Microfluidic Device： A Miniaturized Platform for Chemical Reactions

Microfluidic devices, as a new miniaturized platform stemming from the field of micro-electromechanical sys-tems, have been used in many disciplines. In the field of chemical reactions, microfluidic device-based microreac-tors have shown great promise in building new chemical technologies and processes with increased speed and reli- ability and reduced sample consumption and cost. This technology has also become a new and effective tool for precise, high-throughput, and automatic analysis of chemical synthesis processes. Compared with conventional chemical laboratory batch methodologies, microfluidic reactors have a number of features, such as high mixing ef- ficiency, short reaction time, high heat-transfer coefficient, small reactant volume, controllable residence time, and high surface-to-volume ratio, among others. Combined with recent advances in microfluidic devices for chemical reactions, this review aims to give an overview of the features and applications of microfluidic devices in the field of chemical synthesis. It also aims to stimulate the development of microfluidic device applications in the field of chemical reactions.     

Paper‐Based Inkjet‐Printed Microfluidic Analytical Devices

Rapid, precise, and reproducible deposition of a broad variety of functional materials, including analytical assay reagents and biomolecules, has made inkjet printing an effective tool for the fabrication of microanalytical devices. A ubiquitous office device as simple as a standard desktop printer with its multiple ink cartridges can be used for this purpose. This Review discusses the combination of inkjet printing technology with paper as a printing substrate for the fabrication of microfluidic paper‐based analytical devices (μPADs), which have developed into a fast‐growing new field in analytical chemistry. After introducing the fundamentals of μPADs and inkjet printing, it touches on topics such as the microfluidic patterning of paper, tailored arrangement of materials, and functionalities achievable exclusively by the inkjet deposition of analytical assay components, before concluding with an outlook on future perspectives.     

Microreactors as Tools for Synthetic Chemists—The Chemists' Round‐Bottomed Flask of the 21st Century?

Will microreactors replace the round‐bottomed flask to perform chemical reactions in the near future? Recent developments in the construction of microstructured reaction devices and their wide‐ranging applications in many different areas of chemistry suggest that they can have a significant impact on the way chemists conduct their experiments. Miniaturizing reactions offers many advantages for the synthetic organic chemist: high‐throughput scanning of reaction conditions, precise control of reaction variables, the use of small quantities of reagents, increased safety parameters, and ready scale‐up of synthetic procedures. A wide range of single‐ and multiphase reactions have now been performed in microfluidic‐based devices. Certainly, microreactors cannot be applied to all chemistries yet and microfluidic systems also have disadvantages. Limited reaction‐time range, high sensitivity to precipitating products, and new physical, chemical, and analytical challenges have to be overcome. This concept article presents an overview of microfluidic devices available for chemical synthesis and evaluates the potential of microreactor technology in organic synthesis.     

Fluorescent sensor array in a microfluidic chip

Miniaturization and automation are highly important issues for the development of high-throughput processes. The area of micro total analysis systems (muTAS) is growing rapidly and the design of new schemes which are suitable for miniaturized analytical devices is of great importance. In this paper we report the immobilization of self-assembled monolayers (SAMs) with metal ion sensing properties, on the walls of glass microchannels. The parallel combinatorial synthesis of sensing SAMs in individually addressable microchannels towards the generation of optical sensor arrays and sensing chips has been developed. [figure: see text] The advantages of microfluidic devices, surface chemistry, parallel synthesis, and combinatorial approaches have been merged to integrate a fluorescent chemical sensor array in a microfluidic chip. Specifically, five different fluorescent self-assembled monolayers have been created on the internal walls of glass microchannels confined in a microfluidic chip.     

