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）中轴突连续性的破坏性或病理性过程通常会因受损轴突无法再生而导致永久性残疾。目前的治疗干预措施不足以引发强大的再生反应，从而导致相当程度的功能恢复。最近，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纵提供了新的希望。通过在损伤部位设计一个受控环境，神经桥接装置唤醒了 CMS 轴突在损伤部位内外再生的内在能力，以达到适当的目标。含有具有粘合剂分子和选择性特性细胞的引导提示的材料支架的组合使用进一步赋予了装置活力和弹性。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来修复受损的中枢神经系统神经束。拟议项目旨在构建和评估基于多丝插管方法的组织工程桥接装置，其中将超细丝束插管到半渗透性可生物降解的中空纤维膜套管中。我们的假设是，这种桥接装置将传递强大的单向引导线索，并为轴突再生定义良好控制的环境，从而促进和指导脊髓损伤后的轴突再生，与传统的神经元桥接策略相比，导致更大程度的功能恢复。目标#1 是评估 HFM 插管套筒内丝束的堆积密度对体外轴突的定向生长长度和方向性的影响。目标#2是使用体内脊髓半切模型检查多丝桥接装置促进轴突生长的效率。目标 #3 是确定旨在 1) 增强跨病变间隙的定向再生，2) 抑制设备-宿主界面处神经胶质疤痕形成的组合策略是否会进一步促进腰椎中央模式发生器（CPG；位于 L1-2 段内负责后肢运动功能的完整神经回路）的轴突生长，从而导致解剖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.