Nanoplasmonics-Enhanced CMOS Fluorescence Sensors for Lens-Free Multiplexed Biomolecular Detection

早期和准确的疾病诊断在有效的临床治疗中起着决定性的作用，特别是在最需要做出立即治疗决定的护理点。用于护理点（POC）应用的规范生物标志物测试形式是基于纸测试条的侧向流测定，其便宜、一次性、易于使用并且不需要额外的硬件。然而，这些优点是以低灵敏度和有限的定量测量结果为代价的。基因检测和免疫测定的金标准利用基于荧光的检测，其提供低检测限、高可靠性和多重分析的能力。虽然高度准确，但荧光检测通常需要多个光学组件，使得POC测试的仪器体积庞大且成本高昂。该项目的目标是开发一种新的POC测试平台，该平台结合了基于荧光的测定的高灵敏度和定量分析的优点，以及侧流测试的简单性，便携性和成本效益。该平台利用光学超材料集成光电二极管阵列电路将增强的荧光感测信号转换为放大的电读数，以实现灵敏的检测，而无需光学组件。无透镜的设计保证了装置的小型化，并有利于用于侧向流测试的微流体装置的芯片上集成。该项目促进了多样化的科学和工程劳动力的发展，对纳米尺度的光学，生物传感技术和电路集成有着深刻的理解。该项目的结果将导致一个可扩展的解决方案，使一个敏感的，独立的，定量侧流分析。这利用了现代硅集成电路的功率和规模经济，在过去的五十年中建立了高性能计算和成像，以实现低成本，所提出的方法成功的关键是通过管理荧光报告子之间的耦合来产生增强的荧光和定向光发射。（荧光团或量子点）和光学超材料（Aim 1）的共振。由金属和电介质纳米结构组成的光学超材料利用表面等离子体来控制光。超材料的组成将被设计成调节邻近荧光报告物的自发发射速率，从而提高它们的发射强度。而且，超材料的结构被设计成使光发射的辐射图案变窄，这允许将光朝向光电检测器引导以进行有效的光学检测。该项目探索基于纳米颗粒组装和薄膜沉积的新型纳米制造方法，以在没有复杂光刻的情况下为光学超材料创建大面积纳米结构。将超材料结构单片集成到光电检测器阵列集成电路（IC）基板上允许在没有光学透镜的情况下检测超材料增强的荧光（目标2）。定制的CMOS光电探测器阵列IC还提供片上信号处理和所有传感器的数字化，并具有简单的数字读出功能。将通过在集成传感器基板上的探针阵列的可寻址功能化来实现多路复用传感器。使用共面晶圆级模塑技术封装具有微流体递送的传感器IC将产生用于POC测试的灵敏的小型化荧光检测平台（目标3）。这项工作将阐明纳米尺度下光与物质相互作用的基本原理，创造新的生物传感技术，并为光学纳米结构、微流体和CMOS集成电路的集成提供设计指导，以满足未来广泛的应用。该奖项反映了NSF的法定使命，并被认为值得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来支持。

Early and accurate disease diagnosis plays a decisive role in effective clinical treatment, especially at the point of care when an immediate treatment decision most needs to be made. The canonical biomarker test format for point-of-care (POC) applications is the lateral flow assay based on paper test strips which is cheap, disposable, easy to use and requires no additional hardware. However, the advantages are obtained at the expense of low sensitivity and limited quantitative measurement results. Gold standards for genetic detection and immunoassays utilize fluorescence-based detection, which offers low detection limit, high reliability, and capability of multiplexed analysis. While highly-accurate, fluorescence detection typically requires multiple optical components, making instrumentation bulky and costly for POC tests. The goal of this project is to develop a new POC testing platform that combines the benefits of high-sensitivity and quantitative analysis of fluorescence-based assays, and the simplicity, portability, and cost-effectiveness of lateral flow tests. The platform utilizes optical metamaterials-integrated photodiode array circuits to convert the enhanced fluorescence sensing signals into amplified electrical readouts to achieve sensitive detection without optical components. The lens-free design promises device miniaturization and facilitates the on-chip integration of microfluidic devices for lateral flow tests. The project fosters the development of a diverse science and engineering workforce with a deep understanding of optics at nanoscales, biosensing technology, and circuit integration. The result of the project will lead to a scalable solution that enables a sensitive, self-contained, quantitative lateral flow assay. This leverages the power and economies of scale of modern silicon integrated circuits, built up over the previous fifty years for high-performance computation and imaging, for a low-cost, bioelectronic sensing application.The key to the success of the proposed approach is to generate enhanced fluorescence and directional light emission by managing the coupling between the fluorescent reporters (fluorophores or quantum dots) on biological probes and the resonance of an optical metamaterial (Aim1). The optical metamaterials composed of metal and dielectric nanostructures exploit surface plasmons to control light. The composition of the metamaterial will be engineered to regulate the spontaneous emission rate of proximate fluorescent reporters and thus boost their emission intensity. Also, the structure of the metamaterial is designed to narrow the radiation pattern of light emission that allows guiding the light toward the photodetector for efficient optical detection. The project explores novel nanofabrication methods based on nanoparticle assembly and thin-film depositions to create large-area nanostructures for the optical metamaterials without sophisticated lithography. Monolithic integration of the metamaterial structures onto photodetector array integrated circuit (IC) substrate allows for detection of metamaterial enhanced fluorescence without optical lenses (Aim 2). A custom CMOS photodetector array IC also provides on-chip signal processing and digitization of all sensors in parallel with a simple, digital readout. A multiplexed sensor will be achieved through addressable functionalization of probe arrays on the integrated sensor substrate. Packaging of the sensor IC with microfluidic delivery using a coplanar wafer-level molding technique will result in a sensitive, miniaturized fluorescence detection platform for POC testing (Aim 3). The proposed work will elucidate the fundamentals of light-matter interactions at nanoscales, create new biosensing technologies, and design guidelines for integration of optical nanostructures, microfluidics, and CMOS ICs for a broad set of future applications.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.