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是从肿瘤转移到血液中的恶性细胞，有可能形成转移。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治疗的发展至关重要。生化CTC分离方法已被证明效率极低，因此，目前仅通过血液分析进行预防性筛查是不可靠的。微波到太赫兹介电测量被成功地用于识别癌细胞；它们在肿瘤组织成像方面的能力在临床上被确立为x射线和MRI的可行替代方案。频率范围从10千兆赫到大约1太赫兹，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/中红外范围相比，细胞散射仍然可以忽略不计。由于高达约1太赫兹的水的高电磁吸收，在小型集成微流体储层（团队先前演示过）内具有高质量因子和高度集中电场的电磁谐振器，基本上每次包含一个单元，代表了快速准确介电测量的理想系统。这是因为单个细胞处于自然液体环境中。为了解决血液样本中ctc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-太赫兹谐振器结合在一个芯片上或作为一个多芯片组合，旨在实现临床应用的片上实验室方法。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，以帝国理工学院太赫兹科学与工程中心（由各部门的学者和研究人员组成）联合成员的专业知识为基础。材料，电气和电子工程和物理学)，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）的选定小组，以及来自帝国医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、血清或水的不同浓度的肿瘤细胞悬浮液将成为我们生成不同类型肿瘤细胞介电特性数据库的金标准方法，用于优化不同传感器芯片方法，以及开发细胞检测方法。作为一个关键的里程碑，在项目结束时，我们将展示在人类血液样本中检测CTC。作为该项目的主要工程挑战，基于我们之前对纳米液体测量的硅MEMS技术的研究，我们将研究三种不同的电磁谐振器方法：介电谐振器、光子晶体和基于欺骗等离子体的超材料。先进的微纳米加工技术，如深度反应离子蚀刻、电子束光刻和聚焦离子束蚀刻，将被用于制造完全集成的（亚）太赫兹谐振微流控系统。为了迎接CTC检测的巨大挑战，我们打算研究两种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液样本中膀胱癌细胞的检测。在这两种情况下，预期的细胞丰度都比CTC的情况高得多，但介质细胞识别的方法与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这个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.