Design Of Microfluidic Devices Research Articles

Numerical Simulation of Separation of Circulating Tumor Cells from Blood Stream in Deterministic Lateral Displacement (DLD) Microfluidic Channel

AbstractDeterministic Lateral Displacement (DLD) microfluidic devices provide a reliable label-free separation method for detection of circulating tumor cells (CTCs) in blood samples based on their biophysical properties. In this paper, we proposed an effective design of the DLD microfluidic device for the CTC separation in the blood stream. A typical DLD array is designed and numerical simulations are performed to separate the CTC and leukocyte (white blood cells) in different fluid flow conditions. Fluid-Solid Interaction method is used to investigate the behaviour of these deformable cells in fluid flow. In this study, the effects of critical parameters affecting cell separation in the DLD microfluidic devices (e.g.flow condition, cell deformability, and stress) have been investigated. The obtained results show that unlike leukocytes, the CTC’s motion is independent of the flow condition and is laterally displaced even in higher Reynolds number. Larger cells (CTCs) cannot intercept the low-velocity fluid near the wall of the posts; thus, they move faster and become separated from leukocytes. To reduce the cellular stress during separation process, which causes increase of cell viability and more effective design of microfluidic device, the results obtained here may be used as a significant design parameter for the DLD fabrication.

Integrated microfluidic system with simultaneous emulsion generation and concentration

Because the size, size distribution, and concentration of emulsions play an important role in most of the applications, controlled emulsion generation and effective concentration are of great interest in fundamental and applied studies. While microfluidics has been demonstrated to be able to produce emulsion drops with controlled size, size distribution, and hierarchical structures, progress of controlled generation of concentrated emulsions is limited. Here, we present an effective microfluidic emulsion generation system integrated with an orifice structure to separate aqueous droplets from the continuous oil phase, resulting in concentrated emulsion drops in situ. Both experimental and simulation results show that the efficiency of separation is determined by a balance between pressure drop and droplet accumulation near the orifice. By manipulating this balance via changing flow rates and microfluidic geometry, we can achieve monodisperse droplets on chip that have a concentration as high as 80,000 drops per microliter (volume fraction of 66%). The present approach thus provides insights to the design of microfluidic device that can be used to concentrate emulsions (drops and bubbles), colloidal particles (drug delivery polymer particles), and biological particles (cells and bacteria) when volume fractions as high as 66% are necessary.

Very large scale droplet microfluidic integration (VLDMI) using genetic algorithm

Droplet microfluidics is likely to play a central role in the development of lab-on-a-chip technologies and as a result, significant research is directed toward this field. Understanding the spatiotemporal dynamics of discrete droplets inside microfluidic devices and the design of microfluidic devices for specific tasks are some of the dominant research topics. These works have since resulted in the development of microfluidic devices with functionalities, such as sorting, merging, synchronization, storing etc. However, the anticipated application of microfluidic devices to more complex problems will require more integrated devices that can incorporate the above functionalities on a single chip. In the current work, we present a genetic algorithm optimization-based design tool for discovering very large-scale integration of discrete microfluidic networks for a given objective function. The application of the algorithm is demonstrated through a combinatorial sequencing problem, where the objective is to achieve three different droplet combinatorial sequences for three different droplet types. Multiple fascinating, but nonobvious designs were discovered for this application. It is difficult to imagine such devices being designed using trial and error experimental procedure, which has been the main route for obtaining microfluidic device designs. With advances in technologies for fabrication of microfluidic devices, the current tool can be a significant step toward drastically cutting down on the laborious trial-and-error design process and help in developing droplet microfluidics-based lab-on-a-chip platforms cheaper and faster.

Predicting the behavior of microfluidic circuits made from discrete elements.

