微通道内液-液多相流数值模拟研究进展

液滴微流控技术在化学化工、生物医学等领域具有良好的应用前景,而微通道内的液-液多相流动则是液滴微流控技术中最常见的流动现象,深入研究其机理及其内在规律对相关装置与过程的优化设计具有重要的指导意义。本文系统地综述了研究微通道液-液多相流常用数值研究方法,回顾了连续力学方法与介观动理学方法的研究进展,详细介绍了界面追踪方法与界面捕捉方法的特点以及常用模型,讨论了多种模型的应用情况,论述并对比了不同模型的优势与限制。为进一步开展微通道液-液多相流行为规律及其内在机理的研究提供有益借鉴。微通道内多相流动涉及多种流体与界面的相互耦合,应进一步深入研究在模型简化的基础上实现更精确的界面与流体动力学行为描述。     

Microfluidic-Based Technologies for CTC Isolation: A Review of 10 Years of Intense Efforts towards Liquid Biopsy

The selection of circulating tumor cells (CTCs) directly from blood as a real-time liquid biopsy has received increasing attention over the past ten years, and further analysis of these cells may greatly aid in both research and clinical applications. CTC analysis could advance understandings of metastatic cascade, tumor evolution, and patient heterogeneity, as well as drug resistance. Until now, the rarity and heterogeneity of CTCs have been technical challenges to their wider use in clinical studies, but microfluidic-based isolation technologies have emerged as promising tools to address these limitations. This review provides a detailed overview of latest and leading microfluidic devices implemented for CTC isolation. In particular, this study details must-have device performances and highlights the tradeoff between recovery and purity. Finally, the review gives a report of CTC potential clinical applications that can be conducted after CTC isolation. Widespread microfluidic devices, which aim to support liquid-biopsy-based applications, will represent a paradigm shift for cancer clinical care in the near future.     

微纳米流控芯片传感器研究及其在环境检测中的应用

与传统生物传感器相比,微纳米流体生物传感器在减少样品使用剂量,实现高通量、快速检测、特异性检测,以及简化实验操作等方面都显示出无可比拟的优越性。本文所涉及的微纳米的生物传感器大体上可以分成两大类:第一类是常规的微纳米流控生物传感器(简称微流控芯片),通常以硅、玻璃以及高分子聚合物作为基材;第二类则是最近兴起的试纸条生物传感器,其基材为纸质。本文从以下几方面对当前微流体生物传感器的研究与应用进行总结:微流体生物传感器的基本理论,材料特征与制作工艺方面,以及在环境监测领域的典型性应用,最后对基于各种不同工艺技术制作的微流体生物传感器在技术方面的难点和应用上的局限性进行简要分析。     

Electrochemical microfluidics

Electrochemical microfluidics is a young field, but now achieving substantial successes in science, engineering, and technology. In this review article, the use of electrochemical effects for actuation in microfluidic devices is described, with a focus on electrokinetic flow. Furthermore, the use of electrochemical microfluidic devices in analytic chemistry and biochemistry is detailed, largely for separation and detection, typically exploiting electrophoretic effects. Finally, the use of electrochemical microreactors is explored, with an eye to the synthesis and processing advantages that come from microscale operations. Microfluidic devices are, more than ever, serving as a platform for nanoscience and nanotechnology, with molecular scale manipulation and detection enabled by microfluidic control of the environment.     

Single Cell Electrical Characterization Techniques

Electrical properties of living cells have been proven to play significant roles in understanding of various biological activities including disease progression both at the cellular and molecular levels. Since two decades ago, many researchers have developed tools to analyze the cell’s electrical states especially in single cell analysis (SCA). In depth analysis and more fully described activities of cell differentiation and cancer can only be accomplished with single cell analysis. This growing interest was supported by the emergence of various microfluidic techniques to fulfill high precisions screening, reduced equipment cost and low analysis time for characterization of the single cell’s electrical properties, as compared to classical bulky technique. This paper presents a historical review of single cell electrical properties analysis development from classical techniques to recent advances in microfluidic techniques. Technical details of the different microfluidic techniques are highlighted, and the advantages and limitations of various microfluidic devices are discussed.     

