Towards a programmable magnetic bead microarray in a microfluidic channel

A new hybrid magnetic bead separator that combines an external magnetic field with 175 μm thick current lines buried in the back side of a silicon wafer is presented. A microfluidic channel was etched into the front side of the wafer. The large cross-section of the current lines makes it possible to use larger currents and obtain forces of longer range than from thin current lines at a given power limit. Guiding of magnetic beads in the hybrid magnetic separator and the construction of a programmable microarray of magnetic beads in the microfluidic channel by hydrodynamic focusing is presented.     

Pump-free transport of magnetic particles in microfluidic channels

The use of magnetic particles in microfluidic devices offers new possibilities and a new degree of freedom to sequential synthesis and preparative or analytical procedures in very small volumes. In contrast to most of the traditional approaches where the liquid phase is flushed or pumped along a solid phase, the transport of magnetic particles through a microfluidic channel has the advantage of reduced reagent consumption and simpler, smaller systems. By lining up different reservoirs along the transport direction, reactions with different agents can be accomplished. Here, we present a pump and valve-free microfluidic particle transport system. By creating a simple and very effective layout of soft magnetic structures, which concentrate an external homogeneous magnetic field, a passive, thus easy to operate structure was generated. Most importantly, this layout is based on a simple tube by which fluidic and magnetic parts are separated. The tube itself is disposable and can be replaced prior to vital reactions, thus helping reduce sample cross-contaminations without affecting the particle transport properties. The layout of the device was thoroughly examined by a computer simulation of the particle trajectories, and the results were confirmed by experiments on a micro-machined demonstrator, which revealed an effective transport speed of up to 5 mm/s in 30 mT magnetic fields. Thus, we present a microfluidic transport device that combines the advantages of magnetic particles in microfluidic systems with a simple single-use technology for, e.g., bioanalytical purposes.     

Planar microcoil-based microfluidic NMR probes

Microfabricated small-volume NMR probes consisting of electroplated planar microcoils integrated on a glass substrate with etched microfluidic channels are fabricated and tested. 1H NMR spectra are acquired at 300 MHz with three different probes having observed sample volumes of respectively 30, 120, and 470 nL. The achieved sensitivity enables acquisition of an 1H spectrum of 160 microg sucrose in D2O, corresponding to a proof-of-concept for on-chip NMR spectroscopy. Increase of mass-sensitivity with coil diameter reduction is demonstrated experimentally for planar microcoils. Models that enable quantitative prediction of the signal-to-noise ratio and of the influence of microfluidic channel geometry on spectral resolution are presented and successfully compared to the experimental data. The main factor presently limiting sensitivity for high-resolution applications is identified as being probe-induced static magnetic field distortions. Finally, based on the presented model and measured data, future performance of planar microcoil-based microfluidic NMR probes is extrapolated and discussed.     

Magnetic particle diverter in an integrated microfluidic format

A fully integrated micromagnetic particle diverter and microfluidic system are described. Particles are diverted via an external uniform magnetic field perturbed at the microscale by underlying current straps. The resulting magnetic force deflects particles across a flow stream into one of the two channels at a Y-shaped junction. The basic theoretical framework, design, and operational demonstration of the device are presented.     

Multimode interference devices for focusing in microfluidic channels

Low-cost, compact, automated optical microsystems for chemical analysis, such as microflow cytometers for identification of individual biological cells, require monolithically integrated microlenses for focusing in microfluidic channels, to enable high-resolution scattering and fluorescence measurements. The multimode interference device (MMI), which makes use of self-imaging in multimode waveguides, is shown to be a simple and effective alternative to the microlens for microflow cytometry. The MMIs have been designed, realized, and integrated with microfluidic channels in a silica-based glass waveguide material system. Focal spot sizes of 2.4 μm for MMIs have been measured at foci as far as 43.7 μm into the microfluidic channel.     

Microfabricated polydimethylsiloxane microfluidic system including micropump and microvalve for integrated biosensor

We present a microfluidic system with paraffin-actuated microvalves and a thermopneumatic-actuated micropump that are easily integrated on the same substrate using the same fabrication process. The fabrication process of this microfluidic system using polydimethylsiloxane (PDMS), indium tin oxide (ITO) and glass is relatively simple, and its performance is good for the application of the disposable lab-on-a-chip. A maximum pumping rate of about 2.0 μl/min was measured at a duty ratio of 5% and a frequency of 1 Hz. The flow cut-off powers for the microvalves with the channel depth of 220 μm, were 300 and 350 mW for valve seat diameters of 1.5 and 2.0 mm, respectively. The power for flow cut-off depends on the channel depth and the diameter of the valve seat in the microvalves.     

