Latest Developments in Micro Total Analysis Systems - Analytical

Anal. Chem. 2010, 82, 4830–4847

Latest Developments in Micro Total Analysis Systems Arun Arora,† Giuseppina Simone,† Georgette B. Salieb-Beugelaar,†,| Jung Tae Kim,† and Andreas Manz*,†,‡,§ KIST Europe, Korea Institute of Science and Technology, Campus E71, 66123 Saarbru¨cken, Germany, FRIAS, Freiburg Institute for Advanced Studies, Albert-Ludwigs-Universita¨t Freiburg, Albertstrasse 19, 79104 Freiburg, Germany, IMTEK, Institute for Microsystem Technology, University of Freiburg, Georges-Ko¨hler-Allee 103, 79110 Freiburg, Germany, and MESA+ Institute for Nanotechnology/Lab-on-a-Chip Group, Twente University, Building Carre´, 7500 AE, Enschede, The Netherlands Review Contents Technology Microfabrication Assembly and Interfacing Optical Integration Flow Control Instrumentation Standard Operations Sample Preparation Injection Separation Detection Fluidic Reactors Droplets Applications Clinical Diagnostics General Research Droplets Environment Literature Cited

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The field of micro total analysis systems (µTAS) (1) or lab on a chip (LOC) has extended its usefulness into many new fields and disciplines spanning basic research to commercial applications. The importance of µTAS is reflected in both the growing number and improved quality of published articles. µTAS has expanded into an incredibly diverse number of analytical chemistry applications and has received a great amount of input from a wide spectrum of scientific and engineering disciplines. In this sense, µTAS is highly interdisciplinary and has served as a focal point to bring together multidisciplinary research fields. This work builds on former reviews (2-6) and attempts to chart the most recent developments in µTAS. By cross referencing online keyword searches, several thousand articles were found spread among a wide variety of journals but were most frequently found in the high impact journals such as Science, Nature, PNAS, Analytical Chemistry, Lab on a Chip, and others. The annual international µTAS conference also provided articles on some of the very latest and most promising developments. This review article aims to report the latest achievements in the field of µTAS * To whom correspondence should be addressed. E-mail: manz@ kist-europe.de. † KIST Europe, Korea Institute of Science and Technology. ‡ Albert-Ludwigs-Universita¨t Freiburg. § University of Freiburg. | Twente University.

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by highlighting some of the very best research papers published over the 2 year period between March 2008 and February 2010. Our main goal is to give a broad overview of the latest state-ofthe-art research and to introduce newcomers to the field. We were overwhelmed by the large number of research papers published on cellular analysis, manipulation, and droplet fluidics; therefore, we divided the review into two parts. This first part concentrates on reports related to manufacturing, technology, and instrumentation for molecular analysis, and part two covers applications related to cellular analysis and manipulation, which is referred to as cellson-a-chip (460). The papers we selected on droplet fluidics are distributed throughout both parts of the article according to their applications. We attempted to select papers based on the merit of their contents, which was a difficult task, and we have missed some good articles; for these oversights, we offer our apology in advance. Since this review focuses on novel developments of microfluidic systems for applied analytical chemical applications, publications about sensor arrays (so-called “biochips”), chemical synthesis on microchips (except some papers on particle synthesis using droplets), theory, and simulations, as well as trend articles, have been omitted. Furthermore, we reduced the technology section, as the majority of work is carried out by employing simple planar microchips fabricated in glass or polymers such as silicone elastomers. TECHNOLOGY Microfabrication. Conventional Microfabrication. Many new innovative approaches have been reported in the field of microfabrication. Semicircular cross section channels network microfabricated on a silicon chip by XeF2 etching by Camp et al. (7). These channels allow stress free transportation of cells. Generally, vapor deposited thin film metal electrodes on glass substrates are fragile, and the problem is addressed by the O’Hare group by developing a microfabrication technology for inlaid electrodes and using them for whole column electrochemical detection in high performance liquid chromatography (HPLC) (8). Tamanaha et al. reported a universal mechanism that enables repeatable and rapid-attachment of fluid cells to planar substrates (9). All required components have been quickly prototyped using computer numerical control (CNC) machining. The fabrication of disposable and flexible fluidic 10.1021/ac100969k  2010 American Chemical Society Published on Web 05/12/2010

microchip using thin polymer film by microthermo forming has been developed by the Welle group (10). A two-stage embossing technology has been developed by Koesdjojo et al. to produce a capillary electrophoresis (CE) chip on poly(methyl methacrylate) (PMMA) that is sealed by solvent welding (11). The Sautner group reported the fabrication of 20 nm single lines of cellulose acetate using electron-beam lithography (12). Developments in the field of rapid prototyping have also been reported. Wu et al. developed movable devices and functional microvalves using femtosecond laser-based prototyping (13). Multilayered thiolene microfluidic chips have been produced using photopolymerization and transfer lamination by the Mistura group (14). Sundaram and co-workers synthesized microvascular channel networks with semicircular cross sections for quantitative analysis of particle adhesion (15). Nanofilters in silicon microfluidic channels have been reported by the Chen group for plasma separation (16). Microstructures with 3D features are highly useful for µTAS applications. Therriault and co-workers fabricated a 3D microfluidic network by the direct-write assembly method that consists of a robotized deposition of fugitive ink filaments on an epoxy substrate (17). Thermoresponsive hydrogel poly(N-isopropylacrylamide) has been used by the Han group to create 10 µm patterns on glass substrates for biomedical applications (18). Mass producible microcontainers to encapsulate glass beads, fabricated using conventional lithography, have been reported by Leong et al. (19). The Ugaz group reported on a 3D vascular network by electron beam irradiation to implant electric charge inside various plastic substrates so that the energy released upon discharge vaporizes and factures the surrounding material (20). 3D polystyrene microfluidic chips have fabricated by direct rapid patterning and subsequent stacking by Chen et al. (21). A low cost and easy to use method for fabricating 3D microfluidic devices using threads has been reported by Li et al. (22). Martinez et al. have demonstrated a paper-based 3D microfluidic device fabricated with layered paper and double-sided adhesive tape (23). White cotton-based yarn has been used to fabricate elements of a complex microfluidic circuit (24). 3D channels in glass, fabricated using a powder blasting technology, with varying channel topography has been used as a microfluidic mixer by Gijs and co-workers (25). Klein and co-workers fabricated solenoidal microcoils with a hollow core in borosilicate glass using an anodic wire bonder (26). 3D high aspect ratio microcoils on silicon and pyrex wafers around an epoxy-based negative photoresist (SU8) posts have been reported by the Wallrabe group (27, 28). The Whitesides group has reported paper as a substrate for various microfluidic devices and applications. They used polydimethyldisiloxane (PDMS) barriers to define microchannels on a paper using low cost printing (29); wax printing for micropatterning hydrophobic barriers (30), fast lithographic activation of sheets (31), and paper-based plates containing 96 and 384 microzones (32). Deep and rounded patterns have been fabricated using the shrinkage properties of biaxially oriented polystyrene thermoplastic sheets by Khine and co-workers (33). The Erickson group developed a method for fabricating 60 nm nanochannels using controlled elastomeric collapse of PDMS and used these channels for DNA elongation (34). A concept of rail microfluidics

