Magnetic particle dosing and size separation in a microfluidic channel

Separation of functional magnetic particles or magnetically labeled entities is a key feature for bioanalytical or biomedical applications and therefore also an important component of lab-on-a-chip devices for biological applications. We present a novel integrated microfluidic magnetic bead manipulation device, comprising dosing of magnetic particles, controlled release and subsequent magnetophoretic size separation with high resolution. The system is designed to meet the requirements of specific bioassays, in particular of on-chip agglutination assays for the detection of rare analytes by particle coupling as doublets. Integrated soft-magnetic microtips with different shapes provide the magnetic driving force of the bead manipulation protocol. The magnetic tips that serve as field concentrators of an external electromagnetic field, are positioned in close contact to a microfluidic channel in order to generate high magnetic actuation forces. Mixtures of 1.0 μm and 2.8 μm superparamagnetic beads have been used to characterize the system. Magnetophoretic size separation with high resolution was performed in static conditions and in continuous flow mode. In particular, we could demonstrate the separation of 1.0 μm single beads and doublets in a sample flow.     

Geometry design of herringbone structures for cancer cell capture in a microfluidic device

Cancer cell detection with high capture efficiency is important for its extensive clinical applications. Herringbone structures in microfluidic devices have been widely adopted to increase the cell capture performance due to its chaotic effect. Given the fact of laminar flow in microfluidic devices, geometry-based optimization acting as a design strategy is effective and can help researchers reduce repetitive trial experiments. In this work, we presented a computational model to track the cell motion and used normalized capture efficiency to evaluate the tumor cell capture performance under various geometry settings. Cell adhesion probability was implemented in the model to consider the nature of ligand–receptor formation and breakage during cell–surface interactions. A facile approach was introduced to determine the two lumped coefficients of cell adhesion probability through two microfluidic experiments. A comprehensive geometric study was then performed by using this model, and results were explained from the fluid dynamics. Although most of the geometric guides agree with the general criterion concluded in the literature, we found herringbone structures with symmetric arms rather than a short arm–long arm ratio of 1/3 are optimal. This difference mainly comes from the fact that our model considers the particulate nature of cells while most studies in the literature optimize the geometry merely relying on mixing effects. Thus, our computational model implemented with cell adhesion probability can serve as a more accurate and reliable approach to optimize microfluidic devices for cancer cell capture.     

Characterization and modeling of a microfluidic dielectrophoresis filter for biological species

Microfabricated interdigitated electrode array is a convenient form of electrode geometry for dielectrophoretic trapping of particles and biological entities such as cells and bacteria within microfluidic biochips. We present experimental results and finite element modeling of the holding forces for both positive and negative dielectrophoretic traps on microfabricated interdigitated electrodes within a microfluidic biochip fabricated in silicon with a 12-/spl mu/m-deep chamber. Anodic bonding was used to close the channels with a glass cover. An Experimental protocol was then used to measure the voltages necessary to capture different particles (polystyrene beads, yeast cells, spores and bacteria) against destabilizing fluid flows at a given frequency. The experimental results and those from modeling are found to be in close agreement, validating our ability to model the dielectrophoretic filter for bacteria, spores, yeast cells, and polystyrene beads. This knowledge can be very useful in designing and operating a dielectrophoretic barrier or filter to sort and select particles entering the microfluidic devices for further analysis.     

Microfluidic separation of magnetic particles with soft magnetic microstructures

This paper demonstrates simple and cost-effective microfluidic devices for enhanced separation of magnetic particles by using soft magnetic microstructures. By injecting a mixture of iron powder and polydimethylsiloxane (PDMS) into a prefabricated channel, an iron–PDMS microstructure was fabricated next to a microfluidic channel. Placed between two external permanent magnets, the magnetized iron–PDMS microstructure induces localized and strong forces on the magnetic particles in the direction perpendicular to the fluid flow. Due to the small distance between the microstructure and the fluid channel, the localized large magnetic field gradients result a vertical force on the magnetic particles, leading to enhanced separation of the particles. Numerical simulations were developed to compute the particle trajectories and agreed well with experimental data. Systematic experiments and numerical simulation were conducted to study the effect of relevant factors on the transport of superparamagnetic particles, including the shape of iron–PDMS microstructure, mass ratio of iron–PDMS composite, width of the microfluidic channel, and average flow velocity.     

