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.     

No more bonding,no more clamping,magnetically assisted membrane integration in microfluidic devices

The integration of porous membranes with microfluidic devices allows a simple but high-throughput mass transport control for numerous microfluidic applications, such as single-cell separation, sample analysis, and purification. In this study, we demonstrate a novel integration process of porous membranes into microfluidic devices by applying a magnetic field and hydrodynamically stabilizing them. This new approach simplifies the integration process by removing physicochemical bonding between membranes and microfluidic devices, but overcomes many practical issues observed in current methods, such as device leakage, membrane replacement, and membrane material selection. More importantly, our approach allows us to install membranes with diverse physicochemical features and spatial configurations into a single microfluidic device. This additional ability can significantly improve its performance and capability in applications. Finally, we successfully demonstrate the utilization of our membrane device for simple particle separation.     

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.     

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.     

Cluster formation and growth in microchannel flow of dilute particle suspensions

The lifetime of microfluidic devices depends on their ability to maintain flow without interruption. Certain applications require microdevices for transport of liquids containing particles. However, microchannels are susceptible to blockage by solid particles. Therefore, in this study, the phenomenon of interest is the formation and growth of clusters on a microchannel surface in the flow of a dilute suspension of hard spheres. Based on the present experiments, aggregation of clusters was observed for particle-laden flows in microchannels with particle void fraction as low as 0.001 and particle diameter to channel height ratio as low as 0.1. The incipience and growth of a single cluster is discussed, and the spatial distribution and time evolution of clusters along the microchannel are presented. Although the cluster size seems to be independent of location, more clusters are found at the inlet/outlet regions than in the microchannel center. Similarly as for an individual cluster, as long as particle–cluster interaction is the dominant mode, the total cluster area in the microchannel grows almost linearly in time. The effects of flow rate, particle size, and concentration are also reported.     

Microfluidic devices in superconducting magnets: on-chip free-flow diamagnetophoresis of polymer particles and bubbles

Superconducting magnets enable the study of high magnetic fields on materials and objects, for example in material synthesis, self-assembly or levitation experiments. The setups employed often lack in precise spatial control of the object of interest within the bore of the magnet. Microfluidic technology enables accurate manipulation of fluidic surroundings and we have investigated the integration of microfluidic devices into superconducting magnets to enable controlled studies of objects in high magnetic fields. Polymeric microparticles similar in size to biological cells were manipulated via diamagnetic repulsion. The particles were suspended in an aqueous paramagnetic medium of manganese (II) chloride and pumped into a microfluidic chip, where they were repelled in continuous flow by the high magnetic field. The extent of deflection was studied as a function of increasing (1) particle size, (2) paramagnetic salt concentration, and (3) magnetic field strength. Optimizing these parameters allowed for the spatial separation of two particle populations via on-chip free-flow diamagnetophoresis. Finally, preliminary findings on the repulsion of air bubbles are shown.     

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.     

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.     

Diamagnetic particle focusing using ferromicrofluidics with a single magnet

Focusing particles into a tight stream is critical to many applications such as microfluidic flow cytometry and particle sorting. Current magnetic field-induced particle focusing techniques rely on the use of a pair of repulsive magnets, which makes the device integration and operation difficult. We develop herein a new approach to focusing nonmagnetic particles in ferrofluid flow through a T-microchannel using a single permanent magnet. Particles are deflected across the suspending ferrofluid by negative magnetophoresis and confined by a water flow to the center plane of the microchannel, leading to a focused particle stream flowing near the bottom channel wall. Such three-dimensional diamagnetic particle focusing is demonstrated in a sufficiently diluted ferrofluid through both the top and side views of the microchannel. As the suspended particles can be visualized in bright field, this magnetic focusing method is expected to find applications to label-free (i.e., no magnetic or fluorescent labeling) cellular focusing in lab-on-a-chip devices.     

Numerical investigation of polygonal particle separation in microfluidic channels

We numerically investigate the separation of polygonal particles through an array of solid obstacles in microfluidic devices. Particle–fluid, particle–particle and particle–wall interactions are all considered in our numerical method. Firstly, the separation of circular particles based on size is simulated and the relationship of the migration angle and forcing angle by our simulations is coincided with the experimental results. Then, the simulations of polygon particle separation based on shape are carried out. The results show that the shape of particles can be used for particle separation through an array of solid obstacles. Through reasonable design of the shape of obstacles, separation of polygon particles can be achieved. In addition, the results indicate that our numerical method has the potential to substantially improve the design and optimization of microfluidic devices for the separation of particles.     

Methods for counting particles in microfluidic applications

Microfluidic particle counters are important tools in biomedical diagnostic applications such as flow cytometry analysis. Major methods of counting particles in microfluidic devices are reviewed in this paper. The microfluidic resistive pulse sensor advances in sensitivity over the traditional Coulter counter by improving signal amplification and noise reduction techniques. Nanopore-based methods are used for single DNA molecule analysis and the capacitance counter is useful in liquids of low electrical conductivity and in sensing the changes of cell contents. Light-scattering and light-blocking counters are better for detecting larger particles or concentrated particles. Methods of using fluorescence detection have the capability for differentiating particles of similar sizes but different types that are labeled with different fluorescent dyes. The micro particle image velocimetry method has also been used for detecting and analyzing particles in a flow field. The general limitation of microfluidic particle counters is the low throughput which needs to be improved in the future. The integration of two or more existing microfluidic particle counting techniques is required for many practical on-chip applications.     

