Combined biomaterial scaffold and neuromodulation strategy to promote tissue repair and corticospinal connectivity after spinal cord injury in a rodent model

Spinal cord injury (SCI) damages the trauma site, leading to progressive and secondary structural defects rostral and caudal to the injury. Interruption of ascending and descending pathways produce motor, sensory, and autonomic impairments, driving the need for effective therapies. In this study, we address lesion site repair and promoting descending projections using a combined biomaterial-neuromodulation strategy in a rat model of cervical contusion SCI. To promote tissue repair, we used Chitosan fragmented physical hydrogel suspension (C_fphs), a biomaterial formulation optimized to mitigate inflammation and support tissue remodeling. To promote descending projections, we targeted the corticospinal motor system with dual motor cortex–trans-spinal direct current neuromodulation to promote spared corticospinal tract (CST) axon sprouting rostral and caudal to SCI. C_fphs, injected into the lesion site acutely, was followed by 10 days of daily neuromodulation. Analysis was made at the chronic phase, 8-weeks post-SCI. Compared with SCI only, C_fphs alone or in combination with neuromodulation prevented cavity formation, by promoting tissue remodeling at the injury site, abrogated astrogliosis surrounding the newly formed tissue, and enabled limited CST axon growth into the remodeled injury site. C_fphs alone significantly reduced CST axon dieback and was accompanied by preserving more CST axon gray matter projections rostral to SCI. C_fphs + neuromodulation produced sprouting rostral and caudal to injury. Our findings show that our novel biomaterial-neuromodulation combinatorial strategy achieves significant injury site tissue remodeling and promoted CST projections rostral and caudal to SCI.