Deterministic Lateral Displacement Arrays Research Articles

Sieve-based lateral displacement technology for suspension separation

Sparse lateral displacement arrays are easier to scale up than full deterministic lateral displacement arrays or deterministic ratchets, because they require lower pressure drop and simplify the construction of the device. However, the asymmetry of sparse arrays leads to a non-homogeneous pressure distribution with as a consequence an uneven flow field and limited separation performance. Furthermore, the construction of high throughput displacement sparse ratchet devices that allow separation of small particles is challenging. Therefore, in this study we investigated the use of sieves to replace obstacles in sparse systems. Moreover, we investigated a strategy to optimize the separation performance by adjusting the internal pressure distribution. Our experiments showed in first instance that the introduction of sieves negatively affects separation performance, which was explained by the lower porosity of the sieves. However, via fluid flow calculations and high-speed camera analyses we found that pressure distribution can be optimized by adapting the flow rates of the different outlets preventing high pressure drop across the obstacles arrays near the bottom of the device. Experimental separation data for adjusted outlet flow conditions indeed showed better particle displacement, especially in the bottom region, and as a result improved separation behavior. These findings demonstrate the potential of the scalable sieve-based lateral displacement device to effectively separate particles.

Nanoscale lateral displacement arrays for the separation of exosomes and colloids down to 20 nm

Deterministic lateral displacement (DLD) pillar arrays are an efficient technology to sort, separate and enrich micrometre-scale particles, which include parasites, bacteria, blood cells and circulating tumour cells in blood. However, this technology has not been translated to the true nanoscale, where it could function on biocolloids, such as exosomes. Exosomes, a key target of 'liquid biopsies', are secreted by cells and contain nucleic acid and protein information about their originating tissue. One challenge in the study of exosome biology is to sort exosomes by size and surface markers. We use manufacturable silicon processes to produce nanoscale DLD (nano-DLD) arrays of uniform gap sizes ranging from 25 to 235 nm. We show that at low Péclet (Pe) numbers, at which diffusion and deterministic displacement compete, nano-DLD arrays separate particles between 20 to 110 nm based on size with sharp resolution. Further, we demonstrate the size-based displacement of exosomes, and so open up the potential for on-chip sorting and quantification of these important biocolloids.

An IB-LBM study of continuous cell sorting in deterministic lateral displacement arrays

The deterministic lateral displacement (DLD) is an important method used to sort particles and cells of different sizes. In this paper, the flexible cell sorting with the DLD method is studied by using a numerical model based on the immersed boundary-lattice Boltzmann method (IB-LBM). In this model, the fluid motion is solved by the LBM, and the cell membrane–fluid interaction is modeled with the LBM. The proposed model is validated by simulating the rigid particle sorted with the DLD method, and the results are found in good agreement with those measured in experiments. We first study the effect of flexibility on a single cell and multiple cells continuously going through a DLD device. It is found that the cell flexibility can significantly affect the cell path, which means the flexibility could have significant effects on the continuous cell sorting by the DLD method. The sorting characteristics of white blood cells and red blood cells are further studied by varying the spatial distribution of cylinder arrays and the initial cell–cell distance. The numerical results indicate that a well concentrated cell sorting can be obtained under a proper arrangement of cylinder arrays and a large enough initial cell–cell distance.

Separation of viable and nonviable mammalian cells using a deterministic lateral displacement microfluidic device

Here, we present a deterministic lateral displacement (DLD) microfluidic device that may be used for label-free, passive, and continuous separation of viable and nonviable mammalian cells. Cells undergoing apoptosis (programmed cell death) become smaller than normal viable cells due to shrinkage and fragmentation. We used this distinct difference in size to selectively isolate viable Jurkat cells from nonviable apoptotic cells and their remnants through a DLD array that is capable of size-based fractionation of microparticles. First, we calibrated our DLD devices by separating a mixture of larger (∼15-μm) and smaller (∼8- or ∼10-μm) polystyrene beads that emulated viable and nonviable Jurkat cells, respectively. We then demonstrated the separation of viable and nonviable Jurkat cells by introducing their heterogeneous suspensions into two DLD devices with different design parameters. In a DLD device with a 20-μm gap, we collected viable cells at 100 ± 0% capture efficiency (n = 3), at a capture purity of 23.1 ± 4.8%, with 57.8 ± 8.1% removal efficiency of nonviable apoptotic cells and their remnants from the initial mixture solution. On a DLD device with a 23-μm gap, the capture purity of viable cells increased to 50.2 ± 15.0%, with 89.0 ± 3.5% removal efficiency of nonviable cells, and a lower capture efficiency of 48.2 ± 2.0% (n = 3). This first demonstration of label-free and passive separation of viable and nonviable cells by DLD illustrates its potential for, e.g., regenerative medicine and discovery of anti-cancer drugs.

