Department of Mechanical Engineering, University of Utah, Salt Lake City, Utah.
Department of Bioengineering, University of Utah, Salt Lake City, Utah.
Biotechnol Bioeng. 2019 Jan;116(1):143-154. doi: 10.1002/bit.26837. Epub 2018 Oct 27.
Autologous nerve grafts are the current "gold standard" for repairing large nerve gaps. However, they cause morbidity at the donor nerve site and only a limited amount of nerve can be harvested. Nerve conduits are a promising alternative to autografts and can act as guidance cues for the regenerating axons, without the need to harvest donor nerve. Separately, it has been shown that localized delivery of GDNF can enhance axon growth and motor recovery. FK506, an FDA approved small molecule, has also been shown to enhance peripheral nerve regeneration. This paper describes the design of a novel hole-based drug delivery apparatus integrated with a polytetrafluoroethylene (PTFE) nerve conduit for controlled local delivery of a protein such as GDNF or a small molecule such as FK506. The PTFE devices were tested in a diffusion chamber, and the bioactivity of the released media was evaluated by measuring neurite growth of dorsal root ganglions (DRGs) exposed to the released drugs. The drug delivering nerve guide was able to release bioactive concentrations of FK506 or GDNF. Following these tests, optimized drug releasing nerve conduits were implanted across 10 mm sciatic nerve gaps in a BL6 yellow fluorescent protein (YFP) mouse model, where they demonstrated significant improvement in muscle mass, compound muscle action potential, and axon myelination in vivo as compared with nerve conduits without the drug. The drug delivery nerve guide could release drug for extended periods of time and enhance axon growth in vitro and in vivo.
自体神经移植物是修复大神经间隙的当前“金标准”。然而，它们会在供体神经部位引起发病率，并且只能收获有限量的神经。神经导管是自体移植物的有前途的替代品，可作为再生轴突的导向线索，而无需收获供体神经。另外，已经表明局部递送 GDNF 可以增强轴突生长和运动恢复。FK506 是一种获得 FDA 批准的小分子，也已被证明可以增强周围神经再生。本文描述了一种新型基于孔的药物输送装置的设计，该装置与聚四氟乙烯（PTFE）神经导管集成在一起，用于控制局部递送蛋白质（如 GDNF）或小分子（如 FK506）。在扩散室中测试了 PTFE 装置，并通过测量暴露于释放药物的背根神经节（DRG）的神经突生长来评估释放介质的生物活性。药物输送神经导管能够释放具有生物活性的 FK506 或 GDNF 浓度。在这些测试之后，优化的药物释放神经导管被植入 BL6 黄色荧光蛋白（YFP）小鼠模型中的 10mm 坐骨神经间隙中，与没有药物的神经导管相比，它们在体内显示出肌肉质量，复合肌肉动作电位和轴突髓鞘形成的显着改善。药物输送神经导管可以长时间释放药物，并在体外和体内增强轴突生长。
