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Research Papers

An Inertia-Deformability Hybrid Circulating Tumor Cell Chip: Design, Clinical Test, and Numerical Analysis

[+] Author and Article Information
Hongmei Chen

School of Mathematics and Physics
of Science and Engineering,
Anhui University of Technology,
Maanshan 243002, China;
Division of Nanobionic Research,
Suzhou Institute of Nano-Tech
and Nano-Bionics,
Chinese Academy of Sciences,
Suzhou 215123, Jiangsu, China

Zhifeng Zhang

Mem. ASME
Department of Engineering Science
and Mechanics,
The Pennsylvania State University,
State College, PA 16802
e-mails: zfzhang@psu.edu;
alex.zfzhang@gmail.com

1Corresponding author.

Manuscript received February 13, 2018; final manuscript received July 16, 2018; published online September 21, 2018. Assoc. Editor: Yaling Liu.

J. Med. Devices 12(4), 041004 (Sep 21, 2018) (6 pages) Paper No: MED-18-1031; doi: 10.1115/1.4040986 History: Received February 13, 2018; Revised July 16, 2018

Detection and capture of circulating tumor cells (CTCs) with microfluidic chips hold significance in cancer prognosis, diagnosis, and anti-cancer treatment. The counting of CTCs provides potential tools to evaluate cancer stages as well as treatment progress. However, facing the challenge of rareness in blood, the precise enumeration of CTCs is challenging. In the present research, we designed an inertial-deformability hybrid microfluidic chip using a long spiral channel with trapezoid-circular pillars and a capture zone. To clinically validate the device, the microfluidic chip has been tested for the whole blood and lysed blood with a small number of CTCs (colorectal and nonsmall-cell lung cancer) spiked in. The capture efficiency reaches over 90% for three types of cancer cell lines at the flow rate of 1.5 mL/h. Following numerical modeling was conducted to explain the working principle and working condition (Reynolds number below 10 and Dean number around 1). This design extended the effective capture length, improved the capture efficiency, and made the CTC enumeration much easier. We believe that this hybrid chip is promising clinically in the CTCs enumeration, evaluation of cancer therapy, and pharmacological responses.

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Figures

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Fig. 1

Schematic diagram of the spiral microfluidic chip. An array of pillars is arranged at the center of a microchannel (with a magnified view of the trapezoid-spiral filter).

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Fig. 2

Scanning electron microscopes of trapezoid-spiral filter. (a) Four circular spiral microchannels. (b) Arrays of trapezoidal and circular microstructures are set in the middle of the microtunnel. (c) A magnified view and (d) size of gaps.

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Fig. 3

(a) Ink was introduced into the trapezoid-spiral chip. (b) Merged fluorescence images of Hela cells stained with Calcein AM and Hoechst (scale bar at 100 μm). (c) Capture efficiency for the trapezoid-spiral chip at different flow rates. Capture efficiency can reach 90% at 1.5 mL/h and decrease down to 30% at 3 mL/h.

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Fig. 4

Capture efficiency in phosphate buffered saline and fluorescence images of captured tumor cells stained with Calcein AM and Hoechst. (a) Capture efficiency for MDA-MB-231, Hela, and MCF-7 cells. (b) Fluorescence images of a captured tumor cell stained with Calcein AM and Hoechst (scale bar: 50 μm).

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Fig. 5

Fluorescence images of captured tumor cells stained with Calcein AM and Hoechst. No tumor cells were shown penterating the capture zone (scale bar: 100 μm).

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Fig. 6

Validation of microfluidic chip with blood samples. (a) Number of CTCs captured in samples with colorectal and lung cancer cells. (b) Immunofluorescent staining of a colorectal CTC captured at 1.5 mL/h showing nucleus, the absence of CD45, cytokeratin in a merged field. (c) Immunofluorescent staining of another colorectal CTCs recovered at 1.5 mL/h showing nucleus, the absence of CD45, cytokeratin in a merged field.

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Fig. 7

Fluorescence image of released MCF-7. Cells propagated freely after released from the chip after four days (scale bar: 100 μm).

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Fig. 8

Numerical results of the CTC separation process: (a) initial and boundary setting, (b) flow stream and CTC stuck, (c) pressure contour, and (d) velocity contour

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