Deterministic Lateral Displacement Microfluidic Devices Research Articles

Performance optimization of a DLD microfluidic device for separating deformable CTCs.

Deterministic lateral displacement (DLD) microfluidic devices work based on the streamlines created by an array of micro-posts. The configuration of pillars alters the isolation efficiency of these devices. The present paper optimizes the performance of a DLD device for isolating deformable circulating tumor cells. The input variables include cell diameter (d), Young's modulus ( ), Reynolds number (Re), and tan θ, where θ is the tilted angle of micro-posts. The output, which is the response of the system, is DLD. The numerical simulation results are employed to optimize the device using the response surface method, leading to the proposition of a correlation to estimate DLD as a function of input variables. It is demonstrated that the maximum and minimum impacts on cell lateral displacement correspond to and Re, respectively.

Sorting differentiated mammalian cells using deterministic lateral displacement microfluidic devices.

Separation of differentiated and undifferentiated cells without labeling is required for cell analyses and clinical application of cultured differentiated cells in vitro. To proceed with the passive separation of differentiated cells inside a clean bench, we developed a system of deterministic lateral displacement (DLD) microfluidic devices and applied this system to sort differentiated cells in vitro. The fluid flow is driven by compressed air to the buffer. Priming and sorting can be completed by air pressure control. We use this system to separate C2C12 mononuclear myocytes from multinuclear myotubes. Additionally, using a DLD microfluidic channel of Dc = 20μm, multinuclear myotubes can be effectively sorted as larger particles. We prepared differentiated adipocytes from mouse embryonic fibroblast (MEF) cells and sorted those containing lipid droplets. The diameters of these sorted adipocytes considered larger particles, exceeded 20μm, similar to the Dc of the DLD microfluidic channel. Differentiated cell sorting by cell size will contribute to single-cell analyses and in vitro tissue model preparation for drug discovery.

Investigation on sheathless inertial focusing within low-aspect ratio spiral microchannel for cascaded microfluidic tumor cell separation

The high-precision and high-purity isolation of circulating tumor cells (CTCs) from whole blood is vital to early cancer detection. Cascaded microfluidic separation is highly efficient because it connects multiple-stage separations in series. Here, we numerically investigated sheathless tumor cell separation with size-dependent cascaded inertial and deterministic lateral displacement (DLD) microfluidic device. The inertial microfluidic is arranged in the first-stage unit for particle focusing and rough sorting, and the cascaded DLD microfluidic is arranged in the second stage for realizing further sorting and purification. A parametric study with flow rate range from 100–600 μl/min and aspect ratio range from 60:100 to 60:300 of the first stage was carried out to optimize channel structure for realizing high-efficiency separation. Then, the pre-separation mechanism within the spiral microchannel was analyzed. The purity of the obtained CTCs and the separation efficiency were further improved using a droplet-type microcolumn DLD microfluidic device as the second unit. The cascade eliminates the need for additional force fields and reduces device complexity while simplifying operation and reducing the chance of sample contamination.

Isolation of Extracellular Vesicles from Cell Culture and Blood Through Nano-Targeted DLD Microfluidic Device.

Extracellular vesicles (EVs) are secreted by cells and found in biological fluids such as blood, with concentration correlated with oncogenic signals, making them attractive biomarkers for liquid biopsy. The current gold-standard method for EVs isolation requires an ultracentrifugation (UC) step among others. The cost and complexity of this technique are forbiddingly high for many researchers, as well as for routine use in biological laboratories and hospitals. This chapter reports on a simple microfluidic method for EVs isolation, based on a microfluidic size sorting technique named Deterministic Lateral Displacement (DLD). With the design of micrometric DLD array, we demonstrated the potential of our DLD devices for the isolation of nano-biological objects such as EVs, with main population size distribution consistent with UC technique.

Combining Electrostatic, Hindrance and Diffusive Effects for Predicting Particle Transport and Separation Efficiency in Deterministic Lateral Displacement Microfluidic Devices.

Microfluidic separators based on Deterministic Lateral Displacement (DLD) constitute a promising technique for the label-free detection and separation of mesoscopic objects of biological interest, ranging from cells to exosomes. Owing to the simultaneous presence of different forces contributing to particle motion, a feasible theoretical approach for interpreting and anticipating the performance of DLD devices is yet to be developed. By combining the results of a recent study on electrostatic effects in DLD devices with an advection–diffusion model previously developed by our group, we here propose a fully predictive approach (i.e., ideally devoid of adjustable parameters) that includes the main physically relevant effects governing particle transport on the one hand, and that is amenable to numerical treatment at affordable computational expenses on the other. The approach proposed, based on ensemble statistics of stochastic particle trajectories, is validated by comparing/contrasting model predictions to available experimental data encompassing different particle dimensions. The comparison suggests that at low/moderate values of the flowrate the approach can yield an accurate prediction of the separation performance, thus making it a promising tool for designing device geometries and operating conditions in nanoscale applications of the DLD technique.

