US20170128938A9 - Microfluidic system including a bubble valve for regulating fluid flow through a microchannel - Google Patents
Microfluidic system including a bubble valve for regulating fluid flow through a microchannel Download PDFInfo
- Publication number
- US20170128938A9 US20170128938A9 US14/689,508 US201514689508A US2017128938A9 US 20170128938 A9 US20170128938 A9 US 20170128938A9 US 201514689508 A US201514689508 A US 201514689508A US 2017128938 A9 US2017128938 A9 US 2017128938A9
- Authority
- US
- United States
- Prior art keywords
- microchannel
- reservoir
- bubble
- actuator
- liquid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Classifications
-
- 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
- B01L3/502746—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 for controlling flow resistance, e.g. flow controllers, baffles
-
- 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
- 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
- F16K99/0019—Valves using a microdroplet or microbubble as the valve member
-
- 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
- F16K99/0055—Operating means specially adapted for microvalves actuated by fluids
- F16K99/0061—Operating means specially adapted for microvalves actuated by fluids actuated by an expanding gas or liquid volume
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
- B01L2200/06—Fluid handling related problems
- B01L2200/0605—Metering of fluids
-
- 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
- B01L2300/0848—Specific forms of parts of containers
- B01L2300/0858—Side walls
-
- 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
- B01L2400/06—Valves, specific forms thereof
-
- 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
- B01L2400/08—Regulating or influencing the flow resistance
- B01L2400/082—Active control of flow resistance, e.g. flow controllers
-
- 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
- B01L3/502715—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 interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
-
- 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
- F16K2099/0084—Chemistry or biology, e.g. "lab-on-a-chip" technology
Definitions
- the present invention relates to microscale fluid handling devices and systems. More particularly, the present invention relates to a method and system for controlling liquid flow in a microchannel by the introduction of a gas bubble to a microfluidic system.
- Microfluidic devices and systems provide improved methods of performing chemical, biochemical and biological analysis and synthesis. Microfluidic devices and systems allow for the performance of multi-step, multi-species chemical operations in chip-based micro chemical analysis systems.
- Chip-based microfluidic systems generally comprise conventional ‘microfluidic’ elements, particularly capable of handling and analyzing chemical and biological specimens.
- microfluidic in the art refers to systems or devices having a network of processing nodes, chambers and reservoirs connected by channels, in which the channels have typical cross-sectional dimensions in the range between about 1.0 ⁇ m and about 500 ⁇ m. In the art, channels having these cross-sectional dimensions are referred to as ‘microchannels’.
- Downscaling dimensions allows for diffusional processes, such as heating, cooling and passive transport of species (diffusional mass-transport), to proceed faster.
- diffusional processes such as heating, cooling and passive transport of species (diffusional mass-transport)
- thermal processing of liquids which is typically a required step in chemical synthesis and analysis.
- thermal processing of liquids is accelerated in a microchannel due to reduced diffusional distances.
- Another example of the efficiency of microfluidic systems is the mixing of dissolved species in a liquid, a process that is also diffusion limited.
- Milliliter-sized systems typically require milliliter volumes of these substances, while microliter sized microfluidic systems only require microliters volumes.
- the ability to perform these processes using smaller volumes results in significant cost savings, allowing the economic operation of chemical synthesis and analysis operations.
- the amount of chemical waste produced during the chemical operations is correspondingly reduced.
- a flow control device may be used to regulate the flow of liquid through a microchannel. Regulation includes control of flow rate, impeding of flow, switching of flows between various input channels and output channels as well as volumetric dosing.
- U.S. Pat. No. 6,062,681 describes a bubble valve for a liquid flow channel in which the flow of a liquid is controlled by the generation of a gas bubble in the channel using a heater placed in the liquid. As the heater is activated, a bubble is formed which can be enlarged or reduced in size by increasing or decreasing, respectively, the temperature of the heater.
- the described system presents a number of disadvantages, namely, the required power to operate the valve and the inherent requirement that liquid in the channel be heated upon passing the valve. Even small increases in liquid temperature, by only a couple of degrees, can have disastrous effects on the highly heat sensitive biochemical substances present in the liquids to be controlled in many microfluidic systems.
- the required on-chip electric circuitry for the heater increases the complexity of the described valve and consequently results in unacceptably high costs, particularly if the fluidic system employing the bubble valve only used for a single application.
- valves in the prior art use electrochemical means to produce a bubble in a liquid.
- the present invention provides a bubble valve for controlling, regulating or varying fluid flow through a microfluidic system.
- the bubble valve regulates fluid flow through a channel using an externally operated mechanical or pneumatic actuator.
- the actuator causes a deflection of a fluid meniscus into the interior of the channel to regulate liquid flow.
- the actuator may mechanically force a gas bubble into a fluid carrying microchannel to inhibit liquid flow or to cause liquid flow by applying a sufficiently high pressure to the meniscus.
