WO2002094440A2 - Systeme de pompage electroosmotique multicanaux integre a une puce electronique - Google Patents

Systeme de pompage electroosmotique multicanaux integre a une puce electronique Download PDF

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Publication number
WO2002094440A2
WO2002094440A2 PCT/US2002/016207 US0216207W WO02094440A2 WO 2002094440 A2 WO2002094440 A2 WO 2002094440A2 US 0216207 W US0216207 W US 0216207W WO 02094440 A2 WO02094440 A2 WO 02094440A2
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Prior art keywords
microchannels
microchannel
microfluidic
electroosmotic
microfluidic device
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PCT/US2002/016207
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English (en)
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WO2002094440A3 (fr
Inventor
Iuliana M. Lazar
Barry L. Karger
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Northeastern University
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Priority to US10/478,612 priority Critical patent/US20040208751A1/en
Publication of WO2002094440A2 publication Critical patent/WO2002094440A2/fr
Publication of WO2002094440A3 publication Critical patent/WO2002094440A3/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/416—Systems
    • G01N27/447—Systems using electrophoresis
    • G01N27/44756—Apparatus specially adapted therefor
    • G01N27/44791—Microapparatus
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/50273—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the means or forces applied to move the fluids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502738—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by integrated valves
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F04—POSITIVE - DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS FOR LIQUIDS OR ELASTIC FLUIDS
    • F04B—POSITIVE-DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS
    • F04B17/00—Pumps characterised by combination with, or adaptation to, specific driving engines or motors
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F04—POSITIVE - DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS FOR LIQUIDS OR ELASTIC FLUIDS
    • F04B—POSITIVE-DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS
    • F04B19/00—Machines or pumps having pertinent characteristics not provided for in, or of interest apart from, groups F04B1/00 - F04B17/00
    • F04B19/006—Micropumps
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
    • F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
    • F16K99/00—Subject matter not provided for in other groups of this subclass
    • F16K99/0001—Microvalves
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
    • F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
    • F16K99/00—Subject matter not provided for in other groups of this subclass
    • F16K99/0001—Microvalves
    • F16K99/0003—Constructional types of microvalves; Details of the cutting-off member
    • F16K99/0017—Capillary or surface tension valves, e.g. using electro-wetting or electro-capillarity effects
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
    • F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
    • F16K99/00—Subject matter not provided for in other groups of this subclass
    • F16K99/0001—Microvalves
    • F16K99/0003—Constructional types of microvalves; Details of the cutting-off member
    • F16K99/0025—Valves using microporous membranes
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
    • F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
    • F16K99/00—Subject matter not provided for in other groups of this subclass
    • F16K99/0001—Microvalves
    • F16K99/0034—Operating means specially adapted for microvalves
    • F16K99/0042—Electric operating means therefor
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
    • F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
    • F16K99/00—Subject matter not provided for in other groups of this subclass
    • F16K99/0001—Microvalves
    • F16K99/0034—Operating means specially adapted for microvalves
    • F16K99/0042—Electric operating means therefor
    • F16K99/0049—Electric operating means therefor using an electroactive polymer [EAP]
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/416—Systems
    • G01N27/447—Systems using electrophoresis
    • G01N27/44704—Details; Accessories
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00783—Laminate assemblies, i.e. the reactor comprising a stack of plates
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00851—Additional features
    • B01J2219/00853—Employing electrode arrangements
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00851—Additional features
    • B01J2219/00858—Aspects relating to the size of the reactor
    • B01J2219/0086—Dimensions of the flow channels
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00891—Feeding or evacuation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0864—Configuration of multiple channels and/or chambers in a single devices comprising only one inlet and multiple receiving wells, e.g. for separation, splitting
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0867—Multiple inlets and one sample wells, e.g. mixing, dilution
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0415—Moving fluids with specific forces or mechanical means specific forces electrical forces, e.g. electrokinetic
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0415—Moving fluids with specific forces or mechanical means specific forces electrical forces, e.g. electrokinetic
    • B01L2400/0418—Moving fluids with specific forces or mechanical means specific forces electrical forces, e.g. electrokinetic electro-osmotic flow [EOF]
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
    • F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
    • F16K99/00—Subject matter not provided for in other groups of this subclass
    • F16K2099/0073—Fabrication methods specifically adapted for microvalves
    • F16K2099/0074—Fabrication methods specifically adapted for microvalves using photolithography, e.g. etching
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
    • F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
    • F16K99/00—Subject matter not provided for in other groups of this subclass
    • F16K2099/0082—Microvalves adapted for a particular use
    • F16K2099/0094—Micropumps
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/02—Devices for withdrawing samples
    • G01N1/10—Devices for withdrawing samples in the liquid or fluent state
    • G01N1/14—Suction devices, e.g. pumps; Ejector devices

Definitions

  • microfluidics and instrument miniaturization 1 have experienced significant growth in activity in recent years in response to the significant increase in use of microchips as bioanalytical tools.