Microfluidic devices can be used to execute a variety of continuous flow analytical and synthetic chemistry protocols with a great degree of precision. The growing availability of additive manufacturing has enabled the design of microfluidic devices with new functionality and complexity. However, these devices are prone to larger manufacturing variation than is typical of those made with micromachining or soft lithography. In this report, we demonstrate a design-for-manufacturing workflow that addresses performance variation at the microfluidic element and circuit level, in context of mass-manufacturing and additive manufacturing. Our approach relies on discrete microfluidic elements that are characterized by their terminal hydraulic resistance and associated tolerance. Network analysis is employed to construct simple analytical design rules for model microfluidic circuits. Monte Carlo analysis is employed at both the individual element and circuit level to establish expected performance metrics for several specific circuit configurations. A protocol based on osmometry is used to experimentally probe mixing behavior in circuits in order to validate these approaches. The overall workflow is applied to two application circuits with immediate use at on the bench-top: series and parallel mixing circuits that are modularly programmable, virtually predictable, highly precise, and operable by hand.

Oxidized Porous Silicon Nanostructures Enabling Electrokinetic Transport for Enhanced DNA Detection

Nanostructured porous silicon (PSi) is a promising material for the label‐free detection of biomolecules, but it currently suffers from limited applicability due to poor sensitivity, typically in micromolar range. This work presents the design, operation concept, and characterization of a novel microfluidic device and assay that integrates an oxidized PSi optical biosensor with electrokinetic focusing for a highly sensitive label‐free detection of nucleic acids. Under proper oxidation conditions, the delicate nanostructure of PSi can be preserved, while providing sufficient dielectric insulation for application of high voltages. This enables the use of signal enhancement techniques, which are based on electric fields. Here, the DNA target molecules are focused using an electric field within a finite and confined zone, and this highly concentrated analyte is delivered to an on‐chip PSi Fabry–Pérot optical transducer, prefunctionalized with capture probes. Using reflective interferometric Fourier transform spectroscopy real‐time monitoring, a 1000‐fold improvement in limit of detection is demonstrated compared to a standard assay, using the same biosensor. Thus, a measured limit of detection of 1 × 10−9 m is achieved without compromising specificity. The concepts presented herein can be readily applied to other ionic targets, paving way for the development of other highly sensitive chemical and biochemical assays.

Tilted pillar array fabrication by the combination of proton beam writing and soft lithography for microfluidic cell capture: Part 1 Design and feasibility.

Design, fabrication, integration, and feasibility test results of a novel microfluidic cell capture device is presented, exploiting the advantages of proton beam writing to make lithographic irradiations under multiple target tilting angles and UV lithography to easily reproduce large area structures. A cell capture device is demonstrated with a unique doubly tilted micropillar array design for cell manipulation in microfluidic applications. Tilting the pillars increased their functional surface, therefore, enhanced fluidic interaction when special bioaffinity coating was used, and improved fluid dynamic behavior regarding cell culture injection. The proposed microstructures were capable to support adequate distribution of body fluids, such as blood, spinal fluid, etc., between the inlet and outlet of the microfluidic sample reservoirs, offering advanced cell capture capability on the functionalized surfaces. The hydrodynamic characteristics of the microfluidic systems were tested with yeast cells (similar size as red blood cells) for efficient capture.

Floating Droplet Array: An Ultrahigh-Throughput Device for Droplet Trapping, Real-time Analysisand Recovery

We describe the design, fabrication and use of a dual-layered microfluidic device for ultrahigh-throughput droplet trapping, analysis, and recovery using droplet buoyancy. To demonstrate the utility of this device for digital quantification of analytes, we quantify the number of droplets, which contain a β-galactosidase-conjugated bead among more than 100,000 immobilized droplets. In addition, we demonstrate that this device can be used for droplet clustering and real-time analysis by clustering several droplets together into microwells and monitoring diffusion of fluorescein, a product of the enzymatic reaction of β-galactosidase and its fluorogenic substrate FDG, between droplets.

Single-Fluorophore Detection in Femtoliter Droplets Generated by Flow Focusing.

