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天连续血糖监测仪进行糖尿病管理是一项历史性成就， 现代诊断，但不幸的是，尽管迫切需要实时 在人类疾病管理的更广泛领域（心脏、药物、 剂量、生育力等）。局限性在于葡萄糖传感器是酶促的，限制了它们对其他传感器的普遍性。 分析物（即，酶氧化/还原靶分子）。与酶传感器不同， 基于适体（EAB）的传感器是广泛的推广，通过几个实时的例子证明， 在纳摩尔至微摩尔浓度下进行体内分子监测。不幸的是，体内器械寿命 仍然是临床采用EAB传感器的重大挑战。 EAB传感器常规地使用单层的氧化还原标记的适体和烷基硫醇阻断分子， 金工作电极这些自组装单分子膜（SAMs）在真实的金电极上快速降解 体温37 °C的生物液体。EAB自组装膜的降解机制尚不清楚- 复杂的生物流体中的生物学特性，这就限制了人们追求延长寿命的技术的能力。我们 初步数据现在提供了对SAM降解的真正机制的重要见解。随着这一改进 由于对降解的了解，现在可以进行至少5天的稳定运行。多日 操作将允许EAB被合理地用于葡萄糖以外的应用，并且第一次， 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 工作周（例如结垢、核酸酶攻击等）。 中心假设是，通过阻挡层可以实现至少5天的EAB传感器操作 通过（1）在传感器过程中电化学稳定烷基硫醇阻挡层 制造，或（2）用具有类似密度的无机介电膜代替烷基硫醇阻挡层， 支持有效电子转移的缺陷。5天的手术将在临床相关性方面提供飞跃， 并且比6-12小时的典型极限大10- 20倍。5天的操作将使PI Heikenfeld定位为 进行临床研究，并将点燃与葡萄糖传感器行业领导者急需的合作伙伴关系。 PI Heikenfeld是一名新的NIH研究人员，但他已经做好了充分的准备，以追求这一长寿的突破，因为他的研究结果是， 在生物传感器方面的深厚专业知识，以及他的合作PI的白色和波特在EAB传感器和电化学方面的专业知识 阻挡层。