An Interferometric CMOS DC-Terahertz Lab on a Chip Biosensor

项目名称：干涉型CMODC-太赫兹片上生物传感器简介项目目标：建立一个单细胞传感器平台，用于在极快的交变电场下对细胞及其成分(蛋白质、DNA、分子)进行无标记识别。非技术摘要：意义和重要性：识别细胞，进而识别其成分，对于广泛的医疗保健和科学应用是必不可少的。实时测量是关键，例如在癌症手术期间，留下不明癌细胞会导致癌症复发增加。不幸的是，目前的技术不能在没有附加信号标签的辅助分子的情况下识别生物分子，这通常需要在实验室环境中进行多个步骤。因此，需要快速识别细胞和分子以指导实时临床决策。解决方案：为了能够直接、近乎瞬时地识别分子和单细胞，该方案测量了它们对极高频电场的固有反应，以识别独特的频率特征。特别是，该项目旨在将测量这些特征振动的能力扩展到太赫兹范围，电场在皮秒内交替。在这些速度下，分子的振动被测量，潜在地识别生物分子而不使用二次标记。推进领域：这项研究的首要目标是利用单细胞高频测量平台建立广泛的生物分子和癌细胞系的频率特性。如果发现癌细胞独特的光谱特征，就有可能实现快速无标记鉴定。对社会的益处：癌症治疗的关键是需要识别和治疗所有疾病。通过测量分子本身的固有电学性质，瞬时识别肿瘤细胞成为可能，使组织的瞬时评估能够指导所有肿瘤细胞的切除。此外，以前从未以这种频率对单个细胞进行测量。通过出版物，这些信息将被传播到社区，潜在地使新的生物医学应用成为可能。教育和多样性：这项研究的教育目标包括培训研究生研究人员在太赫兹信号产生、检测和处理方面的艺术和科学，开发新的本科课程，针对大一的电气工程学生，并扩展到代表不足的群体。技术摘要：本研究提案的重点是通过开发从DC到THz制度的传感器平台，获得分子和细胞水平的广泛频谱信息，从而实现对生物系统的无标记研究。这种能力与能够进行单细胞询问的微流体相结合，在表征、鉴定以及可能的疾病诊断方面具有巨大的优势，有可能更快、更便宜地解决各种问题，甚至可能在护理点环境中解决各种问题。这项研究将把最先进的频率提高10倍，并允许廉价和快速的太赫兹细胞和生物分子表征。结合千兆和太赫兹传感，可以收集关于单个细胞和生物分子的广泛信息。移动到更高的频率，从100 GHz到1 THz，打开了检测分子旋转共振信号的可能性，识别细胞的关键分子成分。这项工作分为三个相互关联的突破口。在第一个推力中，重点是DC-THz传感器阵列的发展。我们的团队已经确定了适合在芯片中集成的强大架构，这些架构围绕执行片上压控振荡器(VCO)之间的干涉测量而构建，这些振荡器可以很容易地集成到非常小的面积内。该结构具有很高的灵敏度和对相位噪声的免疫力。在第二个推力中，我们将共同设计微流控封装和传感器接口，以便我们能够可靠和重复地将生物分子或细胞等材料流入传感器进行测量(生物分子为1 THz，细胞为0.5 THz)。在第三个推力中，我们将开始对生物分子和细胞的光谱特征进行广泛的研究，从微波波段到太赫兹区域。

Proposal Title: An Interferometric CMOS DC-Terahertz Lab on a Chip BiosensorBrief description of project Goals: Building a single-cell sensor platform for labelless identification of cells and their components (protein, DNA, molecules) with extremely rapidly alternating electric fields.Nontechnical Abstract:Significance and Importance: Identification of cells, and by extension their components, is essential for a wide range of healthcare and scientific applications. There is key need for real-time measurements, for example during cancer surgery where leaving unidentified cancer cells behind leads to increased cancer recurrence. Unfortunately, current techniques cannot identify biological molecules without the use of secondary molecules with a signaling tag attached, necessitating multiple steps often in a laboratory setting. Therefore there is a need for rapid identification of cells and molecules to guide real-time clinical decision making. The Solution: To enable direct, and near instantaneous, identification of molecules and single cells, this proposal measures their innate response to extremely high frequency electrical fields to identify a unique frequency signature. In particular, this project aims to extend the ability to measure these characteristic vibrations into the Terahertz range, with electric fields alternating within a picosecond. At these speeds, the vibrations of molecules are measured, potentially identifying biological molecules without the use of secondary labels. Advancing the Field: The overarching goal of this research is to establish the frequency characteristics for a wide range of biomolecules and cancer cell lines using a single-cell high frequency measurement platform. If unique spectral signatures of cancer cells are found, the possibility of rapid labelless identification can be realized. Benefits to Society: Of key importance in cancer therapy is the need to identify and treat all disease. Instantaneous identification of tumor cells, made possible by measuring the innate electrical properties of the molecules themselves, enables instantaneous assessment of tissue to guide resection of all tumor cells.Furthermore, measurements on single cells at this frequency have never been done before. Through publications, this information will be disseminated to the community, potentially enabling new biomedical applications.Education and Diversity: The educational goals of this research include the training of graduate student researchers in the art and science of terahertz signal generation, detection, and processing, and the development of a new undergraduate curriculum targeting freshman electrical engineering students and outreach to underrepresented groups.Technical Abstract: The focus of this research proposal is to enable labelless investigation of biological systems by obtaining wide frequency spectrum information on the molecular and cellular level through development of a sensor platform operating from DC to the THz regime. This capability, coupled with microfluidics that enable single cell interrogation, has an immense advantage in the characterization, identification, and, possibly diagnosis of disease, potentially solving a variety of problems faster, less expensively, or perhaps even in a point of care settings. This research will advance the state-of-the-art by 10X in frequency and allows for inexpensive and rapid Terahertz cell and biomolecule characterization. Combining Giga and Terahertz sensing allows a broad range of information to be gathered on individual cells and biomolecules. Moving to higher frequencies, from 100 GHz to 1 THz, opens up the possibility to sense molecular rotational resonance signatures, identifying key molecular components of cells. The work is divided into three interrelated thrusts. In the first thrust, the focus is on the development of the DC-THz sensor array. Our group has identified powerful architectures that are amenable to integration in CMOS, built around performing interferometry between on-chip voltage-controlled oscillators (VCOs), which are easily integrated in CMOS technology into a very small area. The architecture has high sensitivity and immunity from phase noise. In the second thrust, we will be co-designing the microfluidic package and sensor interface so that we can reliably and repeatedly flow materials such as biomolecules or cells into the sensor to perform measurements (1 THz for biomolecules, 0.5 THz for cells). In the third thrust, we will begin an extensive study of the spectral signature of biomolecules and cells from microwave bands up to the terahertz regime.