Effect of angle-of-attacks on deterministic lateral displacement (DLD) with symmetric airfoil pillars.

Deterministic lateral displacement (DLD) is a microfluidic technique for size fractionation of particles/cells in continuous flow with a great potential for biological and clinical applications. Growing interest of DLD devices in enabling high-throughput operation for practical applications, such as circulating tumor cell (CTC) separation, necessitates employing higher flow rates, leading to operation at moderate to high Reynolds number (Re) regimes. Recently, it has been shown that symmetric airfoil shaped pillars with neutral angle-of-attack (AoA) can be used for high-throughput design of DLD devices due to their mitigation of vortex effects and preservation of flow symmetry under high Re conditions. While high-Re operation with symmetric airfoil shaped pillars has been established, the effect of AoAs on the DLD performance has not been investigated. In this paper, we have characterized the airfoil DLD device with various AoAs. The transport behavior of microparticles has been observed and analyzed with various AoAs in realistic high-Re. Furthermore, we have modeled the flow fields and anisotropy in a representative airfoil pillar array, for both positive and negative AoA configurations. Unlike the conventional DLD device, lateral displacement has been suppressed with +5° and + 15° AoA configurations regardless of particle sizes. On the other hand, stronger lateral displacement has been seen with -5° and - 15° AoAs. This can be attributed to growing flow anisotropy as Re climbs, and significant expansion or compression of streamlines between airfoils with AoAs. The findings in this study can be utilized for the design and optimization of airfoil DLD microfluidic devices with various AoAs.

3D deterministic lateral displacement (3D-DLD) cartridge system for high throughput particle sorting.

A new 3D architecture for the deterministic lateral displacement (DLD) microfluidic devices based on ultra-high aspect ratio arch shaped pillars is presented. The proposed system addresses the major flow rate and shear rate limitations of standard planar devices.

Two-dimensional Simulation of Motion of Red Blood Cells with Deterministic Lateral Displacement Devices.

Deterministic lateral displacement (DLD) technology has great potential for the separation, enrichment, and sorting of red blood cells (RBCs). This paper presents a numerical simulation of the motion of RBCs using DLD devices with different pillar shapes and gap configurations. We studied the effect of the pillar shape, row shift, and pillar diameter on the performance of RBC separation. The numerical results show that the RBCs enter “displacement mode” under conditions of low row-shift (∆λ < 1.4 µm) and “zigzag mode” with large row shift (∆λ > 1.5 µm). RBCs can pass the pillar array when the size of the pillar (d > 6 µm) is larger than the cell size. We show that these conclusions can be helpful for the design of a reliable DLD microfluidic device for the separation of RBCs.

Space-time resolution of size-dispersed suspensions in Deterministic Lateral Displacement microfluidic devices

Deterministic Lateral Displacement (DLD) is a relatively recent microfluidics-assisted technique which allows the size-based separation of a population of micrometric particles suspended in a buffer solution. The core of the device is a shallow channel with rectangular cross-section filled with an array of solid obstacles arranged in a spatially periodic lattice, whose directions are slanted with respect to the channel walls. In practical implementations of DLD, particles are continuously introduced at a localized position of the channel entrance and migrate along different average directions downstream the device according to their size. Thus, at steady state, size-sorted subpopulations can be collected at different positions of the channel outlet. Besides, theoretical predictions of recent models of particle transport in these devices suggest that not only the direction of the average particle velocity, but also its magnitude (i.e. the mobility) depends sensitively on particle size. By exploiting this dependence, a novel use of DLD devices is here proposed, where the size-driven separation is realized over time and space by running the process under transient conditions, thus mimicking a classical chromatographic separation. We show how this approach is particularly effective for particles of specific (critical) dimensions, which are known to impair the efficiency of the steady-state separation process. Numerical predictions based on a hard-wall repulsive potential for the particle-obstacle interaction suggest that unprecedented separation performance for near-critical particle size could be obtained in transient conditions within the same channel length used for the time-continuous separation. The case of cylindrical obstacles and spherically shaped particles is considered in detail as an illustrative example.