for the self-assembly of interesting microstructures inside microfluidic channels has been developed by the Kwon group (35). Surface Modification. Surface modification is an important aspect of the microfabrication to achieve application specific desired surface properties in a microfluidic device. PDMS swells significantly in the presence of many organic solvents, thus degrading the material properties and limiting its use in some applications. The Weitz group reported a glass coating for PDMS channels using sol-gel methods (36). In order to resist protein adsorption, Lee and co-workers grafted a polyethylene glycol (PEG) layer on the surface of a microchannel by atom transfer radical polymerization (37). Radha and Kulkarni have patterned sub-100 nm palladium nanowires using a conventional micromolding method (38). Hao et al. have presented an electrodeless method for region selective gold plating on PDMS substrates and allowed thiol-compounds to form self-assembled monolayers (SAM) on their surfaces (39). These gold plates have been used as an integrated amperometric detection element in a PDMS CE chip. The Harrison group photopatterned porous polymer monoliths on-chip for the electrophoretic separation of proteins (40). An optically coated mirror has been embedded in microchannels by Choi and Park to measure hydrophoretic particles ordering in 3D (41). Gan and co-workers have functionalized PDMS microfluidic channels with dextran derivative for enhancing hydrophilicity and protein immobilization (42). Silane dextran has been used to control hydrophilicity on a lateral flow polymer chip for immunoassays by Jonsson et al. (43). The Yager group reported the storage of dry reagents for immunoassays on automated on-card assays, useful for third world clinical diagnostic applications (44). The stored gold-antibody conjugates were dried in a variety of sugar matrixes and have been shown to retain 80-96% of their activity after 60 days of storage at elevated temperatures. Streptavidin coated bead micropatterns have been electrostatically assembled by Gijs and co-workers for on-chip immunoassays (45). Smith et al. reported micropatterned lipid bilayer arrays for high-throughput analysis and biomolecular detection (46). Self-assembled monolayers consisting of immobilized synthetic peptides in microchannels for toxin sensing has been reported by the Beebe group (47). Taylor et al. reported a cross-patterned tethered bilayer lipid membrane array on a PDMS microchip for cell-based receptor protein analysis (48). A DNA oligonucelotide microarray on a glass substrate has been reported by Niemeyer and co-workers for the immobilization of oligonucleotide-tagged compounds (49). The Yoo group has fabricated micropillars in a PDMS microfluidic device for enhancing the detection of hazardous chemicals with a portable surface enhanced Raman scattering (SERS) sensor (50). An electrokinetically active microwell has been fabricated by Erickson and co-workers for enhancing SERS-based detection of biomolecules (51). Wilson et al. have reported SERS signal enhancements (∼50 fM) by in situ synthesis of silver colloid in a microfluidic flow structure (52). A microfluidic device containing an array of gold spots has been reported by Zare and co-workers for immobilization of antigen and antibodies for surface plasmon resonance (SPR) imaging (53). Assembly and Interfacing. Bonding. Most microfluidic applications require sealing of channels either with the substrate of the same material or to a different inert material. Glass to glass Analytical Chemistry, Vol. 82, No. 12, June 15, 2010

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substrate bonding can be difficult, and the process requires optimization batch fabrication. Allen and Chiu reported a Ca2+ assisted glass to glass bonding technique that eliminates 10 h heating and cooling cycles, which are typically required in conventional fusion bonding (54). Fluorinated ethylene propylene (FEP) sheets between two glass or silicon substrates have been used to bond substrates at room temperature by the Gardeniers group. Using this method, an average tensile strength of ∼5 MPa has been reported for silicon-silicon and glass-glass bonded composites (55). Sofla and Martin presented a vapor assisted PDMS to glass substrate bonding method using fluoroalkyl trichlorosilane vapor (56). Vaporized organic solvent and temperature assisted bonding of hard and soft polymer have been reported by Koesdjojo et al. and used for HPLC applications (57). The Zengerle group reported bonding of 3D polystyrene microfluidic structures (58). Bonding processes for a wide variety of polymeric and inorganic materials including flexible substrates with a high strength using nanoadhesive has been reported by Gleason and coworkers (59). Lee and Ram bonded amino-propyltriethoxysilane (APTES) to polycarbonate (PC) and PMMA surfaces (60). The devices were able to withstand peristaltic actuation of 18 psi for 2 weeks. Low temperature (60 °C) bonding of PMMA substrates using ultrasonic energy resulted in a 10-fold increase in bonding strength compared to previous reports according to the Luo group (61). Thermally assisted ultrasonic bonding of 12 PMMA layers for microfluidic applications has been developed by Zhang et al. (62). The Parameswaran group used low cost microwave induction to bond PMMA microfluidic devices (63). Interconnect. Fluidic interconnections may appear unimportant for microfluidic chip research; however, it is a challenging task for non-engineers. Yuen reported a plug-n-play modular microfluidic system (64). The modules can be easily connected together to design and build microfluidic systems for biological and chemical applications. Reusable, rapid, multiple, and planar microfluidic interconnections have been presented by Sabourin and Dufva, which are able to withstand average pressure differences of 5.5 bar (65). A reconfigurable distributed elastomer microfluidic system capable of various liquid manipulations such as pumping, mixing, splitting, and circulating flow have been developed by Chang and Maharbiz (66). Rhee and Burns fabricated assembly blocks for standard microfluidic features like cross channel, zigzag channel, pneumatic valve, culture beds, etc (67). Microfluidic circuit boards with passive channels require interconnections to mount active modular components. A combination of SU8, PDMS, and silicone structures for microfluidic interconnections have been employed by Jaffer and Gray (68). Schmid and co-workers reported a leak-free and reversible fluidic interface for a PMMA chip and a glass chip able to withstand maximum pressures of 2070 kPa (69). A multiaxial stretchable interconnect has developed by the Ziaie group (70). The interconnects are based on liquidalloy-filled elastomeric microchannels. Cooksey et al. used a vacuum manifold for interfacing elastomeric devices with as high as 51 fluid inlets, 144 chambers, and hundreds of pneumatic valves (71). UV curable glue has been used to connect capillaries and optical fibers to a chip fabricated with tappers and stop features by Hartmann et al. (72). A commercially feasible sensor and fluidic 4832


integration process in terms of robustness, scalability, and costs has been presented by the Iersel group for bioanalytical applications (73). The Wheeler group has presented removable polymer coverings (skins) to prevent cross-contamination and to serve reagents on digital microfluidic (DMF) devices (74). Magnetic clamps (75) and connectors (76) have also been used for interconnecting PDMS microfluidic chips to reagent inlets and waste outlets. A threaded needle has been used for high internal microchannel pressure (up to 40 MPa) interfacing for cyclic olefin polymer by DeVoe and co-workers (77). Nonspecific adsorption is a challenge when interfacing DMF. Luo et al. have fabricated semipermeable chitosan membranes by generating pH gradients inside PDMS channel junctions (78). Lipid nanotubes with high axial ratios have been fabricated using microfluidic tweezing by West and co-workers for cellular processes (79). A lock-andrelease lithography method inside a microchannel using masked UV light bursts to polymerize composite microparticles and then releasing them to be collected downstream has been developed by the Doyle group (80). Interfacing. Utilizing the advantages of online sample preparation on a microfluidic chip and coupling it with commercial analytical systems like electrospray ionization mass spectrometry (ESI-MS) or MALDI-MS is very difficult. Lee et al. developed a sequential mixing reaction at nanoliter volumes and dispensed the mixer through a nozzle to a matrix assisted laser desorption/ ionization (MALDI) target plate (81). A glass microfluidic device that incorporates an integrated electrokinetic pressure pump to transport electrophoretically separated components from separation channel to electrospray tip has been reported by the Ramsey group (82). Kelly et al. reported a PDMS microchip consisting of an auxiliary channel to provide electrical contact for stable conejet electrospray without significant sample loss (83). Replaceable on-chip digestion of tryptic and coupling of the chip with ESI-MS has been reported by Foret and co-workers (84). Her and co-workers reported a PMMA-CE microchip and a flat low sheath flow ESI-MS interface with a removal ESI sprayer (85). An electrochemical pump fabricated on a COC substrate with an SU8 tip for electrospray and coupling with ionization MS has been reported by the Craighead group (86). Semicontinuous monitoring of aerosol chemical composition has been achieved by coupling a growth tube particle collector to a CE microfluidic device by the Henry group (87). Design. Application specific objectives of microfluidic systems are achievable through design. Choi et al. have presented an optofluidic CD-based platform for additional enhancements of SERS signals (88). Isoelectric focusing (IEF) has been combined with sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis (PAGE) for protein separation by Yang and co-workers (89). The Locascio group reported a microfluidic palette capable of generating multiple spatial chemical gradients simultaneously (90). Synthetic microvascular network (SMN) on a PDMS chip has been presented by the Kiani group that can serve as an in vitro model of the bifurcations, tortuosities, and cross sectional changes found in vivo networks (91). Airborn narcotics detected using an integrated quartz crystal microbalance and a liquid assay have been reported by Frisk et al. (92). Portability is an important feature for a microfluidic system. A portable high throughput