Microfluidic Impedance Flow Cytometry Enabling High-Throughput Single-Cell Electrical Property Characterization

This article reviews recent developments in microfluidic impedance flow cytometry for high-throughput electrical property characterization of single cells. Four major perspectives of microfluidic impedance flow cytometry for single-cell characterization are included in this review: (1) early developments of microfluidic impedance flow cytometry for single-cell electrical property characterization; (2) microfluidic impedance flow cytometry with enhanced sensitivity; (3) microfluidic impedance and optical flow cytometry for single-cell analysis and (4) integrated point of care system based on microfluidic impedance flow cytometry. We examine the advantages and limitations of each technique and discuss future research opportunities from the perspectives of both technical innovation and clinical applications.     

A comparison of different geometrical elements to model fluid wicking in paper-based microfluidic devices

Recently, microfluidic paper-based analytical devices (μPADs) have outstripped polymeric microfluidic devices in the ease of fabrication and simplicity. Surface tension-based fluid motion in the paper's porous structure has made the paper a suitable substrate for multiple biological assays by directing fluid into multiple assay zones. The widespread assumption in most works for modeling wicking in a paper is that the paper is a combination of capillaries with the same diameter equal to the effective pore diameter. Although assuming paper as a bundle of capillaries gives a good insight into pressure force that drives the fluid inside the paper, there are some difficulties using the effective pore radius. The effective pore radius is totally different from the average geometrical pore radius which makes it impossible to predict wicking in μPADs based on geometrical parameters. In this article, we introduce different analytical and numerical models to investigate the possibility of determining the permeability of the paper, based on geometrical parameters rather than effective parameters. The lattice Boltzmann method is used for numerical simulations. The permeability of each of the proposed models was compared with the experimental permeability. Results indicated that assuming paper as a combination of capillaries and annuluses leads to accurate results that totally depend on average geometrical values rather than effective values. This paves the way for prediction of the fluid wicking only by considering average geometrical pore and fiber diameters.     

Two-phase microfluidic flows

Two phase systems are ubiquitous in processes and products, and in both cases performance is maximized when precise control over the individual phases, and the ensemble, is possible. Microfluidic technologies afford higher levels of control over two-phase systems than is possible in macroscopic process equipment, opening avenues to controlled reactions as well as products having tightly controlled properties including emulsion size distribution. A review of recent progress in two-phase flows in microfluidic devices is presented. The fundamentals of two-phase flows including some important dimensionless numbers are firstly introduced, followed by a review of two-phase flow regimes in gas–liquid and liquid–liquid systems, focusing on microfluidic methods for controlling droplet formation and coalescence. Applications of two-phase microfluidic flows are briefly reviewed, including new approaches to the formation of well-defined complex emulsion which, like a Matryoshka doll, have structure within structure. The large number of recent publications reviewed in this paper highlights the tremendous interest in the fundamental study and use of controlled microfluidic two-phase flows, driven by the promise of highly controlled processes and new products having controlled complexity.     

Nanoscale surface modifications to control capillary flow characteristics in PMMA microfluidic devices

Polymethylmethacrylate (PMMA) microfluidic devices have been fabricated using a hot embossing technique to incorporate micro-pillar features on the bottom wall of the device which when combined with either a plasma treatment or the coating of a diamond-like carbon (DLC) film presents a range of surface modification profiles. Experimental results presented in detail the surface modifications in the form of distinct changes in the static water contact angle across a range from 44.3 to 81.2 when compared to pristine PMMA surfaces. Additionally, capillary flow of water (dyed to aid visualization) through the microfluidic devices was recorded and analyzed to provide comparison data between filling time of a microfluidic chamber and surface modification characteristics, including the effects of surface energy and surface roughness on the microfluidic flow. We have experimentally demonstrated that fluid flow and thus filling time for the microfluidic device was significantly faster for the device with surface modifications that resulted in a lower static contact angle, and also that the incorporation of micro-pillars into a fluidic device increases the filling time when compared to comparative devices.     

