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

脊髓损伤(SCI)导致运动皮质(MCx)和脊髓运动回路之间的连接中断。我们 提出一种新的治疗脊髓损伤后瘫痪和虚弱的方法：(1)双MCx和 脊髓刺激促进皮质脊髓束(CST)轴突生长和活性依赖突触的形成 和(2)植入水凝胶生物材料的脊髓损伤部位。 MCx硬膜外刺激是一种上调mTOR和JAK/STAT信号的神经调制方法 对CST轴突再生和CST损伤依赖的萌发至关重要的通路-促进CST轴突萌发， 损伤后突触的形成和运动功能。阴阳极可增强MCx刺激疗法的疗效 经脊髓直流电刺激(TsDCS)，这是一种非侵入性的神经调节方法，可以从轮尾部- 目标是激活脊髓。 然而，基于活动的修复策略可以实现的恢复受到物理损坏和 伤口处的空洞。我们的双重神经调节策略，单独不能实现足够的CST增长和 创伤性脊髓损伤后，需要电路修复来恢复显著的功能。为了实现脊髓损伤后更好的运动恢复，我们 将神经调节与植入壳聚糖作为碎裂的物理水凝胶悬浮液相结合 (壳聚糖-全氟辛烷)。这种新的专利配方重塑了受伤部位。壳聚糖-FPHS有助于消除物理 在损伤部位形成屏障，促进进入和穿过损伤的轴突生长。壳聚糖-FPHS治疗显着 改善胸部半切术后的运动功能。 在这项建议中，我们使用成年大鼠C4中线挫伤模型，并结合已发表的生物材料植入和 神经调节方法以一种新的方式修复运动系统。在目标1中，我们将确定 壳聚糖-FPHS水凝胶植入联合双重神经调节疗法促进CST轴突生长 OutGrowth和MCx可引起脊髓和肌肉反应。在目标2中，我们将确定壳聚糖的功效- FPHS水凝胶植入联合双神经调节疗法改善颈椎术后运动功能 SCI。 总之，我们的神经调节和生物材料相结合的方法旨在诱导持久的结构性 脊髓损伤后的可塑性。这种方法可能会在我们的动物模型中恢复实质性的运动控制，并可能 翻译为改善脊髓损伤患者的功能。

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.