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

循环肿瘤细胞(CTCs)的无标记检测被认为是生物传感的圣杯之一。CTC是从肿瘤进入血流的恶性细胞，具有确定转移的可能性。这些细胞的分离和随后的特征对于癌症诊断和个性化癌症治疗的发展至关重要。生化CTC分离方法被证明是非常低效的，因此，目前通过单一血液分析进行预防性筛查是不可靠的。微波至太赫兹介电测量被成功地用于识别癌细胞；它们的肿瘤组织成像能力在临床上被确立为X射线和核磁共振的可行替代品。从10 GHz到大约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。由于细胞膜极化效应的减弱，细胞膜变得透明，但与可见光和近/中红外范围内的散射相比，细胞散射仍然可以忽略不计。由于对水的高电磁吸收高达约1太赫兹，具有高品质因数和小型集成微流体库内高度集中电场的电磁谐振器(团队以前演示过)，基本上一次包含一个单元，是快速和准确介电测量的理想系统。这是因为单个细胞处于它们的自然液体环境中。为了解决血液样本中CTCs丰度极低的问题，我们打算将微流控分离技术与集成的微波至太赫兹谐振器集成在一个芯片上或作为多芯片组合，旨在实现临床应用的芯片实验室方法。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，以帝国太赫兹科学与工程中心(由各部门的学者和研究人员组成)的相关成员的专业知识为基础。来自材料、电气电子工程和物理学专业的专家小组，以及来自生命科学专门领域(包括癌细胞生物学和细胞生物传感)的小组，以及来自帝国理工学院的肿瘤学家的专业知识。从小鼠模型中提取的基于全血、血清或水的各种确定浓度的肿瘤细胞悬浮液将是我们的黄金标准方法，用于生成不同类型的肿瘤细胞的介电特性数据库，用于优化不同的传感器芯片方法，以及用于开发细胞检测方法。作为一个关键的里程碑，在项目接近尾声时，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，我们将基于我们之前在用于纳升液体测量的硅MEMS技术方面的工作，研究三种不同的电磁谐振器方法：介质谐振器、光子晶体和欺骗等离子激元超材料。先进的微纳加工技术，如深度反应离子刻蚀、电子束光刻和聚焦离子束刻蚀将被用于制造全集成(亚)太赫兹谐振器-微流体系统。在迎接CTC检测这一重大挑战的道路上，我们打算研究两个可能在较短时间内产生临床影响的潜在应用：小鼠模型中白血病细胞的无标记检测和人类尿样中的膀胱癌细胞检测。在这两种情况下，预期的细胞丰度都比CTC的情况高得多，但介电细胞识别的方法与CTC检测相同。后续项目，包括临床研究以及产业界的更大参与，可能会在该项目的时间跨度内启动。

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.