Fast Mixing Research Articles

Design of a microfluidic mixer channel: First steps into creating a fluorescent dye-based biosensor for mAb aggregate detection.

A major challenge in the transition to continuous biomanufacturing is the lack of process analytical technology (PAT) tools which are able to collect real-time information on the process and elicit a response to facilitate control. One of the critical quality attributes (CQAs) of interest during monoclonal antibodies production is aggregate formation. The development of a real-time PAT tool to monitor aggregate formation is then crucial to have immediate feedback and process control. Miniaturized sensors placed after each unit operation can be a powerful solution to speed up an analytical measurement due to their characteristic short reaction time. In this work, a micromixer structure capable of mixing two streams is presented, to be employed in the detection of mAb aggregates using fluorescent dyes. Computational fluid dynamics (CFD) simulations were used to compare the mixing performance of a series of the proposed designs. A final design of a zigzag microchannel with 45° angle was reached and this structure was subsequently fabricated and experimentally validated with colour dyes and, later, with a FITC-IgG molecule. The designed zigzag micromixer presents a mixing index of around 90%, obtained in less than 30 seconds. Therefore, a micromixer channel capable of a fast and efficient mixing is hereby demonstrated, to be used as a real-time PAT tool for a fluorescence based detection of protein aggregation.

Numerical Analysis of Mixing Performance in an Electroosmotic Micromixer with Cosine Channel Walls.

Micromixers have significant potential in the field of chemical synthesis and biological pharmaceuticals, etc. In this study, the design and numerical simulations of a passive micromixer and a novel active electroosmotic micromixer by assembling electrode pairs were both presented with a cosine channel wall. The finite element method (FEM) coupled with Multiphysics modeling was used. To propose an efficient micromixer structure, firstly, different geometrical parameters such as amplitude-to-wavelength ratio (a/c) and mixing units (N) in the steady state without an electric field were investigated. This paper aims to seek a high-quality mixing solution. Therefore, based on the optimization of the above parameters of the passive micromixer, a new type of electroosmotic micromixer with an AC electric field was proposed. The results show that the vortices generated by electroosmosis can effectively induce fluid mixing. The effects of key parameters such as the Reynolds number, the number of electrode pairs, phase shift, voltage, and electrode frequency on the mixing performance were specifically discussed through numerical analysis. The mixing efficiency of the electroosmotic micromixer is quantitatively analyzed, which can be achieved at 96%. The proposed micromixer has a simple structure that can obtain a fast response and high mixing index.

Taming Highly Unstable Radical Anions and 1,4-Organodilithiums by Flow Microreactors: Controlled Reductive Dimerization of Styrenes.

The reduction of styrenes with lithium arenide in a flow microreactor leads to the instantaneous generation of highly unstable radical anions that subsequently dimerize to yield the corresponding 1,4-organodilithiums. A flow reactor with fast mixing is essential for this reductive dimerization as the efficiency and selectivity are low under batch conditions. A series of styrenes undergo dimerization, and the resulting 1,4-organodilithiums are trapped with various electrophiles. Trapping with divalent electrophiles affords precursors for useful yet less accessible cyclic structures, for example, siloles from dichlorosilanes. Thus, we highlight the power of single-electron reduction of unsaturated compounds in flow microreactors for organic synthesis.

Generation of Dynamic Concentration Profile Using A Microfluidic Device Integrating Pneumatic Microvalves.

Generating and maintaining the concentration dilutions of diffusible molecules in microchannels is critical for high-throughput chemical and biological analysis. Conventional serial network microfluidic technologies can generate high orders of arbitrary concentrations by a predefined microchannel network. However, a previous design requires a large occupancy area and is unable to dynamically generate different profiles in the same chip, limiting its applications. This study developed a microfluidic device enabling dynamic variations of both the concentration in the same channel and the concentration distribution in multiple channels by adjusting the flow resistance using programmable pneumatic microvalves. The key component (the pneumatic microvalve) allowed dynamic adjustment of the concentration profile but occupied a tiny space. Additionally, a Matlab program was developed to calculate the flow rates and flow resistance of various sections of the device, which provided theoretical guidance for dimension design. In silico investigations were conducted to evaluate the microvalve deformation with widths from 100 to 300 µm and membrane thicknesses of 20 and 30 µm under the activation pressures between 0 and 2000 mbar. The flow resistance of the deformed valve was studied both numerically and experimentally and an empirical model for valve flow resistance with the form of was proposed. Afterward, the fluid flow in the valve region was characterized using Micro PIV to further demonstrate the adjustment mechanism of the flow resistance. Then, the herringbone structures were employed for fast mixing to allow both quick variation of concentration and minor space usage of the channel network. Finally, an empirical formula-supported computational program was developed to provide the activation pressures required for the specific concentration profile. Both linear ( = −0.2k + 1) and nonlinear = concentration distribution in four channels were varied using the same device by adjusting microvalves. The device demonstrated the capability to control the concentration profile dynamically in a small space, offering superior application potentials in analytical chemistry, drug screening, and cell biology research.

