Bioengineering bridges to promote axon regeneration following spinal cord injury

描述(申请人提供)：撞击伤后脊髓修复的许多病理障碍之一是形成一个充满液体的囊，再生轴突必须穿过该囊以重新支配其远端靶点。为此，在之前发表的一项研究中，我们检查并演示了利用电子旋转来设计用于轴突引导的可植入极化矩阵的潜在用途。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来桥接损伤部位，并提供营养支持、定向指导线索和中和生长抑制化合物，以最大限度地提高轴突再生和功能恢复的潜力。有鉴于此，我们提出了一种新的方法，将药物整合到电纺引导矩阵中，以促进神经元存活并中和与胶质瘢痕相关的抑制蛋白。具体地说，在目标1中，我们计划使用体外研究来评估这些营养因子、指导线索和中和酶可以有效地电旋转到基质中以影响神经元性生长的程度。随后，在目标2中，我们计划在大鼠完全性脊髓横断损伤模型中手术植入并测试这些增强的基质。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。总而言之，建议的研究结果应该导致开发一种单一的干预策略，促进脊髓损伤后强大的轴突再生，并伴随着功能恢复的改善。 与公共卫生相关：目前有超过25万美国人患有脊髓损伤(SCI)，这是一种残疾，给患者和家人带来了数不清的身体、情感和经济困难。人们认识到，成功的脊髓损伤治疗需要一种多方面的方法来桥接损伤部位，并提供营养支持、定向指导线索和中和再生抑制化合物，以最大限度地促进神经元再生和功能恢复。这项建议描述了一种新的方法来产生可植入的电纺基质，该基质与具有上述性质的治疗剂结合在一起，并随后在大鼠脊髓损伤模型中测试这些基质。

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.