Portable, fluorescence-based bio-molecular sensor on CMOS chip with integrated nano-optics for massively multiplexed assays

分子诊断学是医学诊断学日益发展的领域之一，旨在通过检测和测量特定的基因序列或蛋白质来评估一个人的健康状况。基于荧光标记的亲和力传感仍然是最流行的生物分子传感形式之一，虽然它们通常用于医院、参考实验室和血库中的传染病筛查，但当前的基于光学的传感技术仍然很复杂，由电子、光学和机械组件组成，包括透镜、物镜、准直器、多层薄膜滤光器、单色仪、光电倍增管、光纤、精密机械扫描仪等，使得系统体积大、体积大、价格昂贵且不可携带。另一方面，互补金属氧化物半导体(CMOS)技术为极其复杂的系统集成提供了无与伦比的平台，以经济高效的方式实现了高成品率。该方案的目标是采用CMOS技术，并结合新的方法在芯片上集成光学元件，实现便携式、芯片级、基于荧光的生物分子传感技术。用低成本的光激发源将整个荧光传感系统从生化平台到传感器和扫描仪微型化在一个芯片上，可能会打开体外和体内传感和成像的全新方法。在快速和多路检测平台中同时检测多个遗传和蛋白质生物标记物的能力也可以显著改善检测的统计数据，这对诊断至关重要。这一项目的横切方法将吸引和培训跨多个学科的研究生和本科生。PI还将吸引当地学校的高三学生，并通过他的本科和研究生课程以及出版物、研讨会和研讨会广泛传播知识。基于亲和力的生物传感器平台的检测方法依赖于通过捕获探针来选择目标生物分子，并且使用阻抗光谱、电分析、拉曼散射或磁性、介电或光学标记等方法无标记地对化学进行传感。虽然在基于cmos的图像传感器中检测光场的变化已经成熟，但在缺乏高性能集成光学元件的情况下，cmos中的荧光传感系统的小型化依赖于具有同步源或外部生长的滤光器和/或准直器的时间分辨技术，这可能会增加系统的复杂性和成本。该方案的目的是研究在可见光范围内利用金属-光子纳米结构与入射光场的亚波长相互作用，在标准的cmos工艺中实现光场操纵的方法。具体地说，这项工作提出了电子-纳米光子学体系结构、信号处理技术和芯片上集成的3D纳米光子学元件的生物接口的设计，用于大规模多路复用的基于荧光的生物分析。这些结构能够在广泛的入射角范围内抑制激发光，并允许荧光信号通过，并在大量传感器位置上被检测和处理，从而实现高密度功能化光学生物传感器芯片。在可见光范围内与嵌入式电子学相结合的集成纳米等离子体结构可以导致复杂和小型化的光学系统-片上光学系统在传感和成像方面的新应用。

Molecular diagnostics is one of the growing areas of medical diagnostics and aims to assess a person's health by detecting and measuring specific genetic sequences or proteins. Affinity-based sensing with fluorescence-based labels remains one of the most prevalent form of sensing of bio-molecules and while they are routinely used in hospitals, reference labs, and blood banks to screen for infectious diseases, current optical-based sensing technology is still complex consisting of an assembly of electronic, optical and mechanical components including lenses, objectives, collimators, multilayer thin film filters, monchrometers, photo-multiplier tubes, fiber optics, precision mechanical scanners etc., making the system large, bulky, expensive and non-portable. On the other hand, Complementary-metal-oxide-semiconductor (CMOS) technology, provides an unparalleled platform for integration of extremely complex systems, with high yield in a cost-efficient manner. The goal of the proposal is to co-opt CMOS technology and combine with new methods to integrate optical elements on the chip to realize portable, chip-scale, fluorescence-based biomolecular sensing technology. Miniaturizing an entire fluorescence sensing system from the biochemical platform to the sensor and scanner on one chip with a low-cost, optical excitation source can potentially open up completely new methodologies of in-vitro and in-vivo sensing and imaging. The ability to simultaneously sense multiple genetic as well as protein biomarkers in a rapid and multiplexed detection platform can also drastically improve the statistics of detection, critically important for diagnostics. The crosscut approach towards this project will engage and train both graduate and undergraduate students across multiple disciplines. The PI will also engage high-school seniors from local schools and broadly disseminate the knowledge through his undergraduate and graduate courses and through publications, seminars and workshops.The detection methodology for an affinity-based bio-sensor platform relies on selective target biomolecules by capturing probes and the chemistry is transduced label-free using methods such as impedance-spectroscopy, electro-analysis, Raman scattering or with magnetic, dielectric or optical labels. While detecting changes in the optical fields are mature in CMOS-based image sensors, in absence of high-performance integrated optical components, miniaturization of a fluorescence sensing system in CMOS has relied on time-resolved techniques with synchronized sources or externally grown optical filters and/or collimators which can add complexity and cost to the system. The goal of this proposal is to investigate methods by which optical field manipulation can be achieved in standard CMOS technology exploiting sub-wavelength interaction of metal-photonic nanostructures with incident optical fields in the visible range. Specifically, this work proposes design of electronic-nanophotonic architectures, signal-processing techniques and bio-interfaces on-chip with integrated 3D nanophotonic elements for massively multiplexed, fluorescence-based bio-assays. These structures are capable of excitation light suppression across a wide range of incidence angles and allow the fluorescence signal to pass, and get detected and processed over a multitude of sensor sites to enable high-density functionalized optical biosensor chips. Integrated nanoplasmonic structures in the visible range in CMOS with embedded electronics can lead to complex and miniaturized optical systems-on-chip for new applications in sensing and imaging.