- the bubble valve effectively controls the flow of liquids in microfluidic systems, without heating the fluid and without complex on-chip circuitry.
- the microfluidic system includes a microchannel and a sealed, gas-filled reservoir positioned adjacent to and connected to the microchannel.
- the gas filled reservoir has a movable wall and a meniscus formed by a liquid in the microchannel that forms an interface between the reservoir and the microchannel interior.
- the meniscus may form a portion of the side wall of the microchannel.
- An external mechanical actuator may be used to deflect the movable wall of the reservoir. As the movable wall is deflected, the volume of the reservoir decreases and the gas pressure inside the reservoir increases, causing the meniscus to deflect into the microchannel, thereby modifying the cross-sectional area of the microchannel and consequently varying the flow of liquid through the channel.
- the increased pressure in the reservoir pushes gas from the reservoir into the microchannel.
- the gas may result in a local gas bubble being forced into the microchannel from the gas-filled reservoir.
- the resulting gas bubble occupies a portion of the cross-section of the channel, allowing liquid flow through the channel to be effectively controlled by controlling the size of the gas bubble via the external actuator.
- the meniscus may comprise a virtual wall formed in a side wall of the microchannel.
- the virtual wall is a meniscus formed by a liquid in the microchannel that fills an aperture formed in the side wall of the microchannel and essentially replaces the removed portion of the side wall without affecting the properties of liquid flow through the channel.
- a gas bubble can be forced into the channel by applying a gas pressure at the opening using an external pneumatic actuator. The gas pressure forces the meniscus inside the channel, which varies the flow of liquid through the channel interior.
- the microchannel includes a hydrophobic patch spanning the width of the microchannel at the location where the gas bubble is introduced to enhanced on-off switching of the bubble valve.
- the hydrophobic patch anchors the bubble in a particular location in the microchannel. If the introduced gas bubble covers the whole area of the patch, the bubble is effectively retained by capillary forces and blocks any liquid flow up to a certain pressure difference, depending on the level of hydrophobicity of the patch.
- the microchannel can be locally shaped into a cavity for receiving and anchoring the gas bubble.
- the bubble can be kept in place during operation, reducing the risk that the gas bubble is carried away with the liquid.
- a microfluidic device comprises a microchannel having an interior bounded by a side wall and a valve for regulating the flow of fluid through the microchannel.
- the valve comprises a gas-filled reservoir, a fluid meniscus interfacing the reservoir and the interior and an actuator for varying the volume of the reservoir to increase an internal pressure of the reservoir to vary the flow of liquid through the channel.
- a microfluidic device comprising a first plate having a groove formed therein defining a microchannel, a second plate for enclosing the microchannel and a flexible membrane.
- the second plate is bonded to the first plate and has an aperture adjacent to the groove sized and dimensioned to form a meniscus when the microchannel is filled with a liquid.
- the aperture defines a reservoir adjacent to the microchannel, wherein the meniscus forms an interface between the microchannel and the reservoir.
- the flexible membrane is bonded to the second plate to seal the reservoir.
- a method of making a bubble valve comprises providing a microchannel having an interior bounded by a side wall, an aperture formed in the side wall and a valve chamber adjacent to the aperture in communication with the interior, filling the microchannel with a liquid to form a meniscus of the liquid in the aperture, whereby the step of filling traps a gas in the valve chamber and providing an actuator for increasing the pressure in the valve chamber to deflect the meniscus into the interior.
- a method of making a bubble valve comprises providing a microchannel having an interior bounded by a side wall, an aperture formed in the side wall and a valve chamber adjacent to the aperture in communication with the interior, filling the microchannel with a liquid to form a meniscus of the liquid in the aperture and applying and sealing an actuator comprising a chamber to a top surface of the microchannel to form a gas-filled chamber adjacent to the meniscus.
- the actuator varies the pressure in the gas-filled chamber to deflect the meniscus into the interior, thereby regulating fluid flow.
- a microfluidic device comprising a microchannel having an interior bounded by a side wall, a bubble valve for creating and injecting a bubble into the microchannel interior to regulate fluid flow through the microchannel and a hydrophobic patch for retaining the bubble in a predetermined position in the microchannel interior.
- a bubble valve in a particle sorting device for separating particles having a predetermined characteristic from particles not having a predetermined characteristic.
- the bubble valve comprises a gas-filled reservoir, a side channel in communication with a channel through which a stream of particles in a carrier fluid passes, wherein the carrier fluid forms a meniscus in the side channel adjacent to the gas-filled reservoir and an actuator for deflecting the meniscus to create a pressure pulse to selectively deflect a particle having the predetermined characteristic from the stream of particles.
- a method of varying an electrical resistance in a microchannel comprises generating a bubble and injecting the bubble into a liquid in the microchannel, whereby the bubble varies the electrical resistance of the microchannel.
- an electrophoretic system comprising an electrokinetically operated microchannel, a sample well for providing an sample to the microchannel, a voltage source and a bubble valve for injecting a bubble into the microchannel to vary the electrical resistance of the microchannel.