Microfluidic chips for mass spectrometry‐based proteomics

Microfluidic devices coupled to mass spectrometers have emerged as excellent tools for solving the complex analytical challenges associated with the field of proteomics. Current proteome identification procedures are accomplished through a series of steps that require many hours of labor‐intensive work. Microfluidics can play an important role in proteomic sample preparation steps prior to mass spectral identification such as sample cleanup, digestion, and separations due to its ability to handle small sample quantities with the potential for high‐throughput parallel analysis. To utilize microfluidic devices for proteomic analysis, an efficient interface between the microchip and the mass spectrometer is required. This tutorial provides an overview of the technologies and applications of microfluidic chips coupled to mass spectrometry for proteome analysis. Various approaches for combining microfluidic devices with electrospray ionization (ESI) and matrix‐assisted laser desorption/ionization (MALDI) are summarized and applications of chip‐based separations and digestion technologies to proteomic analysis are presented. Copyright © 2009 John Wiley & Sons, Ltd.     

微流控芯片上的免疫分析

近20年来,随着微流控芯片加工技术的不断发展,微流控分析已从一个概念发展为当前世界上最前沿的科技领域之一,微流控芯片上免疫分析的方法研究也取得重要进展。这些芯片包含传输流体的微通道和免疫分析程序中部分或全部的必要组件。微流控技术用于免疫分析在减少试剂用量、缩短分析时间、自动化等方面提高了分析性能。本文综述了微流控芯片上免疫分析的发展、分类,并评述了各类微流控免疫分析芯片的性能及优缺点。     

Microfluidics with MALDI analysis for proteomics—A review

Various microfluidic devices have been developed for proteomic analyses and many of these have been designed specifically for mass spectrometry detection. In this review, we present an overview of chip fabrication, microfluidic components, and the interfacing of these devices to matrix-assisted laser desorption ionization (MALDI) mass spectrometry. These devices can be directly coupled to the mass spectrometer for on-line analysis in real-time, or samples can be analyzed on-chip or deposited onto targets for off-line readout. Several approaches for combining microfluidic devices with analytical functions such as sample cleanup, digestion, and separations with MALDI mass spectrometry are discussed.     

Skin‐worn Soft Microfluidic Potentiometric Detection System

A flexible skin‐mounted microfluidic potentiometric device for simultaneous electrochemical monitoring of sodium and potassium in sweat is presented. The wearable device allows efficient natural sweat pumping to the potentiometric detection chamber, containing solid‐contact ion‐selective Na⁺ and K⁺ electrodes, during exercise activity. The fabricated microchip electrolyte‐sensing device displays good analytical performance and addresses sweat mixing and carry‐over issues of early epidermal potentiometric sensors. Such soft skin‐worn microchip platform integrates potentiometric measurement, microfluidic technologies with flexible electronics for real‐time wireless data transmission to mobile devices. The new fully integrated microfluidic electrolyte‐detection device paves the way for practical fitness and health monitoring applications.     

Microfluidics technology for manipulation and analysis of biological cells

Analysis of the profiles and dynamics of molecular components and sub-cellular structures in living cells using microfluidic devices has become a major branch of bioanalytical chemistry during the past decades. Microfluidic systems have shown unique advantages in performing analytical functions such as controlled transportation, immobilization, and manipulation of biological molecules and cells, as well as separation, mixing, and dilution of chemical reagents, which enables the analysis of intracellular parameters and detection of cell metabolites, even on a single-cell level. This article provides an in-depth review on the applications of microfluidic devices for cell-based assays in recent years (2002–2005). Various cell manipulation methods for microfluidic applications, based on magnetic, optical, mechanical, and electrical principles, are described with selected examples of microfluidic devices for cell-based analysis. Microfluidic devices for cell treatment, including cell lysis, cell culture, and cell electroporation, are surveyed and their unique features are introduced. Special attention is devoted to a number of microfluidic devices for cell-based assays, including micro cytometer, microfluidic chemical cytometry, biochemical sensing chip, and whole cell sensing chip.     

