Breakthrough Blocking-Layer Stability for Broader Clinical Utility of Continuous Aptamer Biosensors

突破性的阻断层稳定性使连续适体生物传感器具有更广泛的临床应用

• 批准号: 10571431
• 负责人: Jason Heikenfeld
• 金额: $ 15.42万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10571431
• 关键词: Achievement; Acute; Adoption; Biosensor; Body Temperature; Cardiac; Cardiac health; Chemistry; Clinical; Clinical Research; Complex; Data; Defect; Dermal; Devices; Diagnostic; Disease Management; Dose; Electrodes; Electron Transport; Enzymes; Fertility; Film; Glucose; Gold; Growth; Hour; Industry; Intercellular Fluid; Kinetics; Knowledge; Letters; Longevity; Measures; Modernization; Molecular; Monitor; Outcome; Oxidation-Reduction; Oxides; Pharmaceutical Preparations; Positioning Attribute; Property; Research; Research Personnel; Resistance; Serum; Signal Transduction; Silanes; Surface; System; Techniques; Technology; Thick; Time; United States National Institutes of Health; aptamer; base; bioelectronics; clinical application; clinically relevant; density; diabetes management; drug metabolism; glucose monitor; glucose sensor; human disease; improved; in vivo; insight; monolayer; nanomolar; nuclease; operation; prevent; real time monitoring; sensor; success

PROJECT SUMMARY The use of 10-14 day continuous glucose monitors for diabetes management is a historical achievement in modern diagnostics, but unfortunately it remains an isolated success despite acute needs for the real-time monitoring of many other molecules across the broader field of human disease management (cardiac, drug dosing, fertility, etc.). The limitation is that glucose sensors are enzymatic, limiting their generalizability to other analytes (i.e., enzymes oxidize/reduce the target molecule). Unlike enzymatic sensors, electrochemical aptamer-based (EAB) sensors are broadly generalizable, demonstrated by several examples of real-time, in- vivo molecular monitoring at nanomolar to micromolar concentrations. Unfortunately, in-vivo device longevity remains a significant challenge for the clinical adoption of EAB sensors. EAB sensors conventionally use a monolayer of redox-tagged aptamers and alkylthiol blocking molecules on a gold working electrode. These self-assembled monolayers (SAMs) rapidly degrade on gold electrodes in real biofluids at body temperature of 37 °C. The mechanisms of degradation of EAB SAMs have not been well- understood in complex biofluids, which then limits the ability to pursue techniques to improve longevity. Our preliminary data now provides major insights into the true mechanisms of SAM degradation. With this improved understanding of degradation, its is now feasible to pursue stable operation for at least 5 days. Multi-day operation would then allow EABs to be credibly pursued for applications beyond glucose, and for the first time, proper research could begin on resolving the next expected longevity bottlenecks that would likely prevent 1-2 week operation (e.g. fouling, nuclease attack, etc.). The central hypothesis is that at minimum 5 day EAB sensor operation can be achieved through a blocking layer with superior stability achieved by either (1) electrochemically stabilizing an alkylthiol blocking layer during sensor fabrication, or (2) replacing an alkylthiol blocking layer with a inorganic dielectric film that has a similar density of defects supporting efficient electron transfer. 5 day operation would provide a leap forward in clinical relevance, and is 10-20X greater the typical limit of 6-12 hours. 5 day operation would then position the PI Heikenfeld to pursue clinical research, and would ignite critically-needed partnerships with industry leaders in glucose sensors. The PI Heikenfeld is a new NIH investigator, but is well-prepared to pursue this longevity breakthrough given his deep expertise in biosensors, and his co-PI’s White and Porter’s expertise in EAB sensors and electrochemical blocking layers.

项目摘要 使用10-14天连续葡萄糖监测器进行糖尿病管理是一项历史成就 现代诊断，但不幸的是，它仍然是实时的成功目的地的急性需求 监测整个更广泛的人类疾病管理领域（心脏，药物）的许多其他分子 剂量，生育等）。限制是葡萄糖传感器是酶促的，将其推广到其他 分析物（即氧化酶/降低靶分子）。与酶传感器不同，电化学 基于APATMER的（EAB）传感器是可以广泛概括的，这是实时，In-的几个例子 在纳摩尔到微摩尔浓度下的体内分子监测。不幸的是，体内设备的寿命 对于EAB传感器的临床采用仍然是一个重大挑战。 EAB传感器通常在A上使用氧化还原标签的适体和烷基硫醇阻断分子的单层 黄金工作电极。这些自组装的单层（SAM）在金电极上迅速降解 体温为37°C的生物流体。 EAB SAM降解的机制尚未很好 在复杂的生物流体中理解齿，然后限制了追求改善寿命的技术的能力。我们的 现在，初步数据为SAM退化的真实机制提供了重大见解。有了改进 了解降解，现在可以至少进行5天进行稳定的操作是可行的。多日 然后，操作将允许EAB可靠地用于葡萄糖以外的应用，这是第一次 适当的研究可以开始解决下一个预期的寿命瓶颈，这可能会阻止1-2 一周的操作（例如污染，核酸酶攻击等）。 中心假设是至少5天，EAB传感器操作可以通过阻止层实现 通过（1）在传感器期间烷基硫醇阻断层实现了出色的稳定性 制造，或（2）用无机涂层膜代替醇硫醇阻塞层，该膜的密度相似 支持有效电子传输的缺陷。 5天的操作将在临床相关性方面飞跃， 并且典型的6-12小时典型限制更大。然后，5天的操作将将Pi Heikenfeld放置在 进行临床研究，并将与葡萄糖传感器的行业领导者建立急需的伙伴关系。 Pi Heikenfeld是一名新的NIH调查员，但考虑到他 生物传感器的深厚专业知识，以及他的Co-Pi的White和Porter在EAB传感器和电化学方面的专业知识 阻塞层。