Aqueous microdroplets with a volume of a few femtoliters are an ideal sample size for single-molecule fluorescence experiments. In particular, they enable prolonged measurements to be made on individual molecules that can diffuse freely in the surrounding medium. However, the rapid production of monodisperse droplets in a hydrodynamic flow, such as microfluidic flow focusing, will often involve volumes that are typically too large (>0.5 pL) for single-molecule studies. Desired volumes of a few femtoliters, or smaller, can be produced by either tip streaming or step emulsification in a flow-focusing device; however, in both of these methods, the aqueous droplets are dispersed in a large volume of the continuous phase, where individual droplets can diffuse perpendicular to the flow direction, and the monodispersity of droplet size produced by tip streaming is difficult to sustain for more than transient time scales. We show here that the optimized design and fabrication of microfluidic devices with shallow channel depths can result in the reliable production of stable droplets of a few femtoliters at a high rate in the dripping regime of flow focusing. Furthermore, the generated microdroplets are localized in a two-dimensional plane to enable immediate analysis. We have demonstrated the fluorescence monitoring of single molecules of encapsulated green fluorescent protein. The apparatus is straightfoward, inexpensive, and readily assembled within an ordinary laboratory environment.

Preface to the special issue on “Thin films and fluid interfaces”

Free-surface problems, where the boundary of a moving body of fluid evolves as part of the dynamics, are one of the most interesting and challenging areas in the field of fluid dynamics. Such problems are ubiquitous in natural settings over a wide range of physical scales, from the propagation of surface waves on oceans to the spreading of raindrops on plant leaves. These systems exhibit intricate behaviors and have inspired many different types of applied studies in physics and engineering such as using fluid wetting to test substrate material properties, improving transport in designs of microfluidic devices, and investigating self-assembly of patterned materials. Likewise, free-surface problems have been a long-standing source of fundamental mathematical questions on how to formulate models, analyze systems of nonlinear partial differential equations, and compute efficient numerical simulations. Within the broad spectrum of free-surface problems, one of the most developed branches concerns the behaviors produced by slender bodies of fluids, such as jets and thin sheets [1]. These problems are fundamental to many physical situations including coating processing that involve the spreading of thin films of fluids on solid substrates [2]. The governing equations for these flows are derived through the use of longwave asymptotics and lubrication theory. The resulting mathematical models are higher-order nonlinear partial differential equations that include the influences of surface tension and the geometry of the problem. Some notable papers have given overviews of physical [3–10], mathematical [11–14], and computational [15,16] aspects of this field. Contributing to this rich and active field of research, the motivation for this special issue of the Journal of Engineering Mathematics came from the workshop on “Thin Liquid Films and Fluid Interfaces: Models, Experiments and Applications” held at the Banff International Research Station (BIRS) on December 9–14, 2012 [17]. The workshop added to the growing list of focused meetings organized by various members of this research community. Some of the other conferences in the field were held at BIRS in 2003–2010 [18–21], UCLA’s IPAM center in 2006 [22], the EUROMECH 490 workshop in London in 2007 [23], two meetings at ICMS in Edinburgh in 1999 and 2009 (EUROMECH 497) [24,25], at the Fields Institute in 2012 [26], and the 2013 programme at the Newton Institute at Cambridge University [27]. Several of these meetings have inspired special issues of journals containing new research results on thin film problems [28–32]. An international and interdisciplinary array of researchers in physics, engineering, and applied mathematics attended the 2012 BIRS workshop. Physical problems discussed at the meeting spanned applications from nanoscale to geophysical settings and physiological to industrial contexts. Mathematical questions on modeling of complex fluids and fluid–structure interactions also led to spirited interactions among the conference participants.

Deformation and Interaction of Droplet Pairs in a Microchannel Under ac Electric Fields

The deformation and interaction of a droplet pair in an electric field determine the success of droplet coalescence. Electric intensity and initial droplet separation are crucial parameters in this process. In this work, a combined theoretical and numerical analysis is performed to study the electrohydrodynamics of confined droplet pairs in a rectangular microchannel under ac electric fields. We develop a theoretical model to predict the relationship between critical electric intensity and droplet separation. A geometrical model relating the initial droplet separation to the cone angle is also established to determine the critical separation for partial coalescence. These models are validated by comparisons with existing experimental observations. According to the initial separation and electric intensity, five regimes of droplet interactions are classified by direct numerical simulations, namely noncoalescence, coalescence, partial coalescence, ejection after coalescence, and ejection with partial coalescence. According to their controlling mechanisms, the five regimes are distinguished by three well-defined boundaries. The detailed dynamics of the partial coalescence phenomenon is resolved when the droplet separation exceeds the critical value. A dynamic liquid bridge between the droplets is sustained by the competition between surface tension and electric stress. The dynamics of ejected microjets at the exterior ends are also addressed to showtheir responses to the oscillating electric field. The full understanding of the droplet dynamics under electric fields can be used to predict the droplet fusion behaviors and thus to facilitate the design of droplet-based microfluidic devices.