  • a major aspect of microfluidics refers to the manipulation of fluid flows in the microchip channels .
  • flow streams are typically generated using electrical forces (electroosmotic flow, or EOF) .
  • EOF electroosmotic flow
  • EOF is dependent on the surface charge of the channel walls and consequently is sensitive to the physicochemical properties of the sample (pH, ionic strength, organic content) .
  • the EOF can be easily reduced or even suppressed if the channel surface is altered by contact with specific sample types.
  • fluid flows on microchips may, or must, be generated by differential pressure. 6-8
  • this is accomplished by connecting external devices to the microchip, e.g., vacuum, gas pressure generators or syringe pumps.
  • external devices e.g., vacuum, gas pressure generators or syringe pumps.
  • the connection of external devices to microchips while effective, increases the complexity of the system, and integration and multiplexing capabilities may be compromised.
  • micropumps have been described in the art.
  • Mechanical pumps that use a membrane actuated by various forces e.g., piezoelectric, electromagnetic, pneumatic 9-15 are capable of pumping fluids of various physicochemical properties; however, the flow is pulsed, and the fabrication of the micropu p is relatively complex.
  • Non-mechanical pumps, with no moving parts, that operate on the basis of a large variety of principles (e.g., electrokinetic, centrifugal, electrohydrodynamic, etc.) 16-29 have been implemented.
  • the flow produced by these pumps is generally pulse free and varies from a fe nL/min to hundreds of ⁇ L/min. However, the generated pressures are low, up to only a few psi. Fabrication procedures are often complex, as well.
  • electroosmosis for pressurized pumping was advanced almost forty years ago 30 ' 31 and demonstrated later in open 32 and packed 16 ' 17 capillary columns, and for open-channel microchip platforms . 18-22 While packed electroosmotic pumps were shown to be capable of generating both flow and pressure, having packed particles or porous materials within the pump structure may, inter alia, impose limitations on the pumping channel size, may necessitate additional steps in pump fabrication and may affect reproducibility from one pump to another.
  • the open-channel configurations were capable of producing flow but not sufficient pressure for the intended applications..
  • microchip-integrated pumping device that simultaneously generates both sufficient flow and pressure for most analytical applications on a microchip and that is easy to fabricate, implement and use. Furthermore, an optimum pump design would ensure that a generated EOF is delivered to the analysis system and is not leaked out of the pump itself.
  • the invention is directed to a microchip integrated microfabricated, microfluidic, multichannel, preferably electroosmotic pump and pumping system.
  • the electroosmotic pump of the invention comprises a plurality of microchannels, which begin and end in common compartments, complexed into an array.
  • the microchannels within the pump have substantially identical, optimal dimensions of cross-section and length such that sufficient pressure for optimal flow of fluid (e.g., liquid or gas) and pressure is generated by the pump and flow rates are stable and reproducible.
  • the microchannels of the electroosmotic pump of the invention are open channels, i.e., not containing packed or porous materials.
  • an electroosmotic pump of the invention is coupled to a single channel of a larger cross-section.
  • a similar structure is also used in an electroosmotic valve of the invention, where samples are introduced into an analytical device.
  • the microfluidic electroosmotic pumping system of the invention generates sufficient flow and pressures by optimizing the dimensional parameters of cross-section and length of the microchannels.