Reversible sequential-binding probe receptor-ligand interactions in single cells

With the reversible sequential (ReSeq) binding assay,we present a novel approach for the ultrasensitive profiling of receptor function in single living cells. This assay is based on the repetitive application of fluorescent ligands that have fast association-dissociation kinetics. We chose the nicotinic-acetylcholine receptor (nAChR) as a prototypical example and performed ReSeq equilibrium, kinetic, and competition-binding assays using fluorescent derivatives of the antagonist alpha-conotoxin GI (alpha-CnTx). Thereby, we determined the binding constants of unlabeled alpha-CnTx and d-tubocurarine. The high selectivity of alpha-CnTx for muscle-type nAChR made it possible to observe specific binding even in the presence of other nAChR subtypes. Imaging of individual nAChRs and ligand-binding cycles to single cells in microfluidic devices demonstrated the ultimate miniaturization and accuracy of ReSeq-binding assays even at low receptor-expression levels. We expect our approach to be of generic importance for functional screening of compounds or membrane receptors, and for the detailed characterization of rare primary cells.     

Micro Electromechanical Systems (MEMS) Based Microfluidic Devices for Biomedical Applications

Micro Electromechanical Systems (MEMS) based microfluidic devices have gained popularity in biomedicine field over the last few years. In this paper, a comprehensive overview of microfluidic devices such as micropumps and microneedles has been presented for biomedical applications. The aim of this paper is to present the major features and issues related to micropumps and microneedles, e.g., working principles, actuation methods, fabrication techniques, construction, performance parameters, failure analysis, testing, safety issues, applications, commercialization issues and future prospects. Based on the actuation mechanisms, the micropumps are classified into two main types, i.e., mechanical and non-mechanical micropumps. Microneedles can be categorized according to their structure, fabrication process, material, overall shape, tip shape, size, array density and application. The presented literature review on micropumps and microneedles will provide comprehensive information for researchers working on design and development of microfluidic devices for biomedical applications.     

Mass transport and surface reactions in microfluidic systems

We provide analysis of different regimes of diffusion and laminar flow convection combined with bimolecular surface reactions relevant to biochemical assays performed in microfluidic devices. Analytic solutions for concentration fields are compared to predictions from two-dimensional finite element simulations for the various operation regimes. The analytic and numerical results extend the transport models beyond the models commonly used to interpret results from surface plasmon resonance (SPR) experiments. Particular emphasis is placed on the characterization of transport in shallow microfluidic channels in which the fully developed transport regime dominates rather than the mass transfer boundary layer transport typically encountered in SPR. Under fast reaction and diffusion conditions, the surfaces saturate following moving front kinetics similar to that observed in chromatographic columns. Two key parameters relevant to on-chip biochemical assays and microfluidic sensors are studied and compiled: the capture fraction of the bulk analyte at the surface and the saturation time scale of the reactive surfaces. The physical processes in the different regimes are illustrated with data from the relevant microfluidics literature.     

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.     

Recent developments in scale-up of microfluidic emulsion generation via parallelization

Microfluidics affords precise control over the flow of multiphasic fluids in micron-scale channels. By manipulating the viscous and surface tension forces present in multiphasic flows in microfluidic channels, it is possible to produce highly uniform emulsion droplets one at a time. Monodisperse droplets generated based on microfluidics are useful templates for producing uniform microcapsules and microparticles for encapsulation and delivery of active ingredients as well as living cells. Also, droplet microfluidics have been extensively exploited as a means to enable highthroughput biological screening and assays. Despite the promise droplet-based microfluidics hold for a wide range of applications, low production rate (<<10mL/hour) of emulsion droplets has been a major hindrance to widespread utilization at the industrial and commercial scale. Several reports have recently shown that one way to overcome this challenge and enable mass production of microfluidic droplets is to parallelize droplet generation, by incorporating a large number of droplet generation units (N>>100) and networks of fluid channels that distribute fluid to each of these generators onto a single chip. To parallelize droplet generation and, at the same time, maintain high uniformity of emulsion droplets, several considerations have to be made including the design of channel geometries to ensure even distribution of fluids to each droplet generator, methods for large-scale and uniform fabrication of microchannels, device materials for mechanically robust operation to withstand high-pressure injection, and development of commercially feasible fabrication techniques for three-dimensional microfluidic devices. We highlight some of the recent advances in the mass production of highly uniform microfluidics droplets via parallelization and discuss outstanding issues.     