Separation of carbohydrates on electrophoresis microchips with controlled electrolysis

This study reports the separation of fructose, galactose, glucose, lactose and sucrose on glass microchip electrophoresis (ME) devices using a microfluidic platform adapted with external reservoirs for controlling the electrolysis phenomenon. The connections between external reservoirs and microfluidic platform were performed by saline bridges created using silicone tubing filled with BGE. The separation conditions were optimized and the best results were achieved using a BGE containing 75 mmol/L NaOH and 15 mmol/L trisodium phosphate. Electrophoretic separations were monitored using a capacitively coupled contactless conductivity detection system. The controlled electrolysis has successfully allowed the application of a higher voltage on the separation channel promoting the baseline separation of five carbohydrates within 180 s with great run‐to‐run repeatability (RSD < 1%). The achieved efficiencies ranged from 45 000 ± 6000 to 70 000 ± 3000 plates/m demonstrating a performance better than ME devices without controlled electrolysis. The proposed system offered good linearity from 1 to 10 mmol/L and LODs between 150 and 740 μmol/L. The use of external tubes for controlling the electrolysis phenomenon on ME devices has solved common problems associated to run‐to‐run repeatability and analytical reliability required for routine and quantitative analysis.     

A rapid,maskless 3D prototyping for fabrication of capillary circuits: Toward urinary protein detection

Proteinuria is an established risk marker for progressive renal function loss and patients would significantly benefit from a point‐of‐care testing. Although extensive work has been done to develop the microfluidic devices for the detection of urinary protein, they need the complicated operation and bulky peripherals. Here, we present a rapid, maskless 3D prototyping for fabrication of capillary fluidic circuits using laser engraving. The capillary circuits can be fabricated in a short amount of time (<10 min) without the requirements of clean‐room facilities and photomasks. The advanced capillary components (e.g., trigger valves, retention valves and retention bursting valves) were fabricated, enabling the sequential liquid delivery and sample‐reagent mixing. With the integration of smartphone‐based detection platform, the microfluidic device can quantify the urinary protein via a colorimetric analysis. By eliminating the bulky and expensive equipment, this smartphone‐based detection platform is portable for on‐site quantitative detection.     

Photopolymerized sol–gel monoliths for separations of glycosylated proteins and peptides in microfluidic chips

Photopolymerized silica sol–gel monoliths, functionalized with boronic acid ligands, have been developed for protein and peptide separations in polydimethylsiloxane microfluidic devices. Pore size characterization of the monoliths was carried out with SEM, image analysis, and differential scanning calorimetry to evaluate both the micron‐sized macropores and the nanometer‐sized mesopores. Monoliths were functionalized with boronic acid using three different immobilization techniques. Batch experiments were conducted to determine the capacity of the monoliths and selectivity toward cis‐diol‐containing compounds. Conalbumin was used as a model glycoprotein, and a tryptic digest of the glycoprotein horseradish peroxidase was used as a peptide mixture to demonstrate proof‐of‐concept extraction of glycoproteins and glycopeptides by the monoliths formulated in polydimethylsiloxane microfluidic chips. For proteins, fluorescence detection was used, whereas the peptide separations employed off‐line analysis using MALDI‐MS.     

Microfluidics: Applications for analytical purposes in chemistry and biochemistry

In this review, we present recent advancements and novel developments in fluidic systems for applied analytical purposes in chemistry, biochemistry, and life science in general that employ and reflect the full benefits of microfluidics. A staggering rise in publications related to integrated, all‐in‐one microfluidic chips capable of separation, reaction, and detection have been observed, all of which realise the principal of micro total analysis systems or lab‐on‐a‐chip. These integrated chips actively adopt the scaling law concepts, utilising the highly developed fabrication techniques. Their aim is to multi‐functionalise and fully automate devices believed to assist the future advancements of point‐of‐care, clinical, and medical diagnostics.     