Simplified fluid-structure coupled analysis of particle movement for designing of microfluidic cell sorter.

Recently, methods of the separation and selection of cells using a microfluidic device are receiving a lot of attention as the latest technology and those devices are called microfluidic cell sorter. Those methods have many advantages compared to conventional methods. There are a lot of researches on the microfluidic cell sorting but there isn't the automated design method of this device in spite of the necessary. To achieve the automated design of the microfluidic cell sorter, the analysis of the movement of cells in the microfluidic device and optimum design of the microfluidic cell sorter corresponding to kind of various cells are required. In the former case, the fluid-structure interaction analysis of fluid and cell movement is needed. However, it is very complex and needs a lot of computational time. Therefore, we focused on this problem in the fluid-structure interaction analysis for designing the microfluidic cell sorter. We assume cell is a sphere particle and propose the simplified fluid-structure coupled analysis which combines the CFD analysis with the motion equation of a sphere particle.

Microfluidic device design, fabrication, and testing protocols

Microfluidic device design, fabrication, and testing protocols

Theory of a microfluidic serial dilution bioreactor for growth of planktonic and biofilm populations.

We present the theory of a microfluidic bioreactor with a two-compartment growth chamber and periodic serial dilution. In the model, coexisting planktonic and biofilm populations exchange by adsorption and detachment. The criteria for coexistence and global extinction are determined by stability analysis of the global extinction state. Stability analysis yields the operating diagram in terms of the dilution and removal ratios, constrained by the plumbing action of the bioreactor. The special case of equal uptake function and logistic growth is analytically solved and explicit growth curves are plotted. The presented theory is applicable to generic microfluidic bioreactors with discrete growth chambers and periodic dilution at discrete time points. Therefore, the theory is expected to assist the design of microfluidic devices for investigating microbial competition and microbial biofilm growth under serial dilution conditions.

Flow of a micropolar fluid in a micro-channel under the action of an alternating electric field: Estimates of flow in bio-fluidic devices

The paper is devoted to a study of the electro-osmotic flow of a micropolar bio-fluid, when the flow takes place between two plates that are in a state of periodic vibrations. Considering blood as a micropolar fluid, it is found that the amplitude of oscillation of the microparticles of blood increases when the micropolar effect is pronounced more and more and that a rise in Debye- Hückel parameter enhances both the velocity and microrotation gradient. The results provide guidelines for the improvement of design of bio-sensing and micro-fluidic devices. The study leads to the conclusion that electrical double layers formed in the vicinity of the wall can significantly alter the flow dynamics of physiological fluids in micro-bio-fluidic devices.

Radial wettable gradient of hot surface to control droplets movement in directions.

A radial wettable gradient was fabricated on the surface of graphite plate by a simple one-step anodic oxidation process. It was found that the direction and value of the wettable gradient could be easily controlled by adjusting current and oxidation time gradient. With the increase of surface temperature, droplets on surface not only exhibited the transition of boiling mode, but also showed the controlled radial spreading, evaporation and movement behaviors. These phenomena could be attributed to the cooperation of wettability force, hysteresis force and vapor pressure (Leidenfrost effect). Especially, the controlled radial convergence or divergence of droplets with high velocity were realized on the surfaces with either inside or outside radial gradient, which would have crucial applications in the design of microfluidic devices and the exploration of the biotechnology.

