Microfluidic Applications in Drug Development: Fabrication of Drug Carriers and Drug Toxicity Screening.

Microfluidic technology has been highly useful in nanovolume sample preparation, separation, synthesis, purification, detection and assay, which are advantageous in drug development. This review highlights the recent developments and trends in microfluidic applications in two areas of drug development. First, we focus on how microfluidics has been developed as a facile tool for the fabrication of drug carriers including microparticles and nanoparticles. Second, we discuss how microfluidic chips could be used as an independent platform or integrated with other technologies in drug toxicity screening. Challenges and future perspectives of microfluidic applications in drug development have also been provided considering the present technological limitations.

Nonspecular Reflection of Droplets.

The bouncing of droplets on super-repellent surfaces normally resembles specular reflection that obeys the law of reflection. Here, the nonspecular reflection of droplet impingement onto solid surfaces with a dimple for energy-efficient, omnidirectional droplet transport is reported. With the dimple of the radius being comparable to that of the droplet, all the symmetries in the law of reflection can be broken down so that the droplet is endowed with a translational velocity finely tunable in both its direction and magnitude simply by varying the radii of the droplet and the dimple, the impinging position, and droplet Weber number. Tailoring the initial and translational velocity of impinging droplets would steer their reflected trajectories at will, thus enabling versatile droplet manipulation including trapping, shedding, antigravity transport, targeted positioning, and on-demand coalescence of droplets.

Microfluidics-Based Systems in Diagnosis of Alzheimer's Disease and Biomimetic Modeling.

Early detection and accurate diagnosis of Alzheimer's disease (AD) is essential for patient care and disease treatment. Microfluidic technology is emerging as an economical and versatile platform in disease detection and diagnosis. It can be conveniently integrated with nanotechnology and/or biological models for biomedical functional and pre-clinical treatment study. These strengths make it advantageous in disease biomarker detection and functional analysis against a wide range of biological backgrounds. This review highlights the recent developments and trends of microfluidic applications in AD research. The first part looks at the principles and methods for AD diagnostic biomarker detection and profiling. The second part discusses how microfluidic chips, especially organ-on-a-chip platforms, could be used as an independent approach and/or integrated with other technologies in AD biomimetic functional analysis.

Engineering a Bi-Conical Microchip as Vascular Stenosis Model.

Vascular stenosis is always associated with hemodynamic changes, especially shear stress alterations. Herein, bi-conical shaped microvessels were developed through flexibly and precisely controlled templated methods for hydrogel blood-vessel-like microchip. The blood-vessel-like microvessels demonstrated tunable dimensions, perfusable ability, and good cytocompatibility. The microchips showed blood-vessel-like lumens through fine embeddedness of human umbilical vein endothelial cells (HUVECs) on the interior surface of hydrogel microchannels, which closely reproduced the morphology and functions of human blood vessels. In the gradual narrowing region of bi-conical shape, fluid flow generated wall shear stress, which caused cell morphology variations. Wall shear rates at the gradual narrowing region were simulated by FLUENT software. The results showed that our microchannels qualified for performance as a vascular stenosis-like model in evaluating blood hydrodynamics. In general, our blood-vessel-on-a-chip could offer potential applications in the prevention, diagnosis, and therapy of arterial thrombosis.

Microfluidics and numerical simulation as methods for standardization of zebrafish sperm cell activation.

Sperm cell activation plays a critical role in a range of biological and engineering processes, from fertilization to cryopreservation protocol evaluation. Across a range of species, ionic and osmotic effects have been discovered that lead to activation. Sperm cells of zebrafish (Danio rerio) initiate motility in a hypoosmotic environment. In this study, we employ a microfluidic mixer for the purpose of rapidly diluting the extracellular medium to initiate the onset of cell motility. The use of a microchannel offers a rapid and reproducible mixing profile throughout the device. This greatly reduces variability from trial to trial relative to the current methods of analysis. Coupling these experiments with numerical simulations, we were able to investigate the dynamics of intracellular osmolality as each cell moves along its path through the micromixer. Our results suggest that intracellular osmolality, and hence intracellular ion concentration, only slightly decreases, contrary to the common thought that larger changes in these parameters are required for activation. Utilizing this framework, microfluidics for controlled extracellular environments and associated numerical modeling, has practical applicability in standardizing high-throughput aquatic sperm activation, and more fundamentally, investigations of the intracellular environment leading to motility.

Control of the breakup process of viscous droplets by an external electric field inside a microfluidic device.

Droplet-based microfluidic devices have received extensive attention in the fields of chemical synthesis, biochemical analysis, lab-on-chip devices, etc. Conventional passive microfluidic hydrodynamic flow-focusing devices (HFFDs) control the droplet breakup process by manipulating the flow ratios of the continuous phase to the dispersed phase. They confront difficulties in controlling droplet sizes in the dripping regime especially when the dispersed phase has a large viscosity. Previous studies have reported that an external electric field can be utilized as an additional tool to control the droplet breakup process in microfluidic devices. In this computational fluid dynamics (CFD) study, we have investigated the effect of an external static electric field on the droplet breakup process using the conservative level-set method coupled with the electrostatic model. The numerical simulations have demonstrated that the interaction of the electric field and the electric charges on the fluid interface induces the electric force, which plays a significant role in controlling the droplet formation dynamics. If the microfluidic system is applied with the electric field of varying strength, the droplet breakup process experiences three distinct regimes. In Regime 1, where low electric voltages are applied, the droplet size decreases almost linearly with the increase of voltage. Then the droplet size increases with the applied voltages in Regime 2, where the electric field has moderate strength. In Regime 3, where very large voltages are applied, the droplet size decreases with the applied voltage again. These interesting variations in the droplet breakup processes are explained by using transient pressure profiles in the dispersed phase and the continuous phase. The droplet breakup processes regulated by an external electric field that are revealed in this study can provide useful guidance on the design and operations of such droplet-based systems.

