Biomicrofluidics

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Biosensors for immune cell analysis—A perspective

Alexander Revzin, Emanual Maverakis, and H.-C. Chang

Biomicrofluidics 6, 021301 (2012); http://dx.doi.org/10.1063/1.4706845 (13 pages)

Online Publication Date: 26 April 2012

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Massively parallel analysis of single immune cells or small immune cell colonies for disease detection, drug screening, and antibody production represents a “killer app” for the rapidly maturing microfabrication and microfluidic technologies. In our view, microfabricated solid-phase and flow cytometry platforms of the future will be complete with biosensors and electrical/mechanical/optical actuators and will enable multi-parametric analysis of cell function, real-time detection of secreted signals, and facile retrieval of cells deemed interesting.

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87.80.Ek	Mechanical and micromechanical techniques
87.85.-d	Biomedical engineering
47.61.-k	Micro- and nano- scale flow phenomena
47.85.Np	Fluidics
85.85.+j	Micro- and nano-electromechanical systems (MEMS/NEMS) and devices
87.17.-d	Cell processes

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Preface to Special Topic: Multiphase Microfluidics

Saif A. Khan

Biomicrofluidics 6, 021901 (2012); http://dx.doi.org/10.1063/1.4707391 (2 pages)

Online Publication Date: 24 April 2012

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85.85.+j	Micro- and nano-electromechanical systems (MEMS/NEMS) and devices
47.85.Np	Fluidics
87.80.Ek	Mechanical and micromechanical techniques
87.15.nt	Crystallization
87.14.E-	Proteins
47.55.db	Drop and bubble formation

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Calcium carbonate polymorph control using droplet-based microfluidics

Alexandra Yashina, Fiona Meldrum, and Andrew deMello

Biomicrofluidics 6, 022001 (2012); http://dx.doi.org/10.1063/1.3683162 (10 pages) | Cited 1 time

Online Publication Date: 6 April 2012

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Calcium carbonate (CaCO₃) is one of the most abundant minerals and of high importance in many areas of science including global CO₂ exchange, industrial water treatment energy storage, and the formation of shells and skeletons. Industrially, calcium carbonate is also used in the production of cement, glasses, paints, plastics, rubbers, ceramics, and steel, as well as being a key material in oil refining and iron ore purification. CaCO₃ displays a complex polymorphic behaviour which, despite numerous experiments, remains poorly characterised. In this paper, we report the use of a segmented-flow microfluidic reactor for the controlled precipitation of calcium carbonate and compare the resulting crystal properties with those obtained using both continuous flow microfluidic reactors and conventional bulk methods. Through combination of equal volumes of equimolar aqueous solutions of calcium chloride and sodium carbonate on the picoliter scale, it was possible to achieve excellent definition of both crystal size and size distribution. Furthermore, highly reproducible control over crystal polymorph could be realised, such that pure calcite, pure vaterite, or a mixture of calcite and vaterite could be precipitated depending on the reaction conditions and droplet-volumes employed. In contrast, the crystals precipitated in the continuous flow and bulk systems comprised of a mixture of calcite and vaterite and exhibited a broad distribution of sizes for all reaction conditions investigated.

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87.80.Ek

Mechanical and micromechanical techniques

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CO₂ dissolution in water using long serpentine microchannels

Thomas Cubaud, Martin Sauzade, and Ruopeng Sun

Biomicrofluidics 6, 022002 (2012); http://dx.doi.org/10.1063/1.3693591 (9 pages) | Cited 1 time

Online Publication Date: 6 April 2012

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The evolution of carbon dioxide bubbles dissolving in water is experimentally examined using long microchannels. We study the coupling between bubble hydrodynamics and dissolution in confined geometries. The gas impregnation process in liquid produces significant flow rearrangements. Depending on the initial volumetric liquid fraction, three operating regimes are identified, namely saturating, coalescing, and dissolving. The morphological and dynamical transition from segmented to dilute bubbly flows is investigated. Tracking individual bubbles along the flow direction is used to calculate the temporal evolution of the liquid volumetric fraction and the average flow velocity near reference bubbles over long distances. This method allows us to empirically establish the functional relationship between bubble size and velocity. Finally, we examine the implication of this relationship during the coalescing flow regime, which limits the efficiency of the dissolution process.

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87.80.Ek	Mechanical and micromechanical techniques
07.10.Cm	Micromechanical devices and systems
82.45.Qr	Electrodeposition and electrodissolution
87.15.R-	Reactions and kinetics

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Droplet dispensing in digital microfluidic devices: Assessment of long-term reproducibility

Katherine S. Elvira, Robin Leatherbarrow, Joshua Edel, and Andrew deMello

Biomicrofluidics 6, 022003 (2012); http://dx.doi.org/10.1063/1.3693592 (10 pages) | Cited 1 time

Online Publication Date: 6 April 2012

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We report an in-depth study of the long-term reproducibility and reliability of droplet dispensing in digital microfluidic devices (DMF). This involved dispensing droplets from a reservoir, measuring the volume of both the droplet and the reservoir droplet and then returning the daughter droplet to the original reservoir. The repetition of this process over the course of several hundred iterations offers, for the first time, a long-term view of droplet dispensing in DMF devices. Results indicate that the ratio between the spacer thickness and the electrode size influences the reliability of droplet dispensing. In addition, when the separation between the plates is large, the volume of the reservoir greatly affects the reproducibility in the volume of the dispensed droplets, creating “reliability regimes.” We conclude that droplet dispensing exhibits superior reliability as inter-plate device spacing is decreased, and the daughter droplet volume is most consistent when the reservoir volume matches that of the reservoir electrode.

