Bioengineering bridges to promote axon regeneration following spinal cord injury

描述（由申请人提供）：撞击损伤后脊髓修复的许多病理障碍之一是形成充满液体的囊肿，再生的轴突必须穿过囊肿才能重新支配其远端目标。为此，在之前发表的一项研究中，我们研究并展示了静电纺丝在设计可植入的极化矩阵用于轴突引导方面的潜在用途。然而，人们认识到，成功的脊髓损伤（SCI）治疗需要多方面的方法，包括桥接损伤部位、提供营养支持、定向引导线索和消除生长抑制化合物，从而最大限度地发挥轴突再生和功能恢复的潜力。鉴于此，我们提出了一种新的方法，将促进神经元存活和中和与胶质瘢痕相关的抑制蛋白的药理药物纳入电纺丝引导基质中。具体来说，在Aim 1中，我们计划使用体外研究来评估这些营养因子、引导线索和中和酶在多大程度上可以有效地电纺丝成基质来影响神经炎的生长。随后，在Aim 2中，我们计划在完全性横断性脊髓损伤大鼠模型中手术植入并测试这些增强基质。组织学和行为学实验将分别确定轴突再生和功能改善的程度。总的来说，拟议研究的结果应该导致单一介入策略的发展，促进脊髓损伤后轴突的强大再生，并伴随功能恢复的改善。

DESCRIPTION (provided by applicant): One of the many pathologic obstacles of spinal cord repair following percussive trauma is the formation of a fluid-filled cyst across which regenerating axons have to traverse in order to reinnervate their distal targets. To this end, in a previously published study, we examined and demonstrated the potential use of electrospinning to engineer an implantable polarized matrix for axonal guidance. Nevertheless, it is recognized that successful spinal cord injury (SCI) therapies require a multifaceted approach of bridging the lesion site as well as providing trophic support, directional guidance cues, and neutralizing growth- inhibitory compounds so as to maximize the potential for axonal regrowth and functional recovery. In view of that, we propose a novel approach of incorporating into electrospun guidance matrices pharmacologic agents that can promote neuronal survival and neutralize inhibitory proteins associated with the gliotic scar. Specifically, in Aim 1, we plan to use in vitro studies to assess the extent to which these trophic factors, guidance cues, and neutralizing enzymes can be effectively electrospun into matrices to influence neuritic outgrowth. Subsequently, in Aim 2, we plan to surgically implant and test these enhanced matrices in a rat model of complete transection SCI. Histological and behavioral experiments will be employed to determine the extent of axonal regeneration and functional improvement, respectively. Collectively, the results of the proposed studies should lead to the development of a single interventional strategy that facilitates robust axon regeneration following SCI with concomitant improvements in functional recovery. PUBLIC HEALTH RELEVANCE: More than 250,000 Americans are currently living with spinal cord injury (SCI), a disability that causes untold physical, emotional, and financial hardship for both the patient and the family. It is recognized that successful SCI therapies require a multifaceted approach of bridging the injury site as well as providing trophic support, directional guidance cues, and neutralizing regeneration- inhibitory compounds so as to maximize the potential for neuronal regrowth and functional recovery. This proposal describes a novel approach of generating implantable electrospun matrices that is incorporated with therapeutic agents with the above properties and subsequently testing these matrices in a rat model of SCI.