Efficient microfluidic enrichment of nano-/submicroparticle in viscoelastic fluid

The enrichment and focusing of the nano-/submicroparticle (e.g., 150–1000 nm microvesicle shed from the plasma membrane) in the viscoelastic fluid has great potentials in the biomedical and clinical applications such as the disease diagnosis and the prognostic test for liquid biopsy. However, due to the small size and the resulting weak hydrodynamic force, the efficient manipulation of the nano-/submicroparticle by the passive viscoelastic microfluidic technology remains a major challenge. For instance, a typically long channel length is often required to achieve the focusing or the separation of the nano-/submicroparticle, which makes it difficult to be integrated in small chip area. In this work, a microchannel with gradually contracted cross-section and high aspect ratio (the ratio of the height to the average width of channel) is utilized to enhance the hydrodynamic force and change the force direction, eventually leading to the efficient enrichment of nano-/submicroparticles (500 and 860 nm) in a short channel length (2 cm). The influence of the flow rate, the particle size, the solid concentration, and the channel geometry on the enrichment of the nano-/submicroparticles are investigated. With simple structure, small footprint, easy operation, and good performance, the present device would be a promising platform for various lab-chip microvesicle-related biomedical research and disease diagnosis.     

Impedance‐based viscoelastic flow cytometry

Elastic nature of the viscoelastic fluids induces lateral migration of particles into a single streamline and can be used by microfluidic based flow cytometry devices. In this study, we investigated focusing efficiency of polyethylene oxide based viscoelastic solutions at varying ionic concentration to demonstrate their use in impedimetric particle characterization systems. Rheological properties of the viscoelastic fluid and particle focusing performance are not affected by ionic concentration. We investigated the viscoelastic focusing dynamics using polystyrene (PS) beads and human red blood cells (RBCs) suspended in the viscoelastic fluid. Elasto‐inertial focusing of PS beads was achieved with the combination of inertial and viscoelastic effects. RBCs were aligned along the channel centerline in parachute shape which yielded consistent impedimetric signals. We compared our impedance‐based microfluidic flow cytometry results for RBCs and PS beads by analyzing particle transit time and peak amplitude at varying viscoelastic focusing conditions obtained at different flow rates. We showed that single orientation, single train focusing of nonspherical RBCs can be achieved with polyethylene oxide based viscoelastic solution that has been shown to be a good candidate as a carrier fluid for impedance cytometry.     

Concentration‐controlled particle focusing in spiral elasto‐inertial microfluidic devices

Herein, we proposed a strategy for controlling the particle focusing position in Dean‐coupled elasto‐inertial flows via adjusting the polymer concentration of viscoelastic fluids. The physics behind the control strategy was then explored and discussed. At high polymer concentrations, the flowing particles could be single‐line focused exactly at the channel centerline under the dominated elastic force. The center‐line focusing in our spiral channel may employed as a potential pretreatment scheme for microflow cytometry detection. With further decreasing polymer concentrations, the particles would shift into the outer channel region under the comparable competition between inertial lift force, elastic force and Dean drag force. Finally, the observed position‐shifting was successfully employed for particle concentration at a throughput much higher than most existing elasto‐inertial microfluidics.     

Lateral and cross-lateral focusing of spherical particles in a square microchannel

The inertial migration of particles in micro-scale flows has received much attention due to its promising applications, such as the membrane-free passive separation of particles or cells. The particles suspended in rectangular channels are known to be focused near the center of each channel face as the channel Reynolds number (R(C)) increases due to the lift force balance and the hydrodynamic interactions of the particles with the wall. In this study, the three-dimensional positions of neutrally buoyant spherical particles inside a square microchannel are measured using the digital holographic microscopy technique, and a transition from the lateral tubular pinch to the cross-lateral focusing with increasing R(C) is reported. The particles are found to migrate first in the lateral direction and then cross-laterally toward the four equilibrium positions. A general criterion that can be used to secure the fully developed state of particle focusing in Lab-on-a-Chip applications is also derived. This criterion could be helpful for the accurate estimation of the design parameters of inertial microfluidic devices, such as R(C), channel length and width, and particle diameter.     

