Lateral Flow Based Nanoelectronic Sensing Array for Detection of Chronic Cerebral Hypoperfusion Biomarkers

在过去的几十年里，由于分子生物标志物量化的进步，理解和诊断疾病的能力已经取得了相当大的进步。在临床环境中，定量蛋白质标记物的常用方法是免疫浊度法或酶联免疫吸附法。两者都需要一个集中的实验室来分离全血，并在几个小时内执行多个严格的清洗步骤。此外，需要适当的基础设施和更高程度的培训，因此费用昂贵。该项目旨在通过集成高灵敏度的纳米电子免疫分析阵列和侧流设备来开发一种使能技术，以改进的诊断方式检测蛋白质生物标志物，能够使用最少的血液并快速返回结果。这个项目的结果可以导致一个通用平台的发展，用于检测广泛的分子生物标志物，以协助早期疾病诊断、评估和监测治疗结果。由低成本微加工和纳米电子检测构建的应用技术将大大降低医疗保健服务的成本，对医疗保健服务有限的地区尤其有益。此外，该项目还为整合学生在跨学科领域的教育经验提供了机会，激发了学生对科学、技术、工程和数学领域的兴趣，鼓励了代表性不足的群体的参与，开发了新资源的课程，并促进了西弗吉尼亚大学的生物医学工程项目。慢性脑灌注不足被认为是血管性痴呆和阿尔茨海默病的重要原因，与血液供应减少和负责记忆、认知和行为的大脑区域逐渐受损有关。尽早诊断慢性脑灌注不足是至关重要的，因为及时使用增加脑血流量的药物可以改善预后并延缓晚期痴呆的发病。本研究的目的是开发一种集成的多路检测免疫分析法，用于快速检测慢性脑灌注不足的生物标志物。为了完成本研究，提出了三个研究任务。首先，将开发、制作和优化纳米电子免疫分析阵列。纳米电子免疫分析阵列将允许很好地调节电解质的基质效应和测量结果的统计验证。其次，纳米电子免疫分析阵列将与横向流动装置集成，实现便携式毛细管驱动平台，最大限度地减少对片外设备的需求。该集成设备能够进行实际样品预处理、流体输送和单一生物标志物检测。第三，将进行生物标志物的多重检测，并通过临床相关的慢性脑灌注不足模型进行验证，以确定最具信息量的生物标志物组合。通过完成提出的任务，集成设备将允许为临床诊断生成更有意义和结论性的信息。该项目由电气、通信和网络系统（ECCS）部门的电子、光子学和磁性器件（EPMD）计划和促进竞争研究的既定计划（EPSCoR）联合支持。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Ability to understand and diagnose disease has experienced considerable progress over the past decades due to the advances in quantifications of molecular biomarkers. Commonly used methods for quantifying protein markers in a clinical setting are immunonephelometry or enzyme-linked immunosorbent assay. Both require a centralized lab to separate whole blood and to perform multiple strict washing steps over several hours. Also, proper infrastructure and a higher degree of training are required, and therefore expensive. This project aims to develop an enabling technology by integrating highly sensitive nanoelectronic immunoassay arrays and lateral flow devices for detecting protein biomarkers with improved diagnostic modalities, capable of using minimal amounts of blood and of returning rapid results. The results from this project can lead to the development of a generic platform for detecting a broad range of molecular biomarkers in assisting earlier disease diagnostics and assessment and monitoring treatment outcome. The applied technologies built from low-cost microfabrication and nanoelectronic detection would significantly reduce the costs for healthcare delivery, and be especially beneficial for regions with limited access to healthcare. Additionally, this project offers opportunities for integrating students' educational experience across interdisciplinary areas, stimulates students' interests in the fields of science, technology, engineering, and mathematics, encourages the participation of underrepresented groups, develops curriculum with new resources, and boosts the biomedical engineering program at West Virginia University.Chronic cerebral hypoperfusion has been considered a significant cause for vascular dementia and Alzheimer's disease associated with reduced blood supply and gradually damaged regions of the brain which are responsible for memory, cognition, and behavior. It is vital to diagnose chronic cerebral hypoperfusion as early as possible because the prompt institution of drugs for increasing cerebral blood flow improves outcomes and delays the onset of advanced dementia. The objective of the research is to develop an integrated multiplexed detection immunoassay for rapid-detecting chronic cerebral hypoperfusion biomarkers. Three research tasks have been proposed to accomplish the study. First, a nanoelectronic immunoassay array will be developed, fabricated, and optimized. The nanoelectronic immunoassay array will allow well regulation of matrix effects of electrolytes and statistical validation of measured results. Second, the nanoelectronic immunoassay array will be integrated with a lateral flow device to realize a portable and capillary driven platform with minimizing the need for off-chip equipment. The integrated device is capable of real-world sample pretreatment, fluid transport, and single biomarker detection. Third, multiplexed detection of biomarkers will be conducted and corroborated by a clinically relevant chronic cerebral hypoperfusion model to determine the most informative combinations of biomarkers. By accomplishing the proposed tasks, the integrated device will allow generation of more meaningful and conclusive information for clinical diagnosis. This project is jointly supported by the Electronics, Photonics and Magnetic Devices (EPMD) Program of the Electrical, Communications and Cyber Systems (ECCS) Division and the Established Program to Stimulate Competitive Research (EPSCoR).This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.