Transplantation of engineered spinal cord organoids restores functions after spinal cord injury

Generating functional maturation neural organoids to model degenerative disease or replace large damaged central nervous tissue remains an enormous challenge. Here, we developed a novel blood vessel-mimicking nanomaterial system by combining carboxylated cellulose nanofibres (CCN) with Matrigel to create biosafety scaffolds. These engineered scaffolds demonstrated a remarkable capacity to support the long-term growth over 300 days and functional maturation of neural organoids, enabling the development of centimetre-scale organoids without necrotic cores. CCN-engineered human spinal cord organoids (ChSOs) could self-elongate axon tracts, robustly form axon myelination and establish functional neural networks. Following transplantation, ChSOs demonstrated remarkable differentiation potential, generating multiple subtypes of spinal cord neurons, both dorsal and ventral, that could migrate and integrate sufficiently with the host spinal cord tissue. Notably, these grafted ChSOs secrete the axon guidance factor NTN1, enhancing axonogenesis and facilitating the restoration of sensory and motor functions in mice with complete spinal cord injury. These findings show that ChSOs provide a platform for studying neural development and achieving functional spinal cord repair.