capillary array electrophoresis system capable of detecting labeled arginine has been presented by the Wang group (93). Li and coworkers developed double spiral nucleic acid microarray formats with up to 384 assays (94). A slip chip with multiple reagents for protein screening has been described by the Ismagilov group (95). Optical Integration. Optical detection is a popular choice for microfluidic systems due to low output signal contamination. Various designs and methods have been reported for optimized signal enhancement and collection. Lenses and Waveguides. Rosenauer and Vellekoop presented a liquid core 3D lens based on twin cladding waveguide microflow cell fabricated by rapid prototyping (96). Liquid core liquid cladding optofluidic lenses have been modeled and optimized by Song and co-workers (97). Xiong et al. reported a liquid microlens with tunable focal length and transmission properties (98). A dynamically reconfigurable liquid-core/liquid-cladding lens in a microfluidic channel has been developed by the Whitesides group (99). Huang and co-workers have fabricated a tunable liquid gradient lens able to tune the focal distance and redirect the output light direction (100). A planar waveguide embedded in a multichannel PMMA fluidic chip has been reported by Okagbare et al., which generates an evanescent field into the sampling solution (101). Liu et al. have integrated a liquid waveguide-based evanescent wave sensor in which the profile of the output light changes by varying sample concentrations (102). A reconfigurable photonic material has been developed by Erikson and co-workers that is able to transfer light between a liquid and solid optofluidic waveguide (103). The Okada group has demonstrated liquid core waveguide functionality using an organic solvent in a channel made by a tungsten wire in a water-ice chip (104). Flow Control. Pumps. Precise control is required when transporting samples in microfluidic devices, which can be achieved by properly designing channel networks with integrated mechanical or electrical actuation or temperature or pressure gradients. The Grzybowski group has demonstrated liquid flow in an open channel maze using pH gradients (105). An artificial microsurface tension sensitive alveolus at a gas liquid interface in a glass substrate has been reported by Peng et al. to facilitate rapid gas exchange that creates positive pressure in the channels for pumping (106). Dijkink et al. presented a laser induced cavitation pump to achieve flow rates of ∼3.2 µL min-1 with a pressure drop of 3 bar (107). Temperature sensitive hydrogelbased micropumps have been reported by the Klenke group (108). Burns and co-workers reported an acoustically driven programmable liquid motion using resonance cavities capable of producing pressures up to 200 Pa (109). Optically pumping dye molecules through a thin ice sheet by repetitive melting and freezing with a heating laser has been demonstrated in a 10 µm wide channel by Braun and co-workers (110). Using this method, a flow speed of more than 5 cm s-1 was reported. Directional formation of virtual electrowetting channels of ∼20 µm by application of voltage to an array of polymer posts coated with copper and hydrophobic dielectric material has been demonstrated by Dhindsa et al. (461). By specific arrangement of posts the group has demonstrated splitting and merging of channels. Yetter and co-workers reported a hydroxylammonium nitrate (HAN)-based liquid monopropellant microthruster, which was ignited with 45 V to produce a thrust output of 150

mN (111). The use of frequency modulated ultrasonic actuation was reported for the flow free transport of cells in a 5 mm long channel by Manneberg et al. (112). Bowser and Graf fabricated a piezoelectric-based peristaltic micropump capable of delivering flow rates as low as 53 nL min-1 (113). A surface acoustic wave-based ultrafast microfluidics pump has been reported by Yeo et al. (114). Pumping based on external actuation of air bubbles trapped in lateral channels has been reported by Tovar et al. (115). Low power electro-hydraulic pumps which work on gas pressure generated by electrolysis of pumping fluid was reported by the Batt group (116) and Cooper group (117). Collins and co-workers have integrated an electroosmotic flow (EOF)-based high pressure pump on a liquid chromatography (LC) microchip (118). Pneumatic pressure pumping generated by breaking vacuum capillaries encapsulated in a point-of-care immunoassay fluidic card has been reported by Weng et al. (119). Lynn and Dandy have reported the passive pumping in a microfluidic network caused by a small curved meniscus situated along the bottom corner of an outlet reservoir (120). High speed sheer driven flows through 300 nm deep channels microstructured with diamond shaped pillars have been presented by the Desmet group (121). Fahrni et al. demonstrated microfluidic pumping (fluid velocities up to 0.5 mm s-1) caused by magnetic artificial cilia actuation with a rotating magnetic field generated with a compact external electromagnet (122). Valving and Switching. Controlling microfluidic flow and delivering precise volumes are critical components of a microfluidic system. By applying Marangoni flow, which is the movement of liquids due to surface tension gradients, Basu and Gianchandani demonstrated virtual microfluidic traps, filters, and pumps (123). A self-blocking valve has been presented by the Stetten group for a highly wetting fluid (124). Tsougeni et al. fabricated polymeric microfluidics by plasma processing to control wetting and used it for capillary filling and hydrophobic valving (125). Chen et al. demonstrated a light actuated microvalve fabricated with a thermoresponsive nanostructured polymer, able to withstand a leakage pressure up to 1350 psi (126). Pressurebased actuation has been a popular method for operating valves in microfluidics systems (127-132). The Diamond group reported four ionic liquid polymer gel-based light actuated valves which can open the channel in seconds (133). Various screw-based mechanical valves have been reported that use a threaded needle (134), tape underlayment rotary-node (135), small machine screws (136), and 3 mm diameter screws (137). Sugiura et al. used micropatterned photoresponsive hydrogel sheets to control flow by light irradiation (138). Magnetically actuated-based valves have been reported by various groups. Ghosh et al. fabricated microvalves actuated by an oscillating magnetic field (139). Hilt and co-workers used magnetic hydrogel nanocomposites to construct a microfluidic valve (140). An electromagnetically actuated rotary gate microvalve has been presented by Luharuka and Hesketh (141). Mixers. Non-turbulent flow in microfluidic channels make mixing a challenging task. The problem has been addressed in various ways, for example, by integrating mixer design elements, concentration gradients, temperature gradients, and external mechanical actuation. Mair et al. have reported a photopatterned Analytical Chemistry, Vol. 82, No. 12, June 15, 2010

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porous polymer inside a microfluidic channel as a passive micromixer (142). A mixing unit consisting of parallel oblique grooves integrated in a microchannel has been demonstrated by Girault and co-workers (143). The Papautsky group fabricated rectangular obstacles to enhance mixing (144). A mixer consisting of a “T” junction followed by three repeats and an alcove each with a triangular obstruction has been reported by Yeh and coworkers (145). Mei et al. have fabricated staggered herringbone mixers to study luciferase detection (146). Microfluidic mixers using filter posts have been reported for rapid protein folding kinetics investigation by Kane et al. (147). The Yang group have fabricated 3D nanostructures using holography for passive micromixing (148). Obstruction pairs in a microfluidic channel have been integrated for chaotic mixing by Kwon and co-workers (149). Reagent concentration control in microfluidic devices has been achieved by complex channel networks and has been reported by various groups. Zhou et al. have reported the generation of complex concentration profiles by partial diffusive mixing (150). A serial dilution microfluidic device has been fabricated by the Kang group consisting of a ladder network for generating logarithmic or linear concentrations (151). Lee et al. have reported a serial dilution module to generate monotonic and arbitrary gradients (152). A microfluidic perfusion system capable of offering combinatorial choice of inputs, mixtures, gradients patterns, and flow rates to a cell culture chamber has been developed by Folch and co-workers (153). Jiang and co-workers reported a modular microfluidic generator for generating gradients of arbitrary profiles (154). An arbitrary monotonic concentration profile by a serial dilution microfluidic channel network has been reported by Hattori et al. (155). The Hong group fabricated a microfluidic channel network capable of sample metering, mixing, and incubating for the determination of kinetic parameters of an enzymatic reaction (156). External mechanical actuation methods are commonly reported for enhancing mixing in microfluidic devices. Ahmed et al. have used trapped bubble acoustic streaming using a piezo transducer (157). An integrated surface acoustic wave has been used by Charette and co-workers for effective mixing in microchannels (158). The Chung group presented a low voltage polyelectrolytic ion extractor-based micromixer (159). An electroosmotic and electrothermal-based mixer in a flow channel has been reported by Ng et al. (160). Wu and Li have used induced charge electrokinetic flow in a rectangular microfluidic channel with embedded conducting hurdles for micromixing (161). Induced charge electroosmosis has been exploited by Kanouff and coworkers to generate microvortices for mixing (162). The Kurabayashi group has used temperature programmed natural convections in a polymerase chain reaction (PCR) chip for micromixing (163). Microfabricated artificial cilia consisting of electrostatically actuated polymer structures integrated in microfluidic channels have been used by Toonder et al. for micromixing (164). Jesorka and co-workers have reported on a microfluidic diluter based on pulse width flow modulation (165). Instrumentation. This section surveys various types of instrumentation commonly used with microfluidic systems, with the aim of achieving some level of automation and portability. 4834


