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PubMed2000

Patterned deposition of cells and proteins onto surfaces by using three-dimensional microfluidic systems.

Three-dimensional microfluidic systems were fabricated and used to pattern proteins and mammalian cells on a planar substrate. The three-dimensional topology of the microfluidic network in the stamp makes this technique a versatile one with which to pattern multiple types of proteins and cells in complex, discontinuous structures on a surface. The channel structure, formed by the stamp when it is in contact with the surface of the substrate, limits migration and growth of cells in the channels. With the channel structure in contact with the surface, the cells stop dividing once they form a confluent layer. Removal of the stamp permits the cells to spread and divide.

Animals↗

PubMed2003

Gray-scale photolithography using microfluidic photomasks.

The ability to produce three-dimensional (3D) microstructures is of increasing importance in the miniaturization of mechanical or fluidic devices, optical elements, self-assembling components, and tissue-engineering scaffolds, among others. Traditional photolithography, the most widely used process for microdevice fabrication, is ill-suited for 3D fabrication, because it is based on the illumination of a photosensitive layer through a "photomask" (a transparent plate that contains opaque, unalterable solid-state features), which inevitably results in features of uniform height. We have devised photomasks in which the light-absorbing features are made of fluids. Unlike in conventional photomasks, the opacity of the photomask features can be tailored to an arbitrary number of gray-scale levels, and their spatial pattern can be reconfigured in the time scale of seconds. Here we demonstrate the inexpensive fabrication of photoresist patterns that contain features of multiple and/or smoothly varying heights. For a given microfluidic photomask, the developed photoresist pattern can be predicted as a function of the dye concentrations and photomask dimensions. For selected applications, microfluidic photomasks offer a low-cost alternative to present gray-scale photolithography approaches.

Journal Article↗

PubMed2005

Permeation-driven flow in poly(dimethylsiloxane) microfluidic devices.

Poly(dimethylsiloxane) is currently the material of choice for rapidly fabricating microfluidic devices. As the size of these devices decreases, a significant hydrodynamic flow is generated due to permeation of fluid through the channel walls. We develop a theoretical model verified by single bead tracking experiments, which demonstrates that large flow rates (>10 microm/s) can be passively generated in a straight microchannel filled with water. Realizing that this flow may be unwanted in some applications, we present a method to eliminate it by inhibiting mass transfer of water into the poly(dimethylsiloxane) walls. Furthermore, we explore applications to harness this passively generated flow inside a microfluidic device such as bead stacking, chemical concentration, and passive pumping.

Journal Article↗

PubMed2005

A modular microfluidic architecture for integrated biochemical analysis.

Microfluidic laboratory-on-a-chip (LOC) systems based on a modular architecture are presented. The architecture is conceptualized on two levels: a single-chip level and a multiple-chip module (MCM) system level. At the individual chip level, a multilayer approach segregates components belonging to two fundamental categories: passive fluidic components (channels and reaction chambers) and active electromechanical control structures (sensors and actuators). This distinction is explicitly made to simplify the development process and minimize cost. Components belonging to these two categories are built separately on different physical layers and can communicate fluidically via cross-layer interconnects. The chip that hosts the electromechanical control structures is called the microfluidic breadboard (FBB). A single LOC module is constructed by attaching a chip comprised of a custom arrangement of fluid routing channels and reactors (passive chip) to the FBB. Many different LOC functions can be achieved by using different passive chips on an FBB with a standard resource configuration. Multiple modules can be interconnected to form a larger LOC system (MCM level). We demonstrated the utility of this architecture by developing systems for two separate biochemical applications: one for detection of protein markers of cancer and another for detection of metal ions. In the first case, free prostate-specific antigen was detected at 500 aM concentration by using a nanoparticle-based bio-bar-code protocol on a parallel MCM system. In the second case, we used a DNAzyme-based biosensor to identify the presence of Pb(2+) (lead) at a sensitivity of 500 nM in <1 nl of solution.

Biochemistry↗

PubMed2003

Microfluidics without microfabrication.

