Surface Modified Nanofibers for Nerve Regeneration

用于神经再生的表面改性纳米纤维

• 批准号: 7888207
• 负责人: JOSEPH M. COREY
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7888207
• 关键词: Action Potentials; Activities of Daily Living; Adhesions; American; Atrophic; Autologous; Autologous Transplantation; Axon; Binding; Biochemical; Biological Assay; Caliber; Cues; Disabled Persons; Effectiveness; Extracellular Matrix Proteins; Face; Fiber; Glycolic-Lactic Acid Polyester; Growth; Growth Factor; Implant; In Vitro; Inferior; Injury; Integrin Binding; Knowledge; Laminin; Lead; Left; Length; Limb structure; Measures; Membrane; Modeling; Morbidity - disease rate; Motor; Motor Neurons; Muscle; Natural regeneration; Nerve; Nerve Regeneration; Neurites; Neurons; Operative Surgical Procedures; Outcome; Patients; Peptides; Performance; Peripheral Nerves; Peripheral nerve injury; Polymers; Population; Production; Proteins; Rattus; Recovery; Soldier; Solutions; Speed; Spinal; Spinal Ganglia; Surface; Surgeon; Technology; Testing; Time; Transplanted tissue; Travel; Walking; Woman; combat; disability; implantation; improved; in vivo; injured; nanofiber; nerve autograft; nerve gap; nerve injury; neurite growth; prevent; promoter; protein aminoacid sequence; reinnervation; repaired; research study; scaffold; sciatic nerve; standard of care; tissue culture; tool; tyrosyl-isoleucyl-glycyl-seryl-arginine

Two central problems exist in nerve repair after traumatic injury. The first is finding a nerve guide suitable for large gaps in large diameter nerves. The second is that regeneration from proximal injuries occurs too slowly, which allows target muscle to atrophy, preventing reinnervation and functional motor recovery after regenerating neurites arrive. Nerve guides that accelerate regeneration could improve motor recovery after nerve repair. Most nerve guides produce inferior results, even when filled or coated with extracellular matrix proteins (ECM) or growth factors that promote neurite outgrowth, including laminin, regarded as the most potent substrate-bound promoter of neurite outgrowth. Recently, aligned nanofibers have been introduced into nerve guidance channels to provide topographical cues that direct regenerating neurites. These fibers have been found to orient, direct, and promote faster growth of regenerating neurites in vitro and in vivo. However, their performance still lags behind autografts. Since the primary problem in achieving functional regeneration slow speed, we hypothesize that taking peptide sequences from laminin that promote neurite outgrowth and covalently-binding them to aligned nanofibers could speed nerve regeneration and make it more effective. A proposal to fabricate and test such fibers is presented. Specific aim 1 begins with electrospinning poly(lactide-co-glycolide) (PLGA) nanofibers that can be covalently bound to IKVAV, a peptide in laminin that promotes neurite growth. Fibers will be characterized for alignment, diameter, and rate of degradation. Dissociated motor neurons and dorsal root ganglia explants will be grown on these surfaces and their neurite outgrowth assayed to compare to controls without IKVAV and to laminin-coated controls. In specific aim 2, gradients of IKVAV and YIGSR, another laminin peptide, will be covalently bound to PLGA nanofibers to see if gradients cause faster neurite growth. These fibers will be tested similarly as fibers in aim 1. In specific Aim 3, longitudinally-oriented aligned nanofibers will be placed in semipermeable membranes as nerve guides and implanted in rat sciatic nerve gaps. In these experiments, PLGA with covalently bound fibers as developed in the first two aims will be compared against plain fibers and autologous nerve grafts. It is hoped that this project will further knowledge of both the production of functionalized nanofiber nerve guides and their potential to be harnessed as a tool for nerve regeneration.

创伤后神经修复中存在两个核心问题。首先是找到合适的神经指南 对于大直径神经中的较大间隙。第二个是近端受伤的再生 慢慢地，这使目标肌肉能够萎缩，以防止在 再生神经突到达。神经指南，加速再生可以改善运动能力 神经修复。 大多数神经指南都会产生较低的结果，即使填充或涂有细胞外基质蛋白 （ECM）或促进神经突生长的生长因素，包括层粘连蛋白，被认为是最有效的 神经突生长的底物启动子。最近，对齐的纳米纤维已被引入神经 指导渠道提供直接再生神经突的地形线索。这些纤维一直 在体外和体内发现，指导，直接和促进再生神经突的生长。但是，他们 性能仍然落后于自动移植。由于实现功能再生的主要问题慢 速度，我们假设从层层粘连蛋白中服用肽序列，从而促进神经突生长和 将它们共价结合到对齐的纳米纤维可以加快神经再生并使其更有效。 提出了制造和测试此类纤维的建议。特定目标1从静电纺丝开始 聚（乳酸 - 糖糖苷）（PLGA）纳米纤维可以共价结合到IKVAV，这是层粘连蛋白中的肽 促进神经突的生长。纤维的对齐，直径和降解速率的特征。 解离的运动神经元和背根神经节外植体将在这些表面及其神经突在 分析的生长可以与没有IKVAV的对照和粘贴蛋白涂层对照进行比较。在特定的目标2中， IKVAV和YIGSR的梯度是另一种层粘连蛋白肽，将共价绑定到PLGA纳米纤维，以查看是否是否 梯度引起更快的神经突生长。这些纤维的测试将类似于AIM 1中的纤维。在特定的AIM 3中， 纵向的对准纳米纤维将被放置在可半透明的膜中，作为神经指南和 植入大鼠坐骨神经间隙。在这些实验中，具有共价绑定纤维的PLGA在 前两个目标将与普通纤维和自体神经移植物进行比较。 希望该项目能够进一步了解功能化纳米纤维神经的产生 指南及其潜在利用作为神经再生工具的潜力。