Synthesis of crystals and particles by crystallization and polymerization in droplet-based microfluidic devices

The recent advances in crystallization and polymerization assisted by droplet-based microfluidics to synthesize micro-particles and micro-crystals are reviewed in this paper. Droplet-based microfluidic devices are powerful tools to execute some precise controls and operations on the flow inside microchannels by adjusting fluid dynamics parameters to produce monodisperse emulsions or multiple-emulsions of various materials. Major features of this technique are producing particles of monodispersity to control the shape of particles in a new level, and to generate droplets of diverse materials including aqueous solutions, gels and polymers. Numerous microfluidic devices have been employed to generate monodisperse droplets of range from nm to μm, such as T junctions, flow-focusing devices and co-flow or cross-flow capillaries. These discrete, independently controllable droplets are ideal microreactors to be manipulated in the channels to synthesize the nanocrystals, protein crystals, polymer particles and microcapsules. The generated monodisperse particles or crystals are to meet different technical demands in many fields, such as crystal engineering, encapsulation and drug delivery systems. Microfluidic devices are promising tools in the synthesis of micron polymer particles that have diverse applications such as the photonic materials, ion-exchange and chromatography columns, and field-responsive rheological fluids. Processes assisted by microfluidic devices are able to produce the polymer particles (including Janus particles) with precise control over their sizes, size distribution, morphology and compositions. The technology of micro-fluidics has also been employed to generate core-shell microcapsules and solid microgels with precise controlled sizes and inner structures. The chosen “smart” materials are sensitive to an external stimulus such as the change of the pH, electric field and temperature. These complex particles are also able to be functionalized by encapsulating nanoparticles of special functions and by attaching some special groups like targeting ligands. The nucleation kinetics of some crystals like KNO₃ was investigated in different microfluidic devices. Because of the elimination of the interactions among crystallites in bulk systems, using independent droplets may help to measure the nucleation rate more accurately. In structural biology, the droplets produced in microfluidic devices provide ideal platforms for protein crystallization on the nanoliter scale. Therefore, they become one of the promising tools to screen the optimal conditions of protein crystallization.     

Enhancement in the limit of detection of lab-on-chip microfluidic devices using functional nanomaterials

Technological developments in recent years have witnessed a paradigm shift towards lab-on-chip devices for various diagnostic applications. Lab-on-chip technology integrates several functions typically performed in a large-scale analytical laboratory on a small-scale platform. These devices are more than the miniaturized versions of conventional analytical and diagnostic techniques. The advances in fabrication techniques, material sciences, surface modification strategies, and their integration with microfluidics and chemical and biological-based detection mechanisms have enormously enhanced the capabilities of these devices. The minuscule sample and reagent requirements, capillary-driven pump-free flows, faster transport phenomena, and ease of integration with various signal readout mechanisms make these platforms apt for use in resource-limited settings, especially in developing and underdeveloped parts of the world. The microfluidic lab-on-a-chip technology offers a promising approach to developing cost-effective and sustainable point-of-care testing applications. Numerous merits of this technology have attracted the attention of researchers to develop low-cost and rapid diagnostic platforms in human healthcare, veterinary medicine, food quality testing, and environmental monitoring. However, one of the major challenges associated with these devices is their limited sensitivity or the limit of detection. The use of functional nanomaterials in lab-on-chip microfluidic devices can improve the limit of detection by enhancing the signal-to-noise ratio, increasing the capture efficiency, and providing capabilities for devising novel detection schemes. This review presents an overview of state-of-the-art techniques for integrating functional nanomaterials with microfluidic devices and discusses the potential applications of these devices in various fields.     