Particle focusing in microfluidic devices

Focusing particles (both biological and synthetic) into a tight stream is usually a necessary step prior to counting, detecting, and sorting them. The various particle focusing approaches in microfluidic devices may be conveniently classified as sheath flow focusing and sheathless focusing. Sheath flow focusers use one or more sheath fluids to pinch the particle suspension and thus focus the suspended particles. Sheathless focusers typically rely on a force to manipulate particles laterally to their equilibrium positions. This force can be either externally applied or internally induced by channel topology. Therefore, the sheathless particle focusing methods may be further classified as active or passive by the nature of the forces involved. The aim of this article is to introduce and discuss the recent developments in both sheath flow and sheathless particle focusing approaches in microfluidic devices.     

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.     

Rotational motion and lateral migration of an elliptical magnetic particle in a microchannel under a uniform magnetic field

We have numerically investigated the motion of an elliptical magnetic particle in a microfluidic channel subjected to an external uniform magnetic field. By using the direct numerical simulation method and an arbitrary Lagrangian–Eulerian technique, the involved particle–fluid-magnetic field problem can be solved in a fully coupled manner. The numerical predictions of the particle trajectory and orientation with and without a uniform magnetic field are in qualitative agreement with the existing experimental results, and numerical results have revealed the impacts of key parameters such as inlet flow velocity, magnetic field direction, and particle shape on the rotational motion and lateral migration of the elliptical particle. Meanwhile, the shape-based particle separation in a low Reynolds number flow with the aid of an applied uniform magnetic field has also been numerically demonstrated.     

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.     

On the direct employment of dipolar particle interaction in microfluidic systems

This review article will summarize recent developments in the employment of dipolar coupled magnetic particle structures. We will discuss the basics of magnetic dipolar particle interaction in static and rotating magnetic fields. In dependence on the magnetic fields employed, agglomerates of different dimensionality may form within the carrier liquid. The stability and formation dynamics of these particle structures will be presented. Furthermore, we will review recent microfluidic applications based on the interaction of magnetic particles and present methods for surface patterning with micron-sized and nano-sized particles which employ dipolar particle coupling.     

Thin-film electrode based droplet detection for microfluidic systems

We report on a droplet-producing microfluidic system with electrical impedance-based detection. The microfluidic devices are made of polydimethylsiloxane (PDMS) and glass with thin film electrodes connected to an impedance-monitoring circuit. Immiscible fluids containing the hydrophobic and hydrophilic phases are injected with syringe pumps and spontaneously break into water-in-oil droplet trains. When a droplet passes between a pair of electrodes in a medium having different electrical conductivity, the resulting impedance change signals the presence of the particle for closed-loop feedback during processing. The circuit produces a digital pulse for input into a computer control system. The droplet detector allows estimation of a droplet's arrival time at the microfluidic chip outlet for dispensing applications. Droplet detection is required in applications that count, sort, and direct microfluidic droplets. Because of their low cost and simplicity, microelectrode-based droplet detection techniques should find applications in digital microfluidics and in three-dimensional printing technology for rapid prototyping and biotechnology.     

On the importance of carrier fluid viscosity and particle–wall interactions in magnetic-guided assembly of quasi-2D systems

We demonstrate the influence of experimental conditions (carrier fluid viscosity and particle–wall interactions—friction) on the quasi-2D deterministic aggregation kinetics of carbonyl iron magnetic suspensions in rectangular microchannels. On the one hand, the carrier fluid viscosity determines the time scale for aggregation. On the other hand, friction strongly determines the aggregation rate and therefore the kinetic exponent (mean cluster size vs. time dependence). When particle–wall interactions are weak, the mean cluster size increases with a power of 0.65 ± 0.06, for open cavities (≥500 microns channel width), in very good agreement with theories and particle-level simulations. However, when the particle–wall interactions are strong, the kinetic exponent decreases and the aggregation is eventually arrested. This work suggests that particle–wall interactions may be one of the reasons for the discrepancies found in the experimental determination of the aggregation kinetic exponents in the literature.     

Investigation and improvement of reversible microfluidic devices based on glass–PDMS–glass sandwich configuration

Reversibly assembled microfluidic devices are dismountable and reusable, which is useful for a number of applications such as micro- and nano-device fabrication, surface functionalization, complex cell patterning, and other biological analysis by means of spatial–temporal pattern. However, reversible microfluidic devices fabricated with current standard procedures can only be used for low-pressure applications. Assembling technology based on glass–PDMS–glass sandwich configuration provides an alternative sealing method for reversible microfluidic devices, which can drastically increase the sealing strength of reversibly adhered devices. The improvement mechanism of sealing properties of microfluidic devices based on the sandwich technique has not been fully characterized, hindering further improvement and broad use of this technique. Here, we characterize, for the first time, the effect of various parameters on the sealing strength of reversible PDMS/glass hybrid microfluidic devices, including contact area, PDMS thickness, assembling mode, and external force. To further improve the reversible sealing of glass–PDMS–glass microfluidic devices, we propose a new scheme which exploits mechanical clamping elements to reinforce the sealing strength of glass–PDMS–glass sandwich structures. Using our scheme, the glass–PDMS–glass microchips can survive a pressure up to 400 kPa, which is comparable to the irreversibly bonded PDMS microdevices. We believe that this bonding method may find use in lab-on-a-chip devices, particularly in active high-pressure-driven microfluidic devices.