  • FIG. 1 shows a schematic diagram of the microfabricated electroosmotic pumping system in accordance with the invention
  • FIG. 2 shows a schematic diagram of a different embodiment of the microfabricated electroosmotic pumping system in accordance with the invention
  • FIG. 3A shows representative flow, diameter and length in a schematic representation of a micropump with one pumping channel
  • FIG. 3B shows a graph of the flow distribution, or the F/F eof coefficients calculated for a micropump with one microchannel at various di/d ⁇ ratios
  • FIG. 4A shows a schematic representation of a micropump with n pumping channels
  • FIG. 7A shows a schematic diagram of an injection of a well delimited sample plug moving through the electroosmotic valve of the invention
  • FIG. 7B shows a schematic diagram of a sample plug being transported down the channel in the electroosmotic valve of the invention
  • FIG. 8A shows a schematic diagram of an electroosmotic pumping system functioning as an electroosmotic valve
  • FIG. 8B shows a schematic diagram of an electroosmotic pumping system functioning as an electroosmotic valve
  • FIG. 9 shows an exemplary multiplexed pumping system in accordance with the invention.
  • FIG. 10A and FIG. 10B show a cross-sectional view and a plan view, respectively, of a micropump according to the invention having filtering and gating elements .
  • the microfabricated microfluidic pumping system of the invention comprises one or more miniaturized pumping units, which are capable of stable fluid delivery at flow rates and backpressures compatible with common analytical applications carried out on a microchip and sufficiently small to enable multiplexing of individual pumps.
  • a multiple channel micropump based on electroosmotic pumping principles in accordance with the invention comprises a plurality of parallel, small cross- section microchannels (e.g., narrow or shallow) that deliver fluid to a microchannel of larger cross-section. This design allows the simultaneous generation of both flow and pressure and can be implemented in both packed channel and open-channel configuration.
  • an open-channel means that no packed particles or porous materials are added to or contained in the microchannels.
  • the pumping system of the invention offers numerous advantages. First, it can easily be integrated on microfluidic platforms and utilized for fluid propulsion on a microchip. Secondly, its fabrication using standard photolithographic and wet chemical etching technologies (or other microelectromechanical systems (MEMS) technologies) ensures high manufacturing and operating reproducibility. Thirdly, the simplicity of the design ensures robustness, reliability and trouble free operation.
  • the micropump is designed to fit into an integrated microfluidic analysis scheme for delivery of, e.g., peptide samples for, e.g., electrospray ionization-mass spectrometry (ESI-MS) analysis.
  • ESI-MS electrospray ionization-mass spectrometry
  • ⁇ -TAS micro-total analysis systems
  • the principle of ⁇ -TAS is based on integrating all necessary parts and methods for analysis in miniaturized devices.
  • the benefits of miniaturizing an analysis system include, but are not limited to, generation of multiple units at low cost; reduction in sample and reagent consumption and waste production; high throughput assays; small compact design; simple and reliable operation; and integration of several units or with existing systems.
  • the micropump of the invention can be used to deliver fluid flows in electric field free regions and perform sample transfer, gradient generation, or fraction collection/deposition.
  • a large variety of applications can be envisioned for a micropump according to the invention, including, inter alia, eluent flow and/or pressure generation for condensed phase separation techniques (e.g., micro liquid chromatography in open, packed, monolithic or microfabricated channels, pressure assisted capillary electrochromatography or capillary electrophoresis, isoelectric focusing, affinity chromatography, immunoassays) ; single, parallel or sequential sample delivery for electrospray ionization-mass spectrometry (ESI-MS) , matrix assisted laser desorption ionization (MALDI)-MS, optical detectors, or other detection systems; single, parallel or sequential sample delivery systems to microreactors, mixers, preconcentrators, filters, or other functional elements integrated on the microchip; single, parallel or sequential eluent or sample delivery systems to off-chip applications; solvent gradient generation
  • FIG. 1 illustrates a simplified schematic drawing of an exemplary microfabricated electroosmotic pumping system of the invention.
  • a pumping unit 10 can be incorporated on one microchip device. However, multiple pumping units can also be incorporated, e.g., in parallel as shown in FIG. 2 and FIG. 9.
  • the microchip device may be about a few square millimeters, e.g., 5-50 mm 2 .
  • a multiplexed device (see, e . g. , FIG. 9) that may contain, for example, eight, sixteen, or even 96 individual pumps may require a larger size chip.
  • Pumping channel system 11 of pumping unit 10 comprises a plurality of first shallow microchannels 12 (e.g., 2-10,000 microchannels).
  • All pumping channels 12 have first and second ends, which are in fluid communication with a common inlet 14 and a common outlet compartment or reservoir 16, respectively. Electrodes inserted in reservoirs 14 and 16 are connected to high voltage power supply 30 and are used to apply a voltage drop across the pump.