Generation of curcumin-loaded albumin nanoparticles by using off-the-shelf microfluidics driven by gravity

The generation albumin-based nanocarriers by precipitation from solution has great interest in the formulation of advanced nutritional products. Microfluidic techniques enable the implementation of low energy and continuum processes, with fast mass transfer and homogeneous mixing at the microscale. Here we describe the microfluidic generation of curcumin-loaded alpha lactalbumin nanoparticles in a simple and inexpensive way, by using off-the-shelf devices designed to produce solvent-shifting nanoprecipitation in core-sheath flows driven by gravity, which has not been reported before. Nanoparticles were characterized by dynamic light scattering, electron microscopy, and infrared spectroscopy. The microfluidic operating conditions were defined by theory and experiments, and the critical parameters controlling the nanoparticles diameter were identified. The prepared nanoparticles resulted practically monodisperse, the curcumin entrapment efficiency was about 40 %, and almost 70 % of the bioactive was gradually delivered in release experiments. The proposed methodology is a promising route to scale up the microfluidic elaboration of nanoparticles for the entrapment of active ingredients.

Flash nanoprecipitation enables regulated formulation of soybean protein isolate nanoparticles

Soy protein isolate (SPI) is perspective building block for fabrication of cargo-loaded nanoparticles (NPs) based on different formulation strategies. Particularly, precipitation demonstrates an easy and widespread fabrication approach, whereas most of the reported precipitation methods rely on spontaneous aggregation of SPI which typically suffers from the poor control on particle size and limited drug loading capacity. Herein, we reported a flash nanoprecipitation (FNP) method for regulated formulation of lutein-loaded SPI NPs. Specifically, solvent streams containing SPI and lutein are mixed with anti-solvent streams in a multi-inlet vortex mixer. Different control factors including lutein/SPI mass ratio and flow rate are investigated, and the obtained lutein-loaded SPI NPs show regulated particle size (80–122 nm), narrow size distribution (PDI ∼ 0.2), enhanced drug loading content (20%), high stability and improved bioaccessibility of lutein up to 94%. All these desirable properties are related to the kinetically trapped state of NPs due to the rapid mixing of FNP, which shall be hardly achieved with conventional precipitation approaches. Along with other intrinsic features such as fast mixing and continuous production, FNP possesses distinctive advantages for efficient fabrication of drug-loaded SPI NPs with regulated size and properties which are favorable for diverse delivery applications.

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.

Finite-sample analysis of nonlinear stochastic approximation with applications in reinforcement learning

Motivated by applications in reinforcement learning (RL), we study a nonlinear stochastic approximation (SA) algorithm under Markovian noise, and establish its finite-sample convergence bounds under various stepsizes. Specifically, we show that when using constant stepsize (i.e., αk≡α), the algorithm achieves exponential fast convergence to a neighborhood (with radius O(αlog(1/α))) around the desired limit point. When using diminishing stepsizes with appropriate decay rate, the algorithm converges with rate O(log(k)/k). Our proof is based on Lyapunov drift arguments, and to handle the Markovian noise, we exploit the fast mixing of the underlying Markov chain. To demonstrate the generality of our theoretical results on Markovian SA, we use it to derive the finite-sample bounds of the popular Q-learning algorithm with linear function approximation, under a condition on the behavior policy. Importantly, we do not need to make the assumption that the samples are i.i.d., and do not require an artificial projection step in the algorithm. Numerical simulations corroborate our theoretical results.

