Multichannel 3D-Printed Bioactive Scaffold Combined with Small Interfering RNA Delivery to Promote Neurological Recovery after Spinal Cord Injury.

Enhancing axonal regeneration holds promise for restoring neural circuits and locomotion function after spinal cord injury (SCI), while precise guidance of micrometer-scale axons to their natural regions remains a critical challenge. To address this problem, we developed an integrated 3D-printed scaffold featuring internal parallel channels infused with a bioactive hydrogel containing laminin-derived chimeric RADA(4)-IKVAV peptide. This scaffold combined physical guidance cues with molecular modulation synergistically by constructing an incorporated small interfering RNA delivery platform targeting phosphatase and tensin homolog. Comprehensive validations via immunohistochemistry, single-cell RNA sequencing, and behavioral assays demonstrated that this approach effectively protected surrounding tissues in lesion area, enhanced ability of axonal regeneration, and improved locomotion functional recovery of rats significantly. Mechanistic investigations further revealed that the introduced IKVAV peptide specifically up-regulated Ephrin/Eph signaling pathway genes, driving establishment of functional axon networks. Overall, this strategy potentially helps to develop new clinical approach for efficiently treating SCI.