  • the pumping channels are exposed only to buffer solutions and do not come in contact with any sample that may be added to the microchip.
  • the pump size is quite variable and depends on the application (e.g., 1x10, 2x10, 5x50, 1x50 mm).
  • the length of each microchannel may range from, e.g., about 5-50 mm.
  • the channel depth, width, equivalent diameter or cross-section may range from about less than 1 ⁇ m to a few micrometers (e.g., 0.5- 10 ⁇ m) .
  • the number of microchannels in one pump may range from two to more than a thousand (e.g., 2-10,000 channels).
  • the spacing between the microchannels is in the low micrometer range (e.g., 1-50 ⁇ m) .
  • the pump unit of the invention comprises 4 microchannels, 10 microchannels, 25 microchannels, 100 microchannels or 1000 microchannels.
  • the pumping (or valve) system of the invention is activated by introducing into the channels a buffer or solvent, appropriate for preserving or increasing the surface charge on the pumping channel walls.
  • the microchannels 12 can be filled by capillary action or by action of a pressure differential.
  • a potential differential is applied across the microchannels 12.
  • the larger voltage must be applied to the appropriate reservoir, such that the electroosmotic flow will have the desired direction. For example, for a glass micropump having uncoated pumping channel walls, by applying a 2000 V on reservoir 14 and connecting reservoir 16 to ground, electroosmotic flow will be generated from reservoir 14 in the direction of reservoir 16.
  • Electroosmotic flow is created due to the following mechanism.
  • the functional groups on the pumping microchannel walls ionize in the presence of the solvent/fluid that is filling the microchannels and attract a layer of oppositely charged ions.
  • this layer of oppositely charged ions start to move in the direction of the appropriate electrode (negative electrode for positively charged ions) , dragging along bulk fluid flow.
  • this electroosmotic flow is restricted from evolving freely by the structure of the system or by the rest of the microfluidic channel network on the chip, pressure will be created inside the microfluidic structure, and the electroosmotic flow will be distributed through all the channels of the device through a pressure controlled mechanism.
  • the direction of pumping will be reversed, and the pump will draw fluid out from the rest of the channels.
  • the pumping system delivers fluid via a common outlet compartment, connected to reservoir 16, to larger diameter second microchannel 13, which may be connected to a network of channels or to other devices.
  • second microchannel 13 is connected to network channel 20 for, e.g.,, sample infusion or separation.
  • Channel 20 comprises electroosmotic valve 17 of the invention, which is used, e.g., for sample introduction.
  • the electroosmotic valve is open to electroosmotic driven flows and essentially closed to pressure driven flows.
  • an electrospray emitter 32 for example, or a detection or a sample collection device using any of the systems described above, can be integrated for analysis of a sample.
  • Sample injection in a microfabricated analysis systems is accomplished electrokinetically 2,3 or by pressure gradients, 44 and sample manipulations are performed with electrokinetic forces. If sample manipulations are to be performed using pressure driven flows, a fluid valving system, such as described here, is necessary to prevent leakage of the fluid flow into the sample or sample waste reservoirs.
  • electroosmotic valving is accomplished using very narrow channels for the sample injection and waste lines, in a configuration similar to that of the electooosmotic pump. In a pressurized analysis system, narrow injection channels 45 can act as efficient valving components. As shown in FIG.
  • a sample in a valve according to the invention, can be infused electroosmotically from reservoir 22 to reservoir 24 through the sample and sample waste pluralities off channels, 26 and 28, respectively, and a double-T injector 18.
  • the double-T injector can be an open or packed channel, e.g., as part of a preconcentration or ⁇ LC system. After completion of the injection, the pump can be started. For sample introduction and waste channels with similar dimensions to the pumping microchannels, additional pressure driven fluid loss through these channels could be negligible.
  • valve 17 and pump 10 are first filled with an appropriate eluent.
  • Sample is injected into the valve inlet reservoir 22, and a voltage drop is established between reservoirs 22 and 24 to allow for a sample plug to be loaded into microchannel 20.
  • the sample is electroosmotically carried from reservoir 22 in the direction of reservoir 24 by the application of a potential difference, e.g., 2000 V, between reservoir 22 and reservoir 24.
  • a very small voltage drop e.g., 100 V
  • pump reservoir 14 and pump reservoir 16 may be needed on the pump unit 12 as well to help focus the injected plug in the microchannel 20.