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47.85.Np	Fluidics
85.85.+j	Micro- and nano-electromechanical systems (MEMS/NEMS) and devices
47.61.Fg	Flows in micro-electromechanical systems (MEMS) and nano-electromechanical systems (NEMS)
47.61.Jd	Multiphase flows

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Tuning bubbly structures in microchannels

Sharon M. Vuong and Shelley L. Anna

Biomicrofluidics 6, 022004 (2012); http://dx.doi.org/10.1063/1.3693605 (18 pages) | Cited 1 time

Online Publication Date: 6 April 2012

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Foams have many useful applications that arise from the structure and size distribution of the bubbles within them. Microfluidics allows for the rapid formation of uniform bubbles, where bubble size and volume fraction are functions of the input gas pressure, liquid flow rate, and device geometry. After formation, the microchannel confines the bubbles and determines the resulting foam structure. Bubbly structures can vary from a single row (“dripping”), to multiple rows (“alternating”), to densely packed bubbles (“bamboo” and dry foams). We show that each configuration arises in a distinct region of the operating space defined by bubble volume and volume fraction. We describe the boundaries between these regions using geometric arguments and show that the boundaries are functions of the channel aspect ratio. We compare these geometric arguments with foam structures observed in experiments using flow-focusing, T-junction, and co-flow designs to generate stable nitrogen bubbles in aqueous surfactant solution and stable droplets in oil containing dissolved surfactant. The outcome of this work is a set of design parameters that can be used to achieve desired foam structures as a function of device geometry and experimental control parameters.

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87.80.Ek	Mechanical and micromechanical techniques
85.85.+j	Micro- and nano-electromechanical systems (MEMS/NEMS) and devices
07.10.Cm	Micromechanical devices and systems
82.70.Rr	Aerosols and foams

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Tunable spatial heterogeneity in structure and composition within aqueous microfluidic droplets

Su Hui Sophia Lee, Pengzhi Wang, Swee Kun Yap, T. Alan Hatton, and Saif A. Khan

Biomicrofluidics 6, 022005 (2012); http://dx.doi.org/10.1063/1.3694841 (8 pages)

Online Publication Date: 6 April 2012

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In this paper, we demonstrate biphasic microfluidic droplets with broadly tunable internal structures, from simple near-equilibrium drop-in-drop morphologies to complex yet uniform non-equilibrium steady-state structures. The droplets contain an aqueous mixture of poly(ethylene glycol) (PEG) and dextran and are dispensed into an immiscible oil in a microfluidic T-junction device. Above a certain well-defined threshold droplet speed, the inner dextran-rich phase is “stirred” within the outer PEG-rich phase. The stirred polymer mixture is observed to exhibit a near continuum of speed and composition-dependent phase morphologies. There is increasing interest in the use of such aqueous two-phase systems in microfluidic devices for biomolecular applications in a variety of contexts. Our work presents a method to go beyond equilibrium phase morphologies in generating microfluidic “multiple” emulsions and at the same time raises the possibility of biochemical experimentation in benign yet complex biomimetic milieus.

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87.15.B-	Structure of biomolecules
82.35.Pq	Biopolymers, biopolymerization
87.15.N-	Properties of solutions of macromolecules
82.70.Kj	Emulsions and suspensions
87.80.Ek	Mechanical and micromechanical techniques
85.85.+j	Micro- and nano-electromechanical systems (MEMS/NEMS) and devices

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Utilizing microfluidics to synthesize polyethylene glycol microbeads for Förster resonance energy transfer based glucose sensing

Chaitanya Kantak, Qingdi Zhu, Sebastian Beyer, Tushar Bansal, and Dieter Trau

Biomicrofluidics 6, 022006 (2012); http://dx.doi.org/10.1063/1.3694869 (9 pages) | Cited 1 time

Online Publication Date: 6 April 2012

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Here, we utilize microfluidic droplet technology to generate photopolymerizeable polyethylene glycol (PEG) hydrogel microbeads incorporating a fluorescence-based glucose bioassay. A microfluidic T-junction and multiphase flow of fluorescein isothiocyanate dextran, tetramethyl rhodamine isothiocyanate concanavalin A, and PEG in water were used to generate microdroplets in a continuous stream of hexadecane. The microdroplets were photopolymerized mid-stream with ultraviolet light exposure to form PEG microbeads and were collected at the outlet for further analysis. Devices were prototyped in PDMS and generated highly monodisperse 72 ± 2 μm sized microbeads (measured after transfer into aqueous phase) at a continuous flow rate between 0.04 ml/h—0.06 ml/h. Scanning electron microscopy analysis was conducted to analyze and confirm microbead integrity and surface morphology. Glucose sensing was carried out using a Förster resonance energy transfer (FRET) based assay. A proportional fluorescence intensity increase was measured within a 1–10 mM glucose concentration range. Microfluidically synthesized microbeads encapsulating sensing biomolecules offer a quick and low cost method to generate monodisperse biosensors for a variety of applications including cell cultures systems, tissue engineering, etc.

