Mixing In Microfluidic Devices Research Articles

Hydrophobic ion pairing and microfluidic nanoprecipitation enable efficient nanoformulation of a small molecule indolamine 2, 3-dioxygenaseinhibitor immunotherapeutic.

Blockade of programmed cell death-1 (PD-1) is a transformative immunotherapy. However, only a fraction of patients benefit, and there is a critical need for broad-spectrum checkpoint inhibition approaches that both enhance the recruitment of cytotoxic immune cells in cold tumors and target resistance pathways. Indoleamine 2, 3-dioxygenase (IDO) small molecule inhibitors are promising but suboptimal tumor bioavailability and dose-limiting toxicity have limited therapeutic benefits in clinical trials. This study reports on a nanoformulation of the IDO inhibitor navoximod within polymeric nanoparticles prepared using a high-throughput microfluidic mixing device. Hydrophobic ion pairing addresses the challenging physicochemical properties of navoximod, yielding remarkably high loading (>10%). The nanoformulation efficiently inhibits IDO and, in synergy with PD-1 antibodies improves the anti-cancer cytotoxicity of T-cells, in vitro and in vivo. This study provides new insight into the IDO and PD-1 inhibitors synergy and validates hydrophobic ion pairing as a simple and clinically scalable formulation approach.

Performance evaluation of laminar micromixer based on two-degree-of-freedom flow-induced vibration

Solution mixing in microfluidic devices is very common in chemical, biological, medical and other fields, and it is challenging to achieve rapid mixing in laminar flow. In this paper, flow-induced vibration is introduced to promote laminar mixing and the influence of two-degree-of-freedom vibration of bluff body on the mixing performance of solutions are studied numerically. The vibration response of body, mixing concentration, vorticity, and mixing index under different blocking ratios are analyzed, and the motion trajectory under the optimal blocking ratio is presented. It is found that the blocking ratio directly affects the vibration of cylinder, and then has a significant impact on the mixing performance. When the blocking ratio β=1/4, although the mixing index is not the maximum of all the blocking ratios considered, the kinetic energy loss of the fluid is lower than that at larger blocking ratio, resulting in excellent comprehensive mixing performance. When the reduced velocity U*=4 for β=1/4, the best mixing performance is achieved with a mixing index of 0.55, and the pressure drop of the fluid during the mixing process is very small. Besides, the motion trajectory of the cylinder presents a typical shape of "8″. The strong vibration in the y direction and the shedding vortex at the downstream position of the cylinder can effectively promote fluid mixing.

Microfluidic Mixing Device With Integrated Dual-Band Microwave Sensor

Microfluidic Mixing Device With Integrated Dual-Band Microwave Sensor

Investigating the Performance of the Multi-Lobed Leaf-Shaped Oscillatory Obstacles in Micromixers Using Bulk Acoustic Waves (BAW): Mixing and Chemical Reaction

Proper mixing in microfluidic devices has been a concern since the early development stages. Acoustic micromixers (active micromixers) attract significant attention due to their high efficiency and ease of implementation. Finding the optimal geometries, structures, and characteristics of acoustic micromixers is still a challenging issue. In this study, we considered leaf-shaped obstacle(s) having a multi-lobed structure as the oscillatory part(s) of acoustic micromixers in a Y-junction microchannel. Four different types of leaf-shaped oscillatory obstacles, including 1, 2, 3, and 4-lobed structures, were defined, and their mixing performance for two fluid streams was evaluated numerically. The geometrical parameters of the leaf-shaped obstacle(s), including the number of lobes, lobes’ length, lobes’ inside angle, and lobes’ pitch angle, were analyzed, and their optimum operational values were discovered. Additionally, the effects of the placement of oscillatory obstacles in three configurations, i.e., at the junction center, on the side walls, and both, on the mixing performance were evaluated. It was found that by increasing the number and length of lobes, the mixing efficiency improved. Furthermore, the effect of the operational parameters, such as inlet velocity, frequency, and intensity of acoustic waves, was examined on mixing efficiency. Meanwhile, the occurrence of a bimolecular reaction in the microchannel was analyzed at different reaction rates. It was proven that the reaction rate has a prominent effect at higher inlet velocities.