Quake and co-workers have reported on an automated microfluidic immunoprecipitation from 2000 cells (166). A microfluidic system has been reported for toxicity testing of potable water using a trout derived gill cell line (167). Low cost is a key issue for the point of care testing devices and systems. The Ahn group has reported a lab-on-a-chip system with a disposable polymer device capable of detecting glucose lactate and partial oxygen from 3.5 µL in 100 s (168). Detection of antibodies to HIV in saliva has been reported using a timer actuated cassette by the Bau group (169). In this portable system, the automated timely pumping of various reagents was driven by a spring-loaded timer. A portable disk-based enzyme-linked immunosorbent assay (ELISA) system is reported by Lee et al. to test infectious diseases from whole blood in 30 min (170). Rosenauer and Vellekoop reported a compact four color microchip electrophoresis-based genotyping system for DNA sequencing (171). An automated and polymeric cartridge-based system for the simultaneous detection of multiple antibiotics in raw milk has been developed. The authors claimed 95% accuracy for multiplexed measurements (172). Mathies and co-workers have developed a prototype multichannel Mars organic analyzer capable of performing CE assays of organic sugars, aldehydes, and acids (173). A continuous microanalyzer has been developed by integrating microfluidics and electronics for two different analytes K4Fe(CN)6 and free chlorine (174). Sista et al. have developed a point of care testing device based on a digital microfluidic platform capable of performing a rapid immunoassay for cardiac troponin I in less than 8 min (175). A CE system with an integrated high voltage power supply and a laser induced fluorescence (LIF) detector on a 3 mm2 chip has been developed by the Elliott group (176). STANDARD OPERATIONS Sample Preparation. Various articles have been reported that contain specific procedures for sample preparation prior to separation or analysis. Phase Extractions and Concentrations. Castell et al. have reported a continuous solvent extraction on-chip for sample enrichment (177). A protein concentration of 20 000-fold has been reported by Baba and co-workers using isotachophoresis (ITP) (178). Huyang and Yang developed a nanochannel-based concentrator utilizing a concentration polarization effect (179). Bipolar electrodes for localized concentration and enrichment of dye molecules has been reported by Laws et al. The demonstrated efficiency of their device was shown by an enrichment factor of ∼600 in 400 s (180). Timperman and co-workers have investigated zone migration in nanofluidic membrane for analyte concentration (181). Kim and Meyhofer have integrated microtubules and cytoskeletal filaments in a nanofluidic device and used the nanoscopic binding sites for specific target biomolecules (182). Local concentration gradients have been generated by Jong et al. by contacting gas and liquid phases (183). The Toner group has used superparamagnetic nanoparticles for the concentration of virus type 1 virions (184). A microchip-based solid-phase extraction method has been described by Hagan et al. for purification of RNA (185). The Mathies group has integrated PCR sample cleanup and preconcentration steps for forensic short tandem repeat analysis (186). An on-chip preconcentration method by combining field-amplified sample injection and bovine serum albumin (BSA) sweeping for green fluorescent protein (GFP)

detection has been developed by Pan and Zhao (187). The Han group has preconcentrated proteins (188) using nanoporous junctions and also has enhanced sensitivity for immunosensors using a nanofluidic preconcentrator (189). Silicon pillar arrays have been optimized by Hwang et al. for bacterial adhesion to separate them from whole blood (190). Jones and co-workers have enriched and dispensed biomolecules in nanoliter size droplets using dielectrophoresis (DEP) liquid actuation (191). Purification of nucleic acids from whole blood has been demonstrated by the Santiago group using ITP (192). Microevaporation of sample onchip has been reported by Puleo and Wang to achieve an attomolar detection limit (193). Anazawa and co-workers have reported vacuum membrane distillation for rectification of a water-methanol mixture (194). A bead-based concentration method via evaporation at an isolated port has been developed by Frisk et al. for released fluorescent fragments and has been detected using optical microscopy (195). The Powell group has manipulated a fluid to transport protein out of gel into a low EOF-CE microfluidic channel for separation (196). A lipid mesophase has been generated by Perry et al. for membrane protein crystallization (197). Yamamoto et al. have fabricated in situ preconcentrators on a PDMS CE chip (198). Proteins. Sun et al. have reported an affinity monolithic integrated PMMA CE device for protein extraction (199). Genetically engineered short hydrophobic tags have been reported by Singh and co-workers to select the protein of interest by strong bias partitioning into a PEG-rich phase on a microfluidic device (200). DNA. The Landers group has used chitosan coated silica solid phase for RNA purification (201) and acoustic differential extraction of DNA in forensic analysis (202). Magnetic bead-based binding of aptamers and nucleic acid molecules to their molecular targets with high affinity and specificity has been reported by Lou et al. (203). Lee and co-workers have demonstrated magnetic bead-based extraction of RNA (204). Streptavidin coated magnetic particles as solid supports have been reported by Peyman et al. for bioanalysis in continuous flow (205). Zuilhof and co-workers have patterned silicon oxide microchannel photochemically with a functional linker for DNA immobilization (206). Serial DNA immobilization using UV in fused silica microchip channels has been reported by the Kitamori group (207). Hybridization. Swami et al. have used constriction-based DEP and a nanostructured edge sensor within a microfluidic channel for enhancing DNA hybridization (208). Fast DNA hybridization by optimizing fluidic velocities and temperature has been reported by Zhao and co-workers (209). Amplification. Kempitiya et al. have reported localized microwave heating in a microwell that enables fast heating and cooling rates of ∼7 °C s-1 for parallel DNA amplification (210). A platform for rolling-circle and circle-to-circle amplification on a CE microchip for highly specific and fast gene detection has been developed by Baba and co-workers (211). The Kim group has used integrated microheaters and nanoporous sol-gel arrays for elution of aptamers (212). A DNA arrayed thin film transistor photosensor with chemiluminescence detection system has been reported by Hatakeyama et al. for single nucleotide polymorphism (213). Lee and co-workers have demonstrated an integrated tmRNA purification and nucleic

acid sequence-based amplification device incorporating realtime detection (214). The Mathies group has integrated cell preconcentration, purification, PCR, and CE on a microfluidic for E. coli detection (215). Enzymatic Assays. Tsukahara et al. have explored the enzymatic reaction of β-galactoside in a Y-shaped nanospace channel (216). PDMS-gold nanoparticle composite films have been synthesized by Chen and co-workers to immobilize glucose oxidase (GOx) enzyme (217). Injection. Injection and Dispensing. Controlled and repeatable sample injection and precise dispensing of reagents are crucial for the reliable operation of a microfluidic devices. Price et al. have explored the properties of electroactive polymer actuation to control the injection volume in a microfluidic channel (218). A parallel picoliter dispensing system has been developed by Koltay and co-workers (219). Huang and Lee demonstrated a pneumatically driven dispenser for submicroliter pipetting (220). A perfusion system for automated delivery of temporal concentration gradients to islets of Langerhans has been reported by Zhang and Roper (221). The Wheeler group used DMF for sample pretreatment and subsequent injection of droplets for separation in a microfluidic channel (222). Noori et al. have fabricated a microinjector for electroosmotic dosage control (223). Sample transport by EOF from a microchannel to an array of parallel microchannels has been optimized by DeVoe and co-workers (224). The Hardt group used ITP transport for sample handling (225). Hydrostatic pressure sample injection by tilting the device in a disposable CE device has been demonstrated by the Zhu group (226). Hirokawa et al. have combined electrokinetic injection and ITP preconcentration of sample in a separation channel (227). Dielectric elastomer actuators has been integrated in a PDMS microfluidic CE device by Price and Culbertson for varying volume injections (228). Fu and co-workers have observed a droplet splitting phenomenon at the capillary and inlet-end and used this to define picoliter scale injection for CE (229). Separation. Particles Separation. Jung et al. have filtered particles using an acoustic particle filter with adjustable pore size (230). A particle focusing mechanism has been developed by Gossett and Carlo using curved confined flow for the separation of cells and particles (231). Di Carlo et al. have separated particles and blood platelets using differential inertial focusing (232). Continuous particle separation using inertial forces, the Dean rotation force due to the spiral microchannel geometry, and differential migration has been reported by Papautsky and coworkers (233). Park and Jung have separated particles using a series of contraction and expansion microchannels (234). Rail microfluidic for sorting of four directionally oriented microstructures has been used by Park et al (235). Shi et al. have used standing surface acoustic waves for continuous particle separation (236). Acoustically oscillating bubbles have been reported to sort and manipulate particles, beads, and cells (237, 238). The Soh group has integrated acoustic and magnetic elements to direct particle separation into a buffer stream (239). Geometrical magnetic trapping of nanoparticle chains for immunoassays has been reported by Lacharme et al. (240). Gijs and co-workers have manipulated supermagnetic beads for an immune-agglutination assay (241). pH sensitive magnetic nanoparticles have been separated by Stayton and co-workers in continuous flow (242). Analytical Chemistry, Vol. 82, No. 12, June 15, 2010

