Hybrid Optical Interferometry for Quantitative Cancer Cell Diagnosis

Project Information

OptiQ-CanDo

Grant agreement ID: 678316

DOI

10.3030/678316

Project closed

EC signature date 18 February 2016

Start date 1 July 2016

End date 31 December 2022

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 916 250,00

EU contribution

€ 1 916 250,00

Coordinated by

TEL AVIV UNIVERSITY
Israel

Periodic Reporting for period 4 - OptiQ-CanDo (Hybrid Optical Interferometry for Quantitative Cancer Cell Diagnosis)

Reporting period: 2021-01-01 to 2022-12-31

Summary of the context and overall objectives of the project

Invasive cancer is a leading cause of death worldwide. Detecting cancer in its early curable stages is a clear and critical unmet need. Late stage metastatic forms of cancer are fatal. Cancer starts with changes in a single cell or a small group of cells, which cause the cells to grow and divide in an uncontrolled manner. Detecting these changes requires new microscopy capabilities. A major challenge in the field of optical imaging of live cells is to achieve label-free but still fully quantitative measurements, which afford high-resolution morphological and mechanical mapping at the single cell level. In particular, developing efficient, non-subjective, quantitative optical imaging technologies for cancer cell diagnosis is a challenging task. The ground-breaking goal of this research project is to establish a robust experimental toolbox for label-free optical diagnosis and monitoring of live cancer cells in-vitro and their potential of metastasis. Optical interferometry is able to provide a platform for imaging live cells quantitatively without the risk of effects caused by using external contrast agents. By overcoming critical technological barriers, I suggest novel hybrid optical interferometric approaches that provide a powerful nano-sensing tool for label-free quantitative measurement of cancer cells. This will be obtained by recording the dynamic quantitative, three-dimensional sub-nanometric structural and mechanical characterization of live cancer cells in different stages. For this aim, I will develop a novel low-noise broadband, common-path, off-axis interferometric system for sub-nanometric physical thickness and mechanical mapping of live cells in thousands of frames per second. Additionally, I will develop rapid tomographic approach for fully capturing the cell three-dimensional refractive-index distribution, as a tool to characterize cancer progression. Interferometry will be combined with multi-trap holographic optical tweezers and dielectrophoresis to enable complete cell manipulations including full rotation, imaging of non-adherent cells, and mechanical measurement validation. New set of interferometry-based quantitative parameters will be developed to enable characterization of cellular transformations, and used to characterize cancer cells with different metastasis potential, for cell lines and for circulating tumor cells.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The project aims were:

1. Aim 1: Development of hybrid wide-field nano-sensing interferometric platforms for live-cell imaging

We designed and built novel low-noise off-axis interferometric systems, for enabling wide-field cell thickness mapping in live cells with 0.2 nm thickness accuracy, without labeling or scanning.

We published these journal papers for this aim:

Optics Letters 42, 73-76, 2017
Optics Letters 43, 1943-1946, 2018
Optics Letters 43, 2046-2049, 2018
Optics Express 28, 5617-5628, 2020
Frontiers in Physics 8, 611679, 2021

Then, we presented a new method that is able to compress up to six channels into a single hologram (novel paradigm in the field), called six-pack holography:
Optics Letters 42, 4611-4614, 2017.

Optics Express 25, 33400-33415, 2017
Optics Express 27, 26708-26720, 2019
Journal of Optical Society of America A 36, A1-11, 2019
Advances in Optics and Photonics 12, 556-611, 2020
Optics Express 29, 632-646, 2021

We combined new dynamic tomographic approaches:
Science Advances 6, eaay7619, 2020
Optics Express 12, 4, 2021
ACS Photonics 9,1295–1303, 2022


2. Aim 2: Development of interferometry-based mathematical analysis tools for cell characterization:

We develop a novel set of quantitative parameters that can be calculated based on the cell thickness map measured by interferometry, including machine learning and deep learning tools:

We published these journal papers for this aim:
Cytometry A 91, 482-493, 2017.
Medical Image Analysis 57, 176-185, 2019
Frontiers in Physics, 9, 754897, 2021


3. Aim 3: Cancer-cell characterization and monitoring:

We published these journal papers for this aim:
Cytometry A 91, 482-493, 2017.
Biomedical Optics Express 11, 6649-6658, 2020
Cytometry A 99, 511-523, 2021
Cells 10, 3353, 2021

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

We found new ways to decouple refractive index from cell thickness for cancer cells during flow:

G. Dardikman, Y. N. Nygate, I. Barnea, N. A. Turko, G. Singh, B. Javidi, and N. T. Shaked, “Integral refractive index imaging of flowing cell nuclei using quantitative phase microscopy combined with fluorescence microscopy,” Biomedical Optics Express, Vol. 9, Issue 3, pp. 1177-1189, 2018

We found new ways to solve the unwrapping problems in the cell phase profiles measured:

G. Dardikman, S. Mirsky, M. Habaza, Y. Roichman, and N. T. Shaked, “Angular phase unwrapping of optically thick objects with a thin dimension,” Optics Express, Vol. 25, Issue 4, pp. 3347-3357, 2017

G. Dardikman*, G. Singh*, and N. T. Shaked, “Four dimensional phase unwrapping of dynamic objects in digital holography,” Optics Express, Vol. 26, Issue 4, pp. 3772-3778, 2018

We also demonstrated multiplexing holography:
Y. Nygate, G. Singh, N. A. Turko, and N. T. Shaked, “Simultaneous off-axis multiplexed holography and regular fluorescence microscopy of biological cells,” Optics Letters, Vol. 43, No. 1, pp. 2587-2590, 2018
G. Dardikman, N. A. Turko, N. Nativ, S. K. Mirsky, and N. T. Shaked, “Optimal spatial bandwidth capacity in multiplexed off-axis holography for rapid quantitative phase reconstruction and visualization,” Optics Express, Vol. 25, No. 26, pp. 33400-33415, 2017
G. Dardlkman and N. T. Shaked, “Is multiplexed off-axis holography for quantitative phase imaging more spatial bandwidth-efficient than on-axis holography?,” Accepted to Journal of Optical Society of America A, 2018
L. Wolbromsky, M. Dudaie, S. Shinar, M. Dudaie, and N. T. Shaked, “Multiplane imaging with extended field-of-view using a quadratically distorted grating,” Optics Communications, Vol. 463, 125399, pp. 1-5, 2020
These works help in making the ERC project goals become more useful for clinical implementations, allowing the rapid analysis of the quantitative phase maps of cancer cells.

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