Computational investigations of the mixing performance inside liquid slugs generated by a microfluidic T-junction.

Droplet-based microfluidics has gained extensive research interest as it overcomes several challenges confronted by conventional single-phase microfluidics. The mixing performance inside droplets/slugs is critical in many applications such as advanced material syntheses and in situ kinetic measurements. In order to understand the effects of operating conditions on the mixing performance inside liquid slugs generated by a microfluidic T-junction, we have adopted the volume of fluid method coupled with the species transport model to study and quantify the mixing efficiencies inside slugs. Our simulation results demonstrate that an efficient mixing process is achieved by the intimate collaboration of the twirling effect and the recirculating flow. Only if the reagents are distributed transversely by the twirling effect, the recirculating flow can bring in convection mechanism thus facilitating mixing. By comparing the mixing performance inside slugs at various operating conditions, we find that slug size plays the key role in influencing the mixing performance as it determines the amount of fluid to be distributed by the twirling effect. For the cases where short slugs are generated, the mixing process is governed by the fast convection mechanism because the twirling effect can distribute the fluid to the flow path of the recirculating flow effectively. For cases with long slugs, the mixing process is dominated by the slow diffusion mechanism since the twirling effect is insufficient to distribute the large amount of fluid. In addition, our results show that increasing the operating velocity has limited effects on improving the mixing performance. This study provides the insight of the mixing process and may benefit the design and operations of droplet-based microfluidics.

Developing a millifluidic platform for the synthesis of ultrasmall nanoclusters: ultrasmall copper nanoclusters as a case study.

The future of lab-on-a-chip devices for the synthesis of nanomaterials hinges on the successful development of high-throughput methods with better control over their size. While significant effort in this direction mainly focuses on developing "difficult to fabricate" complex microfluidic reactors, scant attention has been paid to the "easy to fabricate" and simple millifluidic systems that could provide the required control as well as high throughput. By utilizing numerical simulation of fluids within the millifluidic space at different flow rates, the results presented here show velocity profiles and residence time distributions similar to the case of microfluidics. By significantly reducing the residence time and residence time distribution, a continuous flow synthesis of ultrasmall copper nanoclusters (UCNCs) with exceptional colloidal stability is achieved. In-situ synchrotron-radiation-based X-ray absorption spectroscopy (XAS) reveal that the as-prepared clusters are about 1 nm, which is further supported by transmission electron microscopy and UV-vis spectroscopy studies. The clusters reported here are the smallest ever produced using a lab-on-a-chip platform. When supported on silica, they are found to efficiently catalyze C-H oxidation reactions, hitherto unknown to be catalyzed by Cu. This work suggests that a millifluidic platform can be an inexpensive, versatile, easy-to-use, and powerful tool for nanoparticle synthesis in general, and more specifically for ultrasmall nanoclusters (UNCs).

Size evolution of gold nanoparticles in a millifluidic reactor.

The size evolution of gold nanoparticles in a millifluidic reactor is investigated using spatially resolved transmission electron microscopy (TEM). The experimental data is supported by numerical simulations, carried out to study the residence-time distribution (RTD) of tracers that have the same properties as Au ions. Size and size distribution of the particles within the channels are influenced by the mixing zones as well as the RTD. However, the Au nanoparticles obtained show a broader size distribution even at the shortest investigated residence time of 3.53 s, indicating that in addition to surface growth reaction kinetics also plays an important role. The comparison of time resolved particle growth within the millifluidic channel with flask-based reactions reveals that the particle size can be controlled better within millifluidic channels. Overall, the results indicate potential opportunities to utilize easy to fabricate millifluidic reactors for the synthesis of nanoparticles, as well as as for carrying out time resolved kinetic studies.

A Planar Microfluidic Mixer Based on Logarithmic Spirals.

A passive, planar micromixer design based on logarithmic spirals is presented. The device was fabricated using polydimethylsiloxane soft photolithography techniques, and mixing performance was characterized via numerical simulation and fluorescent microscopy. Mixing efficiency initially declined as Reynolds number increased, and this trend continued until a Reynolds number of 15 where a minimum was reached at 53%. Mixing efficiency then began to increase reaching a maximum mixing efficiency of 86% at Re = 67. Three-dimensional simulations of fluid mixing in this design were compared to other planar geometries such as the Archimedes spiral and Meandering-S mixers. The implementation of logarithmic curvature offers several unique advantages that enhance mixing, namely a variable cross-sectional area and a logarithmically varying radius of curvature that creates 3-D Dean vortices. These flow phenomena were observed in simulations with multilayered fluid folding and validated with confocal microscopy. This design provides improved mixing performance over a broader range of Reynolds numbers than other reported planar mixers, all while avoiding external force fields, more complicated fabrication processes, and the introduction of flow obstructions or cavities that may unintentionally affect sensitive or particulate-containing samples. Due to the planar design requiring only single-step lithographic features, this compact geometry could be easily implemented into existing micro-total analysis systems requiring effective rapid mixing.