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Ghubade et al. have demonstrated dielectrophoresis (DEP) assisted concentration of microparticles (243). Pulsed DEP-based separation of particles has been reported by Lim and co-workers (244). Applegate and Squier have used a fiber focused diode bar for optical trapping and manipulation of particles (245). Electrohydrodynamically induced vertical flow for particles accumulation, filtering, and separation has been developed by Duschl and co-workers (246). Jellema et al. have sorted charged particles by hydrodynamic and electrokinetic effects (247). Micro and nanoparticle transport and concentration by combining light actuation and AC electroosmosis have been developed by the Wu group (248). Matsue and co-workers have used microwell electrodes for selective manipulation of microbeads (249). Analytes Separation. Ross and Kralj reported multiplexed electrophoretic separation using gradient elution (250). They demonstrated the separation using a 16-channel array device for high-throughput, time-series measurements of enzyme activity and inhibition. Allen et al. have separated the contents of a single mitochondria by CE (251). Fractionation of multiple components from a complex sample and their separation by CE has been reported by Gardeniers and co-workers (252). The Barron group has used a hybrid separation mechanism consisting of a unique polymer matrix capable of sequencing 600 bases in 6.5 min (253). The Sweedler group has reported a multilayered 3D hybrid micro/nanofluidic CE device for multidimensional separation of a chiral amino acid mixture (254). Kato et al. have reported femto liquid chromatography (fLC) consisting of a separation column fabricated on a glass microchip with channel width and depth of a few hundred nanometers resulting in subpicoliter per minute flow rates and injection volumes of a few hundred attoliters (255). A 2 mm stationary phase for the separation of FITC labeled IgG and insulin by capillary electrochromatograpy (CEC) in less than 10 s has been reported by Harrison and co-workers (256). The Wheeler group has implemented gradient elution in electrochromatography, in which multiple run buffers are velocity matched on a microfluidic chip (257). Micellar electrokinetic chromatography (MEKC) for the separation of carbamate pesticides has been developed by Smirnova et al (258). Cai et al. have reported channel free shear driven circular chromatography. They have demonstrated the function of the device by separating model analytes (259). Continuous fractionation of two component mixture by zone electrophoresis has been presented by Zalewski and Gardeniers (260). Kohlheyer and co-workers demonstrated free flow electrophoresis (FFE) in a microfluidic device with integrated Pt electrodes. The bubble generation near the electrodes was suppressed by adding adequate chemical substitutes (261). DNA Separation. Wu et al. have grown aligned carbon nanotubes in a nanochannel and used them for the separation of double strand DNA (dsDNA) fragments (262). A CE quartz chip for selective single strand DNA (ssDNA) and dsDNA fractionation has been reported by Misawa and co-workers. The devices use new blocking, extraction, transfer, and cleaning functions (263). The Patel group has incorporated oligonucleotide hybridization on a microfluidic electrokinetic chip for the separation of ssDNA and dsDNA as a function of sodium ion concentration (264). Mutation. Stenirri et al. integrated single-photon avalanche diodes with a dual color CE microchip for characterization of 4836


mutation in disease genes (265). A dual channel CE chip for rapid mutation detection via heteroduplex analysis has been developed by Kulah and co-workers (266). The Soper group explored ligase detection reaction for the analysis of point of mutation using free solution conjugate electrophoresis in a polymer microfluidic device (267). Xie et al. reported an integrated restriction digestion reaction on a glass-PDMS hybrid CE chip. The chip performs restriction digestion reaction and was used for DNA fragments analysis (268). Proteins. Blood plasma is one of the most important fluids for clinical diagnostics. Changes in plasma protein profile reflect a physiological or pathological condition associated with many human diseases. Fan et al. have reported a multiple DNA-encoded antibody barcode chip capable of separating plasma from a finger prick of blood and in situ measurements of proteins (269). Yu et al. have developed a polymer CE microchip for proteins labeled with a chameleon dye and report a limit of detection (LOD) of 1 µg mL-1 (270). A nanosieve fluidic device has been developed by Yamada et al. for the separation of disease marker proteins (271). Immunoassays. Do and Ahn have reported a magnetic beadbased immunoassay microfluidic device with on-chip sampling and detection of mouse IgG with a LOD of 16.4 ng mL-1 (272). A microfluidic immunoassay for the rapid determination of clenbuterol, one of the most widely used β-agonists by athletes for strength and power enhancement, has been developed by Kong et al. (273). Rasooly and co-workers have reported a microfluidic system for activity analysis of botulinum neurotoxin, a toxin secreted by C. botulinum (274). A microvalve actuated sandwich immunoassay using an integrated microfluidic system has been developed by the Lin group. The device is capable of detecting human IgG with a LOD less than 10 ng mL-1 (275). Gervais and Delamarche have presented a capillary driven PDMS microfluidic device for point of care immunodiagnostics capable of detecting cardiac marker proteins in 5 µL of human serum with a LOD of 1 ng mL-1 within 14 min (276). Others. Boyd et al. have used bubble assisted interphase mass transfer for chemical separations (277). Molecular imprinting on microchannel walls has been reported by Ju and co-workers to produce an amperometric sensor for the detection of separated chiral compounds (278). Hibara et al. have explored microfluidic distillation using micro/nano combined structures (279). An electrofluidic dynamic device to avoid mixing of two solution streams in a microfluidic channel has been developed by Chen and co-workers (280). The Mayhofer group has developed a biomolecular motor driven protein concentrating and sorting technique on a microfluidic chip that does not require external power or control to operate (281). Detection. The success of microfluidic systems depend on suitable detection systems capable of reliable and repeatable measurements. Various detection systems have been reported. X-ray Scattering. Maimiroli et al. characterized small-angle X-ray scattering in a free jet micromixer to study fast chemical reactions. They have demonstrated the functionality of the system by studying formation of calcium carbonate from calcium chloride (282). Kutter and co-workers have used small-angle X-ray scattering detection for protein diffusion in buffer in a 200 nL sample chamber (283).

Surface Plasmon Resonance (SPR). SPR is a well established label free detection technique. Amarie et al. have reported the use of an SPR biosensor for the study of glucose oxidase binding activity in a microcavity (284). SPR has been demonstrated for measuring biomolecular interactions by Krishnamoorthy et al. (285). The Oh group used nanohole arrays and Bragg mirrors for enhancing SPR sensitivity and isolation (286). Mass Spectroscopy (MS). MS is a well established commercial analytical technique. Combining MS with a microfluidic system is a challenging task. MS detection of liquid chromatographically separated heparinoids on-chip has been reported by Staples et al. (287). Kostiainen and co-workers have demonstrated analysis of petroleum using Fourier transform ion cyclotron resonance MS (288). Fluorescence. Fluorescence-based detection is a commonly used method in microfluidic systems for the detection of fluorescent samples and fluorescent labeled analytes. Karlinsey et al. developed a five color short tandem repeat analysis (STR) system using an acousto-optic tunable filter, laser beam, and a single photomultiplier tube (289). Fluorescence polarization spectroscopy has been developed by the Baba group for a homogeneous immunoassay using optical microscopy and a white light source (290). Lo and Ugaz developed an automated whole gel scanning detection method for DNA CE on-chip (291). A disposable LOC with thin film organic electronics for fluorescence detection has been developed by Papautsky and co-workers (292). Wang et al. have integrated organic photodiodes in a microfluidic chip for chemiluminescence detection (293). Broder et al. developed diffractive microbarcodes for encoding biomolecular assays (294). Polarized light emitting electrospun nanofibers have been used as an excitation source for flowing dye chromophores by the Pisignano group (295). Dupont et al. reported immunofluorescence detection of a single magnetic bead (296). A micro gas analyzer has been developed by Arimoto and co-workers for nitric content in breath using fluorescence detection (297). Tseng et al. have developed an opto-fluidic system that contains a fiber optic interferometry sensor for continuous protein detection (298). Electrochemical (EC). EC is a convenient and inexpensive detection system for microfluidic systems. Durand and Renaud have measured ionic conductance in a nanochannel for label free determination of protein surface interaction kinetics (299). In a packaged microfluidic cell, pretreated gold electrodes have been used by Henry et al. for the detection of cancer markers (300). Soh and co-workers have integrated an enzyme coated Pt electrode for DNA sensing using AC voltammetry (301). Topography of a single cell by mapping the spatial distribution of capacitance associated with the membrane of the cell has been presented by Dharia et al. (302). Wang and co-workers have detected amino acids on a PDMS device coated with titanium dioxide nanoparticles using indirect amperometric detection (303). Plasma. Plasma-based detection has been reported for some applications for gas analysis. Tinepont et al. developed a microplasma emission detector, with a lifetime of 3000 analyses, for a portable gas chromatograph capable of detecting phosphorus, sulfur, and chlorine (304). A sealed glass microfluidic chip able of generating microplasma using water electrodes has been reported by the Lee group for detecting water contaminants (305).