Investigation of viscoelastic focusing of particles and cells in a zigzag microchannel

Microfluidic particle focusing has been a vital prerequisite step in sample preparation for downstream particle separation, counting, detection, or analysis, and has attracted broad applications in biomedical and chemical areas. Besides all the active and passive focusing methods in Newtonian fluids, particle focusing in viscoelastic fluids has been attracting increasing interest because of its advantages induced by intrinsic fluid property. However, to achieve a well-defined focusing position, there is a need to extend channel lengths when focusing micrometer-sized or sub-microsized particles, which would result in the size increase of the microfluidic devices. This work investigated the sheathless viscoelastic focusing of particles and cells in a zigzag microfluidic channel. Benefit from the zigzag structure of the channel, the channel length and the footprint of the device can be reduced without sacrificing the focusing performance. In this work, the viscoelastic focusing, including the focusing of 10 μm polystyrene particles, 5 μm polystyrene particles, 5 μm magnetic particles, white blood cells (WBCs), red blood cells (RBCs), and cancer cells, were all demonstrated. Moreover, magnetophoretic separation of magnetic and nonmagnetic particles after viscoelastic pre-focusing was shown. This focusing technique has the potential to be used in a range of biomedical applications.     

Revisit of wall‐induced lateral migration in particle electrophoresis through a straight rectangular microchannel: Effects of particle zeta potential

Previous studies have reported a lateral migration in particle electrophoresis through a straight rectangular microchannel. This phenomenon arises from the inherent wall‐induced electrical lift that can be exploited to focus and separate particles for microfluidic applications. Such a dielectrophoretic‐like force has been recently found to vary with the buffer concentration. We demonstrate in this work that the particle zeta potential also has a significant effect on the wall‐induced electrical lift. We perform an experimental study of the lateral migration of equal‐sized polystyrene particles with varying surface charges under identical electrokinetic flow conditions. Surprisingly, an enhanced focusing is observed for particles with a faster electrokinetic motion, which indicates a substantially larger electrical lift for particles with a smaller zeta potential. We speculate this phenomenon may be correlated with the particle surface conduction that is a strong function of particle and fluid properties.     

Effects of Various Forces on Particle Distribution and Thermal Features of Suspensions Containing Alumina Nanoparticles

The two-phase Euler-Lagrange method has been used in order to investigate the effects of various forces on particle distribution and thermal characteristics of the water-based Al₂O₃ nanofluid flow inside a pipe under uniform wall heat flux. In the Euler-Lagrange approach, the particles are individually tracked in Lagrangian frame, while the fluid is evaluated in Eulerian frame. Brownian, thermophoretic, drag, lift, and virtual mass forces have been considered. Moreover, experimental data from various researchers were used to analyze the results. Concentration distribution is nonuniform at cross section of the pipe which increasing each parameters of Reynolds number, mean concentration and particles size will intensify its nonuniformity. This nonuniformity will make velocity profile flatter. The Brownian force makes the particle distribution more uniform, whereas the thermophoretic force enhances nonuniformity of the particle distribution. The effects of not considering the Brownian and thermophoretic forces on heat transfer are more significant for finer particles and higher concentrations. Furthermore, at lower Reynolds number, the Brownian force incorporates a more significant role especially in farther distances from entrance.      

Elastic-inertial separation of microparticle in a gradually contracted microchannel

Separation of microparticle in viscoelastic fluid is highly required in the field of biology and clinical medicine. For instance, the separation of the target cell from blood is an important prerequisite step for the drug screening and design. The microfluidic device is an efficient way to achieve the separation of the microparticle in the viscoelastic fluid. However, the existing microfluidic methods often have some limitations, including the requirement of the long channel length, the labeling process, and the low throughput. In this work, based on the elastic-inertial effect in the viscoelastic fluid, a new separation method is proposed where a gradually contracted microchannel is designed to efficiently adjust the forces exerted on the particle, eventually achieving the high-efficiency separation of different sized particles in a short channel length and at a high throughput. In addition, the separation of WBCs and RBCs is also validated in the present device. The effect of the flow rate, the fluid property, and the channel geometry on the particle separation is systematically investigated by the experiment. With the advantage of small footprint, simple structure, high throughput, and high efficiency, the present microfluidic device could be utilized in the biological and clinical fields, such as the cell analysis and disease diagnosis.     