Microelectromagnet for magnetic manipulation in lab-on-a-chip systems

We demonstrate a simple scheme for fabrication of microelectromagnets consisting of planar spiral coils semi-encapsulated in soft magnetic yokes using conventional microfabrication techniques. The microelectromagnets are suitable for applications operating at frequencies below 250 kHz. Conventional fabrication schemes for planar microelectromagnets typically rely on five mask steps. We allow the current to flow in the soft magnetic yoke and thereby two mask steps are eliminated. We have characterized the electromagnets electrically, the results agree well with theory, and the implications arising from current flowing in the magnetic yoke are discussed. We have integrated the microelectromagnets with microfluidic channels, and demonstrated separation of commercially available magnetic beads from a fluid in a microfluidic system, i.e. a lab-on-a-chip system.     

A microfluidic rectifier: anisotropic flow resistance at low Reynolds numbers

It is one of the basic concepts of Newtonian fluid dynamics that at low Reynolds number (Re) the Navier-Stokes equation is linear and flows are reversible. In microfluidic devices, where Re is essentially always low, this implies that flow resistance in microchannels is isotropic. Here we present a microfluidic rectifier: a microscopic channel of a special shape whose flow resistance is strongly anisotropic, differing by up to a factor of 2 for opposite flow directions. Its nonlinear operation at arbitrary small Re is due to non-Newtonian elastic properties of the working fluid, which is a 0.01% aqueous solution of a high molecular weight polymer. The rectifier works as a dynamic valve and may find applications in microfluidic pumps and other integrated devices.     

Magnetic separation in microfluidic systems using microfabricated electromagnets—experiments and simulations

We present experiments and simulations of magnetic separation of magnetic beads in a microfluidic channel. The separation is obtained by microfabricated electromagnets. The results of our simulations using FEMLAB and Mathematica are compared with experimental results obtained using our own microfabricated systems.     

Thermophoresis of DNA determined by microfluidic fluorescence

We describe a microfluidic all-optical technique to measure the thermophoresis of molecules. Within micrometer-thick chambers, we heat aqueous solutions with a micrometer-sized focus of infrared light. The temperature increase of about 1 K is monitored with temperature-sensitive fluorescent dyes. We test the approach in measuring the thermophoresis of DNA. We image the concentration of DNA in a second fluorescence-color channel. DNA is depleted away from the heated spot. The profile of depletion is fitted by the thermophoretic theory to reveal the Soret coefficient. We evaluate the method with numerical 3D calculations of temperature profiles, drift, convection and thermophoretic depletion using finite element methods. The approach opens new ways to monitor thermophoresis at the single molecule level, near boundaries and in complex mixtures. The flexible microfluidic setting is a good step towards microfluidic applications of thermophoresis in biotechnology.     

Spectrally resolved flow imaging of fluids inside a microfluidic chip with ultrahigh time resolution

Microfluidics has advanced to become a complete lab-on-a-chip platform with applications across many disciplines of scientific research. While optical techniques are primarily used as modes of detection, magnetic resonance (MR) is emerging as a potentially powerful and complementary tool because of its non-invasive operation and analytical fidelity. Two prevailing limitations currently inhibit MR techniques on microfluidic devices: poor sensitivity and the relatively slow time scale of dynamics that can be probed. It is commonly assumed that the time scale of observation of one variable limits the certainty with which one can measure the complementary variable. For example, short observation times imply poor spectral resolution. In this article, we demonstrate a new methodology that overcomes this fundamental limit, allowing in principle for arbitrarily high temporal resolution with a sensitivity across the entire microfluidic device several orders of magnitude greater than is possible by direct MR measurement. The enhancement is evidenced by recording chemically resolved fluid mixing through a complex 3D microfluidic device at 500 frames per second, the highest recorded in a magnetic resonance imaging experiment. The key to this development is combining remote detection with a time ‘slicing’ of its spatially encoded counterpart. Remote detection circumvents the problem of insensitive direct MR detection on a microfluidic device where the direct sensitivity is less than 10^-5 relative to traditional NMR, while the time slicing eliminates the constraints of the limited observation time by converting the time variable into a spatial variable through the use of magnetic field gradients. This method has implications for observing fast processes, such as fluid mixing, rapid binding, and certain classes of chemical reactions with sub millisecond time resolution and as a new modality for on-chip chromatography.     

