Development of wireless, wearable flow sensors for continuous, long-term tracking of cerebrospinal fluid dynamics in patients with hydrocephalus

脑积水是由脑脊液（CSF）在大脑中积聚引起的一种常见疾病，其症状包括头痛、嗜睡、癫痫发作、昏迷或死亡，在美国影响着100万患者。治疗方法通常是手术植入导管，即脑室分流术，将大脑中多余的脑脊液转移到远端吸收部位。总体而言，美国每年植入或更换125,000个分流器，每年的费用估计为20亿美元。我们已经确定了脑积水诊断中两个未满足的需求：(i)精确、快速、无创地监测分流功能的方法；（ii）由于缺乏直接、连续的血流监测技术，临床对分流术的脑脊液流体动力学知识存在较大差距。为了满足这一需求，Rhaeos开发了第一款用于脑脊液流量监测的可穿戴无线传感器。我们的第一个平台Flow Sense，利用小型化的热传感器和执行器来绘制通过皮肤的热传输图，作为皮下液体流动的测量，以进行快速抽查，解决上述第一个挑战。将这些功能扩展到包括24小时连续监测脑脊液流量，特别是在睡眠期间，将有利于脑积水的治疗、护理和理解。我们假设连续测量将提供并允许强大的门诊监测和增强住院监测能力，特别是在急诊科。由此产生的技术，如果成功，可以减少不必要的住院和缩短病人住院时间，允许在病人家中直接监测。此外，了解睡眠时脑脊液流体动力学将有助于加强对脑积水和淋巴系统的基本科学认识。为了实现这一目标，我们将开发第一个能够连续24小时测量脑脊液流量的传感器。在UG3阶段，我们将修改硬件和软件平台，以确保安全性、舒适性、稳健性和可用性，以便在家中连续、不间断地佩戴。此外，我们将根据FDA和ISO13485的质量管理体系，承担DFMEA和可制造性设计工作。能够连续使用超过一周的传感器的完成和成功的外包制造运行将成为过渡到临床UH3阶段的一系列成功/不成功里程碑的核心。在UH3期，我们将进行为期1周的双臂、单中心、盲法、纵向临床研究，研究对象包括历史稳定的分流器患者和近期分流器改进型患者。

Hydrocephalus is a common condition caused by the accumulation of cerebrospinal fluid (CSF) in the brain, with symptoms that include headaches, lethargy, seizures, coma, or death, and affects > 1 million patients in the United States. It is usually treated with the surgical implantation of a catheter, known as a ventricular shunt, which diverts the excess CSF in the brain to a distal absorptive site. Overall, 125,000 shunts are implanted or replaced annually in United States, with costs estimated at $2 billion per year. We have identified two unmet needs in hydrocephalus diagnostics: (i) precise, rapid, noninvasive way to monitor shunt function; (ii) a large gap in clinical knowledge of CSF hydrodynamics through shunts owing to a lack of a direct, continuous flow monitoring technology. To address this need, Rhaeos has developed the first wearable, wireless sensor for CSF flow monitoring. Our first platform, Flow Sense, exploits miniaturized thermal sensors and actuators to map thermal transport through the skin as a measure of subdermal fluid flow to make rapid spot checks to address the first challenge outlined above. Expanding these capabilities to include continuous monitoring, 24-hour of CSF flow, particularly during periods of sleep, would benefit the treatment, care and understanding of hydrocephalus. We hypothesize that continuous measurements will provide and allow for robust out-patient monitoring and enhancing in-patient monitoring capabilities, particularly in emergency departments. The resulting technology, if successful, could reduce unnecessary hospital admissions and lower in- patient stay periods by allowing for direct monitoring in patient homes. Additionally, understanding CSF hydrodynamics during sleep will be valuable in enhancing a basic scientific understanding of hydrocephalus and the glymphatic system. To address the goal, we will develop the first sensor capable of continuous, 24-hour CSF flow measurements. In the UG3 phase we will modify our hardware and software platform for safety, comfort, robustness, and usability for continuous, uninterrupted wear at home. Additionally, we will undertake DFMEA and design for manufacturability efforts in compliance with an FDA- and ISO13485 compliant quality management system. The completion and successful outsourced manufacturing run of a sensor capable of continuous use over 1 week will form the core of a set of go/no go milestones to transition to the clinical UH3 phase. In the UH3 phase, we will conduct a 1-week double-arm, single-center, blinded, longitudinal clinical study with historically stable shunt patients and patients with recent shunt revisions.