- an electrokinetic column to column switch comprising a first electrokinetically operated microchannel, a second electrokinetically operated microchannel in communication with the first electrokinetically operated microchannel and a bubble valve for selectively blocking flow from the first electrokinetically operated microchannel to the second electrokinetically operated microchannel by selectively injecting a bubble into a microchannel.
- FIG. 1 is a schematic view of a microfluidic system suitable for implementing the illustrative embodiment of the invention.
- FIG. 2 shows an exploded view of a bubble valve according to an illustrative embodiment of the present invention.
- FIG. 3 shows an isometric view of the bubble valve of FIG. 2 .
- FIG. 4 shows a top view of the bubble valve of FIG. 2 .
- FIGS. 5 a - c are cross-sectional views of the bubble valve of FIG. 2 in operation.
- FIG. 6 shows an exploded view of an alternative embodiment of a bubble valve according to the present invention.
- FIG. 7 shows a top view of the bubble valve of FIG. 6 .
- FIGS. 8 a - c are cross-sectional view of the bubble valve of FIG. 6 in operation.
- FIG. 9 shows an application of the bubble valve of an illustrative embodiment of the present invention in a microchannel.
- FIG. 10 shows a Y-intersection in a microfluidic system of an embodiment of the invention that implements a bubble valve to control liquid flow according to the teachings of the present invention.
- FIG. 11 shows a Y-intersection in a microfluidic system of another embodiment of the invention that implements a bubble valve to control liquid flow according to the teachings of the present invention.
- FIGS. 12 a - c shows an electrophoresis system that implements a bubble valve to control electrical current during electrokinetic injection according to the teachings of the present invention.
- FIG. 13 a shows an electrokinetic column-column switch implementing a bubble valve according to the teachings of the present invention.
- FIG. 13 b shows an alternate electrokinetic column-column switch implementing a bubble valve according to another embodiment of the present invention.
- FIG. 14 shows a selective resistance circuit that employs a bubble valve to control electrical current according to the teachings of the present invention.
- FIG. 15 shows an alternative selective resistance circuit that employs a bubble valve to control electrical current according to the teachings of the present invention.
- FIG. 16 shows a particle sorting system that implements a bubble valve of the present invention to produce fluid impulses to sort particles.
- FIGS. 17 a , 17 b and 17 c illustrate the operation of the particle sorting system of FIG. 16 .
- the present invention provides an improved bubble valve for controlling fluid flow through a microchannel in a microfluidic system.
- the invention further provides a method of forming the bubble valve.
- the bubble valve of the present invention can be applied in numerous microfluidic systems for controlling and switching fluid flows. Examples of suitable applications include, but are not limited to: flow cytometry, column switching, 2-D separations, cell or particle sorting applications on a chip, regulating pressurized fluid flows including on-off switching, regulating electrokinetic fluid flows and electrokinetically induced processes including on-off switching and electrokinetic sample injection and channel to channel switching.
- FIG. 1 illustrates a microfluidic system suitable for implementing the illustrative embodiment of the present invention.
- the illustrative microfluidic system 100 comprises a substrate 101 having one or more microchannels 21 disposed therein.
- the microchannels transport fluid through the microfluidic system 100 for processing, handling, and/or performing any suitable operation on a liquid sample.
- microfluidic refers to a system or device for handling, processing, ejecting and/or analyzing a fluid sample including at least one channel having microscale dimensions.
- channel refers to a pathway formed in or through a medium that allows for movement of fluids, such as liquids and gases.
- microchannel refers to a channel preferably formed in a microfluidic system or device having cross-sectional dimensions in the range between about 1.0 ⁇ m and about 500 ⁇ m, preferably between about 25 ⁇ m and about 250 ⁇ m and most preferably between about 50 ⁇ m and about 100 ⁇ m.
- the ranges are intended to include the above-recited values as upper or lower limits.
- the microchannel can have any selected shape or arrangement, examples of which include a linear or non-linear configuration and a U-shaped configuration.
- the microfluidic system 100 may comprise any suitable number of microchannels 21 for transporting fluids through the microfluidic system 100 .
- the microfluidic system 100 includes a bubble valve 10 , 10 ′ shown in FIGS. 2-8 c for controlling liquid flow through a microchannel of the system.
- the microchannel is defined by a side wall having any suitable shape enclosing at least a portion of the interior of the channel.
- the bubble valve may be formed by a gas-filled reservoir positioned adjacent to the microchannel including a meniscus that forms the interface between the reservoir and the microchannel interior. The meniscus may form a portion of the side wall of the microchannel.
- the bubble valve includes an actuator for modifying the pressure in the reservoir to deflect the meniscus into the channel interior, thereby modifying the cross-sectional area of the microchannel and consequently varying the flow of liquid through the channel.
- the bubble valve is formed by a meniscus in a separate side channel that communicates with and intersects a microchannel through which a liquid to be controlled flows.