Rapid mixing of metal atoms ejected in water by pulsed laser ablation of the boundary between jointed Au and Ag target metal plates

We prepared metal alloy nanoparticles by pulsed laser ablation of the boundary between jointed target metal plates of Au and Ag in purified water. When the spot size radius of the focused laser on the target was 2.5 mm, separate Au nanoparticles and Ag nanoparticles were mainly observed with slight alloying. In contrast, when the spot size radius was 0.25 mm, the ejected Au and Ag atoms were found to be more mixed, efficiently forming Au and Ag alloy nanoparticles. The mixing distance of Au and Ag atoms was estimated to be ∼0.5 mm. The dynamics of the plasma plume and the cavitation and their interaction with Au and Ag atoms were quite complex. Hence, we assumed that during plasma plume formation and cavitation formation, Au and Ag atoms diffuse in the plasma plume and cavitation as a uniform medium with a maximum temperature and minimum viscosity. It was suggested that the fast mixing of Au and Ag atoms occurred inside the plasma plume, taking the high temperature, several thousand K of the plasma plume into account. Moreover, the mixing was promoted by the overlapping of plasma plumes, which were generated on Au and Ag plates separately, owing to explosive plasma motions. Then, the alloy nanoparticles were formed in the cavitation bubble where Au and Ag atoms were spatially distributed by plasma plumes. The mixing of the atoms in the cavitation bubble was not likely based on the mixing distance.

Fast mixing of a randomized shift-register Markov chain

AbstractWe present a Markov chain on the n-dimensional hypercube $\{0,1\}^n$ which satisfies $t_{{\rm mix}}^{(n)}(\varepsilon) = n[1 + o(1)]$ . This Markov chain alternates between random and deterministic moves, and we prove that the chain has a cutoff with a window of size at most $O(n^{0.5+\delta})$ , where $\delta>0$ . The deterministic moves correspond to a linear shift register.

Incorporative mixing in microreactors: Influence on reactions and importance of inlet designation

Fast mixing is an essential feature of a microreactor. This study reveals the critical role of microscopic fluid incorporation on fast chemical reactions in a microreactor. The vortices in a microreactor produce tiny fluid segments, and the incorporation of these segments into the surrounding fluid triggers chemical reactions. The selectivity of chemical reactions highly depends on the type of the fluid segment incorporated into the fluid. Microreactor operations that consider incorporative mixing can achieve better reaction results, even with slow mixing. For example, a tee mixer showed better reaction performance with the vertical confluence configuration than with the symmetric configuration, although the symmetric 180-degree confluence provides more intense mixing. Computational fluid dynamics (CFD) simulations showed that vertical confluence enabled the division and incorporation of a stream from the horizontal inlet into another stream. The appropriate inlet designation is vital when two inlets of a microreactor differ in dimensions, directions, or positions because the different inlets provide different mixing profiles. The two inlets of the microreactor were distinguishable even though the fabrication error was insignificant. For instance, feed orientations changed the side-product yield seven times in a 3D-printed microreactor. Moreover, the impact of incorporative mixing on particle synthesis was confirmed. Switching the two inlets significantly influenced the morphology and size of the synthesized particles by changing the initial nucleation environment. In conclusion, considering incorporative mixing and optimal inlet orientation will enhance the performance and flexibility of microreaction technology.

The importance of transport phenomena on the flow synthesis of monodispersed sharp blue-emitting perovskite CsPbBr3 nanoplatelets

This work demonstrates the importance of transport phenomena on the synthesis of halide perovskite nanoplatelets. Illustrated herein for CsPbBr3, we demonstrate the need for fast and homogeneous mixing to achieve monodispered crystals, in this case with sharp blue emission. The modularity of our synthesis method, combining fluid dynamic simulations, bespoke 3D flow reactors and on-line measurements (UV–vis absorbance and photoluminescence) reveals fundamental understanding about the growth of these perovskite nano-materials, which in turn leads to superlative size reducibility (2.2 ± 0.3 nm) and properties (sharp blue emission at 472 nm wavelength, and PLQY 24.5 ± 0.4 %). The counterpart conventional hot injection batch synthesis with the same precursors, conditions and reaction temperature yields a product with PL at 501 nm with large batch to batch variations. Understanding the dynamics of the synthesis in the very early stages (within the first 100–300 ms) shows that mixing of the precursors plays a key role not only during the nucleation step, as previously believed, but also during the growth stage. Such fluid properties can be easily predicted in purposefully designed 3D microreactors to provide a consistent and steady output capable of fulfilling the large demand of blue light emitters for a variety of applications.

Fluid mixing optimization with reinforcement learning

Fluid mixing is crucial in various industrial processes. In this study, focusing on the characteristics that reinforcement learning (RL) is suitable for global-in-time optimization, we propose utilizing RL for fluid mixing optimization of passive scalar fields. For the two-dimensional fluid mixing problem described by the advection–diffusion equations, a trained mixer realizes an exponentially fast mixing without any prior knowledge. The stretching and folding by the trained mixer around stagnation points are essential in the optimal mixing process. Furthermore, this study introduces a physically reasonable transfer learning method of the trained mixer: reusing a mixer trained at a certain Péclet number to the mixing problem at another Péclet number. Based on the optimization results of the laminar mixing, we discuss applications of the proposed method to industrial mixing problems, including turbulent mixing.