Different elution modes and field programming in gravitational field-flow fractionation. 2. Experimental verification of the range of conditions for flow-rate and carrier liquid density programming

Gravitational field-flow fractionation utilises the Earth's gravitational field as an external force that causes the settlement of particles towards the channel accumulation wall. Hydrodynamic lift forces oppose this action by elevating of particles from the channel accumulation wall. Therefore there are several possibilities to modulate the resulting force field acting on particles in gravitational field-flow fractionation. Regarding the force field programming in gravitational field-flow fractionation, this work focused on two topics: changes of the difference between particle density and carrier liquid density in Brownian and focusing elution modes and influencing of lift forces achieved by changing the flow-rate in focusing elution mode. We have found and described the experimental conditions applicable to force field programming in the case of separations of silica gel particles by gravitational field-flow fractionation. It was shown that the effect of carrier liquid viscosity in the water-methanol system is implemented as an additional factor enhancing the desired effect of carrier liquid density. Some other forces influencing the retention behaviour of the model particles are discussed.     

Sheathless elasto-inertial particle focusing and continuous separation in a straight rectangular microchannel

Particle focusing in planar geometries is essentially required in order to develop cost-effective lab-on-a-chips, such as cell counting and point-of-care (POC) devices. In this study, a novel method for sheathless particle focusing, called "Elasto-Inertial Particle Focusing", was demonstrated in a straight microchannel. The particles were notably aligned along the centerline of the straight channel under a pressure-driven flow without any additional external force or apparatus after the addition of an elasticity enhancer: PEO (poly(ethylene oxide)) (～O(100) ppm). As theoretically predicted (elasticity number: El≈O(100)), multiple equilibrium positions (centerline and corners) were observed for the viscoelastic flow without inertia, whereas three-dimensional particle focusing only occurred when neither the elasticity nor the inertia was negligible. Therefore, the three-dimensional particle focusing mechanism was attributed to the synergetic combination of the elasticity and the inertia (elasticity number: El≈O(1-10)). Furthermore, from the size dependence of the elastic force upon particles, we demonstrated that a mixture of 5.9 and 2.4 μm particles was separated at the exit of the channel in viscoelastic flows. We expect that this method can contribute to develop the miniaturized flow cytometry and microdevices for cell and particle manipulation.     

Inertial separation in a contraction-expansion array microchannel

We report a contraction-expansion array (CEA) microchannel that allows inertial size separation by a force balance between inertial lift and Dean drag forces in fluid regimes in which inertial fluid effects become significant. An abrupt change of the cross-sectional area of the channel curves fluid streams and produces a similar effect compared to Dean flows in a curved microchannel of constant cross-section, thereby inducing Dean drag forces acting on particles. In addition, the particles are influenced by inertial lift forces throughout the contraction regions. These two forces act in opposite directions each other throughout the CEA microchannel, and their force balancing determines whether the particles cross the channel, following Dean flows. Here we describe the physics and design of the CEA microfluidic device, and demonstrate complete separation of microparticles (polystyrene beads of 4 and 10 μm in diameter) and efficient exchange of the carrier medium while retaining 10 μm beads.     

Secondary-flow-aided single-train elastic-inertial focusing in low elasticity viscoelastic fluids

Elastic-inertial focusing has attracted increasing interest in recent years due to the three-dimensional (3D) single-train focusing ability it offers. However, multi-train focusing, instead of single-train focusing, was observed in viscoelastic fluids with low elasticity as a result of the competition between inertia effect and viscoelasticity effect. To address this issue, we employed the secondary flow to facilitate single-train elastic-inertial focusing in low elasticity viscoelastic fluids. A three-section contraction-expansion channel was designed to induce the secondary flow to pinch the multiplex focusing trains into a single one exactly at the channel centerline. After demonstrating the focusing process and mechanism in our device, we systematically explored and discussed the effects of particle diameter, operational flow rate, polymer concentration, and channel dimension on particle focusing performances. Our device enables single-train focusing of particles in viscoelastic fluids with low elasticity, and offers advantages of planar single-layer structure, and sheathless, external-field free operation.     