Capillary-driven horseshoe vortex forming around a micro-pillar

Hypothesis: Horseshoe vortices are known to emerge around large-scale obstacles, such as bridge pillars, due to an inertia-driven adverse pressure gradient forming on the upstream-side of the obstacle. We contend that a similar flow structure can arise in thin-film Stokes flow around micro-obstacles, such as used in textured surfaces to improve wettability. This could be exploited to enhance mixing in microfluidic devices, typically limited to creeping-flow regimes.Experiments: Numerical simulations based on the Navier–Stokes equations are carried out to elucidate the flow structure associated with the wetting dynamics of a liquid film spreading around a 50 μm diameter micro-pillar. The employed multiphase solver, which is based on the volume of fluid method, accurately reproduces the wetting dynamics observed in current and previous (Mu et al., Langmuir, 2019) experiments.Findings: The flow structure within the liquid meniscus forming at the foot of the micro-pillar evinces a horseshoe vortex wrapping around the obstacle, notwithstanding that the Reynolds number in our system is extremely low. Here, the adverse pressure gradient driving flow reversal near the bounding wall is caused by capillarity instead of inertia. The horseshoe vortex is entangled with other vortical structures, leading to an intricate flow system with high-potential mixing capabilities.

Microbial stir bars: Light-activated rotation of tethered bacterial cells to enhance mixing in stagnant fluids.

Microfluidics devices are gaining significant interest in biomedical applications. However, in a micron-scale device, reaction speed is often limited by the slow rate of diffusion of the reagents. Several active and passive micro-mixers have been fabricated to enhance mixing in microfluidic devices. Here, we demonstrate external control of mixing by rotating a rod-shaped bacterial cell. This rotation is driven by ion transit across the bacterial flagellar stator complex. We first measured the flow fields generated by rotating a single bacterial cell rotationally locked to rotate either clockwise (CW) or counterclockwise (CCW). Micro-particle image velocimetry (μPIV) and particle tracking velocimetry results showed that a bacterial cell of ∼ 2.75 μm long, rotating at 5.75 ± 0.39 Hz in a counterclockwise direction could generate distinct micro-vortices with circular flow fields with a mean velocity of 4.72 ± 1.67 μm/s and maximum velocity of 7.90 μm/s in aqueous solution. We verified our experimental data with a numerical simulation at matched flow conditions, which revealed vortices of similar dimensions and speed. We observed that the flow-field diminished with increasing z-height above the plane of the rotating cell. Lastly, we showed that we could activate and tune rotational mixing remotely using strains engineered with proteorhodopsin, where rotation could be activated by controlled external illumination using green laser light (561 nm).

One-Step Formation of Targeted Liposomes in a Versatile Microfluidic Mixing Device.

Targeted liposomes, as a promising carrier, have received tremendous attention in COVID-19 vaccines, molecular imaging, and cancer treatment, due to their enhanced cellular uptake and payload accumulation at target sites. However, the conventional methods for preparing targeted liposomes still suffer from limitations, including complex operation, time-consuming, and poor reproducibility. Herein, a facile and scalable strategy is developed for one-step construction of targeted liposomes using a versatile microfluidic mixing device (MMD). The engineered MMD provides an advanced synthesis platform for multifunctional liposome with high production rate and controllability. To validate the method, a programmed death-ligand 1 (PD-L1)-targeting aptamer modified indocyanine green (ICG)-liposome (Apt-ICG@Lip) is successfully constructed via the MMD. ICG and the PD-L1-targeting aptamer are used as model drug and targeting moiety, respectively. The Apt-ICG@Lip has high encapsulation efficiency (89.9 ± 1.4%) and small mean diameter (129.16 ± 5.48nm). In vivo studies (PD-L1-expressing tumor models) show that Apt-ICG@Lip can realize PD-L1 targeted photoacoustic imaging, fluorescence imaging, and photothermal therapy. To verify the versatility of this approach, various targeted liposomes with different functions are further prepared and investigated. These experimental results demonstrate that this method is concise, efficient, and scalable to prepare multifunctional targeted liposomal nanoplatforms for molecular imaging and disease theranostics.

