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

脑积水是一种常见的疾病，由脑脊液(CSF)在大脑中积累引起，症状包括头痛、嗜睡、癫痫、昏迷或死亡，在美国有100万名患者受到影响。它通常是通过外科手术植入导管，即所谓的脑室分流，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12.5万个分流装置，估计每年的成本为20亿美元。我们在脑积水的诊断中发现了两个尚未满足的需求：(I)准确、快速、非侵入性地监测分流功能；(Ii)由于缺乏直接、连续的血流监测技术，通过分流对脑脊液流体动力学的临床知识存在很大差距。为了满足这一需求，Rhaeos开发了第一个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，利用微型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衡量标准，以进行快速抽查，以应对上面概述的第一个挑战。将这些能力扩展到包括24小时连续监测脑脊液流量，特别是在睡眠期间，将有助于脑积水的治疗、护理和了解。我们假设，持续的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，可以通过允许在患者家中进行直接监控来减少不必要的入院人数，并缩短住院时间。此外，了解睡眠期间脑脊液的流体动力学将有助于增强对脑积水和淋巴系统的基本科学了解。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，我们将修改我们的硬件和软件平台，以实现在家连续、不间断穿戴的安全性、舒适性、健壮性和可用性。此外，我们将按照FDA和ISO13485兼容的质量管理体系进行DFMEA和可制造性设计。能够连续使用一周以上的传感器的完成和成功的外包制造运行将构成过渡到临床UH3阶段的一系列进行/不进行里程碑的核心。在UH3阶段，我们将进行一项为期一周的双臂、单中心、盲法、纵向临床研究，研究对象为历史上稳定的分流术患者和近期行分流术翻修的患者。

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.