A passive microfluidic device for continuous microparticle enrichment

A passive microfluidic device is reported for continuous microparticle enrichment. The microparticle is enriched based on the inertial effect in a microchannel with contracting‐expanding structures on one side where microparticles/cells are subjected to the inertial lift force and the momentum‐change‐induced inertial force induced by highly curved streamlines. Under the combined effect of the two forces, yeast cells and microparticles of different sizes were continuously focused in the present device over a range of Reynolds numbers from 16.7 to 125. ～68% of the particle‐free liquid was separated from the sample at Re = 66.7, and ～18 μL particle‐free liquid was fast obtained within 10 s. Results also showed that the geometry of the contracting‐expanding structure significantly influenced the lateral migration of the particle. Structures with a large angle induced strong inertial effect and weak disturbance effect of vortex on the particle, both of which enhanced the microparticle enrichment in microchannel. With simple structure, small footprint (18 × 0.35 mm), easy operation and cell‐friendly property, the present device has great potential in biomedical applications, such as the enrichment of cells and the fast extraction of plasma from blood for disease diagnose and therapy.     

Recent advances in direct current electrokinetic manipulation of particles for microfluidic applications

Microfluidic devices have been extensively used to achieve precise transport and placement of a variety of particles for numerous applications. A range of force fields have thus far been demonstrated to control the motion of particles in microchannels. Among them, electric field‐driven particle manipulation may be the most popular and versatile technique because of its general applicability and adaptability as well as the ease of operation and integration into lab‐on‐a‐chip systems. This article is aimed to review the recent advances in direct current (DC) (and as well DC‐biased alternating current) electrokinetic manipulation of particles for microfluidic applications. The electric voltages are applied through electrodes that are positioned into the distant channel‐end reservoirs for a concurrent transport of the suspending fluid and manipulation of the suspended particles. The focus of this review is upon the cross‐stream nonlinear electrokinetic motions of particles in the linear electroosmotic flow of fluids, which enable the diverse control of particle transport in microchannels via the wall‐induced electrical lift and/or the insulating structure‐induced dielectrophoretic force.     

Low-capacity channel designed for particle separation with controlled electric fields and evaluation of involved forces

Electric field is one of the suitable physical fields applicable to particle separations. Although long rectangular channel is used for particle separation in usual electrical field flow fractionation (FFF), a short low-capacity channel can replace it if the field is precisely controlled. Several separation principles are proposed with this channel. The elution behavior of particles has revealed that the gravitational, diffusion, and hydrodynamic lift force (HLF) play important roles in the determination of the elution behavior of particles. The elution threshold voltage (V(th)) was defined and experimentally determined for various system configurations and particles. The electric force no longer overcomes the other forces, and particles are taken off the wall, when the applied voltage becomes lower than V(th). V(th) values have allowed us not only to estimate surface charge density of a particle but also to evaluate the hydrodynamic lift force against particle.     

Ultrasonic Scattering by a Spheroidal Suspension Including Dissipative Effects

This study treats the axisymmetric interaction of a plane compressional sound wave with a viscoelastic (viscous) prolate spheroidal particle (droplet) suspended in a boundless viscous fluid medium. The method of eigen‐function expansion along with the novel features of Havriliak‐Negami model for viscoelastic material behavior and the linearized equations of Navier‐Stokes for wave motion in a viscous non‐heat‐conducting compressible fluid are employed to develop a closed form series solution involving Spheroidal harmonics of complex argument. The complications arising due to the non‐orthogonality of angular Spheroidal functions corresponding to different wave numbers as well as problems associated with the appearance of additional angular dependent terms in the boundary conditions are all avoided by expansion of the angular Spheroidal functions in terms of Lengedre functions which are themselves expanded in terms of transcendental functions and subsequent integration, leading to a linear set of independent equations in terms of unknown scattering and transmission coefficients. The presented solution demonstrates that the acoustic characteristics of particulate suspensions are strongly influenced by spheroidicity of particle cross‐section. Limiting case involving an elastic (ideal) spheroidal particle (droplet) in an ideal fluid is considered and fair agreement with available solution is established.     