- the meniscus can be located at any location relative to the microchannel through which liquid flows.
- the gas-filled reservoir may be formed when filling the microchannel having an aperture in a side wall and a reservoir formed adjacent to the aperture.
- An empty microchannel may be filled with liquid, forming the meniscus in the aperture, which traps the gas that forms the gas bubble and forms a gas pocket in the reservoir adjacent to the meniscus.
- the creation of the gas pocket on filling provides a sterile gas bubble and reduces contaminants in the system.
- the air pocket may be created by introducing a gas to the reservoir after filling of the microchannel.
- FIG. 2 shows an exploded view of an embodiment of an illustrative bubble valve 10 of the present invention.
- the microfluidic system may be formed by a plurality of stacked layers.
- the illustrative microfluidic system 100 includes a first plate 20 in which a groove defining the microchannel 21 is provided.
- a hydrophobic patch 22 may be applied to an inner wall of the microchannel 21 .
- a second plate 30 for enclosing the microchannel is bonded to the first plate 20 and includes an aperture 31 .
- a third plate 40 is bonded on top of second plate 30 to close and seal the stacked structure.
- the aperture 31 of the intermediate second plate 30 defines a void in the system adjacent to the microchannel 21 .
- FIGS. 3 and 4 illustrates the assembled bubble valve 10 .
- the stacked first plate 20 , second plate 30 and third plate 40 define a closed, gas filled gas reservoir 70 , which can be actuated with a displacement actuator 50 .
- the aperture 31 defining the reservoir 70 comprises a main body 31 a and a slot 31 b extending from the main body 31 a .
- the slot 31 b of the aperture 31 defines a gap in the side wall of the microchannel 21 that provides access to and communicates with the interior of the microchannel 21 .
- the bubble valve 10 operates to control the flow of liquid through the microchannel 21 .
- a meniscus is formed in the aperture 31 , which interfaces with and separates the microchannel interior from the reservoir 70 .
- the meniscus is formed by a liquid filling the microchannel in the slot 31 b .
- the liquid in the slot 31 b is retained in the microchannel by capillary forces.
- the actuator 50 deflects the upper wall of the reservoir, defined by plate 40 , which decreases the volume of the reservoir 70 .
- the actuator 50 may comprise any suitable device for deflecting the wall, such as an electromagnetic actuator or a piezoelectric element.
- the plate 40 may comprises a flexible membrane.
- the decreased volume consequently increases the pressure of the reservoir 70 and causes the meniscus 80 to deflect into the channel interior to create a constriction in the channel, thereby impeding fluid flow or pushing fluid away from the meniscus. If a sufficient pressure is applied to the meniscus, the actuator generates and enlarges a bubble in the liquid of the microchannel, which blocks fluid flow.
- the hydrophobic patch 22 provides an anchor for the bubble and retains the bubble at a selected location in the microchannel.
- FIG. 5 a - c illustrate the operation of the bubble valve according to the teachings of the invention.
- FIG. 5 a shows the bubble valve in an ‘open’ state.
- the meniscus between the reservoir and the interior of the microchannel is defined by the meniscus 80 , formed by the liquid 60 in the slot 31 b in the second plate 30 .
- the ‘open’ state liquid flows freely through the microchannel 21 and the valve does not impose any additional flow resistance in the channel.
- the slot 31 b may be sized and dimensioned to form a “virtual wall” in the microchannel.
- “virtual wall” refers to the meniscus 80 formed by the first liquid 60 in the aperture formed in the side wall of the microchannel 20 , which essentially replaces the removed portion of the side wall without affecting the properties of the microchannel.
- the meniscus surface can be, although not required, substantially co-planar with the wall of the microchannel in which the meniscus is formed.
- the word “virtual” is chosen to express the effect that the overall liquid flow through the microchannel 21 of the microfluidic system 100 is not influenced by the virtual wall, i.e.
- the flow of liquid in the microfluidic system having a virtual wall is substantially identical to the flow of liquid through an identical microfluidic system in which no virtual wall is present.
- the meniscus may be convex or concave, depending on the appropriate system pressure.
- the bubble valve 10 switches to a “pinched” state, as shown in FIG. 5 b , to inhibit fluid flow through the channel interior.
- the actuator 50 deflects the top of the gas reservoir 70 for a certain fraction, increasing the pressure in the reservoir 70 and forcing the meniscus 80 down into the channel 21 .
- the deflection of the meniscus locally reduces the cross-section of the channel 21 and introduces an additional flow resistance to the liquid flow.
- the degree of reduction in the liquid flow through the microchannel corresponds to the amplitude, frequency and duration of the displacement of the meniscus 80 , which are controllable by the actuator 50 .
- any suitable means for varying the pressure within the reservoir 70 may be used to deflect the meniscus 80 , thereby regulating fluid flow.