Principle and application of bubble-based oscillation for fast mixing on microfluidic chip

Mixing in microfluidic devices presents a challenge because of the laminar flow in microchannels. Here, we present an oscillatory-flow-based microfluidic mixer (OFBMM) in which fluids are subjected to a back-and-forth motion by utilizing a periodically changed pressure and an on-chip gas bubble. We developed a low-cost Arduino-based pneumatic system to apply pressure and an OpenCV-based image-processing algorithm to quantitatively analyze the mixing effect. We found that the oscillatory motion of fluids is similar to the charging and discharging process of an RC circuit used in electronics. We investigated the mixing effect by varying the oscillation frequencies, initial bubble volumes, and applied pressures. The results indicated that the increase in both the applied pressure and the initial volume of the gas bubble could promote fluid mixing. A large-scale serial dilution microfluidic chip based on OFBMM was also developed to demonstrate its biochemical potential. We believe that OFBMM will provide a new choice for mixing two or more solutions in a valves-integrated microfluidic system.

The dimensions of an ensemble of collapsed disordered protein molecules under folding conditions

In order to detect the earliest formed intramolecular contacts in the refolding ensembles by detection of the intramolecular distances, we must first determine the dimensions of the transient collapsed ensemble. Does an ensemble of disordered molecules of foldable globular protein under folding conditions follow Flory's theory of collapsed polymers? Using E. coli Adenylate kinase (AK) as a model protein and microfluidic mixing device combined with time resolved FRET measurements (“the double kinetics” method) we tested the hypothesis that at the initiation of refolding, the dependence of the mean of the segmental end-to-end distance on the segment length, Δn, is weak (Δn>∼30).We measured the transient distributions of segmental end to end distances of seven segments of the AK molecule, with Δn from 45 to 196 residues at 50 μs after initiation of mixing.

Computational and Experimental Model to Study Immunobead-Based Assays in Microfluidic Mixing Platforms.

In immunobead-based assays, micro/nanobeads are functionalized with antibodies to capture the target analytes, which can significantly improve the assay's performance. The immunobead-based assays have been recently combined with microfluidic mixing devices and customized for a variety of applications. However, device design and process optimization to achieve the best performance remain a substantial technological challenge. Here, we introduce a computational model that enables the rational design and optimization of the immunobead-based assay in a microfluidic mixing channel. We use numerical methods to examine the effect of the flow rates, channel geometry, bead's trajectory, and the analyte and reagent characteristics on the efficiency of analyte capture on the surface of microbeads. This model accounts for different bead movements inside the microchannel, with the goal of simulating an actual active binding environment. The model is further validated experimentally where different microfluidic channels are tested to capture the target analytes. Our experimental results are shown to meet theoretical predictions. While the model is demonstrated here for the analysis of IgG capture in simple and herringbone-structured microchannels, it can be readily adapted to a broad range of target molecules and different device designs.

3D Printing of Transparent Silicone Elastomers

AbstractIn this paper, inks for transparent elastomers that are formulated by matching the refractive index of silica and polysiloxanes are described. The transparent inks transmit up to ≈90% of 700 nm light through 1 cm and remain transparent when solidified. The inks and solidified materials exhibit a thermochromic effect. This thermochromic effect can be controlled by the refractive index mismatch. Transparency may increase or decrease as temperature increases, depending on the refractive index mismatch of the base polysiloxane and silica. It is found that the rheological properties of the ink depend on the distribution of silica particles, which is dictated by silica functionality, weight content, and processing. Siloxane precursors that vary in chemical functionality are introduced to tailor the mechanical properties of the printed elastomers, which obtain stretchability >65% along with a tensile modulus of 1.9 MPa. After optimizing siloxane chemistry and ink processing, the authors are able to print transparent elastomers. Potential applications are demonstrated for printed structures by printing encapsulation structures for light‐emitting diodes, semitransparent dye‐filled structures, a microfluidic mixing device, and a multimaterial structure that exhibits temperature‐dependent camouflage.

Hydrogels Containing Gradients in Vascular Density Reveal Dose-Dependent Role of Angiocrine Cues on Stem Cell Behavior.