Effects of particle–fluid coupling on particle transport and capture in a magnetophoretic microsystem

A numerical analysis is presented of the effects of particle–fluid coupling on the transport and capture of magnetic particles in a microfluidic system under the influence of an applied magnetic field. Particle motion is predicted using a computational fluid dynamic CFD-based Lagrangian–Eulerian approach that takes into account dominant particle forces as well as two-way particle–fluid coupling. Two dimensionless groups are introduced that characterize particle capture, one that scales the magnetic and hydrodynamic forces on the particle and another that scales the distance to the magnetic field source. An analysis is preformed to parameterize capture efficiency with respect to the dimensionless numbers for both one-way and two-way particle–fluid coupling. For one-way coupling, in which the flow field is uncoupled from particle motion, correlations are developed that provide insight into system performance towards optimization. The difference in capture efficiency for one-way versus two-way coupling is analyzed and quantified. The analysis demonstrates that one-way coupling, in the dilute limit, provides a conservative estimate of capture efficiency in that it overpredicts the magnetic force needed to ensure particle capture as compared with a more rigorous fully coupled analysis. In two-way coupling there is a cooperative effect between the magnetic force and a particle-induced fluidic force that enhances capture efficiency. Thus, while one-way coupling is useful for rapid parametric screening of particle capture performance, more accurate predictions require two-way particle–fluid coupling. This is especially true when considering higher capture efficiencies and/or higher particle concentrations.     

Computational and performance analysis of a continuous magnetophoretic bioseparation chip with alternating magnetic fields

This paper presents the modeling and optimization of a magnetophoretic bioseparation chip for isolating cells, such as circulating tumor cells from the peripheral blood. The chip consists of a continuous-flow microfluidic platform that contains locally engineered magnetic field gradients. The high-gradient magnetic field produced by the magnets is spatially non-uniform and gives rise to an attractive force on magnetic particles flowing through a fluidic channel. Simulations of the particle–fluid transport and the magnetic force are performed to predict the trajectories and capture lengths of the particles within the fluidic channel. The computational model takes into account key forces, such as the magnetic and fluidic forces and their effect on design parameters for an effective separation. The results show that the microfluidic device has the capability of separating various cells from their native environment. An experimental study is also conducted to verify and validate the simulation results. Finally, to improve the performance of the separation device, a parametric study is performed to investigate the effects of the magnetic bead size, cell size, number of beads per cell, and flow rate on the cell separation performance.     

Fabrication and integration of microscale permanent magnets for particle separation in microfluidics

Microfluidic magnetophoresis is an effective technique to separate magnetically labeled bioconjugates in lab-on-a-chip applications. However, it is challenging and expensive to fabricate and integrate microscale permanent magnets into microfluidic devices with conventional methods that use thin-film deposition and lithography. Here, we propose and demonstrate a simple and low-cost technique to fabricate microscale permanent magnetic microstructures and integrate them into microfluidic devices. In this method, microstructure channels were fabricated next to a microfluidic channel and were injected with a liquid mixture of neodymium (NdFeB) powders and polydimethylsiloxane (PDMS). After the mixture was cured, the resulted solid NdFeB–PDMS microstructure was permanently magnetized to form microscale magnets. The microscale magnets generate strong magnetic forces capable of separating magnetic particles in microfluidic channels. Systematic experiments and numerical simulations were conducted to study the geometric effects of the microscale magnets. It was found that rectangular microscale magnets generate larger \(({\mathbf {H}}\cdot \nabla ) {\mathbf {H}}\) which is proportional to magnetic force and have a wider range of influence than the semicircle or triangle magnets. For multiple connected rectangular microscale magnet, additional geometric parameters, including separation distance, height and width of the individual elements, further influence the particle separation and were characterized experimentally. With an optimal size combination, complete separation of yeast cells and magnetic microparticles of similar sizes (\(4\;\upmu \hbox {m}\)) was demonstrated with the multi-rectangular magnet microfluidic device.     

