Tissue engineering in spinal cord regeneration

描述(申请人提供)：破坏成年哺乳动物中枢神经系统(CMS)轴突连续性的损伤或病理过程，通常会由于受损轴突不能再生而导致永久性残疾。目前的治疗干预措施缺乏强大的再生反应，导致相当程度的功能恢复。近年来，基于组织工程原理的神经元桥接器的出现为CMS损伤和疾病的治疗和操作带来了新的希望。通过在损伤部位设计一个受控的环境，神经桥接设备唤醒CMS轴突的内在能力，使其在损伤部位和之外再生，达到其适当的靶点。结合使用含有引导线索的材料支架与粘合分子和具有选择性性质的细胞，进一步增强了设备的活力和弹性。我们的长期目标是开发一种临床适用的组织工程化神经元桥接装置来修复受损的中枢神经系统神经束。该项目旨在构建和评估一种基于多纤维包裹方法的组织工程化桥接装置，在该方法中，将一束束超细纤维吸入到半透可生物降解的中空纤维膜套筒中。我们的假设是，这种桥接装置将传递强烈的单向指导信号，并定义一个良好控制的轴突再生环境，从而促进和引导脊髓损伤后的轴突再生，导致比传统的神经元桥接策略更大程度的功能恢复。目的1评价HFM套管器内纤维束的堆积密度对体外培养轴突定向生长长度和方向性的影响。目的#2利用活体脊髓半横断模型检测多丝桥接装置在促进轴突生长方面的有效性。目的#3确定旨在1)促进跨病变间隙的定向再生和2)抑制装置-主机界面的胶质瘢痕形成的综合策略是否将进一步促进轴突生长到腰椎中央图案生成器(CPG；位于L1-2节段内的一个完整的神经回路，负责后肢运动功能)，从而导致解剖连接和功能恢复。

DESCRIPTION (provided by applicant): A damaging or pathological process that disrupts the continuity of axons in the adult mammalian central nervous system (CMS) often results in permanent disability due to the failure of injured axons to regenerate. Current therapeutic interventions are short of eliciting a robust regenerative response that leads to a decent degree of functional recovery. Recently, the emergence of neuronal bridging devices based upon tissue engineering principles offers new hope for the treatment and manipulation of CMS injuries and diseases. By engineering a controlled environment at the lesion site, neural bridging devices awaken the intrinsic ability of CMS axons to regenerate across and beyond the site of injury to reach their appropriate targets. The combined use of material scaffolds containing guidance cues with adhesive molecules and cells of selective properties further confers vitality and resilience to the devices. Our long-term goal is to develop a clinically applicable tissue-engineered neuronal bridging device to repair damaged CNS nerve tracts. The proposed project aims to construct and evaluate a tissue-engineered bridging device based upon a multi-filament entubulation approach in which bundles of ultra-thin filaments are entubulated into a semi- permeable biodegradable hollow fiber membrane sleeve. Our hypothesis is that such a bridging device will convey strong unidirectional guidance cues and define a well-controlled environment for regenerating axons, and therefore promote and guide axonal regeneration following spinal cord injury, leading to a greater degree of functional recovery compared to conventional neuronal bridging strategies. Aim #1 is to evaluate the effect of the packing density of the filament bundles within the HFM entubulation sleeve on the directional outgrowth length and directionality of axons in vitro. Aim #2 is to examine the efficiency of multifilament bridging device in promoting axonal outgrowth using a spinal cord hemisection model in vivo. Aim #3 is to determine whether a combined strategy aimed at 1) enhancing directional regeneration across the lesion gap, and 2) inhibiting glial scar formation at the device-host interface will further promote axonal growth to the lumbar central pattern generator (CPG; an intact neural circuit located within the L1-2 segment that responsible for hindlimb locomotor function), resulting in both anatomical reconnection and functional recovery.