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

脊髓损伤（SCI）中断了运动皮层（MCX）和脊髓运动回路之间的连接。我们 提出了一种新的方法来治疗脊髓损伤（SCI）后的瘫痪和虚弱，通过结合（1）双重MCX和 脊髓刺激以促进皮质脊髓束（CST）轴突生长和活性依赖性突触形成， 和（2）在脊髓损伤部位植入水凝胶生物材料。 MCX硬膜外刺激是一种上调mTOR和Jak/Stat信号的神经调节方法 CST轴突再生和CST损伤依赖性发芽所必需的途径-促进CST轴突发芽， 突触形成和损伤后的运动功能。MCX刺激疗法的效果通过阴极增强 经脊髓直流电刺激（tsDCS），一种非侵入性的神经调节方法，可以通过吻尾- 旨在激活脊髓 然而，通过基于活动的修复策略可以实现的恢复受到物理损伤的限制， 伤口处的空洞我们的双重神经调节策略，单独使用，不能实现足够的CST生长， 在创伤性SCI后，需要进行电路修复以恢复重要功能。为了在SCI后实现更大的运动恢复，我们 将联合收割机神经调节与作为片段化物理水凝胶悬浮液的壳聚糖植入相结合 （壳聚糖-FPHS）。这种新的专利配方重塑受伤部位。壳聚糖-FPHS有助于消除物理 在损伤部位形成屏障，并增强轴突生长进入并穿过损伤。壳聚糖-FPHS治疗显著 改善胸廓半切术后的运动功能。 在这个建议中，我们使用成年大鼠C4中线挫伤模型，并联合收割机结合已发表的生物材料植入， 神经调节方法以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 生长和MCX诱发脊髓和肌肉反应。在目标2中，我们将确定壳聚糖的功效- FPHS水凝胶植入联合双重神经调节治疗促进颈椎术后运动功能 SCI. 总之，我们结合神经调节和生物材料为基础的方法，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导致我们的动物模型中恢复实质性的运动控制，并且可能 来改善SCI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.