Tissue engineering in spinal cord regeneration

描述（由申请人提供）：破坏成年哺乳动物中枢神经系统（CMS）中轴突连续性的损伤或病理过程通常会因受损轴突无法再生而导致永久性残疾。目前的治疗干预缺乏引起强大的再生反应，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桥接装置的出现为CMS损伤和疾病的治疗和操作提供了新的希望。通过在损伤部位设计一个受控的环境，神经桥接装置唤醒CMS轴突的内在能力，使其跨越损伤部位再生并到达适当的靶点。含有引导线索的材料支架与具有选择性特性的粘附分子和细胞的组合使用进一步赋予装置活力和弹性。我们的长期目标是开发一种临床适用的组织工程神经元桥接装置，以修复受损的中枢神经系统神经束。拟定项目旨在构建和评价一种基于复丝内管化方法的组织工程桥接器械，其中将成束的超薄丝内管化到半渗透性可生物降解中空纤维膜套管中。我们的假设是，这样的桥接装置将传达强大的单向指导线索，并定义一个良好的控制环境再生轴突，因此促进和指导脊髓损伤后轴突再生，导致更大程度的功能恢复相比，传统的神经元桥接策略。目的#1是评价HFM内管套管内丝束的填充密度对体外轴突的定向生长长度和方向性的影响。目的#2是使用脊髓半切模型在体内检查多丝桥接装置在促进轴突生长中的效率。目的#3是确定旨在1）增强病变间隙的定向再生和2）抑制器械-宿主界面处的神经胶质瘢痕形成的组合策略是否会进一步促进轴突生长至腰椎中央模式发生器（CPG;位于负责后肢运动功能的L1-2节段内的完整神经回路），导致解剖学重新连接和功能恢复。

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.