Biomaterials that replicate patterns of microenvironmental signals from the stem cell niche offer the potential to refine platforms to regulate stem cell behavior. While significant emphasis has been placed on understanding the effects of biophysical and biochemical cues on stem cell fate, vascular-derived or angiocrine cues offer an important alternative signaling axis for biomaterial-based stem cell platforms. Elucidating dose-dependent relationships between angiocrine cues and stem cell fate are largely intractable in animal models and 2D cell cultures. In this study, microfluidic mixing devices are leveraged to generate 3D hydrogels containing lateral gradients in vascular density alongside murine hematopoietic stem cells (HSCs). Regional differences in vascular density can be generated via embossed gradients in cell, matrix, or growth factor density. HSCs co-cultured alongside vascular gradients reveal spatial patterns of HSC phenotype in response to angiocrine signals. Notably, decreased Akt signaling in high vessel density regions led to increased expansion of lineage-positive hematopoietic cells. This approach offers a combinatorial tool to rapidly screen a continuum of microenvironments with varying vascular, biophysical, and biochemical cues to reveal the influence of local angiocrine signals on HSC fate.

Cocaine Detection by a Laser-Induced Immunofluorometric Biosensor

The trafficking of illegal drugs by criminal networks at borders, harbors, or airports is an increasing issue for public health as these routes ensure the main supply of illegal drugs. The prevention of drug smuggling, including the installation of scanners and other analytical devices to detect small traces of drugs within a reasonable time frame, remains a challenge. The presented immunosensor is based on a monolithic affinity column with a large excess of immobilized hapten, which traps fluorescently labeled antibodies as long as the analyte cocaine is absent. In the presence of the drug, some binding sites of the antibody will be blocked, which leads to an immediate breakthrough of the labeled protein, detectable by highly sensitive laser-induced fluorescence with the help of a Peltier-cooled complementary metal-oxide-semiconductor (CMOS) camera. Liquid handling is performed with high-precision syringe pumps and microfluidic chip-based mixing devices and flow cells. The biosensor achieved limits of detection of 7 ppt (23 pM) of cocaine with a response time of 90 s and a total assay time below 3 min. With surface wipe sampling, the biosensor was able to detect 300 pg of cocaine. This immunosensor belongs to the most sensitive and fastest detectors for cocaine and offers near-continuous analyte measurement.

CFD analysis and RSM optimization of obstacle layout in Tesla micromixer

Abstract As a kind of fast and efficient mixing equipment, micromixer has been applied to chemical reaction detection. Its application can not only save experimental samples but also reduce the experimental time. In micromixers, Tesla structure is widely used due to its simple structure and special flow mechanism. In this paper, CFD and response surface method are used to analyze and verify the flow field of the configuration of adding diamond obstacles in the Tesla mixer. The results show that the order of layout parameter weight from large to small is obstacle size > vertical offset > horizontal offset. And the Desirability was 0.806, the optimal diamond obstacle size is 46.35 μm and the optimal lateral offset is 18.78 μm. In addition, a constant value OF 20 μm is predicted as the optimal vertical offset of the micromixer. Compared with the Tesla-type micromixer without obstacles, the diamond-shaped barrier Tesla-type micromixer designed in this paper has higher mixing rate and lower pressure drop under the same conditions, which can be applied to chemical reactors, and can also help to improve the accuracy of chemical reaction. It can be demonstrated that the presented optimal design method of obstacles layout in Tesla mixer is a simple and effective technology to improve the liquid mixing in microfluidic devices, and it has a broad application prospect in chemical engineering.

Application of Polyimide‐based Microfluidic Devices on Acid‐catalyzed Hydrolysis of Dimethoxypropane

AbstractMicrofluidic devices intensify transport phenomena and can improve chemical processes. New manufacturing processes and materials are perpetually developed due to constantly growing interest in process intensification. In this contribution, the authors present the design and application of polyimide‐foil‐based microfluidic mixing devices manufactured by reactive ion etching. As appropriate model reaction system, acid‐catalyzed 2,2‐dimethoxypropane (DMP) hydrolysis was chosen and investigated in three different mixing structure with varying flow rate. Energy dissipation rates were calculated to estimate mixing performances. The results show good mixing quality for Reynolds numbers between 10 and 100 and similar mixing times scales for all investigated microstructured mixers.

