Microfluidic Generation of All‐Aqueous Double and Triple Emulsions

Higher order emulsions are used in a variety of different applications in biomedicine, biological studies, cosmetics, and the food industry. Conventional droplet generation platforms for making higher order emulsions use organic solvents as the continuous phase, which is not biocompatible and as a result, further washing steps are required to remove the toxic continuous phase. Recently, droplet generation based on aqueous two‐phase systems (ATPS) has emerged in the field of droplet microfluidics due to their intrinsic biocompatibility. Here, a platform to generate all‐aqueous double and triple emulsions by introducing pressure‐driven flows inside a microfluidic hybrid device is presented. This system uses a conventional microfluidic flow‐focusing geometry coupled with a coaxial microneedle and a glass capillary embedded in flow‐focusing junctions. The configuration of the hybrid device enables the focusing of two coaxial two‐phase streams, which helps to avoid commonly observed channel‐wetting problems. It is shown that this approach achieves the fabrication of higher‐order emulsions in a poly(dimethylsiloxane)‐based microfluidic device, and controls the structure of the all‐aqueous emulsions. This hybrid microfluidic approach allows for facile higher‐order biocompatible emulsion formation, and it is anticipated that this platform will find utility for generating biocompatible materials for various biotechnological applications.     

High Throughput‐Per‐Footprint Inertial Focusing

Matching the scale of microfluidic flow systems with that of microelectronic chips for realizing monolithically integrated systems still needs to be accomplished. However, this is appealing only if such re‐scaling does not compromise the fluidic throughput. This is related to the fact that the cost of microelectronic circuits primarily depends on the layout footprint, while the performance of many microfluidic systems, like flow cytometers, is measured by the throughput. The simple operation of inertial particle focusing makes it a promising technique for use in such integrated flow cytometer applications, however, microfluidic footprints demonstrated so far preclude monolithic integration. Here, the scaling limits of throughput‐per‐footprint (TPFP) in using inertial focusing are explored by studying the interplay between theory, the effect of channel Reynolds numbers up to 1500 on focusing, the entry length for the laminar flow to develop, and pressure resistance of the microchannels. Inertial particle focusing is demonstrated with a TPFP up to 0.3 L/(min cm²) in high aspect‐ratio rectangular microfluidic channels that are readily fabricated with a post‐CMOS integratable process, suggesting at least a 100‐fold improvement compared to previously demonstrated techniques. Not only can this be an enabling technology for realizing cost‐effective monolithically integrated flow cytometry devices, but the methodology represented here can also open perspectives for miniaturization of many biomedical microfluidic applications requiring monolithic integration with microelectronics without compromising the throughput.     

Conductive Polymer Hydrogel Microfibers from Multiflow Microfluidics

Conductive hydrogels are receiving increasing attention for their utility in electronic area applications requiring flexible conductors. Here, it is presented novel conductive hydrogel microfibers with alginate shells and poly (3, 4‐ethylenedioxythiophene): poly (4‐styrenesulfonate) (PEDOT: PSS) cores fabricated using a multiflow capillary microfluidic spinning approach. Based on multiflow microfluidics, alginate shells are formed immediately from the fast gelation reaction between sodium alginate (Na‐Alg) and sheath laminar calcium chloride flows, while PEDOT: PSS cores are solidified slowly in the hollow alginate hydrogel shell microreactors after their precursor solutions are injected in situ as the center fluids. The resultant PEDOT: PSS‐containing microfibers are with features of designed morphology and highly controllable package, because material compositions or the sizes of their shell hydrogels can be tailored by using different concentrations or flow rates of pregel solutions. Moreover, the practical values of these microfibers in stretch sensitivity and bending stability are explored based on various electrical characterizations of the compound materials. Thus, it is believed that these microfluidic spinning PEDOT: PSS conductive microfibers will find important utility in electronic applications requiring flexible electronic systems.     

Computer-controlled microcirculatory support system for endothelial cell culture and shearing

Endothelial cells (ECs) lining the inner lumen of blood vessels are continuously subjected to hemodynamic shear stress, which is known to modify EC morphology and biological activity. This paper describes a self-contained microcirculatory EC culture system that efficiently studies such effects of shear stress on EC alignment and elongation in vitro. The culture system is composed of elastomeric microfluidic cell shearing chambers interfaced with computer-controlled movement of piezoelectric pins on a refreshable Braille display. The flow rate is varied by design of channels that allow for movement of different volumes of fluid per variable-speed pump stroke. The integrated microfluidic valving and pumping system allowed primary EC seeding and differential shearing in multiple compartments to be performed on a single chip. The microfluidic flows caused ECs to align and elongate significantly in the direction of flow according to their exposed levels of shear stress. This microfluidic system overcomes the small flow rates and the inefficiencies of previously described microfluidic and macroscopic systems respectively to conveniently perform parallel studies of EC response to shear stress.     