On the transport of particles/cells in high-throughput deterministic lateral displacement devices: Implications for circulating tumor cell separation

Deterministic lateral displacement (DLD), which takes advantage of the asymmetric bifurcation of laminar flow around the embedded microposts, has shown promising capabilities in separating cells and particles of different sizes. Growing interest in utilizing high-throughput DLD devices for practical applications, such as circulating tumor cell separation, necessitates employing higher flow rates in these devices, leading to operating in moderate to high Reynolds number (Re) regimes. Despite extensive research on DLD devices in the creeping regime, limited research has focused on the physics of flow, critical size of the device, and deformable cell behavior in DLD devices at moderate to high Re. In this study, the transport behavior of particles/cells is investigated in realistic high-throughput DLD devices with hundreds of microposts by utilizing multiphysics modeling. A practical formula is proposed for the prediction of the device critical size, which could serve as a design guideline for high-throughput DLD devices. Then, the complex hydrodynamic interactions between a deformable cell and DLD post arrays are investigated. A dimensionless index is utilized for comparing different post designs to quantify the cell-post interaction. It is shown that the separation performances in high-throughput devices are highly affected by Re as well as the micropost shapes. These findings can be utilized for the design and optimization of high-throughput DLD microfluidic devices.

A novel numerical modeling paradigm for bio particle tracing in non-inertial microfluidics devices

In this work, we report on the design and implementation of a new method for the two dimensional (2D) simulation of rigid spherical particles trajectory which are to be separated in a microfluidics device based on their sizes. The advantages of efficient particle trajectory simulation method (EPTSM) include drastically smaller runtimes as compared with other methods as well as the ability to include particle collisions with channel’s walls and its ability to be extended to 3D simulations. Numerically simulated results were verified using a specifically designed and fabricated deterministic lateral displacement microfluidic device test structure. The method has provided realistic results for the study of multi-particles throughout the entire channel.

Separation of main and satellite droplets in a deterministic lateral displacement microfluidic device

We present a novel DLD microfluidic device for preparing satellite-free main droplets and monodispersed satellite droplets.

Numerical Simulation of Separation of Circulating Tumor Cells from Blood Stream in Deterministic Lateral Displacement (DLD) Microfluidic Channel

AbstractDeterministic Lateral Displacement (DLD) microfluidic devices provide a reliable label-free separation method for detection of circulating tumor cells (CTCs) in blood samples based on their biophysical properties. In this paper, we proposed an effective design of the DLD microfluidic device for the CTC separation in the blood stream. A typical DLD array is designed and numerical simulations are performed to separate the CTC and leukocyte (white blood cells) in different fluid flow conditions. Fluid-Solid Interaction method is used to investigate the behaviour of these deformable cells in fluid flow. In this study, the effects of critical parameters affecting cell separation in the DLD microfluidic devices (e.g.flow condition, cell deformability, and stress) have been investigated. The obtained results show that unlike leukocytes, the CTC’s motion is independent of the flow condition and is laterally displaced even in higher Reynolds number. Larger cells (CTCs) cannot intercept the low-velocity fluid near the wall of the posts; thus, they move faster and become separated from leukocytes. To reduce the cellular stress during separation process, which causes increase of cell viability and more effective design of microfluidic device, the results obtained here may be used as a significant design parameter for the DLD fabrication.

Enrichment of circulating tumor cells in tumor-bearing mouse blood by a deterministic lateral displacement microfluidic device.

Concentration of real tumor cells leaking into blood from cancer was attempted by a deterministic lateral displacement (DLD) microfluidic device. Spiked cultured cell line tumor cells are often used to verify performance of the circulating tumor cells (CTCs) separation methods. Cultured tumor cells are obviously larger than most of hematocytes and considered not to be appropriate as CTC mimics, while there is uncertainty in identifying real CTCs from clinical samples and there is no practical way to examine CTCs leakage into benign cells during the sorting. In this work, blood samples were prepared from tumor-bearing mice whose tumors were induced by implanting cells with GFP expression to living mice. Therefore, CTCs were identified by their fluorescence emission. We succeeded in the enrichment of tumor cells to 0.05% from the blood, in which CTCs were negligibly detected among three million blood cells, and little loss of CTCs was observed.

Fractionation by shape in deterministic lateral displacement microfluidic devices

We investigate the migration of particles of different geometrical shapes and sizes in a scaled-up model of a gravity-driven deterministic lateral displacement (g-DLD) device. Specifically, particles move through a square array of cylindrical posts as they settle in a quiescent fluid under the action of gravity. We performed experiments that cover a broad range of orientations of the driving force (gravity) with respect to the columns (or rows) in the square array of posts. We observe that as the forcing angle increases, particles initially locked to move parallel to the columns in the array begin to move across the columns of obstacles and migrate at angles different from zero. We measure the probability that a particle would move across a column of obstacles, and define the critical angle θ c as the forcing angle at which this probability is 1/2. We show that critical angle depends on both particle size and shape, thus enabling both size- and shape-based separations. Finally, we show that using the diameter of the inscribed sphere as the characteristic size of the particles, the corresponding critical angle becomes independent of particle shape and the relationship between them is linear. This linear and possibly universal behavior of the critical angle as a function of the diameter of the inscribed sphere of the particles could provide guidance in the design and optimization of g-DLD devices used for shape-based separation.