Long-Gap Nerve Regeneration by Pleiotrophic Support in Multiluminal Grafts

多腔移植物中多营养支持的长间隙神经再生

• 批准号: 8196684
• 负责人: Mario Ignacio Romero-Ortega
• 金额: $ 20.95万
• 依托单位: UNIVERSITY OF TEXAS ARLINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8196684
• 关键词: Address; Area; Autologous Transplantation; Axon; Biocompatible Materials; Biological; Biomimetics; Cell Proliferation; Clinical; Clinical Research; Collagen; Defect; Distal; Effectiveness; Electron Microscopy; Electrophysiology (science); Encapsulated; Evaluation; Extracellular Matrix; FDA approved; Failure; Fibroblasts; Filler; Goals; Growth; Growth Factor; Harvest; Hydrogels; Implant; In Vitro; Injury; Label; Mediating; Methods; Mitogens; Modeling; Morbidity - disease rate; Motor; NTF3 gene; Natural regeneration; Neonatal; Nerve; Nerve Growth Factors; Nerve Regeneration; Neural Conduction; Neuroglia; Neurons; Neurotrophin 3; Oryctolagus cuniculus; Peripheral Nerves; Polyglycolic Acid; Polymers; Procedures; Property; Recovery of Function; Relative (related person); Research; Risk; Schwann Cells; Sensory; Spinal Cord; Testing; Tissue Engineering; Tissue Harvesting; Tube; Tubular formation; Vascularization; Wound Healing; axon growth; axon regeneration; base; behavior test; biosynthetic material; cell motility; combinatorial; controlled release; design; injured; morphometry; nerve gap; nerve injury; neurotrophic factor; novel; particle; peroneal nerve; pleiotrophin; receptor; regenerative; repaired; scaffold; standard of care; syndecan

DESCRIPTION (provided by applicant): Several simple hollow tubes made of biosynthetic materials (i.e.,) polylactic-co-e-coprolactone, polyglycolide, collagen) are currently FDA-approved and have demonstrated clinical benefit in the repair of short nerve gaps. However, autografts remain the treatment of choice for nerve defects despite the need of donor nerve harvest and the associated morbidity of this procedure. In contrast to short gap injuries, autografts achieve minimal functional recovery for nerve defects longer than 30 mm and simple tubularization methods fail completely in repairing this critical gap. The regenerative failure of peripheral nerves through long-gaps seems to be due at least in part, to the lack of appropriate growth substrate and trophic support. We hypothesize that a growth factor strategy targeted to a broad cellular base in the regenerating nerves would be highly effective in achieving simultaneous cellularization, vascularization and nerve regeneration through long nerve gaps. A systematic evaluation of the trophic support needed for long-gap nerve repair, as well as the combination of increased regenerative area and pleiotrophic growth factor support is lacking. This study will address this need. In our preliminary studies, we have demonstrated that multiluminal nerve repair and pleiotrophic growth factors can successfully mediate nerve regeneration across a 30 mm gap. The overall goal of the proposed study will be focused on extending these results and systematically test the effect of neurotrophic factors (i.e., NGF and NT-3) alone or combined with PTN in long gap nerve repair. In Specific Aim 1 we will test the regenerative potency of combined Neurotrophin-Pleiotrophin treatment in vitro. In Specific Aim 2 we will evaluate the effect of neurotrophin/pleiotrophic growth factor support over long-gap nerve regeneration of the rabbit common personal nerve. This study is novel in that: 1) utilizes multicellular growth factors to stimulate both glial cellular proliferation and migration, and axonal regeneration, 2) uses collagen-suspended polymeric microparticles with encapsulated growth factors for controlled release, and 3) utilizes a recently developed multiluminal hydrogel nerve scaffold as biomimetic structural support. This research will contribute towards the elucidation of the structural and trophic support required to repair long gap nerve injuries trough biosynthetic nerve implants. PUBLIC HEALTH RELEVANCE: Implantable biosynthetic nerves are promising alternatives to autogenic nerve grafting, the standard of care for gap nerve injuries, due to their ability to mediate functional recovery without the need of sacrificing donor nerves or bearing the risk associated with tissue harvest morbidity. However, repairing critical gaps longer than 30 mm remains a formidable challenge. This research will contribute towards the elucidation of the structural and trophic support required to repair long gap nerve injuries trough biosynthetic nerve implants.

描述（由申请人提供）：目前由FDA批准了几个由生物合成材料（即）polycyco-e-coprolactone，聚乙二醇化蛋白，胶原蛋白制成的简单空心管（即），并且在修复短神经间隙的修复方面已显示出临床益处。 然而，尽管需要供体神经收获以及该过程的相关发病率，但自体移植仍然是神经缺陷的选择治疗。 与短间隙损伤相反，自体移植可实现超过30 mm的神经缺陷的最小功能恢复，而简单的管状方法在修复这一临界差距方面完全失败了。 周围神经通过长距离的再生失败似乎至少部分是由于缺乏适当的生长底物和营养支持。 我们假设针对再生神经中广泛细胞基础的生长因子策略将在通过长神经间隙同时实现同时的细胞化，血管化和神经再生方面非常有效。 缺乏对长期神经修复所需的营养支持的系统评估，以及增加的再生区域和多核营养生长因子支持的组合。 这项研究将满足这一需求。 在我们的初步研究中，我们已经证明了多腔神经修复和多毒性生长因子可以成功介导30 mM间隙的神经再生。 拟议研究的总体目标将集中在扩展这些结果上，并系统地测试单独使用神经营养因素（即NGF和NT-3）的作用，或在长​​间隙神经修复中与PTN结合。 在特定的目标1中，我们将在体外测试神经营养蛋白 - 促发育蛋白治疗的再生效力。 在特定的目标2中，我们将评估神经营养蛋白/多营养营养因子支持对兔子普通神经的长距离神经再生的影响。 这项研究是新颖的：1）利用多细胞生长因子刺激神经胶质细胞增殖和迁移，以及轴突再生，2）使用胶原蛋白悬浮的聚合物微粒微粒具有控制释放的封装生长因子，以及3）使用了最近开发的多氨基型水凝胶Nerve Nerve scapfaffold scapfaffold cackaffold accaffold susteral Support。 这项研究将有助于阐明修复长间隙神经损伤所需的结构和营养支持。 公共卫生相关性：可植入的生物合成神经是自体神经嫁接的有希望的替代方法，这是间隙神经损伤的护理标准，因为它们可以介导功能恢复而无需牺牲供体神经或承受与组织收获的疾病相关的风险。 但是，修复超过30毫米的关键差距仍然是一个巨大的挑战。 这项研究将有助于阐明修复长间隙神经损伤所需的结构和营养支持。