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85.85.+j	Micro- and nano-electromechanical systems (MEMS/NEMS) and devices
82.70.Gg	Gels and sols

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Slow growth of the Rayleigh-Plateau instability in aqueous two phase systems

Sam D. Geschiere, Iwona Ziemecka, Volkert van Steijn, Ger J. M. Koper, Jan H. van Esch, and Michiel T. Kreutzer

Biomicrofluidics 6, 022007 (2012); http://dx.doi.org/10.1063/1.3700117 (11 pages) | Cited 1 time

Online Publication Date: 6 April 2012

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This paper studies the Rayleigh-Plateau instability for co-flowing immiscible aqueous polymer solutions in a microfluidic channel. Careful vibration-free experiments with controlled actuation of the flow allowed direct measurement of the growth rate of this instability. Experiments for the well-known aqueous two phase system (ATPS, or aqueous biphasic systems) of dextran and polyethylene glycol solutions exhibited a growth rate of 1 s⁻¹, which was more than an order of magnitude slower than an analogous experiment with two immiscible Newtonian fluids with viscosities and interfacial tension that closely matched the ATPS experiment. Viscoelastic effects and adhesion to the walls were ruled out as explanations for the observed behavior. The results are remarkable because all current theory suggests that such dilute polymer solutions should break up faster, not slower, than the analogous Newtonian case. Microfluidic uses of aqueous two phase systems include separation of labile biomolecules but have hitherto be limited because of the difficulty in making droplets. The results of this work teach how to design devices for biological microfluidic ATPS platforms.

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82.35.Pq	Biopolymers, biopolymerization
87.15.R-	Reactions and kinetics
83.80.Rs	Polymer solutions
47.85.Np	Fluidics
47.63.-b	Biological fluid dynamics

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Field-free particle focusing in microfluidic plugs

G. K. Kurup and Amar S. Basu

Biomicrofluidics 6, 022008 (2012); http://dx.doi.org/10.1063/1.3700120 (10 pages) | Cited 1 time

Online Publication Date: 11 April 2012

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Particle concentration is a key unit operation in biochemical assays. Although there are many techniques for particle concentration in continuous-phase microfluidics, relatively few are available in multiphase (plug-based) microfluidics. Existing approaches generally require external electric or magnetic fields together with charged or magnetized particles. This paper reports a passive technique for particle concentration in water-in-oil plugs which relies on the interaction between particle sedimentation and the recirculating vortices inherent to plug flow in a cylindrical capillary. This interaction can be quantified using the Shields parameter (θ), a dimensionless ratio of a particle’s drag force to its gravitational force, which scales with plug velocity. Three regimes of particle behavior are identified. When θ is less than the movement threshold (region I), particles sediment to the bottom of the plug where the internal vortices subsequently concentrate the particles at the rear of the plug. We demonstrate highly efficient concentration (∼100%) of 38 μm glass beads in 500 μm diameter plugs traveling at velocities up to 5 mm/s. As θ is increased beyond the movement threshold (region II), particles are suspended in well-defined circulation zones which begin at the rear of the plug. The length of the zone scales linearly with plug velocity, and at sufficiently large θ, it spans the length of the plug (region III). A second effect, attributed to the co-rotating vortices at the rear cap, causes particle aggregation in the cap, regardless of flow velocity. Region I is useful for concentrating/collecting particles, while the latter two are useful for mixing the beads with the solution. Therefore, the two key steps of a bead-based assay, concentration and resuspension, can be achieved simply by changing the plug velocity. By exploiting an interaction of sedimentation and recirculation unique to multiphase flow, this simple technique achieves particle concentration without on-chip components, and could therefore be applied to a range of heterogeneous screening assays in discrete nl plugs.

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87.80.Ek	Mechanical and micromechanical techniques
85.85.+j	Micro- and nano-electromechanical systems (MEMS/NEMS) and devices
47.85.Np	Fluidics
47.60.Dx	Flows in ducts and channels
47.61.Jd	Multiphase flows
47.32.Ef	Rotating and swirling flows

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Vimentin networks at tunable ion-concentration in microfluidic drops

Christian Dammann, Bernd Nöding, and Sarah Köster

Biomicrofluidics 6, 022009 (2012); http://dx.doi.org/10.1063/1.4705103 (10 pages) | Cited 1 time

Online Publication Date: 18 April 2012

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The structure and function of biological systems, for example, cells and proteins, depend strongly on their chemical environment. To investigate such dependence, we design a polydimethylsiloxane-based microfluidic device to encapsulate biological systems in picoliter-sized drops. The content of each individual drop is tuned in a defined manner. As a key feature of our method, the individual chemical composition is determined and related to the drop content. In our case, the drop content is imaged using microscopy methods, while the drops are immobilized to allow for long-time studies. As an application of our device, we study the influence of divalent ions on vimentin intermediate filament networks in a quantitative way by tuning the magnesium concentration from drop to drop. This way we are able to directly image the effect of magnesium on the fluorescently tagged protein in a few hundreds of drops. Our study shows that with increasing magnesium concentration in the drops, the compaction of the networks becomes more pronounced. The degree of compaction is characterized by different morphologies; freely fluctuating networks are observed at comparatively low magnesium concentrations of 5–10 mM, while with increasing magnesium concentration reaching 16 mM they develop into fully aggregated networks. Our approach demonstrates how a systematic study of interactions in biological systems can benefit from the exceptional controllability of microfluidic methods.