- the bubble valve 10 When the actuator is fully actuated, the bubble valve 10 is switched to a closed state, as illustrated in FIG. 5 c .
- the closed state the meniscus 80 deflects fully to form and introduce a gas bubble 81 into the microchannel 21 .
- the gas bubble 81 is retained by the hydrophobic patch 22 formed in the channel wall opposite the slot 31 b .
- the liquid flow in the channel is substantially blocked.
- the bubble valve 10 can be brought from the ‘closed’ state of FIG. 5 c via the ‘pinched’ state of FIG. 5 b back to the ‘open’ state of FIG. 5 a.
- the bubble valve 10 may be used as a check valve for regulating pressure in the microchannel.
- the pressure in the microchannel exceeds a maximum breaking pressure, the bubble collapses, opening the valve and allowing fluid to flow through the channel, thereby reducing the pressure in the microchannel.
- the breaking pressure depends on the hydrophobicity of the hydrophobic patch 22 , as well as the geometry of the microchannel.
- the microchannel 21 can be locally shaped into a cavity for receiving and anchoring the gas bubble 81 .
- the bubble can be kept in place during operation, reducing the risk that the gas bubble is carried away with the liquid.
- the actuator 50 is integrated in the microfluidic chip 100 .
- an external, reusable actuator may also be used to control formation of a gas bubble in the microchannel.
- FIG. 6 shows an alternative embodiment of a microfluidic system 100 ′ including a bubble valve 10 ′ having an external actuator 90 according to the teachings of the invention.
- the microfluidic system 100 ′ includes a first plate 200 including a groove defining the microchannel 210 and a second plate 300 bonded to the first plate 200 for enclosing the microchannel 210 and in which a virtual wall opening 32 is formed.
- the virtual wall opening 32 is sized and dimensioned to form a “virtual wall” when the microchannel 210 is filled with a liquid.
- the microfluidic system further includes an external actuator, illustrated as pressurizer 90 , pressed and sealed onto the top of the second plate 300 to form a tight seal.
- the external pressurizer 90 defines a sealed pressurizing chamber 92 adjacent to the virtual wall 32 a .
- the pressurizer varies the pressure within the pressurizing chamber 92 to control liquid flow through the microchannel 210 by modifying the position of the virtual wall.
- the pressurizer 90 may include a source of pressurized gas (not shown) and a gas inlet 91 to allow a gas pressure to be applied to the virtual wall 32 a in order to move the virtual wall.
- the pressurizer may alternatively include a flexible wall that deflects to vary the volume of the chamber 92 upon activation of an actuator, such as a piezoelectric element or electromagnetic actuator.
- FIG. 8 a shows a cross-section of the bubble valve 10 ′ of FIGS. 6 and 7 in the ‘open’ state.
- a virtual wall 32 a defined by a meniscus 800 , is formed within the virtual wall opening 32 .
- the meniscus essentially replaces the absent portion of the side wall of the microchannel and allows liquid to flow through the channel interior unimpeded and uninfluenced by the virtual wall.
- FIG. 8 b depicts the ‘pinched’ state of the bubble valve, when the pressurizer 90 is activated.
- activation of the pressurizer 90 increases the internal pressure within the pressurizing chamber 92 .
- the increased pressure moves the meniscus 800 down the channel height and into the microchannel interior, thereby regulating liquid flow.
- the pressurized controls the level of the internal pressure in order to control the amount of deflection of the meniscus and therefore the rate of fluid flow.
- the pressurizer 90 applies a large pressure that is sufficient to form and introduce a gas bubble 810 into the channel 210 .
- the hydrophobic patch 220 retains the gas bubble 810 in place.
- the liquid flow in the channel is blocked up to a ‘breaking pressure’, which depends on the hydrophobicity of hydrophobic patch 220 .
- a higher hydrophobicity results in a larger breaking pressure.
- FIG. 9 shows an application of a bubble valve 10 for flow regulation in a microchannel 121 according to one embodiment of the invention.
- a pressure difference is applied over the length of a microchannel 121 .
- a bubble valve 10 can be employed to regulate the flow through the microchannel between zero and a maximum flow rate, depending on the applied pressure difference.
- FIG. 10 shows a portion of a microfluidic system according to an embodiment of the invention forming a Y-intersection comprising two inlet microchannels 121 a and 121 b and an outlet channel 121 c that combines the fluids flowing through the two inlet microchannels.
- the first microchannel 121 a carries a first liquid and the second microchannel 121 b carries a second liquid.
- the microchannels 121 a and 121 b are each controlled by a corresponding bubble valve, 10 a and 10 b , respectively, for regulating the combined composition and flow rate through the outlet microchannel 121 c .
- the number of inlet channels is not limited to two, but is presented here merely as an example.
- FIG. 11 shows a Y-intersection of a microfluidic system according to another embodiment of the invention.
- the Y-intersection comprises an inlet microchannel 221 c and two outlet microchannels 221 a and 221 b for splitting the incoming liquid flow from the inlet microchannel 221 c .
