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. 2020 Jul 20;11(7):699.
doi: 10.3390/mi11070699.

Design and Simulation of an Integrated Centrifugal Microfluidic Device for CTCs Separation and Cell Lysis

Rohollah Nasiri  1   2   3 , Amir Shamloo  1 , Javad Akbari  1 , Peyton Tebon  2   3 , Mehmet R Dokmeci  2   3   4 , Samad Ahadian  2   3
Affiliations

Design and Simulation of an Integrated Centrifugal Microfluidic Device for CTCs Separation and Cell Lysis

Rohollah Nasiri et al. Micromachines (Basel). .

Abstract

Separation of circulating tumor cells (CTCs) from blood samples and subsequent DNA extraction from these cells play a crucial role in cancer research and drug discovery. Microfluidics is a versatile technology that has been applied to create niche solutions to biomedical applications, such as cell separation and mixing, droplet generation, bioprinting, and organs on a chip. Centrifugal microfluidic biochips created on compact disks show great potential in processing biological samples for point of care diagnostics. This study investigates the design and numerical simulation of an integrated microfluidic device, including a cell separation unit for isolating CTCs from a blood sample and a micromixer unit for cell lysis on a rotating disk platform. For this purpose, an inertial microfluidic device was designed for the separation of _target cells by using contraction-expansion microchannel arrays. Additionally, a micromixer was incorporated to mix separated _target cells with the cell lysis chemical reagent to dissolve their membranes to facilitate further assays. Our numerical simulation approach was validated for both cell separation and micromixer units and corroborates existing experimental results. In the first compartment of the proposed device (cell separation unit), several simulations were performed at different angular velocities from 500 rpm to 3000 rpm to find the optimum angular velocity for maximum separation efficiency. By using the proposed inertial separation approach, CTCs, were successfully separated from white blood cells (WBCs) with high efficiency (~90%) at an angular velocity of 2000 rpm. Furthermore, a serpentine channel with rectangular obstacles was designed to achieve a highly efficient micromixer unit with high mixing quality (~98%) for isolated CTCs lysis at 2000 rpm.

Keywords: cell lysis; cell separation; circulating tumor cells; microfluidics; micromixer.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Proposed LOCD device. (A) Two-dimensional schematic of the designed centrifugal-based microfluidic biochip composed of serially arranged separator and mixer subunits. (B) Magnified view of the proposed device. (C) Cell separation unit, the CTCs are separated from the WBC cells by the implementation of inertial contraction–expansion arrays. (D) The mixer unit for cell lysis: (I) serpentine channel without obstacles and (II) with obstacles.
Figure 2
Figure 2
The functions (A) G1 and (B) G2 from [56].
Figure 3
Figure 3
(A) An illustration of the Morijiri et al. [38] model, (B) Numerical simulation results for the velocity field in narrow region. (C,D) particles’ paths for different particles at different sections of the platform.
Figure 4
Figure 4
Simulation of Flow field for the proposed cell separation unit (A) formation of two counter-rotating vortices in a cross-section in the contraction region. (B) Defined vertical line in the cross-section. (C) Radial velocity profile for the different angular velocity of disk. (D) Mesh independency analysis for cell separation unit at three different mesh densities for lateral fluid velocity magnitude along the vertical red line in the middle of the channel cross-section. (E) Lift force magnitude distribution and its vectors in a cross-section of contraction section for 20 µm particles. (F) Lift force magnitude distribution and its vectors in a cross-section of expansion section for 20 µm particles.
Figure 5
Figure 5
Particle tracking in proposed separation unit for different angular velocity. (A–F) Particles’ path lines and location at the outlets of the channel for different angular velocity. (A) 500 rpm, (B) 1000 rpm, (C) 1500 rpm, (D) 2000 rpm, (E) 2500 rpm, (F) 3000 rpm. Red lines show the path lines for CTCs and blue lines show the path lines for WBCs. (G) Separation efficiency for different angular velocity. (H) Path lines for CTCs with 15 and 20 µm diameters and WBCs with a 10 µm diameter.
Figure 6
Figure 6
Validation of the mixing unit for our simulation method vs. La et al.’s experiment. (A) Concentration contour for the simulation model. (B) Comparison of mixing quality at different down-channel locations between numerical and experimental model.
Figure 7
Figure 7
Mixer unit simulation. (A) Mixing pattern for serpentine micromixer without obstacles. (B) Vortex formation in serpentine channel without obstacles. (C) Velocity distribution for micromixer with obstacles at 2000 rpm. (D) Vortex formation in a serpentine channel with obstacles and related lateral velocity distribution within the cross-section. (E) Mixing pattern in proposed micromixer with obstacles at 2000 rpm. (F) Mixing pattern in the proposed micromixer in different cross-sections along the channel.
Figure 8
Figure 8
(A) Mesh independency analysis for mixer unit. (B) Mixing quality assessment along the down-channel length. (C) Mixing quality at different angular velocities.
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