Incorporation of double-walled microspheres into polymer nerve guides for the sustained delivery of glial cell line-derived neurotrophic factor
Incorporation of double-walled microspheres into polymer nerve guides for the sustained delivery of glial cell line-derived neurotrophic factor
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DOI：
10.1016/j.biomaterials.2009.11.075
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发表时间：
2010-03-01
期刊：
影响因子：
14
通讯作者：
Marra, Kacey G.
中科院分区：
文献类型：
--
作者：
Kokai, Lauren E.;Ghaznavi, Amir M.;Marra, Kacey G.
本研究的目的是开发一种可生物降解的聚合物神经引导剂，在横切的周围神经从近端神经残端穿过到远端神经残端所需的一段时间内，局部递送生理相关浓度的生物活性神经营养因子。神经营养因子的输送可能会促进神经再生，并有可能用于克服目前在大缺陷神经修复方面的局限性。神经胶质细胞系衍生神经营养因子（GDNF）是一种已知的轴突延伸和分支的启动子，在神经引导下的神经再生分析中显示出有希望的临床前结果。此外，GDNF已被证明可促进雪旺细胞的增殖和迁移。在这项研究中，我们创建了一个具有生物活性的GDNF的双壁微球递送系统，其体外缓释谱为50天。微球被纳入可降解的聚己内酯神经导管内，其分布可重复。通过大鼠坐骨神经间隙1.5 cm的缺损植入神经导向器，6周后神经导向器管腔近端和远端组织整合均增加。此外，外植体远端区域的横切面显示有雪旺细胞存在，而阴性对照则没有。雪旺细胞向双壁微球的迁移表明，具有生物活性的GDNF被包裹并递送到神经导向的内环境中。由于GDNF增加了神经导管腔内的组织形成，也促进了雪旺细胞的迁移和增殖，因此本研究中提出的神经导管有望开发出一种现成的替代产品，以促进神经再生，而不是目前可用的神经导管。2009爱思唯尔有限公司版权所有。
The purpose of this study was to develop a biodegradable polymer nerve guide that locally delivers bioactive neurotrophic factors in physiologically relevant concentrations for the period required by transected peripheral nerves to cross from the proximal to distal nerve stump. Delivery of a neurotrophic factor may enhance nerve regeneration and could potentially be used to overcome the current limitations in nerve repair across large defects. Glial Cell Line-Derived Neurotrophic Factor (GDNF) is a known promoter of axonal elongation and branching and has shown promising pre-clinical results in analysis of nerve regeneration with nerve guides. In addition, GDNF has been shown to promote Schwann cell proliferation and migration. In this study we have created a double-walled microsphere delivery system for bioactive GDNF with a sustained release profile >50 days in vitro. Microspheres were incorporated within degradable poly(caprolactone) nerve guides in a reproducible distribution. Implantation of nerve guides across a 1.5 cm defect in a rat sciatic nerve gap resulted in an increase in tissue integration in both the proximal and distal segments of the lumen of the nerve guide after 6 weeks. In addition, transverse sections of the distal region of the explanted guides showed the presence of Schwann cells while none were detectable in negative control guides. Migration of Schwann cells to double-walled microspheres indicated that bioactive GDNF was encapsulated and delivered to the internal environment of the nerve guide. Because GDNF increased tissue formation within the nerve guide lumen and also promoted the migration and proliferation of Schwann cells, the nerve guides presented within this study show promise toward the development of an off-the-shelf product alternative that promotes nerve regeneration beyond that capable with currently available nerve guides. (C) 2009 Elsevier Ltd. All rights reserved.