Microfluidic devices create spatially defined, chemically controlled environments at microscopic dimensions. We demonstrate the formation and control of microscopic hydrodynamic and chemical environments by impinging a low-intensity acoustic oscillation on a cylindrical electrode. The interaction of small-amplitude (< or =203 microm), low-frequency (< or =515 Hz) fluid oscillations with a submillimeter cylinder creates four microscopic eddies that circulate adjacent to the cylinder. This steady flow is known as acoustic streaming. Because the steady circulation in the eddies has closed streamlines, reagent dosed from the electrode can escape the eddies only by slow molecular diffusion. As a result, reagent dosing rates of 10 nmol/s produce eddy concentrations as high as 8 mM, without a correspondingly large rise in bulk solution composition. Imaging Raman spectroscopy is used to visualize the eddy concentration distribution for various acoustic oscillation conditions, and point Raman spectra are used to quantify eddy compositions. These results, and corresponding numerical simulations, show that each eddy acts as a microchemical trap with size determined by acoustic frequency and the concentration tuned via reagent dosing rate and acoustic amplitude. Low-intensity acoustic streaming flows can serve as microfluidic elements without the need for microfabrication.

Journal Article↗

PubMed2002

Application of microfluidic devices to proteomics research: identification of trace-level protein digests and affinity capture of target peptides.

This report describes an integrated and modular microsystem providing rapid analyses of trace-level tryptic digests for proteomics applications. This microsystem includes an autosampler, a microfabricated device comprising a large channel (2.4 microl total volume), an array of separation channels, together with a low dead volume enabling the interface to nanoelectrospray mass spectrometry. The large channel of this microfluidic device provides a convenient platform to integrate C(18) reverse phase packing or other type of affinity media such as immobilized antibodies or immobilized metal affinity chromatography beads thus enabling affinity selection of target peptides prior to electrophoretic separation and mass spectrometry analyses on a quadrupole/time-of-flight instrument. Sequential injection, preconcentration, and separation of peptide standards and tryptic digests are achieved with a throughput of up to 12 samples/per h and a concentration detection limit of approximately 5 nM (25 fmol on chip). Replicate injections of peptide mixtures indicated that reproducibility of migration time was 1.2-1.8%, whereas relative standard deviation ranging from 9.2 to 11.8% are observed on peak heights. The application of this device for trace-level protein identification is demonstrated for two-dimensional gel spots obtained from extracts of human prostatic cancer cells (LNCap) using both peptide mass-fingerprint data base searching and on-line tandem mass spectrometry. Enrichment of target peptides prior to mass spectral analyses is achieved using c-myc-specific antibodies immobilized on protein G-Sepharose beads and facilitates the identification of antigenic peptides spiked at a level of 20 ng/ml in human plasma. Affinity selection is also demonstrated for gel-isolated protein bands where tryptic phosphopeptides are captured on immobilized metal affinity chromatography beads and subsequently separated and characterized on this microfluidic system.

Amino Acid Sequence↗

PubMed2002

Generalized Taylor-Aris dispersion in discrete spatially periodic networks: microfluidic applications.

A theory is presented for the lumped parameter, convective-diffusive transport of individual, noninteracting Brownian solute particles ("macromolecules") moving within spatially periodic, solvent-filled networks--the latter representing models of chip-based microfluidic chromatographic separation devices, as well as porous media. Using graph-theoretical techniques, the composite medium is conceptually decomposed into a network of channels (the edges) through which the solute is transported by a combination of molecular diffusion and either "piggyback" entrainment within a flowing solvent or an externally applied force field acting upon the solute molecules. A probabilistic choice of egress channel for a solute particle exiting the intersection (vertex) of the channels is furnished by an imperfect mixing model. A spatially periodic, Taylor-Aris-like "method-of-moments" scheme is applied to this transport model, leading to discrete matrix equations for computing the network-scale particle velocity vector U(*) and dispersivity dyadic D(*) in terms of the prescribed microscale transport parameters and network geometry characterizing the basic unit cell of which the spatially periodic device is comprised. The ensuing algebraic equations governing the vertex-based, discrete unit-cell "fields" P(0)(infinity)(i) and B(i) (i=1,2,...,n), whose paradigmatic summations yield U(*) and D(*), constitute discrete analogs of classical continuous macrotransport phenomenological parameters, P(0)(infinity)(r) and B(r), with r a continuous position vector defined within the unit cell. The ease with which these discrete calculations can be performed for complex networks renders feasible parametric studies of potential microfluidic chip designs, particularly those pertinent to biomolecular separation schemes. Application of this discrete theory to the dispersion analysis of pressure-driven flow in spatially periodic serpentine microchannels is shown to accord with existing results previously derived using classical continuous macrotransport theory.

Journal Article↗

PubMed2001

Dynamic pattern formation in a vesicle-generating microfluidic device.

