Conscious ambulatory bladder monitoring to understand neural control of lower urinary tract function

摘要 神经控制下尿路(LUT)在健康和疾病中的潜在机制，包括病理发展机制，目前尚不清楚。新的神经生理学实验正在清醒的行为动物中进行，以解决知识差距，而不是在麻醉下进行，但在慢性实验期间监测膀胱功能仍然是一个挑战。目前的技术可以通过手术放置的耻骨上导管来无线监测膀胱压力，但这些技术受到限制，因为它们不测量膀胱体积，这是一个重要的变量；导管可能会刺激膀胱并混淆数据；接收线圈不可携带，这需要动物留在有限的空间内进行数据收集；而且该技术不能扩大到未来的人类应用。在清醒、行为正常的动物或人类的慢性实验中，需要一种无线的、无导管的膀胱压力和容量传感器，以阐明LUT在健康和疾病中的神经生理学功能。 我们已经开发了一种小型、无线、无导管的压力传感器原型，它可以充电并可以传输连续的压力数据。在这一成功的基础上，我们增加了容量传感器，并改进了用于膀胱内放置的包装。这种新设备名为尿路意识活动监测仪(UroMOCA)，它将能够连续测量膀胱内的压力和容量数据，并将数据无线传输到一个小型可穿戴接收器单元。我们在动物膀胱中测试了一种潜在的包装形式，以证明它不会排出尿液，也不会阻碍膀胱的排空。我们还测试了一种估算体积的电导法，即在两个外电极之间传递非常小的电流，在膀胱内的尿液中的两个内电极之间测量电压，我们使用这种方法来根据欧姆定律确定电导。通过知道电导、尿液的电导和电极之间的间距，我们能够估计膀胱体积，这种方法可以并入UroMOCA。 这项提案的目标是制定和验证UroMOCA。这项研究的中心假设是，UroMOCA将无线地为未来的神经生理学实验提供准确的膀胱压力和容量测量，这一点得到了标准尿流动力学工具和清醒行走动物测试的验证。拟议工作的目标是(1)开发用于膀胱内压力和体积测量的UroMOCA，方法是在我们以前的设计基础上增加体积测量，并将设备重新封装到新的外形因素中，以及(2)通过在急性死亡和慢性非存活动物实验中的测试来验证设备的生物兼容性和功能。此外，我们正在利用我们的无线传感器平台开发一种肠道传感器系统，该系统将确定肠道充盈度和活动性，用于研究和诊断应用。对于肠道感应，该项目将专注于确定适当的感觉模式、传感器形状因素和确定肠道状态的策略。完成拟议的研究目标将提供重要的工具，这些工具可与神经、心电图、肌电或其他记录结合使用，供研究有意识的非卧床实验期间下尿路或肠道的神经控制的研究人员使用。它还将为下一代神经调节疗法的设计提供信息，以改善或恢复LUT功能，例如通过提供闭环式LUT控制。

ABSTRACT Mechanisms underlying neural control of the lower urinary tract (LUT) in health and disease, including mechanisms of pathology development, are not well understood. New neurophysiology experiments to address knowledge gaps are being conducted in awake, behaving animals, rather than under anesthesia, but monitoring bladder function during chronic experiments remains a challenge. Current technologies can be used to wirelessly monitor bladder pressure via a surgically placed suprapubic catheter, but these technologies are limited because they do not measure bladder volume, which is an important variable; the catheter may irritate the bladder and confound the data; the receiver coil is not portable, which requires the animal to remain in a confined space for data collection; and the technology does not scale up to future human applications. A wireless, catheter-free bladder pressure and volume sensor is needed for chronic experiments in awake, behaving animals or humans to elucidate the neurophysiology of LUT function in health and disease. We have developed a prototype for a small, wireless, catheter-free pressure transducer that is rechargeable and can transmit continuous pressure data. We are building on this success by adding volume sensing and modifying the packaging for intravesical bladder placement. This new device, the Urological Monitor of Conscious Activity (UroMOCA), will be able to continuously measure and wirelessly transmit pressure and volume data from within the bladder to a small, wearable receiver unit. We have tested a potential packaging form factor in an animal bladder to demonstrate that it is not voided, nor does it obstruct bladder emptying. We have also tested an electrical conductance method of estimating volume wherein a very small current is passed between two outer electrodes and voltage is measured between two inner electrodes within the urine contained in the bladder, which we use to determine conductance from Ohm’s Law. By knowing the conductance, the conductivity of the urine, and the spacing between our electrodes, we were able to estimate bladder volume and this method can be incorporated into the UroMOCA. The goal of this proposal is to develop and validate the UroMOCA. The central hypothesis of this research is that the UroMOCA will wirelessly provide accurate bladder pressure and volume measurements for future neurophysiology experiments as validated by standard urodynamics tools and testing in conscious ambulating animals. The objectives of the proposed work are to (1) develop the UroMOCA for intravesical pressure and volume measurements by adding volume measurement to our previous design and repackaging the device into a new form factor and (2) validating the biocompatibility and function of the device by testing in acute nonsurvival and chronic ambulatory animal experiments. In addition, we are leveraging our wireless sensor platform to develop a bowel sensor system that will determine bowel fullness and activity for use in research and diagnostic applications. For bowel sensing, this project will focus on identifying appropriate sensory modalities, sensor form factor, and a strategy for determining bowel state. Completion of the proposed research objectives will provide important tools, which could be used in conjunction with nerve, electrocardiogram, electromyography or other recordings, for use by investigators studying the neural control of the lower urinary tract or bowel during conscious ambulatory experiments. It will also inform the design of next generation neuromodulation therapies to improve or restore LUT function, such as by providing closed-loop LUT control.