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

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.

As discussed in detail within the Pathways to Impact statement, the research to be performed within TERACELL provides a new scientific and technological basis that has a realistic potential to revolutionize cancer diagnosis by blood analysis, and as such it will contribute to early state cancer diagnosis, cancer monitoring, therapy development and cancer research. We expect that during the course of this project we will be able to suggest pathways to novel diagnostic approaches, which will be subject to follow-up projects that include clinical trials. We intend to discuss potential applications on a regular basis with our industry stakeholders, Imperial Innovation and clinical partners. Moreover, proactive action will also be taken if results look promising in other application areas.

The cross-faculty nature of TERACELL, within Imperial's interdisciplinary research landscape, is in accordance with Imperial's Mission. Early cancer detection addresses one of the grand challenges of our modern society, which can only be tackled by a cross-disciplinary team like ours, which combines benchmarking research within Physical Sciences, Advanced Engineering, Life Sciences and Medicine. As such, dissemination of any generated breakthrough by Imperial's internal media and external media connections is guaranteed. However, the main communication path of our results will be via peer reviewed publications in high-impact journals and conference contributions; prior to each, a careful check with respect to a possible patent application will be pursued in close partnership with Imperial Innovations and our industrial stakeholders.

It is interesting to observe the evolutionary development of microwave-to-terahertz technology and UK industry, in the context of the impact of this project. The ending of the cold war (with a corresponding decline in associated funding of microwave-to-THz R&D projects) also saw the revolution of the wireless communications industry. This resulted in a global increase in the commercial side of the microwave market. However, at the same time, there was a global shift in the manufacturing towards Asia, which resulted in a significant decline of UK's - former world leading - microwave industry. Along with security applications (where the PI has generated a commercial impact with his spin-off company), the combination of the now strong life sciences industry within the UK, with the know-how and leading position in millimetre-wave and terahertz technologies, represents a promising opportunity for regaining global leadership by UK industry in a new area of potentially high growth.