Simplifying microfluidic separation devices towards field-detection of blood parasites

By the integration of multiple deterministic lateral displacement arrays of specific depths we present a simple-to-use diagnostics device, actuated by a simple syringe, aimed at point-of-care detection of blood parasites.

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.

Microfluidic chemical processing with on-chip washing by deterministic lateral displacement arrays with separator walls.

We describe a microfluidic device for on-chip chemical processing, such as staining, and subsequent washing of cells. The paper introduces "separator walls" to increase the on-chip incubation time and to improve the quality of washing. Cells of interest are concentrated into a treatment stream of chemical reagents at the first separator wall for extended on-chip incubation without causing excess contamination at the output due to diffusion of the unreacted treatment chemicals, and then are directed to the washing stream before final collections. The second separator wall further reduces the output contamination from diffusion to the washing stream. With this approach, we demonstrate on-chip leukocyte staining with Rhodamine 6G and washing. The results suggest that other conventional biological and analytical processes could be replaced by the proposed device.

Numerical Study of Pillar Shapes in Deterministic Lateral Displacement Microfluidic Arrays for Spherical Particle Separation.

Deterministic lateral displacement (DLD) arrays containing shaped pillars have been found to be more effective in biomedical sample separation. This study aims to numerically investigate the interplay between particles and microfluidic arrays, and to find out the key factors in determining the critical size of a DLD device with shaped pillars. A new formula is thus proposed to estimate the critical size for spherical particle separation in this kind of new DLD microfluidic arrays. The simulation results show that both rectangular and I-shaped arrays have considerably smaller critical sizes. The ratio of sub-channel widths is also found to play an important role in reducing the critical sizes. This paves a valuable way toward designing high-performance DLD microfluidic arrays.

Measuring flow dynamics in a microfluidic chip using optical coherence tomography with 1 µm axial resolution

An experimental verification of simulated flow dynamics in a novel design of microfluidic device can be difficult, especially, in devices such as mixers or deterministic lateral displacement (DLD) arrays. Doppler optical coherence tomography (DOCT) is one of the visualization modalities used to measure flow velocity profiles in microfluidic channels, capillaries and microvascular networks. Previously conducted flow measurements with high speed spectral-domain optical coherence tomography (SD-OCT) devices have had typical axial resolution in the range few microns which can be insufficient for accurate mapping of flow dynamics in microchannels. This paper introduces a high-speed SD-OCT system with an axial resolution of 1.2µm in air (below 1µm in water) to evaluate flow in a microfluidic chip. The A-line acquisition rate of the device is 123kHz. Flow velocities from 1% Intralipid suspension are obtained across the microfluidic channel with the specified height of 20µm and the width of 50µm. The results show that the utilized SD-OCT device can visualize flows as close as 1µm from the channel wall. The flow rate of 0.63µl/min, determined from the cross-sectional velocity map, agreed well with the value of 0.67µl/min set to the syringe pump.

Inhibition of clot formation in deterministic lateral displacement arrays for processing large volumes of blood for rare cell capture.

Microfluidic deterministic lateral displacement (DLD) arrays have been applied for fractionation and analysis of cells in quantities of ~100 μL of blood, with processing of larger quantities limited by clogging in the chip. In this paper, we (i) demonstrate that this clogging phenomenon is due to conventional platelet-driven clot formation, (ii) identify and inhibit the two dominant biological mechanisms driving this process, and (iii) characterize how further reductions in clot formation can be achieved through higher flow rates and blood dilution. Following from these three advances, we demonstrate processing of 14 mL equivalent volume of undiluted whole blood through a single DLD array in 38 minutes to harvest PC3 cancer cells with ~86% yield. It is possible to fit more than 10 such DLD arrays on a single chip, which would then provide the capability to process well over 100 mL of undiluted whole blood on a single chip in less than one hour.

Separation of Microvesicles from Serological Samples Using Deterministic Lateral Displacement Effect

Label-free isolation and detection of extracellular vesicles are essential in many diagnostic and therapeutic approaches. Recently, there has been an interest in methods that avoid the use of biochemical labels, intrinsic biomarkers, or electrical polarizability to identify microvesicles (also referred to as microparticles) from serological samples. Here, we report a microfluidic device to separate circulating extracellular vesicles from serological samples using the deterministic lateral displacement principle. The device continuously fractionates label-free extracellular vesicles and cells according to size and membrane flexibility by displacing them perpendicularly to the fluid flow direction in a micro-fabricated array of posts. Experimental data and computational fluid dynamic simulations are presented to create a compelling argument that microvesicles from serological samples could be separated by deterministic lateral displacement arrays. Direct separation of different-sized micro- and nanospheres were demonstrated using a multi-stage separation strategy thus offering a potential route for novel cancer diagnostic approaches where microvesicles can be targeted and intercepted during cell-to-cell communication.

