TERACELL: Integrated Microwave-to-Terahertz Sensors for label-free circulating tumour cell detection

TERACELL：集成微波到太赫兹传感器，用于无标记循环肿瘤细胞检测

• 批准号: EP/M001121/1
• 负责人: Norbert Klein
• 金额: $ 159.91万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FM001121%2F1
• 关键词: TERACELL; Integrated; Microwave; Terahertz; Sensors

Label-free detection of circulating tumour cells (CTCs) is considered to be one of the holy grails of biosensing. CTCs are malignant cells shed into the bloodstream from a tumour, which have the potential to establish metastases. The separation and subsequent characterization of these cells is of vital importance for cancer diagnosis and development of personalized cancer therapies. Biochemical CTC separation methods have proven to be highly inefficient and, therefore, preventive screening by sole blood analysis is currently not reliable. Microwave-to-terahertz dielectric measurements were successfully used for the identification of cancer cells; their capability for tumour tissue imaging is clinically established as a viable alternative to X-rays and MRI. The frequency range from 10 GHz up to about 1 THz is extremely promising for the detection of single tumour cells. Due to the diminishing cell membrane polarization effects, the cell membrane becomes transparent, but cell scattering is still negligible, in contrast to that found in the visible and near/medium-infrared range. Due to the high electromagnetic absorption of water up to about 1 THz, electromagnetic resonators with high quality factors and highly concentrated electric field within a small integrated microfluidic reservoir (previously demonstrated by the team), which essentially contains one cell at a time, represent an ideal system for fast and accurate dielectric measurements. This is because the single cell lies within their natural liquid environment. In order to tackle the problem of extremely low abundance of CTCs in blood samples, we intend to combine microfluidic separation techniques with integrated microwave-to-terahertz resonators on one chip or as a multichip combination, aiming towards a lab-on-chip approach for clinical applications. In order to achieve this ambitious goal, within this three-year project, we suggest a multidisciplinary approach, based on the expertise of the associated members of Imperial's Centre for Terahertz Science and Engineering (made up of academics and researchers from the Depts. of Materials, Electrical and Electronic Engineering and Physics), along with selected groups from dedicated areas of Life Sciences (which includes cancer cell biology and cell biosensing), plus the expertise of oncologists from Imperial's Faculty of Medicine. A variety of tumour cell suspension of defined concentration based on whole blood, serum or water being derived from a murine model will be our gold standard approach for the generation of a database of dielectric properties of different types of tumour cells, for the optimization of different sensor chip approaches, and for the development of cell detection methods. As a key milestone, towards the end of the project, we will demonstrate CTC detection in human blood samples.As the main engineering challenge of this project, three different electromagnetic resonator approaches will be investigated, based on our previous work on silicon MEMS technology for nanolitre liquid measurements: dielectric resonators, photonic crystals and spoof plasmon-based metamaterials. Advanced micro- and nano-machining techniques like deep reactive ion etching, e-beam lithography and focussed ion-beam etching will be employed for the manufacturing of fully-integrated (sub-) THz resonator-microfluidic systems.On the way towards the grand challenge of CTC detection, we intend to investigate two potential applications, which may generate clinical impact on a shorter timescale: Label-free detection of leukaemia cells within a murine model and bladder cancer cell detection in human urine samples. In both cases, the expected cell abundance is much higher than in the case of CTC, but the methods of dielectric cell recognition are identical to CTC detection. Follow-up projects including clinical studies plus stronger involvement of industry are likely to be launched during the time-span of this project.