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87.15.R-	Reactions and kinetics
07.10.Cm	Micromechanical devices and systems
82.80.-d	Chemical analysis and related physical methods of analysis
87.17.-d	Cell processes
87.15.B-	Structure of biomolecules

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Formation of embryoid bodies using dielectrophoresis

Sneha Agarwal, Anil Sebastian, Lesley M. Forrester, and Gerard H. Markx

Biomicrofluidics 6, 024101 (2012); http://dx.doi.org/10.1063/1.3699969 (11 pages)

Online Publication Date: 3 April 2012

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Embryoid body (EB) formation forms an important step in embryonic stem cell differentiation invivo. In murine embryonic stem cell (mESC) cultures EB formation is inhibited by the inclusion of leukaemic inhibitory factor (LIF) in the medium. Assembly of mESCs into aggregates by positive dielectrophoresis (DEP) in high field regions between interdigitated oppositely castellated electrodes was found to initiate EB formation. Embryoid body formation in aggregates formed with DEP occurred at a more rapid rate—in fact faster compared to conventional methods—in medium without LIF. However, EB formation also occurred in medium in which LIF was present when the cells were aggregated with DEP. The optimum characteristic size for the electrodes for EB formation with DEP was found to be 75–100 microns; aggregates smaller than this tended to merge, whilst aggregates larger than this tended to split to form multiple EBs. Experiments with ESCs in which green fluorescent protein (GFP) production was targeted to the mesodermal gene brachyury indicated that differentiation within embryoid bodies of this size may preferentially occur along the mesoderm lineage. As hematopoietic lineages during normal development derive from mesoderm, the finding points to a possible application of DEP formed EBs in the production of blood-based products from ESCs.

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87.15.Tt	Electrophoresis
87.14.E-	Proteins
87.15.bk	Structure of aggregates
87.15.nr	Aggregation
87.17.Ee	Growth and division
87.18.Ed	Cell aggregation

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New rationale for large metazoan embryo manipulations on chip-based devices

Khashayar Khoshmanesh, Jin Akagi, Chris J. Hall, Kathryn E. Crosier, Philip S. Crosier, Jonathan M. Cooper, and Donald Wlodkowic

Biomicrofluidics 6, 024102 (2012); http://dx.doi.org/10.1063/1.3699971 (14 pages)

Online Publication Date: 3 April 2012

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The lack of technologies that combine automated manipulation, sorting, as well as immobilization of single metazoan embryos remains the key obstacle to high-throughput organism-based ecotoxicological analysis and drug screening routines. Noticeably, the major obstacle hampering the automated trapping and arraying of millimetre-sized embryos on chip-based devices is their substantial size and mass, which lead to rapid gravitational-induced sedimentation and strong inertial forces. In this work, we present a comprehensive mechanistic and design rationale for manipulation and passive trapping of individual zebrafish embryos using only hydrodynamic forces. We provide evidence that by employing innovative design features, highly efficient hydrodynamic positioning of large embryos on a chip can be achieved. We also show how computational fluid dynamics-guided design and the Lagrangian particle tracking modeling can be used to optimize the chip performance. Importantly, we show that rapid prototyping and medium scale fabrication of miniaturized devices can be greatly accelerated by combining high-speed laser prototyping with replica moulding in poly(dimethylsiloxane) instead of conventional photolithography techniques. Our work establishes a new paradigm for chip-based manipulation of large multicellular organisms with diameters well above 1 mm and masses often exceeding 1 mg. Passive docking of large embryos is an attractive alternative to provide high level of automation while alleviating potentially deleterious effects associated with the use of active chip actuation. This greatly expands the capabilities of bioanalyses performed on small model organisms and offers numerous and currently inaccessible laboratory automation advantages.

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87.80.Fe	Micromanipulation of biological structures
47.57.ef	Sedimentation and migration
87.80.Ek	Mechanical and micromechanical techniques
85.85.+j	Micro- and nano-electromechanical systems (MEMS/NEMS) and devices
47.85.Dh	Hydrodynamics, hydraulics, hydrostatics
07.10.Cm	Micromechanical devices and systems

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Novel on-demand droplet generation for selective fluid sample extraction

Robert Lin, Jeffery S. Fisher, Melinda G. Simon, and Abraham P. Lee

Biomicrofluidics 6, 024103 (2012); http://dx.doi.org/10.1063/1.3699972 (10 pages)

Online Publication Date: 3 April 2012

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A novel microfluidic device enabling selective generation of droplets and encapsulation of targets is presented. Unlike conventional methods, the presented mechanism generates droplets with unique selectivity by utilizing a K-junction design. The K-junction is a modified version of the classic T-junction with an added leg that serves as the exit channel for waste. The dispersed phase fluid enters from one diagonal of the K and exits the other diagonal while the continuous phase travels in the straight leg of the K. The intersection forms an interface that allows the dispersed phase to be controllably injected through actuation of an elastomer membrane located above the inlet channel near the interface. We have characterized two critical components in controlling the droplet size—membrane actuation pressure and timing as well as identified the region of fluid in which the droplet will be formed. This scheme will have applications in fluid sampling processes and selective encapsulation of materials. Selective encapsulation of a single cell from the dispersed phase fluid is demonstrated as an example of functionality of this design.