基于微泡共振的快速微流体声学混合方法研究

微流体在生物医学、化学工程等领域应用广泛,并具有重大意义.在预处理中,液体混合也是关键且最为必要的前序.为了提高微流控腔道内液体混合的效率,本文提出基于单微泡振动的声学混合器,通过微泡共振,产生声微流,声微流形成的剪切力将在流体中产生微扰动,实现液体的混合.设计了底面直径为40μm的微孔结构,由于液体表面张力作用形成微泡,在共振频率为165 kHz的压电换能器激励下,气泡发生共振产生声微流.通过对压电换能器输入不同能量,获取混合液体的最优参数,可在37.5 ms内实现混合效果,混合均匀度达到92.7%.本文设计的单微泡振动混合器结构简单、混合效率高、混合时间短、输入能量低,可为生物化学等方面的研究提供强有力的技术支撑.     

基于微流控混合器的连续流动态同步辐射圆二色谱发展

基于微流控混合器,采用连续流探测方法,在北京同步辐射装置真空紫外光谱实验站发展了毫秒动态圆二色谱探测方法。石英微流控混合器采用深度离子刻蚀技术加工,通道深度44.5 μm。混合器采用蛇形通道实现溶液的快速混合。通过荧光倒置显微镜,在模拟真实实验条件的高粘度溶液中,观察蛇形通道内溶液混合的荧光图像,进行混合效率测试。500 μL·min-1流量下,目前可实现4.5～270 μs的时间尺度探测。利用微流控混合器进行动态探测,同步辐射紫外光必须聚焦,但由于聚焦透镜波长色散引起的焦点位移,导致圆二色谱发生畸变。通过精确测试不同波长对应焦点的相对位置,然后在圆二色谱扫描中实现波长和焦点位置精确的反馈控制,获得准确的圆二色谱。利用所发展的方法,测试了去折叠状态下的细胞色素c恢复折叠的动态同步辐射圆二色谱,在4.5 μs处折叠恢复54%。这种方法将为生物大分子折叠动力学研究提供新的探测手段。     

Photonic crystal resonator integrated in a microfluidic system

We report on a novel optofluidic system consisting of a silica-based 1D photonic crystal, integrated planar waveguides, and electrically insulated fluidic channels. An array of pillars in a microfluidic channel designed for electrochromatography is used as a resonator for on-column label-free refractive index detection. The resonator was fabricated in a silicon oxynitride platform, to support electro-osmotic flow, and operated at lambda=1.55 microm. Different aqueous solutions of ethanol with refractive indices ranging from n=1.3330 to 1.3616 were pumped into the column/resonator, and the transmission spectra were recorded. Linear shifts of the resonant wavelengths yielded a maximum sensitivity of Deltalambda/Deltan=480 nm/RIU (refractive index unit), and a minimum difference of Deltan=0.007 RIU was measured.     

Modeling the acoustic radiation force in microfluidic chambers

A procedure is demonstrated to quantitatively evaluate the acoustic radiation forces in microfluidic particle manipulation chambers. Typical estimates of the acoustic pressure and the acoustic radiation force are based on an analytical solution for a simple one-dimensional standing wave pattern. The complexities of a typical microfluidic channel limit the usefulness of this approach. By leveraging finite elements, and a generalized equation for the acoustic radiation force, channel designs can be investigated in two and three dimensions. Calculations and experimental observations in this report and the literature, confirm these claims.     

Dynamic pattern formation in a vesicle-generating microfluidic device

Spatiotemporal pattern formation occurs in a variety of nonequilibrium physical and chemical systems. Here we show that a microfluidic device designed to produce reverse micelles can generate complex, ordered patterns as it is continuously operated far from thermodynamic equilibrium. Flow in a microfluidic system is usually simple-viscous effects dominate and the low Reynolds number leads to laminar flow. Self-assembly of the vesicles into patterns depends on channel geometry and relative fluid pressures, enabling the production of motifs ranging from monodisperse droplets to helices and ribbons.     