Saliva Collection and Quantification from Adult Butterflies (Lepidoptera)

The coilable proboscis is possessed by over 99% of lepidopteran species and is a key innovation contributing to the success of Lepidoptera as the second larg est insect order (Krenn, 2010; Kristensen, 1984; Pogue, 2009). Study of the struc ture and function of the proboscis is applicable to lepidopteran systematics, natural history (Krenn, 2010), and to the design of microfluidic devices (Tsai et al., 2011; Monaenkova, 2012). Saliva plays an important role in proboscis function (Krenn, 2010). Saliva is exuded from the food canal of the proboscis through the tip and through slits between the plate-like dorsal legulae and hook-like ventral legulae. The cuticular surface of the proboscis varies along its length, and has microchannels and grooves which could direct saliva between dorsal and ventral sides (Lehnert et al., 2013). Saliva appears as droplets on the surface of the proboscis during as sem bly (Krenn, 1997), repair (Lehnert et al., 2014), and feeding (Lehnert et al., 2014). Methods used for collection of butterfly saliva have included rinsing the proboscis with water or buffer (Eberhard et al., 2007), or prompting saliva deposition onto glass (Tokarev et al., 2013). In this paper I describe a new procedure for collecting the saliva of adult butterflies directly from the proboscis into capil lary tubes, and I report the volumes of saliva collected from different species. I also report the appearance of a yellow liquid exuded from the proboscis by some lepidopteran adults.

Топологии микрофлюидных устройств для изучения миграции клеток в градиентах химических веществ (обзор)

Топологии микрофлюидных устройств для изучения миграции клеток в градиентах химических веществ (обзор)

Measuring flow dynamics in a microfluidic chip using optical coherence tomography with 1 µm axial resolution

An experimental verification of simulated flow dynamics in a novel design of microfluidic device can be difficult, especially, in devices such as mixers or deterministic lateral displacement (DLD) arrays. Doppler optical coherence tomography (DOCT) is one of the visualization modalities used to measure flow velocity profiles in microfluidic channels, capillaries and microvascular networks. Previously conducted flow measurements with high speed spectral-domain optical coherence tomography (SD-OCT) devices have had typical axial resolution in the range few microns which can be insufficient for accurate mapping of flow dynamics in microchannels. This paper introduces a high-speed SD-OCT system with an axial resolution of 1.2µm in air (below 1µm in water) to evaluate flow in a microfluidic chip. The A-line acquisition rate of the device is 123kHz. Flow velocities from 1% Intralipid suspension are obtained across the microfluidic channel with the specified height of 20µm and the width of 50µm. The results show that the utilized SD-OCT device can visualize flows as close as 1µm from the channel wall. The flow rate of 0.63µl/min, determined from the cross-sectional velocity map, agreed well with the value of 0.67µl/min set to the syringe pump.

Recent microfluidic devices for studying gamete and embryo biomechanics

The technical challenges of biomechanic research such as single cell analysis at a high monetary cost, labor, and time for just a small number of measurements is a good match to the strengths of microfluidic devices. New scientific discoveries in the fertilization and embryo development process, of which biomechanics is a major subset of interest, is crucial to fuel the continual improvement of clinical practice in assisted reproduction. The following review will highlight some recent microfluidic devices tailored for gamete and embryo biomechanics where biomimicry arises as a major theme of microfluidic device design and function, and the application of fundamental biomechanic principles are used to improve outcomes of cryopreservation.

Droplet-based dielectrophoresis device for on-chip nanomedicine fabrication and improved gene delivery efficiency

In this article, we present the design, fabrication, and experimental verification of a droplet-based microfluidic device for effective on-chip fabrication and separation of polymer-based nanoparticles using dielectrophoresis (DEP) effect. The separated polyplexes nanoparticles were used in cells for improved gene transfection efficiency. By adjusting the flow rate of PEI600-CyD-FA (H1) and DNA plasmids, polyplexes products can be mixed and self-assembled inside droplets within approximately a nanoliter volume. This procedure ensures synthesized particles to have a narrow size distribution. In addition, a new microchannel design was developed to automatically coalesce two moving aqueous droplets and to directly extract aqueous polyplex products from oil. Finally, the H1-DNA polyplexes of ~116 nm diameter were separated via negative DEP force under 8 Vpeak–peak and 20 MHz conditions by passing three times through a non-uniform electric field. The biological findings demonstrated that the DEP-treated polyplexes still possessed the ability to enter HUVEC cells and that the gene transfection efficiency was raised to 15 %, as opposed to the control group’s 4 % where the polyplexes had no DEP treatment. The quantitative comparison was done by counting the number of cells produced via positive EPFG expression. These hydrodynamic and electrodynamic techniques provide an integrated microfluidic platform for fabricating and screening nanoscale drugs.