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）：由生物合成材料制成的几个简单空心管（即，）聚乳酸-共-ε-己内酯、聚乙交酯、胶原蛋白）目前是FDA批准的，并且已经证明在修复短神经间隙中的临床益处。 然而，自体移植物仍然是治疗神经缺损的选择，尽管需要供体神经收获和相关的发病率，这一程序。 与短间隙损伤相比，对于长度超过30 mm的神经缺损，自体移植物实现了最小的功能恢复，并且简单的管状化方法完全无法修复这一关键间隙。 周围神经通过长间隙的再生失败似乎至少部分是由于缺乏适当的生长基质和营养支持。 我们假设，一个生长因子的战略，以广泛的细胞基础，在再生的神经将是非常有效的，在实现同时细胞化，血管化和神经再生通过长神经间隙。 缺乏对长间隙神经修复所需的营养支持以及增加再生面积和多效性生长因子支持的组合的系统评价。 本研究将满足这一需求。 在我们的初步研究中，我们已经证明，多腔神经修复和多效性生长因子可以成功地介导神经再生跨越30毫米的差距。 拟议研究的总体目标将集中在扩展这些结果并系统地测试神经营养因子的作用（即，NGF和NT-3）单独或与PTN联合用于长间隙神经修复。 在具体目标1中，我们将在体外测试神经营养因子-多效营养因子组合治疗的再生效力。 在具体目标2中，我们将评估神经营养因子/多效性生长因子支持对兔个人总神经长间隙神经再生的影响。 本研究的新颖之处在于：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）使用胶原悬浮的聚合物微粒与封装的生长因子进行控制释放，以及3）利用最近开发的多腔水凝胶神经支架作为仿生结构支撑。 这项研究将有助于阐明所需的结构和营养支持，以修复长间隙神经损伤通过生物合成神经植入物。 公共卫生关系：可植入生物合成神经是自体神经移植的有前途的替代品，自体神经移植是间隙神经损伤的护理标准，因为它们能够介导功能恢复，而不需要牺牲供体神经或承担与组织收获发病相关的风险。 然而，修复超过30毫米的关键间隙仍然是一个艰巨的挑战。 这项研究将有助于阐明所需的结构和营养支持，以修复长间隙神经损伤通过生物合成神经植入物。