Wirelessly-operated Implantable MEMS Micropumps for Drug Infusion in Mice

描述（由申请人提供）：小鼠，特别是人类疾病的转基因和基因敲除模型，已用于实验室研究和临床前研究，并对许多领域产生了深远的影响，包括神经科学，医学和药理学。然而，很少有实用的工具存在慢性药物给药小鼠。传统方法最常使用口服、静脉内和腹膜内途径，这些途径涉及对动物的限制和密集处理。动物的手动处理仅提供间歇性给药，已知会诱导应激和其他可能改变实验结果的显著生理影响。使用外部输注泵或植入式渗透泵可实现连续给药。外部泵需要限制自然运动并重塑正常行为的导管系绳。渗透泵具有固定的药物有效载荷，并且不能再填充，这限制了其在慢性研究中的使用。目前没有可植入的泵， 是无线操作的并且可以实现任何期望的药物释放曲线。这些功能的结合将为小鼠和其他较小动物的长期研究中的精确药物给药提供一种新的工具，而无需处理。 为了实现这一目标，我们提出了一种无线操作和可再填充的植入式输液泵，适用于小鼠的慢性给药。该泵平台是基于我们之前为大鼠和兔子等大型动物开发植入式泵的经验。在这里，我们将解决工程挑战，使规模减少十倍，实现鼠标泵。这是通过使用微制造技术来减小泵组件的尺寸而不影响其电气或机械性能来实现的（具体目标1）。泵将与无线遥测和软件图形用户界面组装和集成，使用户能够在标准小鼠笼内的任何位置启动泵的远程激活（特定目标2）。我们将证明药物给药的精确控制，从而可以通过使用WIIP将化合物递送到模拟生物材料中来实现任何期望的药物释放曲线（具体目标3）。WIIP将在长期实验中以免手、免针和免栓的方式实现前所未有的体内药物分布控制。通过这样做，WIIP将使研究能够在更自然的环境中进行，更可靠地评估药物反应，而不会产生与压力相关的伪影，并允许通过人工动物/人类相互作用进行全天候药物输送。WIIP为实验室研究和临床前研究提供了一种变革性的新工具，适用于广泛的生物医学应用。

DESCRIPTION (provided by applicant): Mice, especially transgenic and knockout models of human diseases, have been used in laboratory research and preclinical studies and have had profound impact on many fields, including neuroscience, medicine, and pharmacology. However, few practical tools exist for chronic drug administration in mice. Traditional methods most frequently utilize the oral, intravenous, and intraperitoneal routes that involve restraining and intensive handling of animals. Manual handling of animals provides only intermittent dosing and is known to induce stress and other significant physiological impacts that may alter experimental outcomes. Continuous dosing is possible with external infusion pumps or implantable osmotic pumps. External pumps require catheter tethers that limit natural movement and reshapes normal behavior. Osmotic pumps have a fixed drug payload and cannot be refilled which limits their use in chronic studies. No implantable pump is currently available that is wirelessly-operated and can achieve any desired drug release profile. The combination of these capabilities will provide a new tool for precise drug administration in chronic studies in mice and other smaller animals without the need for handling. To achieve this goal, we propose a wirelessly-operated and refillable implantable infusion pump that is suitable for chronic drug administration in mice. This pump platform is based on our prior experience developing implantable pumps for larger animals such as rats and rabbits. Here, we will address the engineering challenges to enable a tenfold reduction in scale required to realize a mouse pump. This is enabled by using microfabrication techniques to reduce the size of pump components without compromising their electrical or mechanical performance (Specific Aim 1). Pumps will be assembled and integrated with wireless telemetry and a software graphical user interface that enables user-initiated remote activation of the pump anywhere within a standard mouse cage (Specific Aim 2). We will demonstrate precise control of drug administration such that any desired drug release profile can be achieved by using WIIP to deliver compounds into simulated biological materials (Specific Aim 3). WIIP will enable unprecedented control of drug profiles in vivo in long term experiments in a hands-free, needle-free, and tether-free manner. In doing so, WIIP will enable studies in more naturalistic environments, more reliable assessment of drug responses without stress-related artifacts, and allow around-the-clock drug delivery with artificial animal/human interactions. WIIP provides a transformative new tool for both laboratory research and preclinical studies that is applicable to a broad range of biomedical applications.