- the flow of each outlet channel is regulated by a corresponding bubble valve 200 a and 200 b , respectively.
- the incoming liquid flow from the inlet microchannel 221 c can be split between microchannel 221 a and microchannel 221 b in any required ratio.
- the number of inlet channels is not limited to two, but is presented here merely as an example.
- FIG. 12 a -12 c shows the implementation of an electrophoresis system 110 comprising five bubble valves, 10 a - e of the present invention, arranged with a crossed microchannel configuration.
- Regulation of the bubble valve 10 a regulates the electric current through the associated electrokinetically operated microchannel 115 a .
- the pinching of the liquid in the electrokinetically operated microchannel 115 a by a bubble valve will result in an increased electrical resistance in the microchannel 115 a .
- the migration of charged species and electro-osmotic flow in the electrokinetically operated microchannel 115 a can be regulated.
- a voltages difference for the injection of sample from a well storing a supply of a sample 125 between the bubble valve 10 a and the crossing point 111 of the microchannels and consecutive separation are provided via wells V+ and V0. Electrodes are placed in the V+ and V0 wells and energized with a constant voltage difference during the operation of the electrophoresis system.
- valves 10 a , 10 b , 10 c and 10 d are substantially in the open position, allowing passage of electrical current up to a required level for injection ( FIG. 12 b shows direction of current/sample), while bubble valve 10 e is closed.
- the valves are kept in this position long enough for the sample to move from the sample well 125 towards and past the central injection crossing 111 .
- Varying the opening ratio of valves 10 a , 10 b and 10 d can be adjusted to confine the sample to a narrow flow through the injection cross 111 , as shown in FIG. 12 c (i.e. ‘pinched injection’).
- a plug of sample is injected and separated in the separation column 115 a (microchannel which runs horizontally in figure) by closing bubble valves 10 a , 10 d and 10 c and opening valves 10 b and 10 e .
- the total voltage difference is applied longitudinally over the separation channel, resulting in the separation of the constituents in the sample ( FIG. 12 c ).
- FIG. 13 a illustrates another application of the bubble valve of the present invention implemented in a column-column switch 130 for electrokinetically transferring a substance from a first electrokinetically operated microchannel 215 a to a second electrokinetically operated microchannel 215 b .
- the column-column switch 130 comprises a bubble valve 10 b of the present invention that connects the first electrokinetically operated microchannel 215 a to the second electrokinetically operated microchannel 215 b .
- Both electrokinetically operated microchannel 215 a and electrokinetically operated microchannel 215 b are connected to corresponding wells well 220 a - d .
- the two electrokinetically operated microchannel 215 a and electrokinetically operated microchannel 215 b are operated independently and the connecting bubble valve 10 b is in the ‘closed’ state whilst bubble valve 10 a and bubble valve 10 c are in the ‘open’ state.
- bubble valve 10 a and bubble valve 10 c are switched to the closed state, and the connecting bubble valve 10 b is opened momentarily to allow passage of an amount of substance from the electrokinetically operated microchannel 215 a to the electrokinetically operated microchannel 215 b .
- the amount transferred depends directly upon the time bubble valve 10 b is opened.
- the connecting bubble valve 10 b is closed and the bubble valve 10 a and bubble valve 10 b are opened again.
- FIG. 13 b illustrates the implementation of another column to column switch 130 ′ to exchange liquid from a first column 215 a ′ selectively into a second column 215 b ′.
- the first column and the second column are each crossed by a transfer column 250 , operated by a first bubble valve 10 a arranged on one end of the transfer column 250 and a second bubble valve 10 b arranged on the opposite end of the transfer column 250 .
- the first one of the bubble valves is attached to the first column 215 a ′ and is actuated upon transiently by an external actuator for increasing the pressure within the bubble valve reservoir.
- FIG. 14 shows a selective resistance circuit employing a bubble valve of the present invention for selectively including a predefined electrical resistance in an electrokinetic circuit.
- the circuit 140 comprises an inlet microchannel 321 , which splits into two paths.
- the first path 322 includes a fluidic resistor 240 a and a bubble valve 10 a
- the second parallel path 323 includes a fluidic resistor 240 b and a bubble valve 10 b .
- the fluidic resistors 240 a - b comprise a channel of appropriate length to results in a certain electrical resistance.
- the bubble valve 10 a and the bubble valve 10 b can be switched each to either on to allow fluid flow through the associated microchannel or off to block fluid flow through the associated microchannel.
- the overall electrical resistance of the electrokinetic circuit can be switched between four values: infinite (both bubble valves 10 a - b are off), the resistance of fluidic resistor 240 a (bubble valve 10 a on, bubble valve 10 b off), the resistance of fluidic resistor 240 b (bubble valve 10 a off, bubble valve 10 b on) and the parallel resistance of fluidic resistor 24 a - b (both bubble valves 10 a and 10 b on).