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87.80.Ek	Mechanical and micromechanical techniques
47.85.Np	Fluidics
47.55.db	Drop and bubble formation
87.16.D-	Membranes, bilayers, and vesicles
07.10.Cm	Micromechanical devices and systems
85.85.+j	Micro- and nano-electromechanical systems (MEMS/NEMS) and devices

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Dielectrophoretic differentiation of mouse ovarian surface epithelial cells, macrophages, and fibroblasts using contactless dielectrophoresis

Alireza Salmanzadeh, Harsha Kittur, Michael B. Sano, Paul C. Roberts, Eva M. Schmelz, and Rafael V. Davalos

Biomicrofluidics 6, 024104 (2012); http://dx.doi.org/10.1063/1.3699973 (13 pages)

Online Publication Date: 3 April 2012

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Ovarian cancer is the leading cause of death from gynecological malignancies in women. The primary challenge is the detection of the cancer at an early stage, since this drastically increases the survival rate. In this study we investigated the dielectrophoretic responses of progressive stages of mouse ovarian surface epithelial (MOSE) cells, as well as mouse fibroblast and macrophage cell lines, utilizing contactless dielectrophoresis (cDEP). cDEP is a relatively new cell manipulation technique that has addressed some of the challenges of conventional dielectrophoretic methods. To evaluate our microfluidic device performance, we computationally studied the effects of altering various geometrical parameters, such as the size and arrangement of insulating structures, on dielectrophoretic and drag forces. We found that the trapping voltage of MOSE cells increases as the cells progress from a non-tumorigenic, benign cell to a tumorigenic, malignant phenotype. Additionally, all MOSE cells display unique behavior compared to fibroblasts and macrophages, representing normal and inflammatory cells found in the peritoneal fluid. Based on these findings, we predict that cDEP can be utilized for isolation of ovarian cancer cells from peritoneal fluid as an early cancer detection tool.

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87.15.Tt	Electrophoresis
87.19.xj	Cancer
07.10.Cm	Micromechanical devices and systems
87.80.Ek	Mechanical and micromechanical techniques
85.85.+j	Micro- and nano-electromechanical systems (MEMS/NEMS) and devices
47.85.Np	Fluidics

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Microfluidics based on ZnO/nanocrystalline diamond surface acoustic wave devices

Y. Q. Fu, L. Garcia-Gancedo, H. F. Pang, S. Porro, Y. W. Gu, J. K. Luo, X. T. Zu, F. Placido, J. I. B. Wilson, A. J. Flewitt, and W. I. Milne

Biomicrofluidics 6, 024105 (2012); http://dx.doi.org/10.1063/1.3699974 (11 pages)

Online Publication Date: 3 April 2012

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Surface acoustic wave (SAW) devices with 64 μm wavelength were fabricated on a zinc oxide (ZnO) film deposited on top of an ultra-smooth nanocrystalline diamond (UNCD) layer. The smooth surface of the UNCD film allowed the growth of the ZnO film with excellent c-axis orientation and low surface roughness, suitable for SAW fabrication, and could restrain the wave from significantly dissipating into the substrate. The frequency response of the fabricated devices was characterized and a Rayleigh mode was observed at ∼65.4 MHz. This mode was utilised to demonstrate that the ZnO/UNCD SAW device can be successfully used for microfluidic applications. Streaming, pumping, and jetting using microdroplets of 0.5 and 20 μl were achieved and characterized under different powers applied to the SAW device, focusing more on the jetting behaviors induced by the ZnO SAW.

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85.85.+j	Micro- and nano-electromechanical systems (MEMS/NEMS) and devices
47.85.Np	Fluidics
07.10.Cm	Micromechanical devices and systems
81.15.Gh	Chemical vapor deposition (including plasma-enhanced CVD, MOCVD, ALD, etc.)
47.55.dr	Interactions with surfaces

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A microfluidic platform for controlled biochemical stimulation of twin neuronal networks

Emilia Biffi, Francesco Piraino, Alessandra Pedrocchi, Gianfranco B. Fiore, Giancarlo Ferrigno, Alberto Redaelli, Andrea Menegon, and Marco Rasponi

Biomicrofluidics 6, 024106 (2012); http://dx.doi.org/10.1063/1.3699975 (10 pages)

