in the linear axon alignment of more than 90% of cells. In addition, by an external magnetic field, spatiotemporal controllability of NGF release was obtained and permitted neurite elongation that was almost 2-fold longer than that in the group with external addition of NGF. Finally, an NGC prototype was fabricated and implanted into the injured sciatic nerve. The patterned implant, assisted by magnetic stimulation, demonstrated accelerated restoration of motor function within 14 days after implantation. It further contributed to the enhancement of axon outgrowth and remyelination after 28 days. This NGC, with controllable mechanical, biochemical, and topographical cues, is a promising platform for the enhancement of nerve