Analytical solutions and validation of electric field and dielectrophoretic force in a bio-microfluidic channel

In a microbiological device, cell or particle manipulation and characterization require the use of electric field on different electrodes in several configurations and shapes. To efficiently design microelectrodes within a microfluidic channel for dielectrophoresis focusing, manipulation and characterization of cells, the designer will seek the exact distribution of the electric potential, electric field and hence dielectrophoresis force exerted on the cell within the microdevice. In this paper we describe the approach attaining the analytical solution of the dielectrophoretic force expression within a microchannel with parallel facing same size electrodes present on the two faces of channel substrates, with opposite voltages on the pair electrodes. Simple Fourier series mathematical expressions are derived for electric potential, electric field and dielectric force between two distant finite‐size electrodes. Excellent agreement is found by comparing the analytical results calculated using MATLAB? with numerical ones obtained by Comsol. This analytical result can help the designer to perform simple design parametric analysis. Bio‐microdevices are also designed and fabricated to illustrate the theoretical solution results with the experimental data. Experiments with red blood cells show the dielectrophoretic force contour plots of the analytical data matched to the experimental results.     

Characterization and optimization of liquid electrodes for lateral dielectrophoresis

Using the concept of insulator-based "electrodeless" dielectrophoresis, we present a novel geometry for shaping electric fields to achieve lateral deviation of particles in liquid flows. The field is generated by lateral planar metal electrodes and is guided along access channels to the active area in the main channel. The equipotential surfaces at the apertures of the access channels behave as vertical "liquid" electrodes injecting the current into the main channel. The field between a pair of adjacent liquid electrodes generates the lateral dielectrophoretic force necessary for particle manipulation. We use this force for high-speed deviation of particles. By adding a second pair of liquid electrodes, we focus a particle stream. The position of the focused stream can be swept across the channel by adjusting the ratio of the voltages applied to the two pairs. Based on conformal mapping, we provide an analytical model for estimating the potential at the liquid electrodes and the field distribution in the main channel. We show that the simulated particle trajectories agree with observations. Finally, we show that the model can be used to optimize the device geometry in different applications.     

Focusing particles by induced charge electrokinetic flow in a microchannel

A novel method of sheathless particle focusing by induced charge electrokinetic flow in a microchannel is presented in this paper. By placing a pair of metal plates on the opposite walls of the channel and applying an electrical field, particle focusing is achieved due to the two pairs of vortex that constrain the flow of the particle solution. As an example, the trajectories of particles under different electrical fields with only one metal plate on one side channel wall were numerically simulated and experimentally validated. Other flow focusing effects, such as the focused width ratio (focused width/channel width) and length ratio (focused length/half‐length of metal plate) of the sample solution, were also numerically studied. The results show that the particle firstly passes through the gaps between the upstream vortices and the channel walls. Afterwards, the particle is focused to pass through the gap between the two downstream vortices that determine the focused particle position. Numerical simulations show that the focused particle stream becomes thin with the increases in the applied electrical field and the length of the metal plates. As regards to the focused length ratio of the focused stream, however, it slightly increases with the increase in the applied electrical field and almost keeps constant with the increase in the length of the metal plate. The size of the focused sample solution, therefore, can be easily adjusted by controlling the applied electrical field and the sizes of the metal plates.     

Insulator-based dielectrophoretic focusing and trapping of particles in non-Newtonian fluids

Insulator-based dielectrophoretic (iDEP) microdevices have been limited to work with Newtonian fluids. We report an experimental study of the fluid rheological effects on iDEP focusing and trapping of polystyrene particles in polyethylene oxide, xanthan gum, and polyacrylamide solutions through a constricted microchannel. Particle focusing and trapping in the mildly viscoelastic polyethylene oxide solution are slightly weaker than in the Newtonian buffer. They are, however, significantly improved in the strongly viscoelastic and shear thinning polyacrylamide solution. These observed particle focusing behaviors exhibit a similar trend with respect to electric field, consistent with a revised theoretical analysis for iDEP focusing in non-Newtonian fluids. No apparent focusing of particles is achieved in the xanthan gum solution, though the iDEP trapping can take place under a much larger electric field than the other fluids. This is attributed to the strong shear thinning-induced influences on both the electroosmotic flow and electrokinetic/dielectrophoretic motions.