A microfluidic spiral for size-dependent fractionation of magnetic microspheres

Magnetic microspheres (MMS) are useful tools for a variety of medical and pharmaceutical applications. Typically, commercially manufactured MMS exhibit broad size distributions. This polydispersity is problematic for many applications. Since the direct synthesis of monodisperse MMS is often fraught with technical challenges, there is considerable interest in and need associated with the development of techniques for size-dependent fractionation of MMS. In this study we demonstrated continuous size-dependent fractionation of sub-micron scale particles driven by secondary (Dean effect) flows in curved microfluidic channels. Our goal was to demonstrate that such techniques can be applied to MMS containing superparamagnetic nanoparticles. To achieve this goal, we developed and tested a microfluidic chip for continuous MMS fractionation. Our data address two key areas. First, the densities of MMS are typically in the range 1.5–2.5 g/cm³, and thus they tend be non-neutrally buoyant. Our data demonstrate that efficient size-dependent fractionation of MMS entrained in water (density 1 g/cm³) is possible and is not significantly influenced by the density mismatch. In this context we show that a mixture comprising two different monodisperse MMS components can be separated into its constituent parts with 100% and 88% success for the larger and smaller particles, respectively. Similarly, we show that a suspension of polydisperse MMS can be separated into streams containing particles with different mean diameters. Second, our data demonstrate that efficient size-dependent fractionation of MMS is not impeded by magnetic interactions between particles, even under application of homogeneous magnetic fields as large as 35 kA/m. The chip is thus suitable for the separation of different particle fractions in a continuous process and the size fractions can be chosen simply by adjusting the flow velocity of the carrier fluid. These facts open the door to size dependent fractionation of MMS.     

Fluorescence monitoring of microchip capillary electrophoresis separation with monolithically integrated waveguides

Using femtosecond laser writing, optical waveguides were monolithically integrated into a commercial microfluidic lab-on-a-chip device, with the waveguides intersecting a microfluidic channel. Continuous-wave laser excitation through these optical waveguides confines the excitation window to a width of 12 microm, enabling high-resolution monitoring of the passage of different types of fluorescent analytes when migrating and being separated in the microfluidic channel by microchip capillary electrophoresis. Furthermore, we demonstrate on-chip-integrated waveguide excitation and detection of a biologically relevant species, fluorescently labeled DNA molecules, during microchip capillary electrophoresis. Well-controlled plug formation as required for on-chip integrated capillary electrophoresis separation of DNA molecules, and the combination of waveguide excitation and a low limit of detection, will enable monitoring of extremely small quantities with high spatial resolution.     

Analytical model for the magnetophoretic capture of magnetic microspheres in microfluidic devices

Magnetic microspheres are used as mobile substrates in micro-total-analysis systems (μTAS), since the particles can be selectively functionalized to attach different bioconjugates and can be precisely manipulated using external magnetic field gradients. A large number of MEMS-based bio-analytical devices employ magnetophoretic separation as an important step during their operation. An analytical technique is proposed in this paper that describes the magnetophoretic transport of magnetic microspheres under an imposed magnetic field when there is a pressure-driven or electroosmotic flow through a microchannel. Successful magnetophoretic capture occurs if the strength of the field-inducing magnetic dipole exceeds a critical value, or if the particles are larger than a critical size. The magnetophoretic separator performance is characterized in terms of capture efficiency. The analysis shows that the capture efficiency is a function of two independent non-dimensional parameters, λ and γ that in turn involve all the physical design and operating parameters of the microfluidic separator, e.g., the dipole strength, particle size and susceptibility, fluid viscosity and velocity, channel height, and the separation of the dipole. Parametric plots of capture efficiency as function of λ and γ helps in choosing the right design and operation parameter of a practical microfluidic separator for a target level of performance.     

Spatial confinement of ultrasonic force fields in microfluidic channels

We demonstrate and investigate multiple localized ultrasonic manipulation functions in series in microfluidic chips. The manipulation functions are based on spatially separated and confined ultrasonic primary radiation force fields, obtained by local matching of the resonance condition of the microfluidic channel. The channel segments are remotely actuated by the use of frequency-specific external transducers with refracting wedges placed on top of the chips. The force field in each channel segment is characterized by the use of micrometer-resolution particle image velocimetry (micro-PIV). The confinement of the ultrasonic fields during single- or dual-segment actuation, as well as the cross-talk between two adjacent fields, is characterized and quantified. Our results show that the field confinement typically scales with the acoustic wavelength, and that the cross-talk is insignificant between adjacent fields. The goal is to define design strategies for implementing several spatially separated ultrasonic manipulation functions in series for use in advanced particle or cell handling and processing applications. One such proof-of-concept application is demonstrated, where flow-through-mode operation of a chip with flow splitting elements is used for two-dimensional pre-alignment and addressable merging of particle tracks.