Long-Gap Nerve Regeneration by Pleiotrophic Support in Multiluminal Grafts

描述(申请人提供)：几种由生物合成材料制成的简单中空管(即，聚乳酸-共聚-e-共丙内酯、聚乙交酯、胶原)目前已获得FDA批准，并已在修复短神经间隙方面显示出临床益处。然而，尽管需要供体神经采集和相关的并发症，自体移植仍然是治疗神经缺损的首选方法。与短间隙损伤相比，对于大于30 mm的神经缺损，自体移植可以实现最小的功能恢复，而简单的管状化方法完全无法修复这个关键的间隙。周围神经通过长时间的缝隙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，以再生神经中广泛的细胞基础为靶点的生长因子策略将非常有效地通过长时间的神经间隙实现同时的细胞化、血管化和神经再生。缺乏对长间隙神经修复所需的营养支持的系统评估，以及增加的再生面积和多营养生长因子支持的组合。这项研究将解决这一需求。在我们的初步研究中，我们已经证明了多腔神经修复和多营养生长因子可以成功地跨30 mm的间隙介导神经再生。这项研究的总体目标将集中于推广这些结果，并系统地测试神经营养因子(即NGF和NT-3)单独或与PTN联合应用在长间隙神经修复中的作用。在特定的目标1中，我们将测试神经营养因子-多效营养因子联合治疗的体外再生能力。在特定的目标2中，我们将评估神经营养因子/多营养生长因子支持对长间隙神经再生的影响。本研究的创新之处在于：1)利用多细胞生长因子刺激神经胶质细胞的增殖、迁移和轴突再生，2)利用胶原蛋白悬浮的聚合物微粒与生长因子复合进行控制释放，3)利用新近开发的多腔水凝胶神经支架作为仿生结构支架。本研究将有助于阐明通过生物合成神经植入物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移植的有希望的替代方案，自体神经移植是治疗缝隙神经损伤的标准，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毫米的关键缺口仍然是一项艰巨的挑战。本研究将有助于阐明通过生物合成神经植入物修复长间隙神经损伤所需的结构和营养支持。

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.