- FIG. 15 shows an alternative resistance circuit 150 according to another application of the invention, now for the selective application of a voltage.
- the voltage imposed on an outgoing channel 523 can be selected.
- Fluidic resistor 245 a and 245 b function to limit the electric current in either of the two states to a predetermined value.
- FIG. 16 illustrates another application of the bubble valve 10 of the present invention in a particle sorting application, wherein the bubble valve is positioned in a side channel that communicates with a channel through which particles in suspension flow.
- a particle sorter 160 comprises a closed channel system of capillary size for sorting particles, such as cells.
- the channel system comprises a first supply duct 162 for introducing a stream of particles and a second supply duct 164 for supplying a carrier liquid.
- the first supply duct 162 ends in a nozzle, and a stream of particles is introduced into the flow of carrier liquid.
- the first supply duct 162 and the second supply duct 164 enter a measurement duct 166 , which branches into a first branch 172 a and a second branch 172 b at a branch point 171 .
- a measurement region 182 a is defined in the measurement duct 166 and is associated with a detector 182 b to sense a predetermined characteristic of particles in the measurement region 182 a .
- Two opposed bubble valves 10 a and 10 b are positioned in communication with the measurement duct 166 and are spaced opposite each other.
- the bubble valves 10 a , 10 b communicate with the measurement duct 166 through a pair of opposed side passages 174 a and 174 b , respectively.
- Liquid is allowed to partly fill these side passages 174 a and 174 b to form a meniscus 175 therein.
- An external actuator 176 is also provided for actuating the bubble valves 10 a , 10 b , which momentarily causes a flow disturbance in the duct to deflect the flow therein when activated by the actuator 176 .
- a suspension introduced by the first supply duct 162 two types of particles can be distinguished, normal particles 180 a and particles of interest 180 b .
- the flow rates in both branches 172 a and 172 b are adjusted so that the stream of particles normally flows through the second branch 172 b .
- the detector 182 b Upon sensing the predetermined characteristic in the particles in the measurement region 182 a , the detector 182 b raises a signal.
- the external actuator 176 activates the bubble valves 10 a , 10 b when signaled by the detector 182 b in response to sensing the predetermined characteristic, to create a flow disturbance in the measurement duct 166 between the sideway passages 174 a , 174 b , to deflect the particle having the predetermined characteristic so that it flows down the first branch duct 172 a rather than the second branch duct 172 b .
- the detector communicates with the actuator 176 , so that when the detector 182 b senses a predetermined characteristic in a particle, the actuator activates the first bubble valve 10 a to cause pressure variations in the reservoir 70 of the first bubble valve.
- the activation of the first bubble valves causes a transient pressure variation in the first side passage 174 a .
- the second side passage 174 b and the second bubble valve 10 b absorb the transient pressure variations in the measurement duct 166 induced via the actuator 176 .
- the reservoir 70 b of the second bubble valve 10 b is a chamber having a resilient wall or contains a compressible fluid such as a gas. The resilient properties allow the flow of liquid from the measurement duct into the second side passage 174 b.
- FIGS. 17 a -17 c illustrate the operation of the particle sorting system 160 of FIG. 16 .
- the detector raises a signal to activate the actuator.
- the pressure within the reservoir of the first bubble valve 10 a is increased, causing a transient discharge of liquid from the first side passage 174 a as indicated by the arrow.
- the sudden pressure increase caused at this point in the duct causes liquid to flow into the second side passage 174 b because of the resilient properties of the reservoir of the second bubble valve 10 b .
- This movement of liquid into the second side passage 174 b is indicated with an arrow.
- the flow through the duct is deflected causing the selected particle of interest 178 b located between the first side passage 174 a and the second side passage 174 b to be shifted perpendicular to its flow direction in the normal state.
- the flow resistances to the measurement duct 166 , the first branch 172 a and the second branch 172 b is chosen so that the preferred direction of the flow to and from the first side passage 174 a and the second side passage 174 b has an appreciable component perpendicular to the normal flow through the measurement duct 166 .
- This goal can for instance be reached by the first branch 172 a and the second branch 172 b so that their resistances to flow is large in comparison with the flow resistances of the first side passage 174 a and the second side passage 174 b.
- FIG. 17 b shows the particle sorting system 160 during the relief of the first bubble valve reservoir when the particle of interest 178 b has left the volume between the first side passage 174 a and the second side passage 174 b .
- the actuator 176 is deactivated, causing the pressure inside the reservoir to return to the normal pressure.
- this relief phase there is a negative pressure difference between the two reservoirs of the bubble valves, causing a liquid flow through the first side passage 174 a and the second side passage 174 b opposite to the liquid flow shown in the previous figure and is indicated by the arrows.
- FIG. 17 c shows the particle sorting system 160 after completion of the switching sequence.
- the pressures inside the reservoirs of the bubble valves has been equalized so the flow through the measurement duct 166 is normalized.