Spatiotemporal pattern formation occurs in a variety of nonequilibrium physical and chemical systems. Here we show that a microfluidic device designed to produce reverse micelles can generate complex, ordered patterns as it is continuously operated far from thermodynamic equilibrium. Flow in a microfluidic system is usually simple-viscous effects dominate and the low Reynolds number leads to laminar flow. Self-assembly of the vesicles into patterns depends on channel geometry and relative fluid pressures, enabling the production of motifs ranging from monodisperse droplets to helices and ribbons.

Journal Article↗

PubMed2003

Discrete Boltzmann equation for microfluidics.

We propose a discrete Boltzmann model for microfluidics based on the Boltzmann equation with external forces using a single relaxation time collision model. Considering the electrostatic interactions in microfluidics systems, we introduce an equilibrium distribution function that differs from the Maxwell-Boltzmann distribution by an exponential factor to represent the action of an external force field. A statistical mechanical approach is applied to derive the equivalent external acceleration force exerting on the lattice particles based on a mean-field approximation, resulting from the electro-static potential energy and intermolecular potential energy between fluid-fluid and fluid-substrate interactions.

Journal Article↗

PubMed2004

Geometrically mediated breakup of drops in microfluidic devices.

Microfluidic technology offers capabilities for the precise handling of small fluid volumes dispersed as droplets. To fully exploit this potential requires simultaneous generation of multiple size droplets. We demonstrate two methods for passively breaking larger drops into precisely controlled daughter drops using pressure-driven flow in simple microfluidic configurations: (i) a T junction and (ii) flow past isolated obstacles. We quantify conditions for breakup at a T junction and illustrate sequential breakup at T junctions for making small drops at high dispersed phase volume fractions.

Journal Article↗

PubMed2004

Induced-charge electrokinetic phenomena: theory and microfluidic applications.

We give a general, physical description of "induced-charge electro-osmosis" (ICEO), the nonlinear electrokinetic slip at a polarizable surface, in the context of some new techniques for microfluidic pumping and mixing. ICEO generalizes "ac electro-osmosis" at microelectrode arrays to various di-electric and conducting structures in weak dc or ac electric fields. The basic effect produces microvortices to enhance mixing in microfluidic devices, while various broken symmetries--controlled potential, irregular shape, nonuniform surface properties, and field gradients--can be exploited to produce streaming flows. Although we emphasize the qualitative picture of ICEO, we also briefly describe the mathematical theory (for thin double layers and weak fields) and apply it to a metal cylinder with a dielectric coating in a suddenly applied dc field.

Journal Article↗

PubMed2006

Hybrid approach to high-frequency microfluidic mixing.

We report the experimental verification of the predicted chaotic mixing characteristics for a polydimethylsioxane microfluidic chip, based on the mechanism of multistage cross-channel flows. While chaotic mixing can be achieved within short passage distances, there is an optimal side channel flow pulsation frequency beyond which the mixing becomes ineffective. Based on the physical understanding of a Poincaré section analysis, we propose the installation of passive flow baffles in the main microfluidic channel to facilitate high-frequency mixing. The combined hybrid approach enables chaotic mixing at enhanced frequency and reduced passage distance in two-dimensional flows.

Journal Article↗

PubMed1999

Contoured elastic-membrane microvalves for microfluidic network integration.

A contoured elastic-membrane microvalve is presented that enables integrated microfluidic processing at the network level. This method takes advantage of two ideas to improve performance: flexible elastic membranes (which enable high-performance shutoff and reduced footprint), and three-dimensionally contoured valve geometries (which reduce dead volume, improve fluidic priming, and reduce susceptibility to cavitation at high fluid velocities). We describe the use of laser-induced etching for microfluidic manifold fabrication, discuss the nonlinear load-deflection behavior of elastic membranes that can occur below 30 psi, and present flow-rate data for microvalves under inlet pressures of 0-20 psi with zero applied membrane pressure. Valve-closure data for inlet pressures of 0-30 psi are presented for fully assembled microvalve structures. The microvalve structures under test were capable of turning off flows of > 20 microL/s. These flow rates were shown to be limited by inlet and outlet flow resistances and not by the valve structure itself, so that higher maximum flow rate capabilities should be readily achieved.

Computer-Aided Design↗

PubMed2003

Programmed adsorption and release of proteins in a microfluidic device.