Other Methods. Various groups have reported interesting and innovative detection methods for microfluidic systems. Waggoner et al. developed nanomechanical resonators for the detection of prostate specific antigen with a LOD of 50 fg mL-1 (306). A microfluidic calorimeter-based detection system has been reported by Roukes and co-workers for biological and chemical applications (307). Ou et al. have integrated a dialysis membrane in a PDMS chip for IEF of proteins. The device is capable of measuring whole channel optical absorption of a wavelength of 280 nm (308). Radio frequency device for measurement of dielectric property changes in a microfluidic channel has been reported by Song and Wang (309). Chan and co-workers have used attenuated total reflection-Fourier transform (ATR-FT) for chemical imaging (310). A total internal reflection-based detection method has been reported by Sugiyama and coworkers for single molecule detection (311). Bergner et al. described a two channel coherent anti-stokes Raman scattering (CARS) microscopy system (312). A holographic optical tweezer microfluidic platform that can be used as a reconfigurable force sensor array has been reported by Uhrig et al. (462). Using this platform, forces as small as piconewton have been measured. Force measurements in this range are useful for the investigation of chemomechanical processes. Fluidic Reactors. Ji et al. reported digested proteins in nanozeolite-assembled microchip reactors to form a large surface to volume network (313). These networks provide a biocompatible microenvironment for enzyme immobilization. Nicholas and coworkers have determined enzyme kinetics in a porous silicon microfluidic channel coupled with MS (314). A continuous flow microreactor has been developed by the Jamison group for aminolysis (315). Lee et al. have fabricated enzyme loaded alginate hollow fiber reactors for enzyme base reactions (316). A 200 nL RT-PCR reactor with a single cell capture pad has been reported by Toriello et al. for single cell gene express analysis (317). Vaultier and co-workers used soft wall free microreactors for organic synthesis (318). An acoustically levitated drop has been used for sample handling and monitoring of reaction chemical kinetics by Pierre et al. (319). Droplets. Droplets have been reported for isolated analytical/ biological processes. There has been a significant increase in the articles published related to droplet generations, separation, and manipulation. Droplet Generators. Lai et al. have integrated pneumatic microchoppers and microswitches for the formation and collection of droplets (320). A nozzle-free acoustic transducer has been used by Kim and co-workers for the generation of subpicoliter droplets (321). Duraiswamy and co-workers have demonstrated the generation of dynamic reversible gas and liquid droplet pairs that are useful for chemical synthesis, molecular separation, and screening (322). A multicolor fast switching microfluidic dye laser capable of switching its emission at frequencies up to 3.6 kHz has been used by Tang et al. for droplet generation (323). Nisisako and Torii have developed a microfluidic device for mass production of droplets and particles (324). Simultaneous generation of multiple aqueous droplets in a microfluidic device has been reported by Lorenz et al. (325). Liu and co-workers have developed a droplet optical diffraction grating array (326). A computer controlled valve integrated with a microfluidic system Analytical Chemistry, Vol. 82, No. 12, June 15, 2010

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for generating droplets on-demand has been reported by the Garstecki group (327). Hashimoto et al. have used flow focusing geometries for parallel generation of droplets (328). Kameoka and co-workers have generated polygonal water droplets in microchannel (329). Shui et al. reported geometry controlled droplet generation in head-on microfluidic devices (330). A microfluidic device for the generation of double emulsion droplets of water-oil-water (W-O-W) has been developed by Lao et al. In their setup, they were able to control the number of inner droplets (331). The Weitz group reported a droplet generator capable of generating high order (up to quintuple) multiple emulsions in a PDMS microfluidic device (332). Microfluidic jetting for unilamellar vesicle formation has been developed by Stachowiak et al. (333). Electrowetting on dielectric (EWOD) actuation has been explored for DMF where small packets of liquid are generated and manipulated on a two-dimensional surface. Gong et al. have reported an EWOD-based digital microfluidics with a feedback control to define the droplets volume (334). Microchannels of various heights in a DMF system has been used by Abedian and co-workers (335). The Wheeler group has demonstrated DMF droplet manipulation on a range of geometries which includes inclined, declined, vertical, twisted, and upside down (336). Collection and separation of EWOD DM droplets has been achieved using magnets as reported by Shah and Kim (463). Droplet Sorting. Baret et al. have developed a fluorescence activated droplet sorting based on enzymatic activity in a microfluidic cell (337). Kuo and co-workers have reported a microfluidic device for separating satellite droplets in side channels from their parent droplets to enhance size uniformity (338). Hydrodynamic size fractionation for droplet sorting has been used by Mazutis and Griffiths (339). The Wixforth group has controlled the motion of droplets using a surface acoustic wave (SAW) device that directs individual droplets into separate microchannel paths (340). Droplet Storage. Frenz et al. have reported incubation of droplets in delay-lines for up to an hour (341). Storing droplets in channel loops and extracting them safely when required has been demonstrated by Farden and co-workers (342). Weitz and co-workers have fabricated arrays of chambers to immobilize thousands of femtoliter to picoliter droplets suspended in an inert carrier oil (343). Droplets Manipulation. Zagnoni and Cooper developed a high throughput microfluidic device for electrocoalescence of droplets capable of fusing droplets based on voltage, frequency, and droplet size (344). A pillar-based microfluidic device for merging droplets in less than 40 µs has been reported by Niu et al. (345). Seemann and co-workers developed a microfluidic device for the manipulation of gel emulsions by varying channel geometry (346). Coalescence and splitting of droplets at microfluidic junctions by varying flow speed and droplets size has been achieved by the Anna group (347). Sassa et al. have formed various length liquid plugs and manipulated them for attachment, division, and sorting (348). Droplets containing fibrin networks in a microfluidic system have been manipulated by Evans et al. (349). The Huck group has selected individual droplets based on their contents and selectively electrocoalescence them as required (350). Heating of droplets up to 30 °C in 15 ms using a microwave induction in a microfluidic device has been demonstrated by Westervelt and 4838


co-workers (351). Zhang et al. have used external magnets for generation, transport, sorting, mixing, deformation, and manipulation of picoliter superparamagnetic droplets (352). Holographically generated optical patterns have been used for thermocapillary manipulation of droplets in a microchannel by the McGloin group (353). Wu and co-workers used photosensitive surfaces and scanning lasers for droplet transport, splitting, and trapping (354). A droplet actuation mechanism based on light induced dielectrophoresis for droplet manipulation has been developed by Park et al. (355). The Yang group has encoded microparticles using double emulsion droplets with photocurable shell phase (356). Loading droplets with particles and then packing them closely for storage has been demonstrated by the Weitz group (357). Holtze et al. have reported the use of biocompatible surfactants in droplet generation and then the loading of the droplets with yeast cells (358). Mixing and manipulation of picoliter volumes in vesicles using magnets has been reported by Frankie et al. (359). Fluidic Processors. DMF-based activities have been reported by some groups. Mazutis et al. have reported a DMF processor capable of performing multiple operations to analyze complex and sequential multistep reactions (360). The Pamula group has reported DMF for sandwich heterogeneous immunoassay magnetic beads (361). Miller and Wheeler have used DMF for enzyme assays (362). The Chang group has carried out DNA ligation in submicrovolumes using DMF (363). Kumaresan et al. report the amplification of a single copy of DNA in nanoliter droplets (364). Jebrail and Wheeler used DMF for protein extraction by precipitation (365). Particle Sorting. Wong et al. have reported a sorting microfluidic device for biopolymer particles from an oil phase to an aqueous phase (366). Continuous 3D dielectrophoresis for bioparticle sorting has been presented by Chang and co-workers (367). The Renaud group has developed a dielectrophoretic-based exchanger capable of sorting and surface functionalization with fluorescent tags to avidin-modified 880 nm diameter particles (368). The Funatsu group has developed a particle and cell sorter by fluorescence spectrum detection capable of separating four kinds of particles and three kinds of E. coli cells (369). APPLICATIONS Clinical Diagnostics. Biofluids. Thrombin in blood is an important marker for various hemostasis-related diseases. Soper and co-workers have reported a PMMA microchip for the analysis of thrombin in blood plasma using affinity gel CE of aptamer protein complexes (370). A plug-based microfluidic chip capable of performing agglutination assays for ABO and D (Rh) blood typing and blood group has been developed by Kline et al. (371). Gartner and co-workers have designed a microfluidic cartridge for blood group determination in 2 min using an agglutination assay (372). Bedside monitoring and analysis of free bilirubin for jaundiced infants in critical condition is an important application. Nie and Fung reported a microchip-CE for frontal analysis of free bilirubin at clinically significant levels (373). A point of care blood polymer chip that uses a sandwich immunoassay has been developed by Browne et al. for the detection of cTnT (cardiac troponin T) (374). Lenshof et al. have developed a acoustophoresis-based separation chip that prepares diagnostic plasma from whole blood for prostate specific antigen at clinically relevant levels