Molecular Dynamics-Assisted Design of High Temperature-Resistant Polyacrylamide/Poloxamer Interpenetrating Network Hydrogels.

Polyacrylamide has promising applications in a wide variety of fields. However, conventional polyacrylamide is prone to hydrolysis and thermal degradation under high temperature conditions, resulting in a decrease in solution viscosity with increasing temperature, which limits its practical effect. Herein, combining molecular dynamics and practical experiments, we explored a facile and fast mixing strategy to enhance the thermal stability of polyacrylamide by adding common poloxamers to form the interpenetrating network hydrogel. The blending model of three synthetic polyacrylamides (cationic, anionic, and nonionic) and poloxamers was first established, and then the interaction process between them was simulated by all-atom molecular dynamics. In the results, it was found that the hydrogen bonding between the amide groups on all polymers and the oxygen-containing groups (ether and hydroxyl groups) on poloxamers is very strong, which may be the key to improve the high temperature resistance of the hydrogel. Subsequent rheological tests also showed that poloxamers can indeed significantly improve the stability and viscosity of nonionic polyacrylamide containing only amide groups at high temperatures and can maintain a high viscosity of 3550 mPa·S at 80 °C. Transmission electron microscopy further showed that the nonionic polyacrylamide/poloxamer mixture further formed an interpenetrating network structure. In addition, the Fourier transform infrared test also proved the existence of strong hydrogen bonding between the two polymers. This work provides a useful idea for improving the properties of polyacrylamide, especially for the design of high temperature materials for physical blending.

Milliscale reactors for integration of continuous precipitation and filtration

AbstractBACKGROUNDThe development of integrated continuous biomanufacturing processes faces a significant challenge when the parameters for the design of the process cannot be accurately estimated from those of batch experiments. Process design is even more challenging if the outcome of one unit operation highly influences the performance of the subsequent one, such as in harvesting of a precipitate by filtration. In the case of protein precipitation, results from the batch and continuous experiements deviate and their scale‐down is limited. Microfluidics suffer from poor mixing characteristics. Thus, milliscale devices were developed to maintain mixing performance but at the expense of a slightly larger scale.RESULTSMilliscale devices were developed for the precipitation of antibodies in continuous tubular reactors to compare different dosage times in small scale. The reactors have multiple addition points for precipitant for the continuous, controlled and precise addition of the precipitating agent without valves. The designed devices have a narrow residence time distribution to achieve fast mixing and a small volume that reduces the time and cost for experiments tenfold. Milliscale devices were used to evaluate the most appropriate dosage time for protein precipitation, thus improving purity by a factor of 3 compared to single addition. The resulting filterability of precipitates in tangential flow filtration and depth filtration was improved.CONCLUSIONResults demonstrated that multiple additions were more beneficial than single addition because they help to reduce pressure and increase filter capacity. Such devices can be used to determine and adjust the precipitation methodology to optimize floc formation and improve solid–liquid separation while reducing development time and cost. © 2022 The Authors. Journal of Chemical Technology and Biotechnology published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry (SCI).

Fabrication of resveratrol-loaded zein nanoparticles based on flash nanoprecipitation

Resveratrol (Res) has drawn great interests due to its potential benefits on human health, while applications of Res in nutritional and pharmaceutical fields are limited due to its poor water solubility, low bioavailability and instability. Here in this work, an advanced anti-solvent precipitation strategy, flash nanoprecipitation (FNP), has been applied for controlled fabrication of Res-loaded nanoparticles (NPs). Specifically, solvent streams containing Res and zein (stabilizing polymers) blend with anti-solvent streams in a multi-inlet vortex mixer (MIVM), which enables fast mixing on the order of millisecond and creates kinetically trapped NPs. The efficient fabrication and effects of different control factors on the particle formation and properties have been fully explored by means of static and dynamic light scattering, TEM, fourier-transform infrared and fluorescence. The obtained NPs exhibit tunable sizes from 50 to 108 nm with narrow size distribution (PDI ∼ 0.1), enhanced drug loading content (30–57 %), improved stability and antioxidant capacity. These satisfied properties are assigned to the kinetic control of FNP, our study therefore develops a facile and alternative fabrication strategy for controlled preparation of Res-loaded NPs.

