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Open AccessArticle

Size Distribution Analysis with On-Chip Multi-Imaging Cell Sorter for Unlabeled Identification of Circulating Tumor Cells in Blood

1
Organization for University Research Initiatives, Waseda University, 3-14-9 Okubo, Shinjuku, Tokyo 169-0072, Japan
2
Waseda Bioscience Research Institute in Singapore (WABOIS), Helios, 11 Biopolis Way, Singapore 138667, Singapore
3
Biomedical Research Institute, Advanced Industrial Science and Technology (AIST), 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan
4
Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, 1-1-2 Nakao, Asahi-ku, Yokohama 241-0815, Japan
5
Department of Pure and Applied Physics, Graduate School of Advanced Science and Engineering, Waseda University, 3-4-1 Okubo, Shinjuku, Tokyo 169-8555, Japan
6
Department of Physics, School of Advanced Science and Engineering, Waseda University, 3-4-1 Okubo, Shinjuku, Tokyo 169-8555, Japan
*
Author to whom correspondence should be addressed.
Micromachines 2019, 10(2), 154; https://doi.org/10.3390/mi10020154
Received: 6 November 2018 / Revised: 13 December 2018 / Accepted: 20 December 2018 / Published: 25 February 2019
(This article belongs to the Special Issue State-of-the-Art Lab-on-a-Chip Technology in Japan)
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Abstract

We report a change of the imaging biomarker distribution of circulating tumor cell (CTC) clusters in blood over time using an on-chip multi-imaging flow cytometry system, which can obtain morphometric parameters of cells and those clusters, such as cell number, perimeter, total cross-sectional area, aspect ratio, number of nuclei, and size of nuclei, as “imaging biomarkers”. Both bright-field (BF) and fluorescent (FL) images were acquired at 200 frames per second and analyzed within the intervals for real-time cell sorting. A green fluorescent protein-transfected prostate cancer cell line (MAT-LyLu-GFP) was implanted into Copenhagen rats, and the blood samples of these rats were collected 2 to 11 days later and measured using the system. The results showed that cells having BF area of 90 μm2 or larger increased in number seven days after the cancer cell implantation, which was specifically detected as a shift of the cell size distribution for blood samples of implanted rats, in comparison with that for control blood. All cells with BF area of 150 μm2 or larger were arranged in cell clusters composed of at least two cells, as confirmed by FL nucleus number and area measurements, and they constituted more than 1% of all white blood cells. These results indicate that the mapping of cell size distribution is useful for identifying an increase of irregular cells such as cell clusters in blood, and show that CTC clusters become more abundant in blood over time after malignant tumor formation. The results also reveal that a blood sample of only 50 μL is sufficient to acquire a stable size distribution map of all blood cells to predict the presence of CTC clusters. View Full-Text
Keywords: imaging biomarker; circulating tumor cell (CTC); multi-imaging cell sorter; cell cluster; size distribution analysis imaging biomarker; circulating tumor cell (CTC); multi-imaging cell sorter; cell cluster; size distribution analysis
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Odaka, M.; Kim, H.; Nakamura, Y.; Hattori, A.; Matsuura, K.; Iwamura, M.; Miyagi, Y.; Yasuda, K. Size Distribution Analysis with On-Chip Multi-Imaging Cell Sorter for Unlabeled Identification of Circulating Tumor Cells in Blood. Micromachines 2019, 10, 154.

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