Reliable magnetic reversible assembly of complex microfluidic devices: fabrication, characterization, and biological validation

Current standard procedures for fabrication of microfluidic devices combine polydimethylsiloxane (PDMS) replica molding with subsequent plasma treatment to obtain an irreversible sealing onto a glass/silicon substrate. However, irreversible sealing introduces several limitations to applications and internal accessibility of such devices as well as to the choice of materials for fabrication. In the present work, we describe and characterize a reliable, flexible and cost effective approach to fabricate devices that reversibly adhere to a substrate by taking advantage of magnetic forces. This is shown by implementing a PDMS/iron micropowder layer aligned onto a microfluidic layer and coupled with a histology glass slide, in union with either temporary or continuous use of a permanent magnet. To better represent the complexity of microfluidic devices, a Y-shaped configuration including lower scale parallel channels on each branch has been employed as reference geometry. To correctly evaluate our system, current sealing methods have been reproduced on the reference geometry. Sealing experiments (pressure control, flow control and hydraulic characterization) have been carried out, showing consistent increases in terms of maximum achievable flow rates and pressures, as compared to devices obtained with other available reversible techniques. Moreover, no differences were detected between cells cultured on our magnetic devices as compared to cells cultured on permanently sealed devices. Disassembly of our devices for analyses allowed to stain cells by hematoxylin and eosin and for F-actin, following traditional histological processes and protocols. In conclusion, we present a method allowing reversible sealing of microfluidic devices characterized by compatibility with: (i) complex fluidic layer configurations, (ii) micrometer sized channels, and (iii) optical transparency in the channel regions for flow visualization and inspection.     

Aggregation dynamics of particles in a microchannel due to an applied magnetic field

Functionalized magnetic microspheres have promising applications in different microfluidic devices including MEMS-scale biosensors. These particles exhibit magnetic field-induced aggregation, which can be harnessed to achieve several practical tasks in microfluidic devices. For this, the particle aggregation needs to be well characterized. Herein, a numerical simulation and experimental validation of particle-chaining is presented. Simulations show that the particle aggregation time scales linearly with a group parameter. The predicted growth of one- two- and three-particle chains with time shows a similar trend as that found in the experiments. The results of the study could help predicting the performance of magnetic aggregate-based lab-on-a-chip devices.     

Modelling immunomagnetic cell capture in CFD

The separation of cells from a complex sample by immunomagnetic capture has recently obtained increased attention for microfluidic applications. Here, we present a simulation approach for immunomagnetic separation in a flow-through microfluidic environment that for the first time takes binding kinetics of beads to target cells as well as binding of multiple beads per cell into account. The approach is implemented into a computational fluid dynamics code and facilitates the tailored design of microfluidic magnetophoretic devices with an optimised separation performance. Although the specific computational model under study is constrained to a 2D geometry, appropriate parameter sets that allow for a continuous separation of cell/bead complexes from non-magnetic particles could be derived. In addition, based on magnetophoretic mobilities, a critical threshold value of beads per cell is revealed, where further binding is considerably reduced or the reaction cascade ceases.     

Magnetofluidic spreading in microchannels

We investigate the spreading phenomena caused by the interaction between a uniform magnetic field and a magnetic fluid in microchannels. The flow system consists of two liquids: a ferrofluid and a mineral oil. The ferrofluid consists of superparamagnetic nanoparticles suspended in an oil-based carrier. Under a uniform magnetic field, the superparamagnetic particles are polarized and represent magnetic dipoles. The magnetization of the magnetic nanoparticles leads to a force resulting in the change of diffusion behavior inside the microchannel. Mixing due to secondary flow close to the interface also contributes to the spreading of the ferrofluid. The magnetic force acting on the liquid/liquid interface is caused by the mismatch of magnetization between the nanoparticles and surrounding liquid in a multiphase flow system. This paper examines the roles of magnetic force in the observed spreading phenomena. The effect of particles on the flow field is also considered. These phenomena would allow simple wireless control of a microfluidic system without changing the flow rates. These phenomena can potentially be used for focusing and sorting in cytometry.     