Mixing enhancement of supersonic flow induced by splitter plate cavity

Fast and efficient mixing of fuel and oxidizer in a RBCC combustor is crucial for the efficiency improvement of engine propulsion system. Whereas, the existence of compressibility effects of high-speed flow notably suppresses the mixing process. In present work, the strategy of splitter plate cavity is proposed to promote mixing. The influences of splitter plate cavity with different length to depth ratio (r) on mixing process are researched. Fine vortex structures are well captured and the newly found T-shaped structures and their evolution dynamics induced by the cavity instability are thoroughly analyzed. The results indicate that tremendous growth of the mixing layer in flow transition region is realized. For the dimensionless streamwise velocity distribution, the recognized appearance of multiple peaks at far flow field for splitter plate cavity with r=4 and 8 leads to great velocity gradient in local position, which can promote mixing process of upper and lower streams. The distributions of streamwise turbulence intensity, turbulent kinetic energy and transversely integrated turbulent kinetic energy suggest that vigorous dynamic behaviors of T-shaped structures can obviously increase local turbulence, especially for splitter plate cavity with r=8. The structure topology analysis results reveal that larger size of the evolutionary T-shaped structure and more intense rotation process of these structures can undoubtedly engulf more main stream into the mixing region to achieve mixing augmentation.

Biochemical Reaction Acceleration by Electrokinetic Mixing in a Microfluidic Chip.

In the past two decades, a large number of micromixers have been studied and reported to solve the low mass transfer in microchannels. However, there is still a lack of research on how much biochemical reaction efficiency or detection sensitivity can be improved by microfluidic rapid mixing. In this study, using our previously developed ultrafast microelectrokinetic turbulent (μEKT) mixing method, taking glucose oxidation reaction as the research object, we investigated the effect of increasing microfluidic mass transfer efficiency on the efficiency and sensitivity of biochemical reactions. The results showed that fast mixing could improve the enzymatic reaction efficiency by improving the mass transfer efficiency. Further detection of glucose in glucose solutions and blood samples showed that the fast mixing could significantly improve the sensitivity of detection. These results indicate that mixing enhancement can be a significant step of microfluidics-based applications such as POCT, liquid biopsy, food safety, and so on.

Measuring the velocity profile of spinning particles and its impact on Cr(VI) sequestration

The evolution and development of magnetic nanoparticles (MNPs) are of great interest to researchers owing to their novel properties and wide-ranging applications. Essentially, MNPs coupled with magnetic fields (MF) have been used in biomedical separation, catalysis, cell separation, magnetic target drug delivery, hyperthermia, nucleic acid separation and wastewater treatment. In that regard, this paper reports the investigation of the sorption phenomena of chromium six (Cr(VI)) to MNPs interaction spun under the influence of alternating MF utilizing this unique particle shadow velocimetry technique. Under an alternating MF, the velocity field of spinning particles was observed to increase with magnetic field intensification. The determined mean velocity field for the spinning particles in the Cr(VI) solution increases from 0.0075-0.0125 m/s at a MF range of 16.54-25.54 mT. The rotating MF was observed to improve the magnetic force and torque induced on the particles, with particle aggregates reorienting with the magnetic moment of the field. The variability observed at the liquid-particle interface led to a fast mixing, with chaotic flow behaviour in the channel wall induced by the magnetic force observed. The induced cluster particle rotation and broad magnetic velocity distributions also led to cluster particle collisions hence the enhanced sorption process.

Characteristics of enhanced mixing induced by plate jet actuation in supersonic flow

The fast and efficient mixing of fuel and oxidizers under supersonic conditions is of great importance for improving the performance of scramjet engines. The mixing process in the inner flow of a scramjet combustor is heavily inhibited by compressibility effects. In this paper, the novel strategy of plate jet actuation is proposed, and its effects on mixing augmentation are analyzed by employing numerical programs developed in-house. The fine vortex structures induced by the plate jet actuation are well captured, and the dynamic behaviors of newly observed T-shaped structures are analyzed in detail. It is found that in plate jet actuation flow, Kelvin–Helmholtz (K–H) vortices induced by K–H instability coexist with T-shaped structures induced by jet actuation instability. The interaction of adjacent T-shaped structures leads to the distortion and breakup of large-scale structures, which can obviously improve the interfaces of upper and lower streams. The distribution of the turbulence intensity along the streamwise direction suggests that with the introduction of plate jet actuation, more intense fluctuations occur in the flow. The growth process of mixing layer thickness indicates that with plate jet actuation, a sharp increase in mixing thickness can be achieved in the near flow field. The results of structural topology analysis show that upper plate jet actuation can produce structures with larger sizes, and the distortion and penetration process of these structures can entrain more upper and lower streams into the mixing region. It is suggested that the present proposed strategy is a good candidate for mixing enhancement with the application of scramjet combustors.