Transplantation of Pre‐Differentiated 3D Neural Spheroids in Decellularized Extracellular Matrix Microgels Promotes Neuronal Network Reconstruction and Functional Recovery after Severe Spinal Cord Contusion

Abstract Traumatic spinal cord injury (SCI) causes massive death of neurons in the spinal cords and almost complete neurological dysfunctions. Transplantation of neural stem/progenitor cells (NSPCs) is acknowledged as one of the viable SCI treatments for complementing lost neurons and neural network reconstruction. However, administration of NSPCs suffers from extremely low survival rate and uncontrolled differentiation of the transplanted cells, which impairs the therapeutic effects significantly. Herein, NSPCs are encapsulated in decellularized spinal cord matrix (DSCM) microgels using a customized microfluidic system, then the obtained NSPCs‐encapsulated DSCM microgels (NSPC@DSCM‐MGs) are subjected to neuronal differentiation induction. Consequently, the resulting pre‐mature 3D neural spheroids are injected into severely contused spinal cords in rats. The DSCM microgels effectively protected the transplanted cells from shear damage and the inflammatory microenvironment at the lesion site. The survival and accommodation of the pre‐differentiated NSPC@DSCM‐MGs actively contributed to axonal regeneration, inhibiting glial scar formation, as well as remodeling the microenvironment that facilitated endogenous cell recruitment and neuronal network reconstruction. Consequentially, administration of the neural spheroids led to maintenance of spinal cord integrity, and significantly improved hindlimb locomotor function. This biomaterial‐based transplantation strategy has shown unique assets in cell protection and cell‐fate manipulation, which holds great promise in versatile biomedical applications.