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

Lead Research Organisation: Imperial College London
Department Name: Materials

Abstract

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.

Planned Impact

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.
 
Description We have identified and investigated two promising methods for single cell measurements in the microwave and millimetre wave frequency range: a coupled dielectric / split resonator system measuring liquids in microfluidic chips (invited talk at the International Biosensor conference 2016, regular publication in progress) and the photonic crystal resonator for 100 GHz (S.Hanham et al., APPLIED PHYSICS LETTERS, 107, 2015).

One key finding within the last 12 months is that we found a way of microwave single cell detection, by using a coupled split ring - dielectric resonator. 2 invited conference talks have resulted from this achievement, a patent was filed and a publication is in progress.

Based on a new and more reliable technology for the microfluidic channels we intend to perform further studies which will lead to clinical trials.

We have demonstrated a microbeam and a slotted-microbeam resonators based on micromachined high-resistive silicon for the THz band (Hanham SM et al., IEEE Transactions on Terahertz Science and Technology, 1-10, 2017) which opens up new avenues for integrated high quality factor resonators for sensing applications and THz system components. We are currently working on single cell detection with microbeam resonators using disposable microcapillaries.

Photoprinted terahertz waveguides for broadband liquid sensing have been demonstrated, publication accepted.
Exploitation Route As a side aspect of this project, we are preparing a systematic study on pancreatic fluid and urine samples from patients with Cancer, in order to test whether the cavity method being developed in this project can be used as a basis for a liquid biopsy. Depending on the success of these preliminary measurements, we consider a research proposal for medical verification, as a natural step towards an early medical application of on of the techniques being developed within TERACELL.

A related research proposal was submitted recently to EPSRC Healthcare Technologies, pending.
Sectors Education,Healthcare

URL https://www.imperial.ac.uk/people/n.klein/research.html
 
Description The split ring resonator method for microwave dielectric measurements on single cells has been further refined and a publication has been submitted to Lab on the Chip, which is currently under review. We could show that microwave measurement enable water content detection in flowing cells, verified by Raman measurements. This results is a key milestone for tumor cell detection in blood, a follow up proposal is in progress. Single cell measurements on a refined photonic bandgap structure are currently in progress, preliminary results indicate a very high sensitivity. Finally, we have improved our understanding of analyzing permittivity data from thz transmission measurements, as documented by a recent publication in IEEE Access. We have refined the fabrication technology for microfluidic channels and have optimized the channel design, which make the results much more reproducible. We expect that the system will be ready soon for first clinical trials. Within a new proposal submitted to EPSRC Healthcare Technologies we suggest to combine the microwave detection with dielectrophoretic and accoustic cell sorting. This proposal contains clinical validation.
First Year Of Impact 2019
Sector Healthcare
 
Description responsive mode Healthcare Technolgies
Amount £1,200,000 (GBP)
Funding ID EP/P02985X/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 01/2018 
End 12/2020
 
Description Advanced graphene device characterization 
Organisation National Physical Laboratory
Country United Kingdom 
Sector Academic/University 
PI Contribution graphene deposition and device fabrication
Collaborator Contribution Kelvin probe microscopy, microwave near field microscopy
Impact mots recent joint publications: Adabi M, Lischner J, Hanham SM, Shaforost O, Wang R, Mihai, Hao L, Petrov P, Klein Nclose, Microwave study of field-effect devices based on graphene/aluminum nitride/graphene structures, Scientific Reports, ISSN: 2045-2322 (accepted) Gajewski K, Goniszewski S, Szumska A, Moczala M, Kunicki P, Gallop J, Klein N, Hao L, Gotszalk Tclose, 2016, Raman Spectroscopy and Kelvin Probe Force Microscopy characteristics of the CVD suspended graphene, DIAMOND AND RELATED MATERIALS, Vol: 64, Pages: 27-33, ISSN: 0925-9635 Goniszewski S, Adabi M, Shaforost O, Hanham SM, Hao L, Klein Nclose, 2016, Correlation of p-doping in CVD Graphene with Substrate Surface Charges, SCIENTIFIC REPORTS, Vol: 6, ISSN: 2045-2322 Gregory AP, Blackburn JF, Lees K, Clarke RN, Hodgetts TE, Hanham SM, Klein Nclose, 2016, Measurement of the permittivity and loss of high-loss a Near-Field Scanning Microwave Microscope, ULTRAMICROSCOPY, Vol: 161, Pages: 137-145, ISSN: 0304-3991 Goniszewski S, Gallop J, Adabi M, Gajewski K, Shaforost O, Klein N, Sierakowski A, Chen J, Chen Y, Gotszalk T, Hao Lclose, 2015, Self-supporting graphene films and their applications, IET CIRCUITS DEVICES & SYSTEMS, Vol: 9, Pages: 420-427, ISSN: 1751-858X
Start Year 2013
 
Description Combined accoustic / electromagnetic biosensors, graphene biosensors 
Organisation Imperial College London
Department Department of Chemical Engineering
Country United Kingdom 
Sector Academic/University 
PI Contribution - development of methodology and chip development for microwave detection of single cells - development of biofunctionalization of graphene layers - preparation of large area CVD layers for biuosensors
Collaborator Contribution - development of cell sorting by surface accoustic waves. - development of biofunctionalization of graphene layers
Impact - joint research proposal under preparation: combined accoustic / electromagnetic microfluidic device for marker free circulating tumoiur cell detection. - collaboration between postdocs and PhD students from both groups. - joint publication currently under reviews
Start Year 2016
 
Description Combined photonic and terahertz CMOS compatible lab on chip devices 
Organisation University of Exeter
Department Centre for the Study of War, State and Society
Country United Kingdom 
Sector Academic/University 
PI Contribution Silicon Terahertz and microwave lab on chip devices
Collaborator Contribution Photonic CMOS compatible lab on chip devices
Impact - design studies of combined photonic / thz lab on chip devices for health applications
Start Year 2015