Bio-electrochemical detectors for in vivo continuous monitoring

总结。我们的目标是开发和验证一种可以测量多种药物的技术， 活体受试者血液、尿液和间质液中的代谢物和生物标志物 时间，这一能力将彻底改变生物医学研究和医疗保健的许多方面。要做到这一点 目标我们将结合基于电化学适配子的传感器(它们是无试剂和免洗涤的，并且可以 直接在复杂的样品中操作，没有污染)，具有生物兼容的抗凝血膜和 先进的漂移校正方法，直接在活体内实现连续、实时、多天的测量。 作为支持这一目标的初步结果，我们演示了四个连续、实时的测量 不同药物直接注入麻醉大鼠颈静脉5小时以上20秒 时间分辨率和亚微摩尔精度。利用这些初步结果，我们在这里提出了三个进一步的 进展：第一，我们将把平台扩展到另外九种药物的体内测量和 代谢物，这将展示该平台的多功能性。二是提高平台稳定性 这样我们就可以在几天内进行高精度的活体测量，这将使 持续测量长效药物并捕获临床上重要的昼夜代谢变化。 最后，我们将把该平台扩展到同时测量多个分子和/或跨 多个身体隔间(如血液、组织、脑、膀胱)，使其成为一种强大的新工具 了解药代动力学和生理学。通过创造一个前所未有的窗口来了解病人的 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，包括患者特定药代动力学的高精度测量，连续 通过对特定生物标志物的实时测量来监测健康状况，并最终反馈- 有控制的药物输送。

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.