Long-Gap Nerve Regeneration by Pleiotrophic Support in Multiluminal Grafts

描述（由申请人提供）：几种由生物合成材料（即聚乳酸-co-e-coprolactone，聚甘油内酯，胶原蛋白）制成的简单中空管目前已获得fda批准，并已证明在修复短神经间隙方面具有临床益处。然而，自体移植物仍然是神经缺损的治疗选择，尽管需要供体神经采集和相关的发病率。与短间隙损伤相比，对于长度大于30 mm的神经缺损，自体移植物的功能恢复最小，简单的管状化方法完全不能修复这一关键间隙。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，针对再生神经的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细胞化，血管化和神经再生方面非常有效。对于长间隙神经修复所需的营养支持，以及增加再生面积和多营养生长因子支持的结合，缺乏系统的评估。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介导30毫米间隙的神经再生。本研究的总体目标将集中在扩展这些结果，系统地测试神经营养因子（即NGF和NT-3）单独或联合PTN在长间隙神经修复中的作用。在特异性目标1中，我们将在体外测试神经营养-多营养联合治疗的再生能力。在专项目标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、迁移和轴突再生；2)利用胶原悬浮聚合物微粒包裹生长因子控释；3)利用新开发的多腔水凝胶神经支架作为仿生结构支撑。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.