NT3-chitosan enables de novo regeneration and functional recovery in monkeys after spinal cord injury

Abstract

Spinal cord injury (SCI) often leads to permanent loss of motor, sensory, and autonomic functions. We have previously shown that neurotrophin3 (NT3)-loaded chitosan biodegradable material allowed for prolonged slow release of NT3 for 14 weeks under physiological conditions. Here we report that NT3-loaded chitosan, when inserted into a 1-cm gap of hemisectioned and excised adult rhesus monkey thoracic spinal cord, elicited robust axonal regeneration. Labeling of cortical motor neurons indicated motor axons in the corticospinal tract not only entered the injury site within the biomaterial but also grew across the 1-cm-long lesion area and into the distal spinal cord. Through a combination of magnetic resonance diffusion tensor imaging, functional MRI, electrophysiology, and kinematics-based quantitative walking behavioral analyses, we demonstrated that NT3-chitosan enabled robust neural regeneration accompanied by motor and sensory functional recovery. Given that monkeys and humans share similar genetics and physiology, our method is likely translatable to human SCI repair.

Local Serpin Treatment via Chitosan-Collagen Hydrogel after Spinal Cord Injury Reduces Tissue Damage and Improves Neurologic Function

“…The chitosan-collagen carrier was chosen based on well-characterized properties of tunable structural stability, excellent biocompatibility, low antigenicity, and high biodegradability [43,58,59]. Other researchers have already demonstrated that chitosan-collagen carriers can deliver therapeutic agents to the spinal cord [21,41]. In prior work neurotrophin-3 (NT3), a neurotrophic growth factor that promotes proliferation of neural stem cells, enhanced functional recovery after SCI in rats when delivered by chitosan-collagen carriers [21,41].…”

“…Many minimally invasive and regenerative therapeutics are under investigation ranging from regenerative therapy with hydrogel implants, stem cells, growth factors, magnesium and antioxidants, among others, but without proven long term benefits at this time [1,2,[4][5][6][7][11][12][13]17,18]. Chitosan hydrogels with or without growth factors have been proven to promote SCI restoration and axon regeneration in rat and monkey models [19][20][21].…”

“…However, continuous infusion by indwelling catheters posed an increased risk for nosocomial infections and trauma with increased morbidity. Prior work in SCI models has also demonstrated that creating a "bridge" with an implanted biodegradable material, such as chitosan, can improve recovery after SCI [21] but other studies identified severe destructive inflammation initiated by the spinal crush injury as a major impediment in studying cellular and synthetic implants [21,39]. Therefore, addressing the post-SCI inflammation remains a fundamental issue in therapeutic strategies in neurotrauma.…”

Image correction for diffusion tensor imaging of Rhesus monkey thoracic spinal cord

“…Some studies have achieved favorable effect in rodent models, so preclinical studies have further expanded to non-human primates (NHPs). 7 SCI repair studies of NHP usually require the use of an in vivo longitudinal examination technique because a long time period is needed for spinal cord tissue regeneration.…”

“…Detailed surgical procedures were executed as described in previous studies. 7,34 Briefly, spinal cord tissue injury was performed after laminectomy under an operation microscope. A tissue mass with 5 mm length (in the superioinferior direction) and 2-3 mm width (in the left-right direction) was excised by using microscissors.…”