Bio‐microfluidics: Biomaterials and Biomimetic Designs

Bio‐microfluidics applies biomaterials and biologically inspired structural designs (biomimetics) to microfluidic devices. Microfluidics, the techniques for constraining fluids on the micrometer and sub‐micrometer scale, offer applications ranging from lab‐on‐a‐chip to optofluidics. Despite this wealth of applications, the design of typical microfluidic devices imparts relatively simple, laminar behavior on fluids and is realized using materials and techniques from silicon planar fabrication. On the other hand, highly complex microfluidic behavior is commonplace in nature, where fluids with nonlinear rheology flow through chaotic vasculature composed from a range of biopolymers. In this Review, the current state of bio‐microfluidic materials, designs and applications are examined. Biopolymers enable bio‐microfluidic devices with versatile functionalization chemistries, flexibility in fabrication, and biocompatibility in vitro and in vivo. Polymeric materials such as alginate, collagen, chitosan, and silk are being explored as bulk and film materials for bio‐microfluidics. Hydrogels offer options for mechanically functional devices for microfluidic systems such as self‐regulating valves, microlens arrays and drug release systems, vital for integrated bio‐microfluidic devices. These devices including growth factor gradients to study cell responses, blood analysis, biomimetic capillary designs, and blood vessel tissue culture systems, as some recent examples of inroads in the field that should lead the way in a new generation of microfluidic devices for bio‐related needs and applications. Perhaps one of the most intriguing directions for the future will be fully implantable microfluidic devices that will also integrate with existing vasculature and slowly degrade to fully recapitulate native tissue structure and function, yet serve critical interim functions, such as tissue maintenance, drug release, mechanical support, and cell delivery.     

Electroosmotic flows in microchannels with finite inertial and pressure forces

Emerging microfluidic systems have spurred an interest in the study of electrokinetic flow phenomena in complex geometries and a variety of flow conditions. This paper presents an analysis of the effects of fluid inertia and pressure on the velocity and vorticity field of electroosmotic flows. In typical on-chip electrokinetics applications, the flow field can be separated into an inner flow region dominated by viscous and electrostatic forces and an outer flow region dominated by inertial and pressure forces. These two regions are separated by a slip velocity condition determined by the Helmholtz-Smoulochowski equation. The validity of this assumption is investigated by analyzing the velocity field in a pressure-driven, two-dimensional flow channel with an impulsively started electric field. The regime for which the inner/outer flow model is valid is described in terms of nondimensional parameters derived from this example problem. Next, the inertial forces, surface conditions, and pressure-gradient conditions for a full-field similarity between the electric and velocity fields in electroosmotic flows are discussed. A sufficient set of conditions for this similarity to hold in arbitrarily shaped, insulating wall microchannels is the following: uniform surface charge, low Reynolds number, low Reynolds and Strouhal number product, uniform fluid properties, and zero pressure differences between inlets and outlets. Last, simple relations describing the generation of vorticity in electroosmotic flow are derived using a wall-local, streamline coordinate system.     

Temperature Gradients Drive Bulk Flow Within Microchannel Lined by Fluid–Fluid Interfaces

Surface tension gradients induce Marangoni flow, which may be exploited for fluid transport. At the micrometer scale, these surface‐driven flows can be quite significant. By introducing fluid–fluid interfaces along the walls of microfluidic channels, bulk fluid flows driven by temperature gradients are observed. The temperature dependence of the fluid–fluid interfacial tension appears responsible for these flows. In this report, the design concept for a biocompatible microchannel capable of being powered by solar irradiation is provided. Using microscale particle image velocimetry, a bulk flow generated by apparent surface tension gradients along the walls is observed. The direction of flow relative to the imposed temperature gradient agrees with the expected surface tension gradient. The phenomenon's ability to replace bulky peripherals, like traditional syringe pumps, on a diagnostic microfluidic device that captures and detects leukocyte subpopulations within blood is demonstrated. Such microfluidic devices may be implemented for clinical assays at the point of care without the use of electricity.     