Online Publication Date: 3 April 2012

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Spatially and temporally resolved delivery of soluble factors is a key feature for pharmacological applications. In this framework, microfluidics coupled to multisite electrophysiology offers great advantages in neuropharmacology and toxicology. In this work, a microfluidic device for biochemical stimulation of neuronal networks was developed. A micro-chamber for cell culturing, previously developed and tested for long term neuronal growth by our group, was provided with a thin wall, which partially divided the cell culture region in two sub-compartments. The device was reversibly coupled to a flat micro electrode array and used to culture primary neurons in the same microenvironment. We demonstrated that the two fluidically connected compartments were able to originate two parallel neuronal networks with similar electrophysiological activity but functionally independent. Furthermore, the device allowed to connect the outlet port to a syringe pump and to transform the static culture chamber in a perfused one. At 14 days invitro, sub-networks were independently stimulated with a test molecule, tetrodotoxin, a neurotoxin known to block action potentials, by means of continuous delivery. Electrical activity recordings proved the ability of the device configuration to selectively stimulate each neuronal network individually. The proposed microfluidic approach represents an innovative methodology to perform biological, pharmacological, and electrophysiological experiments on neuronal networks. Indeed, it allows for controlled delivery of substances to cells, and it overcomes the limitations due to standard drug stimulation techniques. Finally, the twin network configuration reduces biological variability, which has important outcomes on pharmacological and drug screening.

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87.18.Sn	Neural networks and synaptic communication
85.85.+j	Micro- and nano-electromechanical systems (MEMS/NEMS) and devices
87.85.eg	Electrode stimulation
87.85.dq	Neural networks
87.19.lj	Neuronal network dynamics
07.10.Cm	Micromechanical devices and systems

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Construction and operation of a microrobot based on magnetotactic bacteria in a microfluidic chip

Qiufeng Ma, Changyou Chen, Shufeng Wei, Chuanfang Chen, Long-Fei Wu, and Tao Song

Biomicrofluidics 6, 024107 (2012); http://dx.doi.org/10.1063/1.3702444 (12 pages)

Online Publication Date: 10 April 2012

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Magnetotactic bacteria (MTB) are capable of swimming along magnetic field lines. This unique feature renders them suitable in the development of magnetic-guided, auto-propelled microrobots to serve in target molecule separation and detection, drug delivery, or target cell screening in a microfluidic chip. The biotechnology to couple these bacteria with functional loads to form microrobots is the critical point in its application. Although an immunoreaction approach to attach functional loads to intact MTB was suggested, details on its realization were hardly mentioned. In the current paper, MTB-microrobots were constructed by attaching 2 μm diameter microbeads to marine magnetotactic ovoid MO-1 cells through immunoreactions. These microrobots were controlled using a special control and tracking system. Experimental results prove that the attachment efficiency can be improved to ∼30% via an immunoreaction. The motility of the bacteria attached with different number of loads was also assessed. The results show that MTB can transport one load at a velocity of ∼21 μm/s and still move and survive for over 30 min. The control and tracking system is fully capable of directing and monitoring the movement of the MTB-microrobots. The rotating magnetic fields can stop the microrobots by trapping them as they swim within a circular field with a controllable size. The system has potential use in chemical analyses and medical diagnoses using biochips as well as in nano/microscale transport.

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87.85.St	Robotics
47.85.Np	Fluidics
85.85.+j	Micro- and nano-electromechanical systems (MEMS/NEMS) and devices
87.17.Uv	Biotechnology of cell processes
87.50.cf	Biophysical mechanisms of interaction

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High-performance microfluidic rectifier based on sudden expansion channel with embedded block structure

Chien-Hsiung Tsai, Che-Hsin Lin, Lung-Ming Fu, and Hui-Chun Chen

Biomicrofluidics 6, 024108 (2012); http://dx.doi.org/10.1063/1.4704504 (9 pages)

Online Publication Date: 13 April 2012

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A high-performance microfluidic rectifier incorporating a microchannel and a sudden expansion channel is proposed. In the proposed device, a block structure embedded within the expansion channel is used to induce two vortex structures at the end of the microchannel under reverse flow conditions. The vortices reduce the hydraulic diameter of the microchannel and, therefore, increase the flow resistance. The rectification performance of the proposed device is evaluated by both experimentally and numerically. The experimental and numerical values of the rectification performance index (i.e., the diodicity, Di) are found to be 1.54 and 1.76, respectively. Significantly, flow rectification is achieved without the need for moving parts. Thus, the proposed device is ideally suited to the high pressure environment characteristic of most micro-electro-mechanical-systems (MEMS)-based devices. Moreover, the rectification performance of the proposed device is superior to that of existing valveless rectifiers based on Tesla valves, simple nozzle/diffuser structures, or cascaded nozzle/diffuser structures.

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87.80.Ek	Mechanical and micromechanical techniques
07.10.Cm	Micromechanical devices and systems
85.85.+j	Micro- and nano-electromechanical systems (MEMS/NEMS) and devices

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Linear conversion of pressure into concentration, rapid switching of concentration, and generation of linear ramps of concentration in a microfluidic device

Micha Adler and Alex Groisman

Biomicrofluidics 6, 024109 (2012); http://dx.doi.org/10.1063/1.3687379 (16 pages)

Online Publication Date: 13 April 2012

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Mixing of liquids to produce solutions with different concentrations is one of the basic functionalities of microfluidic devices. Generation of specific temporal patterns of concentration in microfluidic devices is an important technique to study responses of cells and model organisms to variations in the chemical composition of their environment. Here, we present a simple microfluidic network that linearly converts pressure at an inlet into concentration of a soluble reagent in an observation region and also enables independent concurrent linear control of concentrations of two reagents. The microfluidic device has an integrated mixer channel with chaotic three-dimensional flow that facilitates rapid switching of concentrations in a continuous range. A simple pneumatic setup generating linear ramps of pressure is used to produce smooth linear ramps and triangular waves of concentration with different slopes. The use of chaotic vs. laminar mixers is discussed in the context of microfluidic devices providing rapid switching and generating temporal waves of concentration.

