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.
The outcome of this research plan will be a wirelessly-operated implantable pump suitable for use in mice for laboratory research and preclinical studies. This electronically-operated pump uniquely offers remote user-initiated drug administration and allows any drug release profile. Our technology opens new avenues for drug administration in drug-induced, transgenic, and knockout mouse models, and provides a unique experimental tool for applications in many fields including neuroscience, pharmacology, animal behavior, and physiology.