High throughput capture of circulating tumor cells using an integrated microfluidic system

In this work, we introduced an integrated microfluidic system for fast and efficient circulating tumor cell (CTC) isolation and capture. In this microfluidic platform, a combination of microfluidic deterministic lateral displacement array and affinity-based cell capture architecture, allows for the high efficiency cancer cell enrichment and continuous high throughput and purity cancer cell capture. Using this device to isolate breast cancer cells from spiked blood samples, we achieved an enrichment factor of 1500×, and a high processing throughput of 9.6mL/min with 90% capture yield and more than 50% capture purity at cell concentration 102cells/mL. This integrated platform offers a promising approach for CTC capture with high recovery rates, purity and stability, and exhibits potential capability in cancer cell culture and drug screening.

Rapid isolation of cancer cells using microfluidic deterministic lateral displacement structure

This work reports a microfluidic device with deterministic lateral displacement (DLD) arrays allowing rapid and label-free cancer cell separation and enrichment from diluted peripheral whole blood, by exploiting the size-dependent hydrodynamic forces. Experiment data and theoretical simulation are presented to evaluate the isolation efficiency of various types of cancer cells in the microfluidic DLD structure. We also demonstrated the use of both circular and triangular post arrays for cancer cell separation in cell solution and blood samples. The device was able to achieve high cancer cell isolation efficiency and enrichment factor with our optimized design. Therefore, this platform with DLD structure shows great potential on fundamental and clinical studies of circulating tumor cells.

Deterministic separation of cancer cells from blood at 10 mL/min

Circulating tumor cells (CTCs) and circulating clusters of cancer and stromal cells have been identified in the blood of patients with malignant cancer and can be used as a diagnostic for disease severity, assess the efficacy of different treatment strategies and possibly determine the eventual location of metastatic invasions for possible treatment. There is thus a critical need to isolate, propagate and characterize viable CTCs and clusters of cancer cells with their associated stroma cells. Here, we present a microfluidic device for mL/min flow rate, continuous-flow capture of viable CTCs from blood using deterministic lateral displacement (DLD) arrays. We show here that a DLD array device can isolate CTCs from blood with capture efficiency greater than 85% CTCs at volumetric flow rates of up to 10 mL/min with no effect on cell viability.

Deterministic Separation of Cancer Cells from Blood at 10 mL/min

AbstractCirculating tumor cells (CTCs) and circulating clusters of cancer and stromal cells have been identified in the blood of patients with malignant cancer and can be used as a diagnostic for disease severity, assess the efficacy of different treatment strategies and possibly determine the eventual location of metastatic invasions for possible treatment. There is thus a critical need to isolate, propagate and characterize viable CTCs and clusters. Here, we present a microfluidic device for mL/min flow rate, continuous-flow capture of viable CTCs from blood using deterministic lateral displacement arrays. We show here that a deterministic bump array can be designed such that it will isolate with efficiency greater than 85% CTCs over a large range in sizes from millimeter volume clinical blood samples in minutes, with no effect on cell vitality so that further culturing and analysis of the cells can be carried out.

Scaling deterministic lateral displacement arrays for high throughput and dilution-free enrichment of leukocytes

A disposable device for fractionation of blood into its components that is simple to operate and provides throughput of greater than 1 mL min−1 is highly sought after in medical diagnostics and therapies. This paper describes a device with parallel deterministic lateral displacement devices for enrichment of leukocytes from blood. We show capture of 98% and approximately ten-fold enrichment of leukocytes in whole blood. We demonstrate scaling up through the integration of six parallel devices to achieve a flow rate of 115 µL of undiluted blood per minute per atmosphere of applied pressure.

Improved performance of deterministic lateral displacement arrays with triangular posts

Deterministic lateral displacement arrays have shown great promise for size-based particle analysis and purification in medicine and biology. Here, we demonstrate that the use of an array of triangular rather than circular posts significantly enhances the performance of these devices by reducing clogging, lowering hydrostatic pressure requirements, and increasing the range of displacement characteristics. Experimental data and theoretical models are presented to create a compelling argument that future designs of deterministic lateral displacement arrays should employ triangular posts. The effect of practical considerations, such as vertex rounding, post size, and shape, is also discussed.