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Biophysical phenotyping of cells via impedance spectroscopy in parallel cyclic deformability channels - PubMed

  • ️Tue Jan 01 2019

. 2019 Jul 18;13(4):044103.

doi: 10.1063/1.5099269. eCollection 2019 Jul.

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Biophysical phenotyping of cells via impedance spectroscopy in parallel cyclic deformability channels

Xiang Ren et al. Biomicrofluidics. 2019.

Abstract

This paper describes a new microfluidic biosensor with capabilities of studying single cell biophysical properties. The chip contains four parallel sensing channels, where each channel includes two constriction regions separated by a relaxation region. All channels share a pair of electrodes to record the electrical impedance. Single cell impedance magnitudes and phases at different frequencies were obtained. The deformation and transition time information of cells passing through two sequential constriction regions were gained from the time points on impedance magnitude variations. Constriction channels separated by relaxation regions have been proven to improve the sensitivity of distinguishing single cells. The relaxation region between two sequential constriction channels provides extra time stamps that can be identified in the impedance plots. The new chip allows simultaneous measurement of the biophysical attributes of multiple cells in different channels, thereby increasing the overall throughput of the chip. Using the biomechanical parameters represented by the time stamps in the impedance results, breast cancer cells (MDA-MB-231) and the normal epithelial cells (MCF-10A) could be distinguished by 85%. The prediction accuracy at the single-cell level reached 97% when both biomechanical and bioelectrical parameters were utilized. While the new label-free assay has been tested to distinguish between normal and cancer cells, its application can be extended to include cell-drug interactions and circulating tumor cell detection in blood.

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Figures

FIG. 1.
FIG. 1.

Micrographs depicting the morphology of (a) breast cancer cell line MDA-MB-231 and (b) normal epithelial cell line MCF-10A.

FIG. 2.
FIG. 2.

(a) Device fabrication processes and experimental setup: ① PDMS replica molding, ② PDMS to glass bonding after the plasma treatment; (b) illustration of the channel configurations; SC: sensing channel; CR: constriction region; RR: relaxation region; CRxy, x: row number (x = 1, 2, 3, 4), y: column number (y = 1, 2).

FIG. 3.
FIG. 3.

The impedance plot of an example cell through the device: (a) MDA-MB-231 (two cells); (b) MCF-10A (one cell).

FIG. 4.
FIG. 4.

CA (cancer cells MDA-MB-231, n = 101) and NR (normal cells MCF-10A, n = 103) distinguished at the population level with the use of selected parameters: (a) total transit time; (b) transit time ratio of the passing time in CRx1 and CRx2; (c) the sum of rise time to passing time ratio in CRx1 and CRx2; (d) amplitude ratio: the ratio of relative impedance peak and impedance baseline; (e) phase shifts; (f) the ratio of the difference of impedance rise in CRx1 and CRx2 to the impedance rise in CRx1; (g) rise time ratio; (h) impedance rise slope in CRx1; (i) impedance drop ratio; (j) phase drop ratio. The blue box plot depicts the quantile numbers: maxima (upper dash whisker), Q75, Q50 (median, red bar), Q25, and minima (lower dashed whisker).

FIG. 5.
FIG. 5.

Scatter plot distinguishes at single-cell level cancer cells (MDA-MB-231, n = 101) and normal cells (MCF-10A, n = 103): (a) biomechanical parameters of rise time ratio; (b) bioelectrical parameters of impedance drop and phase drop ratios; and (c) combined biomechanical and bioelectrical properties.

FIG. 6.
FIG. 6.

ROC curve depicting the ability to discriminate CA (MDA-MB-231) and NR (MCF-10A) using different biophysical parameters. (ROC curve of other parameters is available in the

supplementary material

.)

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