  • a large voltage drop e.g., 2000 V
  • the electrodes in reservoirs 22 and 24 are maintained at the same value as the voltage on reservoir 16, or they are removed from these reservoirs, in order to suppress the electroosmotic flow in the direction of the sample and sample waste reservoirs.
  • the voltage drop across the pump will generate electroosmotic flow in the pump and pressurized flow in the rest of the system.
  • the large hydraulic resistance in the sample inlet and outlet channels will prevent back pressure leakage, or will allow for only a small flow leakage through these channels. Consequently, the sample plug will be transported only down the microchannel 20.
  • an electroosmotic pumping system composed of two parallel pumps can function, alternatively, as an electroosmotic valve, as well.
  • One of the pumps e.g., pump 10
  • the other pump e.g., pump 100
  • Small, well delimited sample plugs cannot be injected with this configuration.
  • a large voltage drop is applied across pump 100, for example, 2000 V between reservoir 104 and reservoir 106.
  • the voltage on reservoirs 14 and 16 is maintained at the same value as the voltage on reservoir 106, or the electrodes are removed from these reservoirs.
  • the voltage drop across the pump 100 will generate electroosmotic flow in this pump, and pressurized flow in the rest of the system. For properly designed pumping channel diameters, the pressurized leakage flow through pump 12 will be minimal.
  • the potential differential for electroosmotic flow (EOF) generation is applied between the inlet and outlet reservoirs and may be provided by a power supply.
  • EEF electroosmotic flow
  • the necessary voltage drop for the operation of the electroosmotic micropump may vary from a few tens to thousands of volts (e.g., 50-2000 V/cm) .
  • outlet compartment or reservoir 16 can be common for systems with multiple pumps.
  • a semi-permeable gate 34 that allows for an exchange of ions but not of the bulk eluent flow (liquid or gas) , is created at the bottom of the outlet reservoir.
  • the gate prevents EOF leakage in the direction of the exit electrode 35' placed in the outlet reservoir.
  • a porous glass disc e.g., 5 mm in diameter, 0.8-1 mm in width, and 40-50 A pore size, prepared by Chang Associates (Worcester, MA)
  • other materials e.g., graphite, polymeric organic or inorganic membrane materials.
  • reservoir 16 is fabricated from a PEEK external nut.
  • the porous glass disc is secured (e.g., between two gasket elements) at the bottom of reservoir 16 with a corresponding internal nut. This arrangement provides for robustness and exchangeability of the porous glass disc.
  • a short filter element 36 (e.g., 100 ⁇ m in length), of the same size and density as the collection of pumping channels, can be introduced, preferably at each end of the pump. Filter elements 36 are spaced from the ends of the pumping channels by intermediate compartments 38 and terminate at end compartments 14' and 16', respectively. In the embodiment shown, end compartments 14', 16' are connected to orifaces 40 in the substrate, which make connection with reservoirs 14 and 16 on the exterior surface of the substrate.
  • the pump can be fabricated in a variety of substrate materials such as, inter alia, glass, quartz, silicon, polysilicon, polymeric materials (organic or inorganic) , ceramic, or other materials.
  • the micropumps can be made using microfabrication techniques, for example, photolithography and wet chemical etching, or other microelectromechanical systems (MEMS) technologies (e.g., dry etching, laser ablation, injection molding, embossing, stamping) .
  • MEMS microelectromechanical systems
  • Microfabricated devices that contain an electroosmotic micropump of the invention can be fabricated from one or two substrates made of any of the materials described above.
  • the microfluidic channels can be made using one of the substrates described above by any of the microfabrication techniques. For example, micropump and sample handling channels defined on a photomask by 2 and 20 ⁇ m wide lines (other dimensions are possible) are transferred to the substrate using photolithography. After exposure, substrate etching is conducted to achieve channel depths of 0.5-10 ⁇ m for the micropump and 20-100 ⁇ m for sample handling. This substrate is placed into contact with the second (or top) substrate such that the surface of the second substrate is covering the channels of the first substrate. The two substrates are then bonded together to seal the enclosed channels.
  • the micropump channels may be fabricated in the bottom substrate, while the rest of the microfluidic network of channels and chambers may be fabricated in the top substrate, made of the same or a different material as the bottom substrate. They come in contact with each other by proper alignment prior to bonding.
  • the micropump may be fabricated in a substrate that is sandwiched between other two substrates.