循环肿瘤细胞（CTC）的无标记检测被认为是生物传感的圣杯之一。CTC是从肿瘤脱落到血流中的恶性细胞，其具有建立转移的潜力。这些细胞的分离和随后的表征对于癌症诊断和个性化癌症疗法的开发至关重要。生物化学CTC分离方法已被证明是非常低效的，因此，通过单独的血液分析进行预防性筛查目前是不可靠的。微波-太赫兹介电测量成功地用于癌细胞的识别;其肿瘤组织成像的能力在临床上被确立为X射线和MRI的可行替代方案。从10 GHz到约1 THz的频率范围对于单个肿瘤细胞的检测是非常有希望的。由于细胞膜偏振效应的减弱，细胞膜变得透明，但细胞散射仍然可以忽略不计，这与可见光和近/中红外范围内的散射相反。由于水的高电磁吸收高达约1 THz，具有高品质因数和高度集中电场的电磁谐振器在小型集成微流体储液器（之前由团队演示）中，基本上每次包含一个细胞，代表了快速准确的介电测量的理想系统。这是因为单细胞位于其天然液体环境中。为了解决血液样品中CTC丰度极低的问题，我们打算将联合收割机微流体分离技术与集成的微波-太赫兹谐振器结合在一个芯片上或作为多芯片组合，旨在实现用于临床应用的芯片上实验室方法。为了实现这一雄心勃勃的目标，在这个为期三年的项目中，我们建议采用多学科方法，基于帝国太赫兹科学与工程中心相关成员的专业知识（由来自部门的学者和研究人员组成）。材料，电气和电子工程和物理），沿着从生命科学（包括癌细胞生物学和细胞生物传感）的专门领域的选定组，加上来自帝国理工医学院的肿瘤学家的专业知识。基于来自小鼠模型的全血、血清或水的限定浓度的各种肿瘤细胞悬浮液将是我们用于生成不同类型肿瘤细胞的介电性质的数据库、用于优化不同传感器芯片方法以及用于开发细胞检测方法的金标准方法。作为一个重要的里程碑，在项目的最后阶段，我们将演示在人体血液样本中检测CTC。作为该项目的主要工程挑战，我们将研究三种不同的电磁谐振器方法，基于我们以前在硅MEMS技术上的工作，用于纳升液体测量：介电谐振器，光子晶体和欺骗等离子体基超材料。先进的微米和纳米加工技术，如深反应离子蚀刻，电子束光刻和聚焦离子束蚀刻，将用于制造完全集成的（亚）太赫兹谐振器-微流体系统。在迈向CTC检测的巨大挑战的道路上，我们打算研究两个潜在的应用，这可能会在较短的时间内产生临床影响：小鼠模型中白血病细胞的无标记检测和人尿样中膀胱癌细胞的检测。在这两种情况下，预期的细胞丰度远高于CTC的情况，但介电细胞识别的方法与CTC检测相同。后续项目，包括临床研究和更强的行业参与，可能会在该项目的时间跨度内启动。

项目成果

Polymer-Based 3-D Printed Ku-Band Steerable Phased-Array Antenna Subsystem

基于聚合物的 3D 打印 Ku 波段可操纵相控阵天线子系统

• DOI: 10.1109/access.2019.2932431
• 发表时间: 2019
• 期刊: IEEE Access
• 影响因子: 3.9
• 作者: Shin S

Dielectric measurements of nanoliter liquids with a photonic crystal resonator at terahertz frequencies

• DOI: 10.1063/1.4927242
• 发表时间: 2015-07-20
• 期刊: APPLIED PHYSICS LETTERS
• 影响因子: 4
• 作者: Hanham, S. M.;Watts, C.;Klein, N.
• 通讯作者: Klein, N.

3D printed 1.1 THz waveguides

• DOI: 10.1049/el.2016.4662
• 发表时间: 2017-02
• 期刊: Electronics Letters
• 影响因子: 1.1
• 作者: W. J. Otter;N. Ridler;Hiroyuki Yasukochi;Kentaro Soeda;K. Konishi;J. Yumoto;M. Kuwata-Gonokami;S. Lucyszyn

THz metal mesh filters on electrically thick fused silica substrates

电厚熔融石英基底上的太赫兹金属网过滤器

• DOI: 10.1109/irmmw-thz.2014.6956406
• 发表时间: 2014
• 作者: Otter W

Terahertz particle-in-liquid sensing with spoof surface plasmon polariton waveguides

• DOI: 10.1063/1.4998566
• 发表时间: 2017-11-01
• 期刊: APL PHOTONICS
• 影响因子: 5.6
• 作者: Ma, Zhijie;Hanham, Stephen M.;Maier, Stefan A.
• 通讯作者: Maier, Stefan A.