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85.85.+j	Micro- and nano-electromechanical systems (MEMS/NEMS) and devices
47.60.Dx	Flows in ducts and channels
47.15.-x	Laminar flows
47.51.+a	Mixing
47.52.+j	Chaos in fluid dynamics
47.85.Np	Fluidics

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Microstripes for transport and separation of magnetic particles

Marco Donolato, Bjarke Thomas Dalslet, and Mikkel Fougt Hansen

Biomicrofluidics 6, 024110 (2012); http://dx.doi.org/10.1063/1.4704520 (6 pages)

Online Publication Date: 13 April 2012

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We present a simple technique for creating an on-chip magnetic particle conveyor based on exchange-biased permalloy microstripes. The particle transportation relies on an array of stripes with a spacing smaller than their width in conjunction with a periodic sequence of four different externally applied magnetic fields. We demonstrate the controlled transportation of a large population of particles over several millimeters of distance as well as the spatial separation of two populations of magnetic particles with different magnetophoretic mobilities. The technique can be used for the controlled selective manipulation and separation of magnetically labelled species.

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87.80.Ek	Mechanical and micromechanical techniques
07.10.Cm	Micromechanical devices and systems
85.85.+j	Micro- and nano-electromechanical systems (MEMS/NEMS) and devices

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Covalently immobilized biomolecule gradient on hydrogel surface using a gradient generating microfluidic device for a quantitative mesenchymal stem cell study

Zongbin Liu, Lidan Xiao, Baojian Xu, Yu Zhang, Arthur FT Mak, Yi Li, Wing-yin Man, and Mo Yang

Biomicrofluidics 6, 024111 (2012); http://dx.doi.org/10.1063/1.4704522 (12 pages)

Online Publication Date: 13 April 2012

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Precisely controlling the spatial distribution of biomolecules on biomaterial surface is important for directing cellular activities in the controlled cell microenvironment. This paper describes a polydimethylsiloxane (PDMS) gradient-generating microfluidic device to immobilize the gradient of cellular adhesive Arg-Gly-Asp (RGD) peptide on poly (ethylene glycol) (PEG) hydrogel. Hydrogels are formed by exposing the mixture of PEG diacrylate (PEGDA), acryloyl-PEG-RGD, and photo-initiator with ultraviolet light. The microfluidic chip was simulated by a fluid dynamic model for the biomolecule diffusion process and gradient generation. PEG hydrogel covalently immobilized with RGD peptide gradient was fabricated in this microfluidic device by photo-polymerization. Bone marrow derived rat mesenchymal stem cells (MSCs) were then cultured on the surface of RGD gradient PEG hydrogel. Cell adhesion of rat MSCs on PEG hydrogel with various RGD gradients were then qualitatively and quantitatively analyzed by immunostaining method. MSCs cultured on PEG hydrogel surface with RGD gradient showed a grated fashion for cell adhesion and spreading that was proportional to RGD concentration. It was also found that 0.107–0.143 mM was the critical RGD concentration range for MSCs maximum adhesion on PEG hydrogel.

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87.80.Ek	Mechanical and micromechanical techniques
07.10.Cm	Micromechanical devices and systems
82.35.Pq	Biopolymers, biopolymerization
85.85.+j	Micro- and nano-electromechanical systems (MEMS/NEMS) and devices
87.15.Vv	Diffusion
87.17.Rt	Cell adhesion and cell mechanics

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Geometrical effects in microfluidic-based microarrays for rapid, efficient single-cell capture of mammalian stem cells and plant cells

Anthony Lawrenz, Francesca Nason, and Justin J. Cooper-White

Biomicrofluidics 6, 024112 (2012); http://dx.doi.org/10.1063/1.4704521 (17 pages)