Fast production of microfluidic devices by CO2 laser engraving of wax‐coated glass slides

Glass is one of the most convenient materials for the development of microfluidic devices. However, most fabrication protocols require long processing times and expensive facilities. As a convenient alternative, polymeric materials have been extensively used due their lower cost and versatility. Although CO₂ laser ablation has been used for fast prototyping on polymeric materials, it cannot be applied to glass devices because the local heating causes thermal stress and results in extensive cracking. A few papers have shown the ablation of channels or thin holes (used as reservoirs) on glass but the process is still far away from yielding functional glass microfluidic devices. To address these shortcomings, this communication describes a simple method to engrave glass‐based capillary electrophoresis devices using standard (1 mm‐thick) microscope glass slides. The process uses a sacrificial layer of wax as heat sink and enables the development of both channels (with semicircular shape) and pass‐through reservoirs. Although microscope images showed some small cracks around the channels (that became irrelevant after sealing the engraved glass layer to PDMS) the proposed strategy is a leap forward in the application of the technology to glass. In order to demonstrate the capabilities of the approach, the separation of dopamine, catechol and uric acid was accomplished in less than 100 s.     

Biosensing in microfluidic channels using fluorescence polarization

Microfabricated microfluidic devices provide useful platforms for sensing and conducting immunoassays for high throughput screening and drug discovery. In this paper, fluorescence polarization (FP) has been used as a technique for probing binding events within 500 μm and smaller microfluidic channels fabricated in polydimethylsiloxane. The binding of concanavalin A to a lectin-dextran and a glycoprotein-acetylcholinesterase has been used to demonstrate the homogeneous, ratioing format of fluorescence polarization for the quick and accurate determination of extremely low concentrations. Concentrations of concanavalin A in the 0.2-1.0 nmole range were detected within 500 μm channels. Polarization has also been used to sense for a polyaromatic hydrocarbon (PAH) within a microfluidic channel using binding to a TRITC-labeled antibody. Specifically, concentrations of pyrene in a 10-40 nmole range were sensed in 500 μm microfluidic channels. We have also demonstrated a simple pH sensor based on the change in anisotropy of a pH sensitive fluorophore-SNAFL. The ease of fabrication and measurement using such polarization-based devices make them extremely suitable for micro-sized sensors, assays and total analysis systems.     

Thermoplastic microfluidic devices and their applications in protein and DNA analysis

Microfluidics is a platform technology that has been used for genomics, proteomics, chemical synthesis, environment monitoring, cellular studies, and other applications. The fabrication materials of microfluidic devices have traditionally included silicon and glass, but plastics have gained increasing attention in the past few years. We focus this review on thermoplastic microfluidic devices and their applications in protein and DNA analysis. We outline the device design and fabrication methods, followed by discussion on the strategies of surface treatment. We then concentrate on several significant advancements in applying thermoplastic microfluidic devices to protein separation, immunoassays, and DNA analysis. Comparison among numerous efforts, as well as the discussion on the challenges and innovation associated with detection, is presented.     

Inexpensive and nonconventional fabrication of microfluidic devices in PMMA based on a soft-embossing protocol

This study describes an inexpensive and nonconventional soft-embossing protocol to produce microfluidic devices in poly(methyl methacrylate) (PMMA). The desirable microfluidic structure was photo-patterned in a poly(vinyl acetate) (PVAc) film deposited on glass substrate to produce a low-relief master. Then, this template was used to generate a high-relief pattern in stiffened PDMS by increasing of curing agent /monomer ratio (1:5) followed by thermal aging in a laboratory oven (200°C for 24 h). The stiffened PDMS masters were used to replicate microfluidic devices in PMMA based on soft embossing at 220–230°C and thermal sealing at 140°C. Both embossing and sealing stages were performed by using binder clips. The proposed protocol has ensured the replication of microfluidic devices in PMMA with great fidelity (>94%). Examples of MCE devices, droplet generator devices and spot test array were successfully demonstrated. For testing MCE devices, a mixture containing inorganic cations was selected as model and the achieved analytical performance did not reveal significant difference from commercial PMMA devices. Water droplets were successfully generated in an oil phase at rate of ca. 60 droplets/min (fixing the continuous phase flow rate at 100 μL/h) with size of ca. 322 ± 6 μm. Glucose colorimetric assay was performed on spot test devices and good detectability level (5 μmol/L) was achieved. The obtained results for two artificial serum samples revealed good agreement with the certified concentrations. Based on the fabrication simplicity and great analytical performance, the proposed soft-embossing protocol may emerge as promising approach for manufacturing PMMA devices.     