On-chip manipulation and trapping of microorganisms using a patterned magnetic pathway

We demonstrate on-chip manipulation and trapping of individual microorganisms at designated positions on a silicon surface within a microfluidic channel. Superparamagnetic beads acted as microorganism carriers. Cyanobacterium Synechocystis sp. PCC 6803 microorganisms were immobilized on amine-functionalized magnetic beads (Dynabead^® M-270 Amine) by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)–N-hydroxysulfosuccinimide coupling chemistry. The magnetic pathway was patterned lithographically such that half-disk Ni₈₀Fe₂₀ (permalloy) 5 μm elements were arranged sequentially for a length of 400 micrometers. An external rotating magnetic field of 10 mT was used to drive a translational force (maximum 70 pN) on the magnetic bead carriers proportional to the product of the field strength and its gradient along the patterned edge. Individual microorganisms immobilized on the magnetic beads (transporting objects) were directionally manipulated using a magnetic rail track, which was able to manipulate particles as a result of asymmetric forces from the curved and flat edges of the pattern on the disk. Transporting objects were then successfully trapped in a magnetic trapping station pathway. The transporting object moves two half-disk lengths in one field rotation, resulting in movement at ~24 μm s^?1 for 1 Hz rotational frequency with 5 μm pattern elements spaced with a 1 μm gap between elements.     

Dynamic motion analysis of magnetic particles in microfluidic systems under an external gradient magnetic field

To gain an insightful understanding of motion behavior of paramagnetic particles suspended in a nonmagnetic fluid under a gradient magnetic field, a coupled fluid–structure model based on a direct numerical scheme is developed in this work. The governing equations of magnetic field, fluid flow field and particle motion are simultaneously solved using an Arbitrary Lagrangian–Eulerian method, taking into account magnetic and hydrodynamic interactions between particles in a fully coupled manner. The accuracy of the proposed method is validated using the magnetic particulate flows of two particles under a uniform magnetic field as the test problem and is then applied to investigate effects of magnetic and hydrodynamic interactions between particles on the particle motion behavior. Results show that neighboring magnetic particles are easy to form chain-like clusters along field direction due to magnetic interactions between particles and then move together toward the surface of magnetic source under the action of gradient magnetic force. More importantly, it has been found that both magnetic and hydrodynamic interactions between particles are conducive to the acceleration of particles and the chain formation of particles. The present method and results could help in understanding the basic mechanism underlying the low-gradient magnetophoretic separation process and designing magnetic aggregate-based microfluidic devices.     

Analytical model of microfluidic transport of non-magnetic particles in ferrofluids under the influence of a permanent magnet

This study describes an analytical model and experimental verifications of transport of non-magnetic spherical microparticles in ferrofluids in a microfluidic system that consists of a microchannel and a permanent magnet. The permanent magnet produces a spatially non-uniform magnetic field that gives rise to a magnetic buoyancy force on particles within ferrofluid-filled microchannel. We obtained trajectories of particles in the microchannel by (1) calculating magnetic buoyancy force through the use of an analytical expression of magnetic field distributions and a nonlinear magnetization model of ferrofluids, (2) deriving governing equations of motion for particles through the use of analytical expressions of dominant magnetic buoyancy and hydrodynamic viscous drag forces, (3) solving equations of motion for particles in laminar flow conditions. We studied effects of particle size and flow rate in the microchannel on the trajectories of particles. The analysis indicated that particles were increasingly deflected in the direction that was perpendicular to the flow when size of particles increased, or when flow rate in the microchannel decreased. We also studied ??wall effect?? on the trajectories of particles in the microchannel when surfaces of particles were in contact with channel wall. Experimentally obtained trajectories of particles were used to confirm the validity of our analytical results. We believe this study forms the theoretical foundation for size-based particle (both synthetic and biological) separation in ferrofluids in a microfluidic device. The simplicity and versatility of our analytical model make it useful for quick optimizations of future separation devices as the model takes into account important design parameters including particle size, property of ferrofluids, magnetic field distribution, dimension of microchannel, and fluid flow rate.     

Creation of single-particle environment by positive dielectrophoresis and liquid dielectrophoresis

Two electrical mechanisms for manipulating particles and fluids, dielectrophoresis (DEP) and liquid dielectrophoresis (LDEP), are integrated in a microfluidic chip for creating the single-particle environment. The fluid is activated by LDEP with a 100-kHz/240-V_pp signal. When the single polystyrene bead approaches the trapping area, positive DEP force is utilized to capture and immobilize the bead. After trapping the bead, the process of liquid cutting and droplet creation is employed to create a droplet containing a single bead by LDEP with a 100-kHz/320-V_pp signal.     

