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

分子诊断是医学诊断的一个不断发展的领域，旨在通过检测和测量特定的基因序列或蛋白质来评估人的健康状况。利用基于荧光的标记的基于亲和力的感测仍然是感测生物分子的最普遍的形式之一，并且虽然它们常规地用于医院、参考实验室和血库以筛查传染病，但是当前基于光学的感测技术仍然是复杂的，其由包括透镜、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，这使得该系统大、笨重、昂贵并且不便携。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，以具有成本效益的方式实现高产量。该提案的目标是增选CMOS技术，并将联合收割机与新方法结合，将光学元件集成在芯片上，实现便携式、芯片级、基于荧光的生物分子传感技术。微型化整个荧光传感系统，从生化平台到传感器和扫描仪在一个芯片上，具有低成本，光学激发源可以潜在地开辟全新的体外和体内传感和成像方法。在快速和多重检测平台中同时感测多种遗传生物标志物以及蛋白质生物标志物的能力也可以大大改善检测的统计数据，这对诊断至关重要。对这个项目的横切方法将从事和培训跨多个学科的研究生和本科生。PI还将与当地学校的高中毕业生合作，并通过他的本科和研究生课程以及出版物、研讨会和讲习班广泛传播知识。基于亲和性的生物传感器平台的检测方法依赖于通过捕获探针选择性靶生物分子，并且使用阻抗光谱法、电分析法、拉曼散射法或磁共振法等方法进行无标记的化学转换。电介质或光学标签。虽然在基于CMOS的图像传感器中检测光场中的变化是成熟的，但是在没有高性能集成光学部件的情况下，CMOS中的荧光感测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，这会增加系统的复杂性和成本。本提案的目标是研究在标准CMOS技术中利用金属光子纳米结构与可见光范围内的入射光场的亚波长相互作用来实现光场操纵的方法。具体而言，这项工作提出了电子纳米光子架构，信号处理技术和生物接口芯片上集成的三维纳米光子元件的大规模多路复用，基于荧光的生物测定的设计。这些结构能够在宽范围的入射角上抑制激发光，并允许荧光信号通过，并在多个传感器位点上被检测和处理，以实现高密度功能化光学生物传感器芯片。 CMOS中可见光范围内的集成纳米等离子体结构与嵌入式电子器件可以导致复杂和小型化的片上光学系统，用于传感和成像的新应用。

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.