Electrothermal flow on electrodes arrays at physiological conductivities

AC electrothermal (ET) flow is inevitable for microfluidic systems dissipating electric energy in a conducting medium. Therefore, many practical applications of biomicrofluidics are prone to ET flow. Here, a series of observations are reported on ET flow in a microfluidic chamber that houses three electrode pairs. The observations indicate that the variations in liquid conductivity and channel height critically impact the structure and magnitude of the flow field. Observations indicate that after a critical conductivity a global ET flow is present in the chamber, while at lower conductivities a vortex is present at every electrode edge. In addition, no ET flow is observed when the chamber height is kept below a critical value at physiological conductivity (∼1.5 S/m). The experimental observations are compared with the numerical simulations of ET flow. The validity of the assumptions made in the current AC ET flow theory is also discussed in the light of the experimental data. The observations can be critical while designing microfluidic systems that involve power dissipation in conductive fluids.Inspec keywords: bioelectric phenomena, microfluidics, numerical analysis, bioMEMSOther keywords: electrode array, physiological conductivity, AC electrothermal flow, microfluidic system, electric energy, biomicrofluidics, microfluidic chamber, liquid conductivity, flow field structure, flow field magnitude, global ET flow, ET flow numerical simulation, AC ET flow theory, power dissipation, conductive fluid     

Foundations of chaotic mixing

The simplest mixing problem corresponds to the mixing of a fluid with itself; this case provides a foundation on which the subject rests. The objective here is to study mixing independently of the mechanisms used to create the motion and review elements of theory focusing mostly on mathematical foundations and minimal models. The flows under consideration will be of two types: two-dimensional (2D) 'blinking flows', or three-dimensional (3D) duct flows. Given that mixing in continuous 3D duct flows depends critically on cross-sectional mixing, and that many microfluidic applications involve continuous flows, we focus on the essential aspects of mixing in 2D flows, as they provide a foundation from which to base our understanding of more complex cases. The baker's transformation is taken as the centrepiece for describing the dynamical systems framework. In particular, a hierarchy of characterizations of mixing exist, Bernoulli --> mixing --> ergodic, ordered according to the quality of mixing (the strongest first). Most importantly for the design process, we show how the so-called linked twist maps function as a minimal picture of mixing, provide a mathematical structure for understanding the type of 2D flows that arise in many micromixers already built, and give conditions guaranteeing the best quality mixing. Extensions of these concepts lead to first-principle-based designs without resorting to lengthy computations.     

High-throughput microfluidic systems for disease detection

Accuracy and rapid response are critical to the detection of an acute infectious disease, not only because the detection results can affect the medical treatment, but also can prevent disease outbreaks. Since the current culture-based technology is time consuming and experience dependent, academia and industrial researchers are using microfluidics and nucleic acids as the fundamental ideas to build pioneering tools against infectious disease. While many point-of-care microfluidic systems have been realized to execute nucleic acid applications, high-throughput microfluidic systems are under development for various nucleic acid applications because of high efficiency and demand from the market. Building a high-throughput system is an interdisciplinary challenge because of the design concerns from science and the manufacturing concerns from engineering, but its realization will be a milestone. This article is aimed to review three essential steps of the nucleic acid-based detection realized in high-throughput formats, including polymerase chain reaction, capillary electrophoresis, and nucleic acid purification.     

Velocity measurement of particles flowing in a microfluidic chip using Shah convolution Fourier transform detection

A noninvasive radiative technique, based on Shah convolution Fourier transform detection, for velocity measurement of particles in fluid flows in a microfluidic chip, is presented. It boasts a simpler instrumental setup and optical alignment than existing measurement methods and a wide dynamic range of velocities measurable. A glass-PDMS microchip with a layer of patterned Cr to provide multiple detection windows which are 40 microns wide and 70 microns apart is employed. The velocities of fluorescent microspheres, which were electrokinetically driven in the channel of the microfluidic chip, were determined. The effects of increasing the number of detection windows and sampling period were investigated. This technique could have wide applications, ranging from the determination of the velocity of particles in pressure-driven flow to the measurement of electrophoretic mobilities of single biological cells.     

