An Interferometric CMOS DC-Terahertz Lab on a Chip Biosensor

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）进行无标签识别。摘要：意义和重要性：细胞及其成分的鉴定对于广泛的医疗保健和科学应用至关重要。实时测量的关键需求，例如在癌症手术期间，留下未识别的癌细胞会导致癌症复发增加。不幸的是，目前的技术无法在不使用附加信号标签的二级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，有必要快速识别细胞和分子，以指导实时临床决策。解决方案：为了实现分子和单个细胞的直接和近乎瞬时的识别，该方案测量了它们对极高频率电场的固有反应，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。在这样的速度下，可以测量分子的振动，有可能在不使用二次标记的情况下识别生物分子。推进该领域：本研究的总体目标是使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。如果能找到癌细胞独特的光谱特征，就有可能实现快速的无标签识别。对社会的益处：癌症治疗中至关重要的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特性，可以实现对肿瘤细胞的瞬时识别，从而实现对组织的瞬时评估，从而指导所有肿瘤细胞的切除。此外，以这种频率对单个细胞进行测量以前从未做过。通过出版物，这些信息将传播给社区，可能促成新的生物医学应用。教育和多样性：本研究的教育目标包括培养太赫兹信号产生、检测和处理的艺术和科学方面的研究生研究人员，以及针对电子工程大一学生和未被充分代表的群体开发新的本科课程。技术摘要：本研究计划的重点是通过开发从直流到太赫兹的传感器平台，获得分子和细胞水平的宽频谱信息，从而实现对生物系统的无标签研究。这种能力与微流体技术相结合，使单细胞审讯成为可能，在表征、鉴定和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，甚至可能在护理环境中。这项研究将使最先进的频率提高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允许广泛的信息收集到单个细胞和生物分子。移动到更高的频率，从100千兆赫到1太赫兹，开启了感知分子旋转共振特征的可能性，识别细胞的关键分子成分。这项工作分为三个相互关联的重点。在第一个推力中，重点是DC-THz传感器阵列的开发。我们的团队已经确定了适合集成在CMOS中的强大架构，围绕在片上压控振荡器（vco）之间进行干涉测量而构建，这些振荡器很容易集成在CMOS技术中，集成到一个非常小的区域。该结构具有较高的灵敏度和抗相位噪声能力。在第二个推力中，我们将共同设计微流体封装和传感器接口，这样我们就可以可靠地、反复地将生物分子或细胞等材料送入传感器进行测量（生物分子为1太赫兹，细胞为0.5太赫兹）。在第三个推力中，我们将开始对生物分子和细胞从微波波段到太赫兹波段的光谱特征进行广泛的研究。

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.