  • the walls of the pumping channels may be the bare, unmodified surface or the chemically/physically altered surface of the substrate material that is used for the fabrication of the device.
  • chemical treatment with, or physical adsorption of an appropriate surface coating agent on the pumping channel walls may be necessary in order to provide for sufficient and adequate charged functional groups on these walls.
  • the holes or the apertures necessary to access the pumping channel and the other channels of the microfabricated device are fabricated prior to bonding in one or both of the substrates. These holes (typically of 1-2 mm in diameter) are used for the introduction of fluids and reagents into the chip, and for the placement of electrodes that ensure electrical contact with the network of microfluidic channels. These holes can also function as reservoirs for the solvent and reagents • that are to be manipulated on the chip. To increase the volume of solvent or reagents that may be handled by the chip, additional reservoir structures may be attached to the access holes. Cooling or heating devices may be attached to the pump for specific applications.
  • the straight microchannels can be replace by a tortuous arrangement, or even a more complicated microfabricated monolithic structure.
  • the electrodes may be embedded in the microfabricated device at appropriate positions. Embedded, electrodes are fabricated using MEMS technologies prior to bonding, of the two substrates.
  • the inlet and outlet reservoirs may be placed not directly on the pump inlet or outlet, but at the terminus of some larger channels, with small electrical resistance, that come in direct contact with the inlet and outlet of the pumping channels.
  • a structure with similar properties to the semi-permeable glass disc that is inserted in the outlet reservoir, can be created by MEMS technologies directly in the microchip body, at appropriate positions.
  • This alternate gate structure can be used as fabricated, or it may be filled before utilization with an electrically conductive polymer that is replaceable. It will have the same function, to allow the exchange of ions but prevent transport of bulk flow.
  • the walls of the pumping microchannels of one or both pumps may be chemically or physically altered such that their surface is positively charged in the case of one of the pumps and negatively charged in the case of the second pump.
  • both pumps will generate electroosmotic flow in the same direction, but one will function under a positive voltage gradient, while the other will function under a negative voltage gradient.
  • This configuration eliminates the need for the outlet reservoir 16 and the semi-permeable gate.
  • the electrospraying or sample deposition capillary 32 may be replaced by a structure fabricated by MEMS technologies .
  • microchannels are filled with solvent or buffer.
  • the solvent or buffer (SA) in reservoir 104 is replaced with a different solvent or buffer (SB) .
  • a porous glass disc 34 is placed and secured in reservoir 16 and 106.
  • An identical voltage is applied to both reservoir 16 and 106.
  • Voltages are then applied to reservoir 14 and 104 in a ratio that will provide the desired solvent mixture.
  • the ratio of the two voltages is modulated (in steps or continuously) to generate a desired solvent gradient that is delivered to the system.
  • the generated flow or pressure is monitored or measured.
  • a pump with a large number of narrow or shallow open microchannels is designed to produce EOF.
  • the multiple microchannels ensure the generation of sufficient flow rate, while the small dimensions of the microchannels result in the necessary hydraulic resistance to pressurized back flow leakage.
  • a single, large diameter open-channel electroosmotic micropump could generate flow only if the backpressure is small, and the flow would be highly dependent on the backpressure.
  • multiple channel pump configurations with small diameters according to the invention overcome this shortcoming, being capable of generating sufficient flow that is independent of backpressure. The pumping principles are further explained below.
  • Electroosmotic flow generation in single channels To illustrate the principle of the open-channel electroosmotic micropump, an ideal system composed of cylindrical capillaries is considered and the conditions that must be met for proper pumping are examined. For this discussion, the contributions of local hydraulic resistances to the total pressure drop will be neglected.
  • the standard equations that describe fluid flow and velocity in pressure driven (F and V ) and electroosmotic driven ( F eof and v e ⁇ f ) open capillary systems are as follows: 38
  • the F eof will distribute into a forward flow through the large channel (F) and a back flow through the narrow channel (F b ) .
  • Pressurized fluid flow will be proportional to di I 'd 2 4 regardless of the method used to produce it.
  • the flow will be distributed in a ratio F/F b of 1:10,000, i.e., essentially all the flow will be directed through the large channel.
  • F/Feof ratio seems to be dependent on channel dimensions, but independent of pressure or the actual EOF in the system.
  • F/F e ⁇ f could be defined as an efficiency coefficient for a given pump, since it will determine what fraction of the originally produced EOF is actually pumped forward in the system.