Synthesis of crystals and particles by crystallization and polymerization in droplet-based microfluidic devices

The recent advances in crystallization and polymerization assisted by droplet-based microfluidics to synthesize micro-particles and micro-crystals are reviewed in this paper. Droplet-based microfluidic devices are powerful tools to execute some precise controls and operations on the flow inside microchannels by adjusting fluid dynamics parameters to produce monodisperse emulsions or multiple-emulsions of various materials. Major features of this technique are producing particles of monodispersity to control the shape of particles in a new level, and to generate droplets of diverse materials including aqueous solutions, gels and polymers. Numerous microfluidic devices have been employed to generate monodisperse droplets of range from nm to μm, such as T junctions, flow-focusing devices and co-flow or cross-flow capillaries. These discrete, independently controllable droplets are ideal microreactors to be manipulated in the channels to synthesize the nanocrystals, protein crystals, polymer particles and microcapsules. The generated monodisperse particles or crystals are to meet different technical demands in many fields, such as crystal engineering, encapsulation and drug delivery systems. Microfluidic devices are promising tools in the synthesis of micron polymer particles that have diverse applications such as the photonic materials, ion-exchange and chromatography columns, and field-responsive rheological fluids. Processes assisted by microfluidic devices are able to produce the polymer particles (including Janus particles) with precise control over their sizes, size distribution, morphology and compositions. The technology of microfluidics has also been employed to generate core-shell microcapsules and solid microgels with precise controlled sizes and inner structures. The chosen “smart” materials are sensitive to an external stimulus such as the change of the pH, electric field and temperature. These complex particles are also able to be functionalized by encapsulating nanoparticles of special functions and by attaching some special groups like targeting ligands. The nucleation kinetics of some crystals like KNO₃ was investigated in different microfluidic devices. Because of the elimination of the interactions among crystallites in bulk systems, using independent droplets may help to measure the nucleation rate more accurately. In structural biology, the droplets produced in microfluidic devices provide ideal platforms for protein crystallization on the nanoliter scale. Therefore, they become one of the promising tools to screen the optimal conditions of protein crystallization.     

A Review of Microfluidic Experimental Designs for Nanoparticle Synthesis

Microfluidics is defined as emerging science and technology based on precisely manipulating fluids through miniaturized devices with micro-scale channels and chambers. Such microfluidic systems can be used for numerous applications, including reactions, separations, or detection of various compounds. Therefore, due to their potential as microreactors, a particular research focus was noted in exploring various microchannel configurations for on-chip chemical syntheses of materials with tailored properties. Given the significant number of studies in the field, this paper aims to review the recently developed microfluidic devices based on their geometry particularities, starting from a brief presentation of nanoparticle synthesis and mixing within microchannels, further moving to a more detailed discussion of different chip configurations with potential use in nanomaterial fabrication.     

Customized Design of Scalable Microfluidic Droplet Generators Using Step‐Emulsification Methods

Customized monodisperse microparticles and microcapsules can be produced by combining microfluidic droplet generation with subsequent particle solidification. Established microfluidic devices for droplet formation like flow‐focusing structures or T‐junctions provide high reproducibility and controllability, but are often limited in terms of throughput or variability. A higher throughput by means of simple numbering‐up can be achieved by applying alternative droplet formation mechanisms like step emulsification. Using laser‐ablated glass reactors designed in‐house, comprehensive studies with varied step geometry and process parameters were performed in order to provide fundamental data for general calculation methods allowing the fast design of customized microfluidic droplet generators.     

Effect of liquid droplet impact velocity on liquid wicking kinetics in surface V-grooves

The liquid droplet inertia effect on liquid wicking in V-groove has direct implications to the liquid sample flow in microfluidic devices using V-groove channels and to the ink wicking along the inter-fibre gaps on uncoated paper surfaces, which is critical to the ink jet print quality. In this study liquid droplet inertia and the V-groove geometry is systematically varied to understand the effect of droplet impact, V-groove apex angle and groove width on the liquid wicking rate in the groove. Our results show that both the apex angle and the groove width influence the rate of liquid wicking in V-grooves forced by liquid droplet inertia. The inertia effect lasts for only a short time and its influence to the sample delivery accuracy in V-groove microfluidic devices can be minimised or eliminated by improving microfluidic channel design. On improving ink jet printing quality of uncoated papers, this work shows that applying surface sizing to uncoated ink jet papers is likely to be an effective way to change the geometry of the inter-fibre gaps and therefore can reduce the feathering effect in ink jet printing.