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Microfluidic device for studying cell migration in single or co-existing chemical gradients and electric fields
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FIG. 1.

Schematic illustration of the microfluidic device. (a) 3D schematic drawing of the PDMS microfluidic device. Green indicates CCL19 solution and orange indicates medium solution. Platinum electrodes were buried in agarose gel blocks and inserted into the electrode wells. The two electrodes were then wired to the blue (cathode) and red (anode) wires, respectively, that were connected to a DC power supply to apply electric fields to the device. The drawing of the side channels was simplified with symmetric configurations. (b) Top view drawing of the microfluidic device with the channel dimensions indicated. (c) Illustration of the cell migration experiment setup. Microfluidic device was placed on a microscope stage; dcEF was applied to the device through a pair of electrodes; chemokine and medium solutions were infused into the device through tubing from syringe pumps for generating chemical gradients; cell migration in the device was then recorded by time-lapse microscopy. (d) Illustration of cell migration data analysis in the microfluidic device. Particularly, the O.I. is defined as the ratio of the displacement of cells (Δy) relative to the electric field or the chemical gradients to the total migration distance (d) using the equation O.I. = Δy/d.

Image of FIG. 2.

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FIG. 2.

Simulation of dcEF in the microfluidic device. (a) Top view of the microfluidic device. A 10 V of electrical potential difference was applied to the device from the two electrode wells. (b) The color map and the arrows indicate the magnitude and the direction of the dcEF in the main channel (0.75 mm (L) × 0.35 mm (W) at ∼7 mm downstream of the main channel). (c) Plot of simulated dcEF across the main channel width in the region as in (b). The dcEF is presented as the average value with the error bar as the standard deviation (SD). The simulation results show that dcEF is relatively uniform in the defined center region of the main channel and its magnitude can be configured to be within the physiological strength range.

Image of FIG. 3.

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FIG. 3.

Simulation of chemical concentration gradients with dcEF application in the microfluidic device. (a) Simulated normalized CCL19 gradient in the main channel of the microfluidic device when a 10 V electrical potential difference is applied to the device through the 2 electrode wells. (b) Enlarged view of the CCL19 gradient in the boxed region in the main channel as indicated in (a) (∼7 mm downstream of the main channel). (c) Plot of simulated gradient across the main channel width in the region as in (b) with (grey) or without (black) the applied dcEF. The simulation results show that the gradient profile is not significantly affected by the applied dcEF. The p value of the F test comparing the gradient profiles is 0.82.

Image of FIG. 4.

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FIG. 4.

Chemotaxis of activated T cells in the microfluidic device. Angular histograms of cell migration angles in the control condition (medium only) or in a 100 nM CCL19 gradient are showed in (a) and (b), respectively. The rose diagrams show the distribution of migration angles of all cells analyzed from multiple independent experiments for each condition. The migration angles were calculated from x-y coordinates at the beginning and the end of the cell tracks and were grouped in 20° intervals, with the radius of each wedge indicating the cell number (i.e., the radius of each circle indicates the cell number with the increment of one). (c) O.I. and speed of cells in the control condition or in a 100 nM CCL19 gradient. The values are presented as the average ± SEM. The results show the effectiveness of the developed microfluidic device for analyzing cell chemotaxis in single chemokine gradients.

Image of FIG. 5.

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FIG. 5.

Electrotaxis of activated T cells in the microfluidic device. (a)–(d) Angular histogram of cell migration angles in different dcEF (i.e., 0 V, 7 V, 10 V, and 15 V electrical potential difference between the two electrode wells). The rose diagrams show the distribution of migration angles of all cells analyzed from multiple independent experiments for each condition. The migration angles were calculated from x-y coordinates at the beginning and the end of the cell tracks and were grouped in 20° intervals, with the radius of each wedge indicating the cell number (i.e., the radius of each circle indicates the cell number with the increment of one). (e) O.I. and speed of cells in different applied dcEF. The values are presented as the average ± SEM. The results show the cathode-directing electrotaxis of cells when a 10 V electrical potential difference was applied to the device and thus demonstrate the effectiveness of the developed microfluidic device for analyzing cell electrotaxis in single dcEF.

Image of FIG. 6.

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FIG. 6.

T cell migration in competing CCL19 gradients and dcEF in the microfluidic device. (a) Migration tracks of 6 cells from a representative experiment with 2 cells (grey) migrating toward the 100 nM CCL19 gradient (left) and 4 cells (black) migrating toward the cathode of the applied dcEF (10 V across the device with the cathode on the right). (b) Angular histogram shows the distribution of migration angles of all cells analyzed from multiple independent experiments. The migration angles were calculated from x-y coordinates at the beginning and the end of the cell tracks and were grouped in 20° intervals, with the radius of each wedge indicating the cell number (i.e., the radius of each circle indicates the cell number with the increment of one). (c) O.I. and speed of T cells in single CCL19 gradient, single dcEF or competing CCL19 gradient and dcEF. The values are presented as the average ± SEM. The results show the stronger cell migration toward the cathode of the applied dcEF in the presence of a competing CCL19 gradient.

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/content/aip/journal/bmf/6/2/10.1063/1.4718721
2012-05-16
2014-04-19

Abstract

Cell migration is involved in physiological processes such as wound healing, host defense, and cancermetastasis. The movement of various cell types can be directed by chemical gradients (i.e., chemotaxis). In addition to chemotaxis, many cell types can respond to direct current electric fields (dcEF) by migrating to either the cathode or the anode of the field (i.e., electrotaxis). In tissues, physiological chemical gradients and dcEF can potentially co-exist and the two guiding mechanisms may direct cell migration in a coordinated manner. Recently, microfluidic devices that can precisely configure chemical gradients or dcEF have been increasingly developed and used for chemotaxis and electrotaxis studies. However, a microfluidic device that can configure controlled co-existing chemical gradients and dcEF that would allow quantitative cell migration analysis in complex electrochemical guiding environments is not available. In this study, we developed a polydimethylsiloxane-based microfluidic device that can generate better controlled single or co-existing chemical gradients and dcEF. Using this device, we showed chemotactic migration of T cells toward a chemokine CCL19 gradient or electrotactic migration toward the cathode of an applied dcEF. Furthermore, T cells migrated more strongly toward the cathode of a dcEF in the presence of a competing CCL19 gradient, suggesting the higher electrotactic attraction. Taken together, the developed microfluidic device offers a new experimental tool for studying chemical and electrical guidance for cell migration, and our current results with T cells provide interesting new insights of immune cell migration in complex guiding environments.

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Scitation: Microfluidic device for studying cell migration in single or co-existing chemical gradients and electric fields
http://aip.metastore.ingenta.com/content/aip/journal/bmf/6/2/10.1063/1.4718721
10.1063/1.4718721
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