Microfluidic Automation Using Elastomeric Valves and Droplets: Reducing Reliance on External Controllers

This paper gives an overview of elastomeric valve‐ and droplet‐based microfluidic systems designed to minimize the need of external pressure to control fluid flow. This Concept article introduces the working principle of representative components in these devices along with relevant biochemical applications. This is followed by providing a perspective on the roles of different microfluidic valves and systems through comparison of their similarities and differences with transistors (valves) and systems in microelectronics. Despite some physical limitation of drawing analogies from electronic circuits, automated microfluidic circuit design can gain insights from electronic circuits to minimize external control units, while implementing high‐complexity and high‐throughput analysis.     

FT-IR spectroscopic imaging of reactions in multiphase flow in microfluidic channels

Rapid, in situ, and label-free chemical analysis in microfluidic devices is highly desirable. FT-IR spectroscopic imaging has previously been shown to be a powerful tool to visualize the distribution of different chemicals in flows in a microfluidic device at near video rate imaging speed without tracers or dyes. This paper demonstrates the possibility of using this imaging technology to capture the chemical information of all reactants and products at different points in time and space in a two-phase system. Differences in the rates of chemical reactions in laminar flow and segmented flow systems are also compared. Neutralization of benzoic acid in decanol with disodium phosphate in water has been used as the model reaction. Quantitative information, such as concentration profiles of reactant and products, can be extracted from the imaging data. The same feed flow rate was used in both the laminar flow and segmented flow systems. The laminar flow pattern was achieved using a plain wide T-junction, whereas the segmented flow was achieved by introducing a narrowed section and a nozzle at the T-junction. The results show that the reaction rate is limited by diffusion and is much slower with the laminar flow pattern, whereas the reaction is completed more quickly in the segmented flow due to better mixing.     

Fabrication and analysis of spatially uniform field electrokinetic flow devices: theory and experiment

A uniform-field design approach can improve the performance of microanalytical, chip-based devices for a number of applications, including separations and sample preparation. The faceted prism paradigm allows the design of microfluidic devices possessing spatially uniform fields in electrokinetically driven flows. We present the first quantitative study of the velocity fields obtained using faceted interfaces between deep and shallow channel sections. Electrokinetic flows were generated in a series of wet-etch fabricated microfluidic channels. The resulting velocity fields were analyzed by particle image velocimetry and compared with simulations of the two-dimensional Laplace equation using both the designed channel geometry and the as-fabricated channel geometry. This analysis found localized differences between the designed and observed flow fields that were directly attributable to the limitations of isotropic substrate etching. Simulations using the as-fabricated channel geometry reproduced the experimental electrokinetic velocity field, quantitatively accounting for speed field variations due to the limits of the fabrication method. The electrokinetic speed fields were also compared to corresponding pressure-driven speed fields.     

Advection Flows‐Enhanced Magnetic Separation for High‐Throughput Bacteria Separation from Undiluted Whole Blood

A major challenge to scale up a microfluidic magnetic separator for extracorporeal blood cleansing applications is to overcome low magnetic drag velocity caused by viscous blood components interfering with magnetophoresis. Therefore, there is an unmet need to develop an effective method to position magnetic particles to the area of augmented magnetic flux density gradients while retaining clinically applicable throughput. Here, a magnetophoretic cell separation device, integrated with slanted ridge‐arrays in a microfluidic channel, is reported. The slanted ridges patterned in the microfluidic channels generate spiral flows along the microfluidic channel. The cells bound with magnetic particles follow trajectories of the spiral streamlines and are repeatedly transferred in a transverse direction toward the area adjacent to a ferromagnetic nickel structure, where they are exposed to a highly augmented magnetic force of 7.68 µN that is much greater than the force (0.35 pN) at the side of the channel furthest from the nickel structure. With this approach, 91.68% ± 2.18% of Escherichia coli (E. coli) bound with magnetic nanoparticles are successfully separated from undiluted whole blood at a flow rate of 0.6 mL h^?1 in a single microfluidic channel, whereas only 23.98% ± 6.59% of E. coli are depleted in the conventional microfluidic device.     

