Spinal cord tissueoid transplantation combined with tail nerve electrical stimulation promotes the voluntary movement of paralyzed hindlimbs in rats with transected spinal cord injury.

The recovery of voluntary movement after complete spinal cord injury (SCI) remains a formidable clinical challenge, as it necessitates both the reconstruction of disrupted spinal cord neural pathways and the restoration of the excitatory/inhibitory balance in sensorimotor neural circuits. To tackle this dual challenge, we transplanted a biomimetic spinal cord tissueoid (SCToid) into the injury cavity to structurally reestablish neural pathways, while concurrently applying tail nerve electrical stimulation (TNES) to functionally reactivate silent sensorimotor neural circuits. The results showed that combined SCToid transplantation and TNES promoted the regeneration of corticospinal tract and sensory afferent axons, which formed functional synapses with SCToid neurons. Moreover, monosynaptic tracer assays revealed direct innervation of lumbar spinal cord central pattern generator (CPG) interneurons by SCToid neurons; some CPG interneurons and sensory afferent axons also exhibited synaptic connectivity with motor neurons. Compared with the control group, transplantation of SCToids combined with TNES increased the ratio of excitatory/inhibitory synaptic terminals on the soma surfaces of CPG interneurons and motor neurons toward the pattern observed in normal spinal cords. This change ultimately enhanced the excitability of sensorimotor neural circuits and restored weight-bearing hindlimb walking. Collectively, these findings establish that reconstructing neural pathways and restoring the excitatory/inhibitory balance within CPG-regulated sensorimotor neural circuits are both necessary and sufficient to enable voluntary movement recovery. This synergistic mechanism establishes a robust theoretical framework for integrating biological and physical therapeutic strategies in SCI treatment, with specific implications for the combined application of transplantable engineered organoids and neurostimulation-based rehabilitation approaches.