Low Reynolds number turbulent flows over elastic walls

We study the laminar and turbulent channel flow over a viscous hyper-elastic wall and show that it is possible to sustain an unsteady chaotic turbulent-like flow at any Reynolds number by properly choosing the wall elastic modulus. We propose a physical explanation for this effect by evaluating the shear stress and the turbulent kinetic energy budget in the fluid and elastic layer. We vary the bulk Reynolds number from 2800 to 10 and identify two distinct mechanisms for turbulence production. At moderate and high Reynolds numbers, turbulent fluctuations activate the wall oscillations, which, in turn, amplify the turbulent Reynolds stresses in the fluid. At a very low Reynolds number, the only production term is due to the energy input from the elastic wall, which increases with the wall elasticity. This mechanism may be exploited to passively enhance mixing in microfluidic devices.

An experimental investigation of oil-water flow in a serpentine channel

The co-current oil-water flow in a horizontal serpentine channel is studied experimentally by high-speed imaging. Due to the channel geometry, the flow exhibits curved streamlines, which can induce secondary flows and alter the flow pattern transition boundaries in comparison with those observed in straight channels. This can have important applications in the development of microfluidic mixing devices. The serpentine channel was cut out in a black polypropylene sheet sandwiched between two transparent polypropylene sheets and bonded by selective laser welding. Different flow patterns were generated by changing independently the superficial velocities of the two fluids using a dual-drive syringe pump. Results enable the construction of a flow pattern map, which shows significant differences with the equivalent map obtained for straight microchannels.

Fabrication of microwell plates and microfluidic devices in polyester films using a cutting printer

This study reports, for the first time, the possibility to manufacture analytical devices on polyester substrates using a cutting printer. The protocol involves the design of a layout in a graphical software, the cut into polyester films and the lamination against one or multiple polyester films coated with a thermosensitive layer. The feasibility of the proposed approach was demonstrated through the fabrication of 96-microwell plates, 3D microfluidic mixing and distance-based microfluidic devices. The printer has enabled cutting microchannels wider than 300 μm on polyester films and a thickness of 250 μm. Urea and glucose assays were performed on microwell plates aiming for their quantification in artificial urine and serum samples. The presented results revealed good agreement with the expected values. The complexation reaction between Fe2+ and o-phenanthroline was selected as model to investigate the feasibility of the 3D mixing device. Absorbance measurements were recorded for the reaction product performed in both on and off-chip modes. Considering the achieved data, the on-chip mixing exhibited similar behavior when compared to off-chip reaction, thus demonstrating to be efficient to perform mixtures due to the turbulence generated inside three-dimensional channels. Lastly, a distance-based device was designed to detect H2O2 based on the displacement of a dye plug promoted by the oxygen generation using a copper-modified paper sheet. The distance-based peroxymeter revealed a linear behavior in the concentration range between 1 and 5% (v/v) and a LOD equal to 0.5% (65.2 mM). Based on the results herein reported, the proposed method represents a simple and alternative protocol to produce microdevices, using affordable and inexpensive raw materials, within 10 min, and at a cost lower than US$ 0.10 per unit.

Torsional artificial muscles

Torsional actuators are of potential application in areas that include smart textiles, exoskeletons, microfluidic mixing, microsensors, photonic displays, and energy-harvesting devices.

Chaotic advection and mixing by a pair of microrotors in a circular domain.

In this work we study chaotic mixing induced by point microrotors in a bounded two-dimensional Stokes flow. The dynamics of the pair of rotors, modeled as rotlets, are non-Hamiltonian in the bounded domain and produce chaotic advection of fluid tracers in subsets of the domain. A complete parametric investigation of the fluid mixing as a function of the initial locations of the rotlets is performed based on pseudophase portraits. The mixing of fluid tracers as a function of relative positions of microrotors is studied using finite-time entropy and locational entropy. The finite-time locational entropy is used to identify regions of the fluid that produce good versus poor mixing, and this is visualized by the stretching and folding of blobs of tracer particles. Unlike the case of the classic blinking vortex dynamics, the velocity field of the flow modeled using rotlets inside a circular boundary is smooth in time and satisfies the no-slip boundary condition. This makes the considered model a more realistic case for studies of mixing in microfluidic devices using magnetic-actuated microspheres.