On-chip fabrication of magnetic alginate hydrogel microfibers by multilayered pneumatic microvalves

Alginate hydrogel has widespread applications in tissue engineering, cancer therapy, wound management and drug/cell/growth factor delivery due to its biocompatibility, hydrated environment and desirable viscoelastic properties. However, the lack of controllability is still an obstacle for utilizing it in the fabrication of 3D tissue constructs and accurate targeting in mass delivery. Here, we proposed a new method for achieving magnetic alginate hydrogel microfibers by dispersing magnetic nanoparticles in alginate solution and solidifying the magnetic alginate into hydrogel fiber inside microfluidic devices. The microfluidic devices have multilayered pneumatic microvalves with hemicylindrical channels to fully stop the fluids. In the experiments, the magnetic nanoparticles and the alginate solution were mixed and formed a uniform suspension. No aggregation of magnetic nanoparticles was found, which is crucial for flow control inside microfluidic devices. By regulating the flow rates of different solutions with the microvalves inside the microfluidic device, magnetic hydrogel fibers and nonmagnetic hydrogel fibers were fabricated with controlled sizes. The proposed method for fabricating magnetic hydrogel fiber holds great potential for engineering 3D tissue constructs with complex architectures and active drug release.     

Magnetic liquid marbles, their manipulation and application in optical probing

Magnetic liquid marbles, an encapsulation of liquid droplet with hydrophobic magnetic particles, show remarkable responsiveness to external magnetic force and great potential to be used as a discrete droplet microfluidic system. In this study, we presented the manipulation of a magnetic liquid marble under an external magnetic field and calculated the maximum frictional force, the magnetic force required for actuating the liquid marbles and the effective surface tension of the magnetic liquid marble, as well as the threshold volume for the transition from quasi-spherical to puddle-like shape. By taking advantage of the unique feature of being opened and closed reversibly, we have proven the encapsulated droplets can be detected optically with a reflection-mode probe. Combining the open-close and optical detection also enables to probe chemical reactions taking place within liquid marbles. These remarkable features offer a simple yet powerful alternative to conventional discrete microfluidic systems and may have wide applications in biomedical and drug discovery.     

Production of uniform droplets using membrane, microchannel and microfluidic emulsification devices

This review provides an overview of major microengineering emulsification techniques for production of monodispersed droplets. The main emphasis has been put on membrane emulsification using Shirasu Porous Glass and microsieve membrane, microchannel emulsification using grooved-type and straight-through microchannel plates, microfluidic junctions and flow focusing microfluidic devices. Microfabrication methods for production of planar and 3D poly(dimethylsiloxane) devices, glass capillary microfluidic devices and single-crystal silicon microchannel array devices have been described including soft lithography, glass capillary pulling and microforging, hot embossing, anisotropic wet etching and deep reactive ion etching. In addition, fabrication methods for SPG and microseive membranes have been outlined, such as spinodal decomposition, reactive ion etching and ultraviolet LIGA (Lithography, Electroplating, and Moulding) process. The most widespread application of micromachined emulsification devices is in the synthesis of monodispersed particles and vesicles, such as polymeric particles, microgels, solid lipid particles, Janus particles, and functional vesicles (liposomes, polymersomes and colloidosomes). Glass capillary microfluidic devices are very suitable for production of core/shell drops of controllable shell thickness and multiple emulsions containing a controlled number of inner droplets and/or inner droplets of two or more distinct phases. Microchannel emulsification is a very promising technique for production of monodispersed droplets with droplet throughputs of up to 100?l?h^?1.     

Monte Carlo particle modelling of small semiconductor devices

We have at Reading developed a self consistent Monte Carlo particle model for simulation of semiconductor devices, and proved that it is capable of correctly reproducing laboratory measurements. The method consists of following the detailed transport histories of individual carriers. Physical processes such as interaction between the carriers (holes and electrons) and the lattice (various types of phonon scattering), and the imperfections (impurities). Electron-hole pair creation (i.e. in devices interacting with light) and recombination, avalanche effects, trapping and tunnelling have been included in the model. Although the method was first developed with GaAs MESFETs in mind, it has now been generalised to all cubic semiconductors and to any sort of device. As the model reflects the basic physics of semiconductor devices, it can be used to deepen the physical understanding of such devices. It can also be used as a design tool to evaluate novel ideas. These aspects are discussed. This model is aimed at describing devices of geometrical dimensions of the order of, and smaller than the free flight path of the carriers. As no assumptions have been made regarding diffusion or relaxation of the carriers, like in previous models, this model can be used where non-stationary transport becomes dominant. A review of device simulation carried out by us so far has been given.