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

CMOS 芯片上的便携式荧光生物分子传感器，具有集成纳米光学器件，适用于大规模多重分析

• 批准号: 1610761
• 负责人: Kaushik Sengupta
• 金额: $ 36万
• 依托单位: Princeton University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1610761&HistoricalAwards=false
• 关键词: Portable; fluorescence; based; bio; molecular

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.

分子诊断是医学诊断不断发展的领域之一，旨在通过检测和测量特定的基因序列或蛋白质来评估人的健康状况。基于荧光标签的亲和感测仍然是最普遍的生物分子感测形式之一，虽然它们通常在医院、参考实验室和血库中用于筛查传染病，但当前基于光学的感测技术仍然很复杂，由电子、光学和机械部件组成，包括透镜、物镜、准直器、多层薄膜滤光片、单色仪、光电倍增管、光纤、精密机械扫描仪等，使系统变得很大，体积大、价格昂贵且不便于携带。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，并以经济高效的方式实现高产量。该提案的目标是采用CMOS技术并结合新方法将光学元件集成在芯片上，以实现便携式、芯片级、基于荧光的生物分子传感技术。使用低成本光学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）小型化在一个芯片上，有可能开辟全新的体外和体内传感和成像方法。在快速多重检测平台中同时检测多种遗传和蛋白质生物标志物的能力也可以极大地改善检测统计数据，这对于诊断至关重要。该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中生，并通过他的本科生和研究生课程以及出版物、研讨会和讲习班广泛传播知识。基于亲和力的生物传感器平台的检测方法依赖于选择性目标生物分子，通过捕获使用阻抗谱、电分析、拉曼散射等方法或使用磁性、介电或光学标记进行无标记的探针和化学物质的转导。虽然基于 CMOS 的图像传感器检测光场变化的技术已经成熟，但在缺乏高性能集成光学元件的情况下，CMOS 中荧光传感系统的小型化一直依赖于具有同步源或外部生长的光学滤波器的时间分辨技术和/或准直器，这会增加系统的复杂性和成本。该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。具体来说，这项工作提出了电子纳米光子架构、信号处理技术和片上生物接口的设计，其中集成了 3D 纳米光子元件，用于大规模多重、基于荧光的生物测定。这些结构能够在较宽的入射角范围内抑制激发光，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，从而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产生复杂且小型化的片上光学系统，用于传感和成像的新应用。