(0.19-21.8 ng/mL, R2 > 0.99) (464). Determination of lithium concentration is relevant for the monitoring and treatment of patients with bipoloar disorder. The Berg group has presented the Medimate multireader point-of-care hand-held device capable of monitoring lithium in blood (459). The device is based on capillary electrophoresis and employs a disposable prefilled microfluidic chip with closed electrode reservoirs and a single sample opening. The lithium concentration was determined by conductivity measurement. Self-powered microfluidic chips for multiplexed protein assays from whole blood has been developed by Heath and co-workers (375). Kartalov et al. have quantified ferritin proteins in human serum by a fluorescence immunoassay in disposable point of care elastomeric microfluidic devices (376). A chip integrated with mixing, electro-kinetic separation, and detection has been presented by the Satomura group for the measurement of a liver cancer marker AFP (R-fetoprotein immunoassay) (377). Determination of β-amyloid secretion from neural cells plays an important role in the pathogenesis of Alzheimer’s disease. Quantification of β-amyloid secretion from single neural cells using an optofluidic chamber array was developed by Lee and co-workers (378). The Park group has analyzed β-amyloid using a microfluidic screening system (379). Low-density lipoprotein (LDL) has been accepted as an emerging cardiovascular risk factor. The Wang group reported a quartz CE chip for LDL detection in a serum sample (380). Determination of small inorganic ions is clinically important for fast disease screening. Kuban and Hauser have developed a contactless conductivity detection method for microchip CE to detect major inorganic ions in serum and urine samples (381). Martinez et al. have described a prototype paper-based microfluidic device that quantifies glucose and protein analysis in urine simultaneously and includes a camera phone for digitizing the intensity of colors associated with each colorimetric assay for offsite laboratory analysis by a trained professional; the diagnosis then can be returned to the healthcare provider in the field (382). Diseases. Lafleur et al. have developed air driven point of care microfluidic cards capable of performing sandwich assays and malaria detection within 9 min (383). A PDMS microchip-beadbased immunoassay system has been reported by Lee and coworkers for the detection of cancer biomarkers in less than an hour (384). Carcino embryonic antigen (CEA) and R-fetoprotein (AFP) levels in human serum are associated with certain tumors. The Su group has described the amperometric detection of CEA and AFP on a microfluidic glass/PDMS hybrid CE chip using an enzyme immunoassay (385). Over 150 million people are infected with the hepatitis C virus (HCV). An HCV target and its pharmacological inhibitors by microfluidic affinity analysis have been discovered by Einav et al. (386). Tuberculosis is a bacterial infection caused by M. tuberculosis, and it is estimated that the one-third of the world population is infected by it. Nagel et al. have developed a direct detection of tuberculosis infection in blood serum using three optical label free approaches (387). Drug Testing. The hetrogeneity of cellular microenvironments in tumors severely limits the efficacy of most cancer therapies. Walsh et al. have reported a multipurpose microfluidic device to mimic microenvironment gradients and to develop targeted cancer therapeutics (388). Adverse reactions to food are relatively

common in infants and children. Bilkova and co-workers have used biofunctionalized magnetic beads packed in microfluidic channels for epitope mapping of allergen ovalbumin for epitope-based vaccines (389). The antimicrobial susceptibility test (AST) is often performed to determine the antibiotic sensitivity of bacterial pathogens in clinical samples such as urine, blood, sputum, or wound swabs. The Wong group has used high surface to volume ratio microchannels for AST at the point of care (390). Ma et al. have developed an integrated microfluidic device for the characterization of drug metabolites and a cytotoxicity assay (391). A 3D hepatocyte chip has been engineered by Yu and co-workers for drug toxicity testing (392). The Singh group has reported an integrated microfluidic chip for sensitive and rapid detection of biological toxins such as ricin, Shiga toxin I, and S. enterotoxin B. A CE microchip for the total analysis of trace tetracycline antibiotics using amperometry has been reported by Lee et al. (393). General Research. Hydrogen peroxide is a stable byproduct of normal cellular metabolism. Gong et al. have synthesized a new fluorogenic reagent for quantitative detection of hydrogen peroxide on a CE microchip (394). Liu and Gomez have studied the binding of ligand to teicoplanin derivatized microbeads using frontal affinity chromatography (395). Hromada et al. reported membrane bound ion channels using a polymer-based bilayer lipid membrane chip for single molecule measurements (396). Odijk et al. studied drug metabolism in a microfluidic chip using electrochemical conversions (397). The study of the effect of carbon dioxide on peak mode ISF has been reported by Khurana and Santiago (398). Brown and co-workers have optimized a microreactor design for microfluidic gradient generation by entire chip imaging (399). Solid state gold/iridium oxide pH electrodes as a prime power source for micro electromechanical energy harvesting powered wireless biometric sensor have been reported by He et al. (400). The Juncker group has developed a chamber and microfluidic probe for micropefusion of organotypic brain slices (401). Brain tissue slices are useful to study pharmacological and physiological properties of neuronal circuits. Single walled carbon nanotubes (SWCNT) are useful because of their surface to volume ratio and surface properties. Continuous extraction of a pure metallic SWCNT in a microfluidic channel has been developed by Shin et al. (402). Lipid bilayer enclosed fluidic systems can be used to study biochemical transports and provide a new class of truly life like microfluidic structures. West et al. have mass produced lipid microstructures in a microfluidic channel (403). A cell free production of the same protein with different conditions to optimize expression with high yield and low reagent cost in a microchannel array has been reported by Fan and co-workers (404). Celiac is an inflammatory disease of the upper small intestine caused from gluten ingestion. A microfluorimeter with disposable polymer chip has been reported by Mairal et al. for the detection of gliadin, a celiac disease toxin (405). Protein kinase enzymes catalyze the phosphorylation of proteins. The Williamson group have determined RNA-protein binding kinetics in an automated microfluidic reactor (406). Raw milk quality control is important to maintain its purity. The Laurell group has developed a harmonic acoustophoresis microchip for online raw milk sample preconditioning of protein and lipid contents for quality control (465). Biomineralization is the process Analytical Chemistry, Vol. 82, No. 12, June 15, 2010

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where biological systems produce well-defined composite structures such as shell, teeth, and bones. In order to study chemomechanical interaction of complex microstructures, Yin et al. used microfluidics for biomineralization screening (407). Understanding the initiation, propagation, and control of blood clotting is crucial for treatment and prevention of cardiovascular diseases. Runyon et al. have used microfluidic channels to study the blood clotting process (408). Glucosinolates are essential natural products occurring in cruciferous plants (broccoli, cabbage, radish, etc.), and their metabolic breakdown products are considered as anticancer agents. Analysis of the plant glucosinolates on a microfluidic chip has been reported by Baba and co-workers (409). Proteins. Measuring a large number of protein-protein interactions is challenging. Gerber et al. have developed a parallel microfluidic affinity assay network capable of monitoring 14 792 protein-protein interactions of 43 S. pneumonide proteins (410). Microchip-based assays for screening monoclonal antibody proteins has been developed by Flynn and co-workers (411). Calmodulin (CaM) protein exists in eukaryotic cells and plays an essential role in Ca2+ signaling, regulating numerous intracellular processes such as cell mobility, growth, proliferation, and apoptosis. The Pollack group has studied conformational changes of CaM upon Ca2+ binding using a microfluidic mixer (412). Transcription factor Abf1 in S. cerevisiae on a microfluidic CE chip has been studied by Yang et al. (413). Lazar and co-workers have reported a microfluidic LC chip coupled with MS for separation and detection of 40-100 proteins from 0.1-1 µg of crude protein extract (414). Carbohydrate-protein interactions on a hydrophobically coated plastic chip have been investigated by Dang et al. (415). Luk and Wheeler have used a DMF approach for proteomic sample processing steps such as reduction, alkylation, and enzyme digestion (416). DNA. Lien et al. developed an integrated system to detect R-thalassemin-1 deletion using saliva samples (417). Eijkel and co-workers studied field dependent DNA mobility in nanoslits (418). A laminar flowcell has been used to study single molecule DNA-protein interactions by Brewer and Bianco (419). Weiner and co-workers developed a microfluidic processor for gene expression profiling of single human embryonic cell (420). Whole genome amplification on a PDMS microchip array has been reported by Chen and co-workers (421). The Mathies group has analyzed a single mammalian cell on a microelectrode array using DNA barcode directed capturing (422). Microfluidic assisted analysis of replicating DNA molecules has been developed by Sidorova et al. (423). Chromo immuno-precipitation (CIP) is a powerful and widely applied technique for detecting the association of individual proteins with a specific genomic region. Oh et al. have developed a microfluidic chip for DNA enhancement (424). Forensics. Tan et al. reported a LOC for the detection of nerve agent sarin in blood (425). A microfluidic-electrochemistry chip has been developed by Rios and co-workers for the separation of vanilla fingerprint markers for confirmation of common frauds (426). The Mathies group has reported fluorescence energy transfer labeled primers for high performance forensic DNA profiling (427). Droplets. Albritton and co-workers have coated a glass/PDMS hybrid device with bilayer membranes by vesicle fusion (428). 4840