Microfluidic Pressure Driven Liquid Chromatography of Biologically Relevant Samples

An overview of the literature regarding the most recent and innovative developments in microfluidic devices for pressure-driven chromatographic separations is given, with a focus on proteomics and metabolomics applications. The applications can be considered as the main driving force for the developments in this research field, since they put high demands on the analytical technology such as for throughput, efficiency, and sensitivity and for the possibilities to interface with mass spectrometry. The developments are evaluated based on the feasibility for use in work flows for the analysis of biologically relevant samples. The literature up to the first half of 2011 is covered. Electrophoretic separations are not within the scope of this review. Several strategies have been described to obtain a retentive phase in microfluidic channels. Open channels with the stationary phase bound to the walls appear to be relatively easy to make. However, the retention in such channels is generally very low for separations of relevant samples. Microfabrication of perfectly ordered topographic structures is the most innovative of the methods discussed for the creation of stationary phases in narrow channels. Several groups work on the improvement of the surface-to-volume ratio in such channels, using different methods, and the developments towards real applications are promising. Channels packed with spherical particles and in situ polymerized monoliths for pressure-driven separations are the most frequently applied. Microfluidic devices with an integrated injection system, a (packed) separation column and a spray tip for coupling to a mass spectrometer are already commercially available, and used in practice in proteomics and metabolomics. Finally, the inherent advantages of microfluidic devices for multidimensional separations have been shown in practice in a number of studies. In these studies, pressure-driven chromatography is coupled (in series or multiplexed) to an electrophoretic separation method. The high peak capacity of such 2-dimensional separations has been shown.

     

Zeta potential determination by streaming current modelization and measurement in electrophoretic microfluidic systems

Electrophoresis in capillary and microfluidic systems, used in analytical chemistry to separate charged species, are quite sensitive to surface phenomena in terms of separation performances. In order to improve theses performances, new surface functionalization techniques are required. There is a need for methods to provide fast and accurate quantification about surface charges at liquid/solid interfaces. We present a fast, simple, and low-cost technique for the measurement of the zeta-potential, via the modelization and the measurement of streaming currents. Due to the small channel cross section in microfluidic devices, the streaming current modelization is easier than the streaming potential measurement. The modelization combines microfluidic simulations based on the Navier-Stokes equation and charge repartition simulations based on the Poisson-Boltzmann equation. This method has been validated with square and circular cross section shape fused-silica capillaries and can be easily transposed to any lab-on-chip microsystems.     

Thread/paper‐ and paper‐based microfluidic devices for glucose assays employing artificial neural networks

This paper describes the fabrication of and data collection from two microfluidic devices: a microfluidic thread/paper based analytical device (μTPAD) and 3D microfluidic paper‐based analytical device (μPAD). Flowing solutions of glucose oxidase (GOx), horseradish peroxidase (HRP), and potassium iodide (KI), through each device, on contact with glucose, generated a calibration curve for each platform. The resultant yellow‐brown color from the reaction indicates oxidation of iodide to iodine. The devices were dried, scanned, and analyzed yielding a correlation between yellow intensity and glucose concentration. A similar procedure, using an unknown concentration of glucose in artificial urine, is conducted and compared to the calibration curve to obtain the unknown value. Studies to quantify glucose in artificial urine showed good correlation between the theoretical and actual concentrations, as percent differences were ≤13.0%. An ANN was trained on the four‐channel CMYK color data from 54 μTPAD and 160 μPAD analysis sites and Pearson correlation coefficients of R = 0.96491 and 0.9739, respectively, were obtained. The ANN was able to correctly classify 94.4% (51 of 54 samples) and 91.2% (146 of 160 samples) of the μTPAD and μPAD analysis sites, respectively. The development of this technology combined with ANN should further facilitate the use of these platforms for colorimetric analysis of other analytes.