Combined Biomaterial and Neuromodulatory Approach to Promote Axonal Outgrowth and Connections After Cervical SCI

Spinal cord injury (SCI) interrupts connections between the motor cortex (MCX) and spinal motor circuits. We propose a novel approach to treat paralysis and weakness after spinal cord injury (SCI) by combining (1) dual MCX and spinal cord stimulation to promote corticospinal tract (CST) axonal outgrowth and activity-dependent synapse formation,

and (2) implantation at the spinal injury site of a hydrogel biomaterial. MCX epidural stimulation is a neuromodulatory approach that upregulates the mTOR and Jak/Stat signaling pathways—essential for CST axon regeneration and CST injury-dependent sprouting—to promote CST axon sprouting, synapse formation, and motor function after injury. The effects of MCX stimulation therapy is potentiated by cathodal

trans-spinal direct current stimulation (tsDCS), a non-invasive neuromodulatory approach that can be rostrocaudally- targeted to activate the spinal cord. However, the recovery that can be achieved by activity-based repair strategies is limited by the physical damage and the cavity at the injury site. Our dual neuromodulatory strategy, alone, cannot achieve sufficient CST outgrowth and

circuit repair needed to restore significant function after a traumatic SCI. To achieve greater motor recovery after SCI, we will combine neuromodulation with implantation of Chitosan engineered as a fragmented physical hydrogel suspension (Chitosan-FPHS). This new and patented formulation remodels the injury site. Chitosan-FPHS helps abrogate physical

barriers at the lesion site and enhances axonal growth into and through the injury. Chitosan-FPHS therapy significantly improves motor function after thoracic hemisection. In this proposal, we use an adult rat C4 midline contusion model and combine published biomaterial implantation and neuromodulation methods in a novel way to repair the motor system. In Aim 1, we will determine the efficacy of

Chitosan-FPHS hydrogel implantation combined with the dual neuromodulation therapy in promoting CST axonal outgrowth and MCX evoked spinal cord and muscle responses. In Aim 2, we will determine the efficacy of Chitosan- FPHS hydrogel implantation combined with dual neuromodulation therapy in promoting motor function after cervical

SCI. Together, our combined neuromodulatory and biomaterial-based approach aims to induce persistent structural

plasticity after SCI. This approach could lead to recovery of substantial motor control in our animal model and could be translated to improve function in people with SCI.