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

结合生物材料和神经调节方法促进宫颈 SCI 后轴突生长和连接

基本信息

批准号：
10323048
负责人：
John H Martin
金额：
$ 15.7万
依托单位：
CITY COLLEGE OF NEW YORK
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10323048
关键词：
Adult Animal Model Anti-Inflammatory Agents Axon Biocompatible Materials Brain Cathodes Cell Survival Cervical Cervical spinal cord injury Chest Chitosan Cicatrix Contusions Corticospinal Tracts Dorsal Electric Stimulation Engineering Environment Extracellular Matrix FRAP1 gene Forelimb Formulation Growth Human Hydrogels Injury Interneurons Interruption Lead Legal patent Lesion Methods Modeling Motor Motor Cortex Movement Muscle Muscle Contraction Neurons Neuropil Neurostimulation procedures of spinal cord tissue Paralysed Persons Property Publishing Rattus Recovery Retinal Ganglion Cells Signal Pathway Signal Transduction Site Spinal Spinal Cord Spinal Injuries Spinal cord injury Suspensions System Tissues Translating axon growth axon regeneration axonal sprouting base functional restoration implantation improved improved functioning injury and repair motor control motor function improvement motor function recovery motor recovery neuroregulation novel novel strategies prevent relating to nervous system repair strategy repaired response skills spinal tract synaptogenesis tissue repair transneuronal degeneration

项目摘要

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.

脊髓损伤（SCI）阻断了运动皮质（MCX）和脊髓运动回路之间的联系。我们