A microfluidic device has been developed that can adsorb proteins from solution, hold them with negligible denaturation, and release them on command. The active element in the device is a 4-nanometer-thick polymer film that can be thermally switched between an antifouling hydrophilic state and a protein-adsorbing state that is more hydrophobic. This active polymer has been integrated into a microfluidic hot plate that can be programmed to adsorb and desorb protein monolayers in less than 1 second. The rapid response characteristics of the device can be manipulated for proteomic functions, including preconcentration and separation of soluble proteins on an integrated fluidics chip.

Acrylic Resins↗

PubMed2002

Physics and applications of microfluidics in biology.

Fluid flow at the microscale exhibits unique phenomena that can be leveraged to fabricate devices and components capable of performing functions useful for biological studies. The physics of importance to microfluidics are reviewed. Common methods of fabricating microfluidic devices and systems are described. Components, including valves, mixers, and pumps, capable of controlling fluid flow by utilizing the physics of the microscale are presented. Techniques for sensing flow characteristics are described and examples of devices and systems that perform bioanalysis are presented. The focus of this review is microscale phenomena and the use of the physics of the scale to create devices and systems that provide functionality useful to the life sciences.

Biosensing Techniques↗

PubMed2005

Rapid self-assembly of DNA on a microfluidic chip.

BACKGROUND: DNA self-assembly methods have played a major role in enabling methods for acquiring genetic information without having to resort to sequencing, a relatively slow and costly procedure. However, even self-assembly processes tend to be very slow when they rely upon diffusion on a large scale. Miniaturisation and integration therefore hold the promise of greatly increasing this speed of operation. RESULTS: We have developed a rapid method for implementing the self-assembly of DNA within a microfluidic system by electrically extracting the DNA from an environment containing an uncharged denaturant. By controlling the parameters of the electrophoretic extraction and subsequent analysis of the DNA we are able to control when the hybridisation occurs as well as the degree of hybridisation. By avoiding off-chip processing or long thermal treatments we are able to perform this hybridisation rapidly and can perform hybridisation, sizing, heteroduplex analysis and single-stranded conformation analysis within a matter of minutes. The rapidity of this analysis allows the sampling of transient effects that may improve the sensitivity of mutation detection. CONCLUSIONS: We believe that this method will aid the integration of self-assembly methods upon microfluidic chips. The speed of this analysis also appears to provide information upon the dynamics of the self-assembly process.

Journal Article↗

PubMed2004

Femtosecond pulsed laser micromachining of glass substrates with application to microfluidic devices.

We describe a technique for surface and subsurface micromachining of glass substrates by using tightly focused femtosecond laser pulses at a wavelength of 1660 nm. A salient feature of pulsed laser micromachining is its ability to drill subsurface tunnels into glass substrates. To demonstrate a potential application of this micromachining technique, we fabricate simple microfluidic structures on a glass plate. The use of a cover plate that seals the device by making point-to-point contact with the flat surface of the substrate is necessary to prevent the evaporation of liquids in open channels and chambers. Methods for protecting and sealing the micromachined structures for microfluidic applications are discussed.

Journal Article↗

PubMed2006

Preparation of liposomes from milk fat globule membrane phospholipids using a microfluidizer.

The isolation of milk fat globule membrane (MFGM) material from buttermilk on a commercial scale has provided a new ingredient rich in phospholipids and sphingolipids. An MFGM-derived phospholipid fraction was used to produce liposomes via a high-pressure homogenizer (Microfluidizer). This technique does not require the use of solvents or detergents, and is suitable for use in the food industry. The liposome dispersion had an average hydrodynamic diameter of 95 nm, with a broad particle-size distribution. Increasing the number of passes through the Microfluidizer, increasing the pressure, or reducing the phospholipid concentration all resulted in a smaller average liposome diameter. Changing these variables did not have a significant effect on the polydispersity of the dispersion. Electron microscopy showed that the dispersions formed had a range of structures, including unilamellar, multilamellar, and multivesicular liposomes. The composition of the MFGM phospholipid material is different from that of the phospholipids usually used for liposome production in the pharmaceutical and cosmetic industries. The MFGM-derived fraction comprises approximately 25% sphingomyelin, and the fatty acids are primarily saturated and monounsaturated. These differences are likely to affect the properties of the liposomes produced from the phospholipid material, and it may be possible to exploit the unique composition of the MFGM phospholipid fraction in the delivery of bioactive ingredients in functional foods.

Chemical Phenomena↗