Pixelation of chemical and biological samples in droplets suspended in a two-phase microflow has been demonstrated by Tachikawa (429). Sarrazin et al. used droplets for chemical reaction imaging using confocal Raman spectroscopy (430). Reaction progression in droplets filled with concentration gradients in parallel channels has been measured by Huck and coworkers using image analysis (431). Edd et al. measured nucleation and solidification in static droplet arrays (432). The mass exchanges between moving water droplets and an externalphase octanol has been studied by Mary et al. (433). Lin and coworkers have used droplet arrays as nanoliter reactors for a parallel gas-liquid chemical reaction (434). Immobilization of protein-polymer nanoreactors for studying enzymatic conversation using vesicles has been reported by the Meier group (435). Shum et al. fabricated monodispersed biodegradable polymersomes with controlled permeability (436). Syntheses of submicrometer nanoporous titania spherical particles have been reported by Shiba and Ogawa using droplet generation (437). Chokkalingam et al. have synthesized silica microparticles by merging reagent droplets (438). Non-viral gene vector formation in monodispersed picoliter incubator has been reported by Lee and co-workers (439). Duraiswamy and Khan have synthesized anisotropic metal nanocrystals (440). Biodegradable microcapsules by selectively surface modified PDMS devices have been formed by Liao and Su (441). Peng et al. have produced magnetically responsive elastic microspheres (442). The detection and counting of single molecules using subnanoliter droplets have been reported by Rane et al. (443). Zheng and co-workers measured rapid enzymatic kinetics using electrochemical detection in droplets (444). In vitro protein expression of E.coli S30 extract has been demonstrated by Sexton and co-workers using a droplet-based system (445). Hartman et al. reported the use of segmented flow and capillary forces for distillation in microchannels (446). Sample dispersion in a rectangular channel microfluidic device has been studied by the Jensen group using segmented flow (447). Environment. Protection of drinking water from chemical contamination can be enhanced by the use of toxicity sensors. Curtis et al. developed a portable cell-based impedance sensor for toxicity monitoring of drinking water (448). Lead can accumulate in the environment and produce numerous toxicological effects. Cropek and co-workers have immobilized DNAzyme catalytic beacons on PMMA for Pb2+ detection (449). The Gascoyne group used a dielectrophoretic field flow fractionation system for detection of eight aquatic toxins (450). Aldehydes are air pollutants produced by incomplete combustion of petroleum fuel and photochemical oxidation of hydrocarbons. Dossi et al. used a CE microchip with electrochemical detection for environmental aldehyde monitoring (451). A microfluidic device for electrochemical determination of halide contents in ionic liquid has been developed by Newton and co-workers (452). The Brown group has developed a chip-based ITP for determination of chlorine containing species in explosive residues (453). Heavy oil is formed from conventional petroleum by removing lighter hydrocarbon components by microbes in the subsurface, which results in a rise of the proportion of asphaltene and carboxylic acids. Bowden et al. have reported a microfluidic device capable of extracting and

detecting asphaltene and carboxylic acids from an oil sample (454). Henry and co-workers have developed a CE microchip for the determination of inorganic anions and oxalates in atmospheric aerosols (455). Analyzed food dyes using a CE microfluidic system have been reported by the Shim group (456). Pesticides used in farming for disease and pest control can also affect other living organisms. Llopis et al. used a magnetic bead-based assay for the detection of carbofuran (a carbamate pesticide toxin) on a glass microchip (457). A continuous gas analysis system for the detection of ammonia in cleanroom air has been developed by Kitamori and coworkers (458). ACKNOWLEDGMENT A.A., G.S., and G.B.S.-B. contributed equally to this work. The authors wish to express their sincere thanks to Prof. Edwin Carlen, Twente University, Dr. Pavel Neuzil and Prof. Jörg Ingo Baumbach, KIST, for proofreading the script and Ms. Gabriele Sprave, KIST, for providing administrative support. Arun Arora obtained his PhD from Imperial College, London with Prof. Andreas Manz where he developed an online wireless electrochemilumenescence detection system for capillary electrophoresis on glass chip. He spent two more years in Imperial College working on various interdisciplinary projects like electrochemical sensors for water quality monitoring with Prof. Nigel Graham, Civil Engineering Department; enzyme electrodes for glucose with Dr. Danny O’Hare, Biosensors group, Bioengineering Department; and solid state gold/iridium oxide pH electrodes as a possible prime power source for a nonresonant electrostatic energy harvesting from a rolling mass with Prof Erik Yeatman, Optical and Semiconductor Devices Group, Department of Electrical and Electronic Engineering. Since November 2009, he has joined Prof. Andreas Manz’s microfluidic group at Korea Institutes of Technology, Saarbrucken, Germany. His interests include exploring and developing new material for microfluidic chip fabrication for droplet-based applications and electrophoresis methods development by employing fluorescence, electrochemiluminescence, and electrochemical detection techniques. Giuseppina Simone received her M.Sc. in Chemical Engineering from the University “Federico II” of Naples, Italy. She spent 3 years doing research on polymers at the University of Naples and at CNR in Milan before embarking on her Ph.D. at the University “La Sapienza” in Rome and at Technical University of Denmark. She studied and characterized organic-inorganic hybrid composites, and she developed an optical sensor based on a nanocomposite for microfluidic devices. At Silicon Biosystems in Bologna, she worked on microfluidic and technologies for rare cell sorting, and she gained an extensive experience in microfluidics and cellomics. She was Postdoctoral fellow at the National Nanotechnology Laboratory of CNR-INFM, at the Department of Medicine of Harvard Medical School and Harvard-MIT Health Sciences and Technology, and at Danish Technological Institute working on microfluidics applied to early cancer diagnosis. Since November 2009, she has joined Prof. Andreas Manz group at Korea Institute of Science and Technology in Germany. Her research interests lie in microfluidics for clinical diagnostics and rare cell detection, in engineering surfaces for the life sciences, and in microfabrication and integration. Georgette B. Salieb-Beugelaar received her M.Sc. in Chemistry in 2003. After working for almost 10 years at the Clinical Genetic Department of the Academic Medical Centre of Amsterdam, where she was involved in epigenetic DNA studies, she decided to switch fields in 2005. In 2009, she obtained her Ph.D. in nanofluidics at the BIOS/Lab on a Chip group of Prof. Albert van den Berg, the MESA+ Institute, Twente University, The Netherlands. Her thesis presents the investigation of the electrokinetic transport of DNA molecules in nanoslits. Presently, she is working as a postdoc in both the Korea Institute of Science and Technology in Germany as well at the University of Twente. Her research interests include micro- and nanofluidics for biomolecular separation, clinical diagnostics, cell studies, tissue engineering, DNA confinement studies, and archaeometry. Jungtae Kim received the B.Sc. and M.Sc. degrees in mechanical engineering from the A-Jou University, Suwon, Korea, in 1996 and 1998,

respectively. In 1998, he joined Korea Institute of Science and Technology (KIST) and worked on the tele-operation for the humanoid robot system. Since 2002, he has been with KIST Europe, Saarbruecken, Germany, and he received a Dr.-Ing, Degree in physics and mechatronics from the University of Saarland, Saarbruecken, Germany, in 2008. He is currently Bio-MEMS research team leader of the Human Engineering Group. His main research fields and interests are the micro cell sorter, micro cell dispenser, bio cell processor, and micro sensors for robots.

Andreas Manz obtained his Ph.D. from the Swiss Federal Institute of Technology (ETH) Zurich, Switzerland, with Professor W. Simon. His thesis dealt with the use of microelectrodes as detectors for picoliter-size volumes. He spent 1 year at Hitachi Central Research Lab in Tokyo, Japan, as a postdoctoral fellow and produced liquid chromatography column on a chip. At Ciba-Geigy, Basel, Switzerland, he developed the concept of miniaturized total analysis systems and built a research team on-chip-based analytical instrumentation during 1988-1995. He was professor for analytical chemistry at Imperial College in London, 1995-2003. Subsequently, he was the head of ISAS in Dortmund, Germany, and a Professor for analytical chemistry at the University of Dortmund. Since October 2009, he has been the head of research at KIST in Saarbrucken. His research interests include microfluidics for chemical analysis, biomimetic microfabrication, nanomedicine, cancer research, and the “Human Document Project”.

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