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

早期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即时治疗决定的护理阶段。医疗点(POC)应用的标准生物标记物测试格式是基于纸质试纸的横向流动分析，这种测试方法廉价、一次性、易于使用，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。基因检测和免疫分析的金标准使用基于荧光的检测，它提供低检测限、高可靠性和多重分析能力。虽然荧光检测精度很高，但通常需要多个光学组件，这使得POC测试的仪器变得笨重和昂贵。该项目的目标是开发一种新的POC测试平台，它结合了基于荧光的分析的高灵敏度和定量分析的优点，以及横向流动测试的简单性、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，将增强的荧光传感信号转换为放大的电读数，实现无需光学元件的灵敏检测。无透镜设计保证了设备的小型化，并促进了用于横向流动测试的微流控设备的芯片上集成。该项目促进了对纳米级光学、生物传感技术和电路集成的深入了解，培养了一支多元化的科学和工程队伍。该项目的结果将导致一种可扩展的解决方案，使敏感、独立、定量的侧向流动分析成为可能。这利用了过去50年为高性能计算和成像而建立的现代硅集成电路的能力和规模经济，用于低成本的生物电子传感应用。所提出的方法的成功的关键是通过管理生物探针上的荧光报告器(荧光团或量子点)之间的耦合和光学超材料(Aim1)的共振来产生增强的荧光和定向光发射。由金属和介电纳米结构组成的光学超材料利用表面等离子体来控制光。这种超材料的组成将被设计成调节接近的荧光记者的自发发射速率，从而提高它们的发射强度。此外，超材料的结构被设计成缩小光发射的辐射图案，该图案允许将光引导到光电探测器以进行有效的光学检测。该项目探索了基于纳米颗粒组装和薄膜沉积的新型纳米制造方法，以创建大面积纳米结构的光学超材料，而不需要复杂的光刻。将超材料结构单片集成到光电探测器阵列集成电路(IC)衬底上，可以在没有光学透镜的情况下检测到超材料增强荧光(目标2)。定制的CMOS光探测器阵列IC还提供片上信号处理和所有传感器的数字化，并提供简单的数字读出。多路传感器将通过集成传感器基板上的探头阵列的可寻址功能化来实现。使用共面晶片级模塑技术将传感器IC与微流控输送封装在一起，将产生用于POC测试的灵敏、小型化的荧光检测平台(AIM 3)。这项拟议的工作将阐明纳米级光-物质相互作用的基本原理，创造新的生物传感技术，并为未来广泛的应用集成光学纳米结构、微流体和CMOSIC设计指南。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.