Bio-electrochemical detectors for in vivo continuous monitoring

摘要我们的目标是开发和验证一种可以测量各种药物的技术， 在活体受试者的血液、尿液和间质液中连续和真实的检测代谢物和生物标志物 这种能力将彻底改变生物医学研究和医疗保健的许多方面。实现这一 我们的目标是将联合收割机电化学适体传感器（无试剂和免清洗， 直接在复杂样品中操作而不结垢），具有生物相容性抗凝膜， 先进的漂移校正方法，可直接在体内实现连续、实时、多日的测量。 作为支持这一目标的初步结果，我们展示了四个连续，实时测量 不同的药物直接在麻醉大鼠的颈静脉中持续20秒超过5小时 时间分辨率和亚微摩尔精度。利用这些初步结果，我们在这里提出三个进一步的 进展：首先，我们将扩展该平台，以在体内测量另外九种药物， 代谢物，这将证明该平台的多功能性。第二，提高平台的稳定性 这样我们就可以在几天内进行高精度的体内测量， 连续测量长寿命药物并捕获临床上重要的昼夜代谢变化。 最后，我们将扩展该平台，以同时测量多个分子和/或跨 多个身体隔室（例如，血液，组织，大脑，膀胱），使其成为一个强大的新工具， 了解药代动力学和生理学。通过创造一个前所未有的窗口进入病人的 分子水平的生理状态，所提出的技术将使许多变革性的临床 应用，包括患者特异性药代动力学的高精度测量， 通过实时测量特定生物标志物监测健康状况，并最终提供反馈- 控制药物输送。

Summary. Our goal is the development and validation of a technology that can measure a wide range of drugs, metabolites, and biomarkers in the blood, urine, and interstitial fluids of living subjects continuously and in real time, an ability that would revolutionize many aspects of biomedical research and healthcare. To achieve this goal we will combine electrochemical aptamer-based sensors (which are reagentless and wash-free and can operate directly in complex samples without fouling) with biocompatible anti-coagulation membranes and advanced drift correction methods to achieve continuous, real-time, multi-day measurements directly in vivo. As preliminary results supporting this goal we demonstrate the continuous, real-time measurement of four different drugs directly in the jugulars of anesthetized rats for periods of more than five hours with 20-second time resolution and sub-micromolar precision. Leveraging these initial results we propose here three further advancements: First, we will expand the platform to the in vivo measurement of nine additional drugs and metabolites, which will demonstrate the platform's versatility. Second, we will improve the platform's stability such that we can perform high-precision in vivo measurements over the course of days, which will enable continuous measurements of long-lived drugs and capture clinically important circadian metabolic variations. Finally, we will expand the platform to the simultaneous measurement of multiple molecules and/or across multiple body compartments (e.g., blood, tissues, brain, bladder), rendering it a powerful new tool for understanding pharmacokinetics and physiology. By creating an unprecedented window into a patient's molecular-level physiological state, the proposed technology would enable many transformative clinical applications, including the high-precision measurement of patient-specific pharmacokinetics, the continuous monitoring of health status via the real-time measurement of specific biomarkers, and, ultimately, feedback- controlled drug delivery.