Tandon Vishal, Kang Woo Seok, Spencer Abigail J, Kim Ernest S, Pararas Erin E L, McKenna Michael J, Kujawa Sharon G, Mescher Mark J, Fiering Jason, Sewell William F, Borenstein Jeffrey T
Charles Stark Draper Laboratory, Cambridge, MA, 02139, England.
Biomed Microdevices. 2015 Apr;17(2):37. doi: 10.1007/s10544-014-9923-8.
One of the major challenges in treatment of auditory disorders is that many therapeutic compounds are toxic when delivered systemically. Local intracochlear delivery methods are becoming critical in emerging treatments and in drug discovery. Direct infusion via cochleostomy, in particular, is attractive from a pharmacokinetics standpoint, as there is potential for the kinetics of delivery to be well-controlled. Direct infusion is compatible with a large number of drug types, including large, complex molecules such as proteins and unstable molecules such as siRNA. In addition, hair-cell regeneration therapy will likely require long-term delivery of a timed series of agents. This presents unknown risks associated with increasing the volume of fluid within the cochlea and mechanical damage caused during delivery. There are three key requirements for an intracochlear drug delivery system: (1) a high degree of miniaturization (2) a method for pumping precise and small volumes of fluid into the cochlea in a highly controlled manner, and (3) a method for removing excess fluid from the limited cochlear fluid space. To that end, our group is developing a head-mounted microfluidics-based system for long-term intracochlear drug delivery. We utilize guinea pig animal models for development and demonstration of the device. Central to the system is an infuse-withdraw micropump component that, unlike previous micropump-based systems, has fully integrated drug and fluid storage compartments. Here we characterize the infuse-withdraw capabilities of our micropump, and show experimental results that demonstrate direct drug infusion via cochleostomy in animal models. We utilized DNQX, a glutamate receptor antagonist that suppresses CAPs, as a test drug. We monitored the frequency-dependent changes in auditory nerve CAPs during drug infusion, and observed CAP suppression consistent with the expected drug transport path based on the geometry and tonotopic organization of the cochlea.
治疗听觉障碍的主要挑战之一是，许多治疗性化合物经全身给药时具有毒性。局部耳蜗内给药方法在新兴治疗和药物研发中变得至关重要。特别是通过蜗窗造口术进行直接输注，从药代动力学角度来看很有吸引力，因为给药动力学有可能得到很好的控制。直接输注与大量药物类型兼容，包括蛋白质等大分子和小干扰RNA等不稳定分子。此外，毛细胞再生疗法可能需要长期定时递送一系列药物。这带来了与耳蜗内液体量增加相关的未知风险以及递送过程中造成的机械损伤。耳蜗内药物递送系统有三个关键要求：（1）高度小型化；（2）一种以高度可控的方式将精确且少量的液体泵入微耳的方法；（3）一种从有限的耳蜗液空间中去除多余液体的方法。为此，我们团队正在开发一种基于微流控技术的头戴式系统，用于长期耳蜗内药物递送。我们利用豚鼠动物模型来开发和演示该装置。该系统的核心是一个注入-抽出微泵组件，与以前基于微泵的系统不同之处在于，它具有完全集成的药物和液体储存隔室。在此，我们对微泵的注入-抽出能力进行了表征，并展示了在动物模型中通过蜗窗造口术进行直接药物输注的实验结果。我们使用了抑制复合动作电位（CAPs）的谷氨酸受体拮抗剂DNQX作为测试药物。在药物输注过程中，我们监测了听神经复合动作电位随频率的变化，并观察到复合动作电位受到抑制，这与基于耳蜗的几何结构和音频定位组织所预期的药物传输路径一致。