Vertically stratified flows in microchannels. Computational simulations and applications to solvent extraction and ion exchange

In this paper, we describe the conditions under which two immiscible fluids flow atop one another (viewed perpendicular to the plane on which the channel is inscribed) in a shallow microfluidic channel. First, we predict the behavior of a two-phase system using fluid dynamic simulations with water-butanol and water-chloroform as model systems. We numerically model the effect of various physical parameters, such as interfacial surface tension, density, viscosity, wall contact angle, and flow velocity on the type of flow observed and find that interfacial surface tension and viscosity are the parameters responsible for formation of vertically stratified, side-by-side, or segmented flows. As predicted by numerical simulations, a water-chloroform system never assumes a vertically stratified configuration, but a water-butanol system does when the two liquids flow at sufficiently high flow velocities. In actual experiments, we test conditions under which potentially useful two-phase systems form stable vertically stratified flows. We also demonstrate that compared to side-by-side flow schemes, shorter diffusion paths are achievable, and thus, the system can be used at higher flow rates to obtain the same performance. We then apply such findings to practical analytical problems, such as solvent extraction and ion exchange.     

Flow Control Through the Use of Topography

In this work, optimal shaft shapes for flow in the annular space between a rotating shaft with axially-periodic radius and a fixed coaxial outer circular cylinder, are investigated. Axisymmetric steady flows in this geometry are determined by solving the full Navier-Stokes equations in the actual domain. A measure of the flow field, a weighted convex combination of the volume averaged square of the L₂-norm of the velocity and vorticity vectors, is employed. It has been demonstrated that boundary shape can be used to influence the characteristics of the flow field, such as its velocity component distribution, kinetic energy, or even vorticity. This ability to influence flow fields through boundary shape may be employed to improve microfluidic mixing or, possibly, to minimize shear in biological applications.     

3D Printed Microfluidic Mixers—A Comparative Study on Mixing Unit Performances

One of the basic operations in microfluidic systems for biological and chemical applications is the rapid mixing of different fluids. However, flow profiles in microfluidic systems are laminar, which means molecular diffusion is the only mixing effect. Therefore, mixing structures are crucial to enable more efficient mixing in shorter times. Since traditional microfabrication methods remain laborious and expensive, 3D printing has emerged as a potential alternative for the fabrication of microfluidic devices. In this work, five different passive micromixers known from literature are redesigned in comparable dimensions and manufactured using high‐definition MultiJet 3D printing. Their mixing performance is evaluated experimentally, using sodium hydroxide and phenolphthalein solutions, and numerically via computational fluid dynamics. Both experimental and numerical analysis results show that HC and Tesla‐like mixers achieve complete mixing after 0.99 s and 0.78 s, respectively, at the highest flow rate (Reynolds number (Re) = 37.04). In comparison, Caterpillar mixers exhibit a lower mixing rate with complete mixing after 1.46 s and 1.9 s. Furthermore, the HC mixer achieves very good mixing performances over all flow rates (Re = 3.7 to 37.04), while other mixers show improved mixing only at higher flow rates.     

Control of flow direction in microfluidic devices with polyelectrolyte multilayers

Electroosmotic flow (EOF) is commonly utilized in microfluidics. Because the direction of the EOF can be determined by the substrate surface charge, control of the surface chemical state offers the potential, in addition to voltage control, to direct the flow in microfluidic devices. We report the use of polyelectrolyte multilayers (PEMs) to alter the surface charge and control the direction of flow in polystyrene and acrylic microfluidic devices. Relatively complex flow patterns with simple arrangements of applied voltages are realized by derivatization of different arms of a single device with oppositely charged polyelectrolytes. In addition, flow in opposite directions in the same channel is possible. A positively derivatized plastic substrate with a negatively charged lid was used to achieve top-bottom opposite flows. Derivatization of the two sides of a plastic microchannel with oppositely charged polyelectrolytes was used to achieve side-by-side opposite flows. The flow is characterized using fluorescence imaging and particle velocimetry.     

On‐Chip Generation of Vortical Flows for Microfluidic Centrifugation

Microcentrifugation constitutes an important part of the microfluidic toolkit in a similar way that centrifugation is crucial to many macroscopic procedures, given that micromixing, sample preconcentration, particle separation, component fractionation, and cell agglomeration are essential operations in small scale processes. Yet, the dominance of capillary and viscous effects, which typically tend to retard flow, over inertial and gravitational forces, which are often useful for actuating flows and hence centrifugation, at microscopic scales makes it difficult to generate rotational flows at these dimensions, let alone with sufficient vorticity to support efficient mixing, separation, concentration, or aggregation. Herein, the various technologies—both passive and active—that have been developed to date for vortex generation in microfluidic devices are reviewed. Various advantages or limitations associated with each are outlined, in addition to highlighting the challenges that need to be overcome for their incorporation into integrated microfluidic devices.