  • F/F eof values can be calculated from equation (5) and represented as a function of d /d ⁇ and L ⁇ /L 2 ( Figure 3B) .
  • small diameter and long pumping channels i.e., small d % /d 2 and large Li/L ⁇ ratios
  • Electroosmotic flow generation in multiple channels For very small di values, the actual EOF in a channel and consequently the overall flow in the system will be quite low.
  • multiple small diameter channels (n) can be connected to one large channel ( Figure 4A) .
  • F will be defined by equation (6) , and F/F eof will be dependent on n :
  • Electroosmotic pressure generation The pressure that can be created in the system is calculated by balancing the input electroosmotic flow in the n narrow channels with the output pressure flow through all channels:
  • the absolute maximum pressure that can be generated with microchannels of a given dimension can be inferred from conditions of zero flow out from the system [i.e., the second term in the denominator of equation (7) is set to zero], and is dependent only on the channel diameter, applied voltage and channel surface properties :
  • microchip implementation of fully integrated micro-LC separations performed on polymeric monolithic stationary phases that are commonly performed under 100 psi 39 thus becomes feasible with the integration of such pumping systems.
  • Theoretically' see equation 10) , if pressure generation and not flow were the main purpose of these 1 micropumps, and if microchip material and connecting elements would be capable -of withstanding the high pressures, hundreds of bars could be produced with sub-micrometer sized channel EOF pumps.
  • a stand-alone microfabricated device with an integrated multichannel EOF pump according to the invention has been constructed for producing controllable pressure driven flows within microfluidic channels.
  • the pump can be constructed as a stand-alone module and can be employed to deliver fluid flow for on-chip or off-chip applications, as well.
  • Micropumps with 4-100 pumping channels were constructed that produced flow rates in the range of 10-400 nL/min and developed pressures up to 80 psi. The flow rate and eluent gradients were adjusted by varying the potential drop over the pump. The experimental results followed closely the trends predicted by the theoretical calculations.
  • microfluidic valving e.g., "electroosmotic valving," in which sample plugs can be injected in pressurized systems, was tested for the investigation of peptide samples by MS analysis .
  • electroosmotic valving in which sample plugs can be injected in pressurized systems
  • the electroosmotic pump according to the invention may be used with any other valving component, and the electroosmotic valve of the invention may be used with any other pump or pressure generating element (in particular, an electroosmotic/electrokinetic pump.
  • the output of a pump and/or valve of the invention may be monitored via connection to a flow or pressure monitoring/controlling sensor and/or controller.
  • a cluster of pumps may be attached to an individual network channel for, e.g., gradient generation or the introduction of a sequence of solvents into the system.
  • a microfluidic device with a multiple channel structure constructed according to the invention allows for material transport driven by any mechanism (electric, magnetic, etc.) other than a pressure driven mechanism.
  • a microfluidic pump according to the invention can serve as an actuator for closing/opening of another valving component.
  • the above microfluidic devices and pumps operate with aqueous and/or organic solutions, or other fluids (e.g., any liquid or gas) .

Abstract

L'invention concerne une pompe et un système de pompage, de préférence électroosmotique, multicanaux, microfluidique, fabriqué à micro-échelle et intégré à une puce électronique. La pompe électroosmotique de l'invention comprend plusieurs microcanaux qui commencent et se terminent dans de compartiments communs réunis en un complexe. Les microcanaux à l'intérieur de la pompe ont des dimensions optimales sensiblement identiques, en coupe comme en longueur, ce qui permet à la pompe de générer une pression suffisante pour l'écoulement d'un fluide (tel qu'un liquide ou un gaz), la pression et le débit de la pompe restant stables et reproductibles. Pour assurer un écoulement efficace de fluide, sans aucun obstacle dû au retour, une pompe électroosmotique de l'invention est couplée à un canal unique ayant une coupe plus grande. Une structure similaire est aussi utilisée dans une vanne électroosmotique de l'invention, à l'endroit où les échantillons sont introduits dans un dispositif analytique. Le système de pompage électroosmotique microfluidique de l'invention génère un flux suffisant pour optimiser les paramètres en termes de dimension de la coupe et de la longueur des microcanaux.
PCT/US2002/016207 2001-05-22 2002-05-22 Systeme de pompage electroosmotique multicanaux integre a une puce electronique WO2002094440A2 (fr)

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