3D bioprinted multifunctional GelMA/TMP scaffold integrated with neural stem cell-derived extracellular vesicles and neural progenitor cells for spinal cord injury repair.

Abstract

Spinal cord injury (SCI) disrupts neural architecture through a cascade of inflammatory, vascular, and glial responses that collectively create a regenerative deadlock. Overcoming this complex, temporally evolving pathology requires the coordinated delivery of structural, cellular, and biochemical cues. Here, we present a 3D bioprinted multifunctional scaffold composed of gelatin methacryloyl (GelMA), tetramethylpyrazine (TMP), neural progenitor cells (NPCs), and neural stem cell-derived extracellular vesicles (NSC-EVs). This combinatorial construct mimics essential features of the neural niche and orchestrates reparative processes across multiple levels. Compared to adipose-derived EVs, NSC-EVs demonstrated a superior cytokine and neurotrophic profile that enhanced angiogenesis and neuronal differentiation. In vitro, the integrated scaffold promoted NPC survival, neurogenesis, angiogenesis and immunomodulation. In a complete transection rat SCI model, the scaffold supported locomotor recovery by reducing cystic cavitation, facilitating axonal regeneration and remyelination, preserving parenchymal integrity, and attenuating neuroinflammation. Our findings suggest that integrated, multimodal interventions can modulate the hostile post-injury microenvironment and stimulate endogenous repair mechanisms, offering a clinically translatable paradigm for SCI regeneration.