Multi-functional Polymer Structures for Promoting Neurite Extension and Myelination

非技术：每年在美国，数百万人遭受由于意外创伤或在手术过程中发生的外周神经损伤。无法恢复受损的神经导致肌肉功能丧失、感觉受损和疼痛性神经病。自体神经移植是外科手术的“金标准”，但存在来源有限、需额外手术、供神经与损伤神经不匹配等缺点。因此，需要合成神经导管来桥接受伤的周围神经残端之间的长间隙。用于制造合适的神经导管的聚合物应具有抗撕裂能力、可缝合性以及易于与支持细胞和神经生长因子（NGF）结合的能力。只有少数可交联和可生物降解的用于神经导管的微制造，并且如何实现最佳的材料环境以最大化神经元和胶质细胞功能和轴突生长在很大程度上是未知的。PI提出了一种创新和独特的解决方案，用于制造具有复杂多组分结构和多种功能的可生物降解聚合物神经导管。通过使用聚合物的广泛物理化学和结构特性进行全面、系统的研究，PI将实现基本的理解和实际有用的医疗设备，以促进材料、生物医学工程和医学研究领域之间的技术知识协同转移。技术：PI建议整合由聚（乙二醇）、聚（ε-己内酯）和聚（L-赖氨酸）合成的光反应性、可生物降解的聚合物和生物活性试剂（例如，神经生长因子和细胞粘附肽），通过无溶剂工艺转化为多组分、多功能结构，具有广泛的物理化学性质和结构特征，可促进周围神经修复。使用这些聚合物结构，PI提出实现基本理解聚合物物理化学性质如何调节神经元的行为和功能（例如，背根神经节神经元）和神经胶质细胞（例如，条件永生化的许旺细胞前体系细胞），然后优化以使神经突延伸和髓鞘形成最大化。除了材料和工艺参数之外，优化的聚合物结构将指导更精确的神经导管的微制造，以及它们的体内动物植入和组织学分析。所提出的制造方法和药物递送系统也可以应用于其他组织工程应用。PI建议提供脚手架和细胞调节的开放访问;生物材料制造和加工课程;本科生，少数民族和代表性不足的群体的夏季研究经验;通过外展计划向K-12学生传播发现;通过大学预科研究学者计划和远程教育为公立高中教师和学生开发实验室/课程模块。

Non-Technical: Each year in the U.S., several million people suffer from peripheral nerve injuries that occur with accidental trauma or during the course of surgery. Failure to restore damaged nerves leads to the loss of muscle function, impaired sensation, and painful neuropathies. Autologous nerve graft, the "gold standard" in surgery, has disadvantages such as limited source, additional surgery, and mismatch between injured nerve and donor nerve. Synthetic nerve conduits are thus needed for bridging the long gap between injured peripheral nerve stumps. Polymers used for fabricating suitable nerve conduits should have capability of resisting tear, suturability, and ease of incorporation with support cells and nerve growth factor (NGF). There only exist a few crosslinkable and biodegradable ones for microfabrication of nerve conduits and it is largely unknown how to achieve optimal material environment to maximize neuronal and glial cell functions and axonal growth. The PI proposes an innovative and unique solution to manufacture biodegradable polymer nerve conduits with complex multi-component structures and multiple functionalities. By performing comprehensive, systematic studies using a wide range of physicochemical and structural characteristics of polymers, the PI will achieve both fundamental understanding and practically useful medical devices for fostering the synergistic transfer of know-how among research communities of materials, biomedical engineering, and medicine.Technical: The PI proposes to integrate photo-reactive, biodegradable polymers synthesized from poly(ethylene glycol), poly(epsilon-caprolactone), and poly(L-lysine), and bioactive reagents (e.g., NGF and cell-adhesive peptides), via solvent-free processes into multi-component, multi-functional structures with a wide range of physicochemical properties and structural features for promoting peripheral nerve repair. Using these polymer structures, the PI proposes to achieve fundamental understanding how polymer physicochemical properties regulate the behaviors and functions of both neuronal (e.g., dorsal root ganglion neurons) and glial cells (e.g., conditionally immortalized Schwann cell precursor line cells), and then optimized to maximize neurite extension and myelination. As well as the materials and processing parameters, the optimized polymer structures will guide more precise micro-fabrication of nerve conduits, and their in vivo animal implantation and histological analysis. The proposed fabrication method and drug delivery systems can also be applied to other tissue engineering applications. The PI proposes to provide an open access of scaffolding and cell regulation; curriculum on Biomaterials Fabrication and Processing; summer research experience for undergraduates, minorities, and underrepresented groups; disseminate discoveries to K-12 students through outreach programs; and develop lab/course modules for public high-school teachers and students through Pre-collegiate Research Scholars Program and distance education.