Online Publication Date: 17 April 2012

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In this paper, a detailed numerical and experimental investigation into the optimisation of hydrodynamic micro-trapping arrays for high-throughput capture of single polystyrene (PS) microparticles and three different types of live cells at trapping times of 30 min or less is described. Four different trap geometries (triangular, square, conical, and elliptical) were investigated within three different device generations, in which device architecture, channel geometry, inter-trap spacing, trap size, and trap density were varied. Numerical simulation confirmed that (1) the calculated device dimensions permitted partitioned flow between the main channel and the trap channel, and further, preferential flow through the trap channel in the absence of any obstruction; (2) different trap shapes, all having the same dimensional parameters in terms of depth, trapping channel lengths and widths, main channel lengths and widths, produce contrasting streamline plots and that the interaction of the fluid with the different geometries can produce areas of stagnated flow or distorted field lines; and (3) that once trapped, any motion of the trapped particle or cell or a shift in its configuration within the trap can result in significant increases in pressures on the cell surface and variations in the shear stress distribution across the cell’s surface. Numerical outcomes were then validated experimentally in terms of the impact of these variations in device design elements on the percent occupancy of the trapping array (with one or more particles or cells) within these targeted short timeframes. Limitations on obtaining high trap occupancies in the devices were shown to be primarily a result of particle aggregation, channel clogging and the trap aperture size. These limitations could be overcome somewhat by optimisation of these device design elements and other operational variables, such as the average carrier fluid velocity. For example, for the 20 μm polystyrene microparticles, the number of filled traps increased from 32% to 42% during 5–10 min experiments in devices with smaller apertures. Similarly, a 40%–60% reduction in trapping channel size resulted in an increase in the amount of filled traps, from 0% to almost 90% in 10 min, for the human bone marrow derived mesenchymal stem cells, and 15%–85% in 15 min for the human embryonic stem cells. Last, a reduction of the average carrier fluid velocity by 50% resulted in an increase from 80% to 92% occupancy of single algae cells in traps. Interestingly, changes in the physical properties of the species being trapped also had a substantial impact, as regardless of the trap shape, higher percent occupancies were observed with cells compared to single PS microparticles in the same device, even though they are of approximately the same size. This investigation showed that in microfluidic single cell capture arrays, the trap shape that maximizes cell viability is not necessarily the most efficient for high-speed single cell capture. However, high-speed trapping configurations for delicate mammalian cells are possible but must be optimised for each cell type and designed principally in accordance with the trap size to cell size ratio.

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85.85.+j	Micro- and nano-electromechanical systems (MEMS/NEMS) and devices
87.17.Uv	Biotechnology of cell processes
87.80.Ek	Mechanical and micromechanical techniques
02.60.-x	Numerical approximation and analysis
07.10.Cm	Micromechanical devices and systems

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An integrated, multiparametric flow cytometry chip using “microfluidic drifting” based three-dimensional hydrodynamic focusing

Xiaole Mao, Ahmad Ahsan Nawaz, Sz-Chin Steven Lin, Michael Ian Lapsley, Yanhui Zhao, J. Philip McCoy, Wafik S. El-Deiry, and Tony Jun Huang

Biomicrofluidics 6, 024113 (2012); http://dx.doi.org/10.1063/1.3701566 (9 pages)

Online Publication Date: 20 April 2012

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In this work, we demonstrate an integrated, single-layer, miniature flow cytometry device that is capable of multi-parametric particle analysis. The device integrates both particle focusing and detection components on-chip, including a “microfluidic drifting” based three-dimensional (3D) hydrodynamic focusing component and a series of optical fibers integrated into the microfluidic architecture to facilitate on-chip detection. With this design, multiple optical signals (i.e., forward scatter, side scatter, and fluorescence) from individual particles can be simultaneously detected. Experimental results indicate that the performance of our flow cytometry chip is comparable to its bulky, expensive desktop counterpart. The integration of on-chip 3D particle focusing with on-chip multi-parametric optical detection in a single-layer, mass-producible microfluidic device presents a major step towards low-cost flow cytometry chips for point-of-care clinical diagnostics.

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87.85.Ox	Biomedical instrumentation and transducers, including micro-electro-mechanical systems (MEMS)
07.10.Cm	Micromechanical devices and systems
85.85.+j	Micro- and nano-electromechanical systems (MEMS/NEMS) and devices

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Flow biosensing and sampling in indirect electrochemical detection

Francesco Lamberti, Camilla Luni, Alessandro Zambon, Pier Andrea Serra, Monica Giomo, and Nicola Elvassore

Biomicrofluidics 6, 024114 (2012); http://dx.doi.org/10.1063/1.4705368 (13 pages)

Online Publication Date: 20 April 2012

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Miniaturization in biological analyses has several advantages, such as sample volume reduction and fast response time. The integration of miniaturized biosensors within lab-on-a-chip setups under flow conditions is highly desirable, not only because it simplifies process handling but also because measurements become more robust and operator-independent. In this work, we study the integration of flow amperometric biosensors within a microfluidic platform when analyte concentration is indirectly measured. As a case study, we used a platinum miniaturized glucose biosensor, where glucose is enzymatically converted to H₂O₂ that is oxidized at the electrode. The experimental results produced are strongly coupled to a theoretical analysis of fluid dynamic conditions affecting the electrochemical response of the sensor. We verified that the choice of the inlet flow rate is a critical parameter in flow biosensors, because it affects both glucose and H₂O₂ transport, to and from the electrode. We identify optimal flow rate conditions for accurate sensing at high time resolution. A dimensionless theoretical analysis allows the extension of the results to other sensing systems according to fluid dynamic similarity principles. Furthermore, we developed a microfluidic design that connects a sampling unit to the biosensor, in order to decouple the sampling flow rate from that of the actual measurement.

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87.80.Ek	Mechanical and micromechanical techniques
87.80.Kc	Electrochemical techniques
82.45.Fk	Electrodes
82.45.Rr	Electroanalytical chemistry
47.85.-g	Applied fluid mechanics

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