- the particle of interest 178 b has been displaced radially, it will flow into the first branch 172 a as was the objective of the switching operation.
- the cross-sectional dimensions of a microchannel including a bubble valve may be varied locally to affect the pressure within the microchannel interior.
- the microchannel may be narrowed or widened at certain locations to increase or decrease the capillary forces acting on a fluid in the microchannel interior.
- One of ordinary skill in the art will be able to determine a suitable cross-sectional dimension to achieve a desired pressure within the microchannel interior.
- the bubble valve of the present invention may be implemented in a variety of microfluidic devices used for many applications.
- the bubble valve is implemented in a flow-cytometer based instrument for sorting or physically separating particles of interest from a sample or for measuring selected physical and chemical characteristics of cells or particles in suspension as they travel past a particular site.
- the bubble valve may also be employed in devices for sequencing or manipulating DNA, medical diagnostic instruments, devices for drug discovery, chemical analysis and so on.
- the present invention provides an improved system and method for regulating fluid flow in a microchannel for a variety of applications.
- the bubble valve of the present invention is easy to operate and control, simple to manufacture and economical.
- the bubble valve does not adversely affect the liquid in the microchannel.
- the bubble valve effectively controls the flow of liquids in microfluidic systems, without heating the fluid and without complex on-chip circuitry.
Abstract
Description
- This application is a continuation of U.S. patent application Ser. No. 13/527,331, entitled “Microfluidic System Including a Bubble Valve for Regulating Fluid Flow Through A Microchannel”, filed on Jun. 19, 2012, which is a continuation of U.S. patent application Ser. No. 11/433,781, entitled “Microfluidic System Including a Bubble Valve for Regulating Fluid Flow Through A Microchannel”, filed on May 12, 2006, which is a continuation of U.S. patent application Ser. No. 11/021,251 filed Dec. 21, 2004 which, in turn, is a continuation of U.S. patent application Ser. No. 10/179,586 filed Jun. 24, 2002, which claims priority to U.S. Provisional Patent Application No. 60/373,256 filed Apr. 17, 2002; and is related to U.S. patent application Ser. No. 10/179,488, entitled “Method and Apparatus for Sorting Particles”, filed Jun. 24, 2002. The contents of all of the above-referenced applications are herein incorporated by reference in their entirety.
- The present invention relates to microscale fluid handling devices and systems. More particularly, the present invention relates to a method and system for controlling liquid flow in a microchannel by the introduction of a gas bubble to a microfluidic system.
- In the chemical, biomedical, bioscience and pharmaceutical industries, it has become increasingly desirable to perform large numbers of chemical operations, such as reactions, separations and subsequent detection steps, in a highly parallel fashion. The high throughput synthesis, screening and analysis of (bio)chemical compounds, enables the economic discovery of new drugs and drug candidates, and the implementation of sophisticated medical diagnostic equipment. Of key importance for the improvement of the chemical operations required in these applications are an increased speed, enhanced reproducibility, decreased consumption of expensive samples and reagents, and the reduction of waste materials.
- Microfluidic devices and systems provide improved methods of performing chemical, biochemical and biological analysis and synthesis. Microfluidic devices and systems allow for the performance of multi-step, multi-species chemical operations in chip-based micro chemical analysis systems. Chip-based microfluidic systems generally comprise conventional ‘microfluidic’ elements, particularly capable of handling and analyzing chemical and biological specimens. Typically, the term microfluidic in the art refers to systems or devices having a network of processing nodes, chambers and reservoirs connected by channels, in which the channels have typical cross-sectional dimensions in the range between about 1.0 μm and about 500 μm. In the art, channels having these cross-sectional dimensions are referred to as ‘microchannels’.
- By performing the chemical operations in a microfluidic system, potentially a number of the above-mentioned desirable improvements can be realized. Downscaling dimensions allows for diffusional processes, such as heating, cooling and passive transport of species (diffusional mass-transport), to proceed faster. One example is the thermal processing of liquids, which is typically a required step in chemical synthesis and analysis. In comparison with the heating and cooling of liquids in beakers as performed in a conventional laboratory setting, the thermal processing of liquids is accelerated in a microchannel due to reduced diffusional distances. Another example of the efficiency of microfluidic systems is the mixing of dissolved species in a liquid, a process that is also diffusion limited. Downscaling the typical dimensions of the mixing chamber thereby reduces the typical distance to be overcome by diffusional mass-transport, and consequently results in a reduction of mixing times. Like thermal processing, the mixing of dissolved chemical species, such as reagents, with a sample or precursors for a synthesis step, is an operation that is required in virtually all chemical synthesis and analysis processes. Therefore, the ability to reduce the time involved in mixing provides significant advantages to most chemical synthesis and analysis processes.
- Another aspect of the reduction of dimensions is the reduction of required volumes of sample, reagents, precursors and other often very expensive chemical substances. Milliliter-sized systems typically require milliliter volumes of these substances, while microliter sized microfluidic systems only require microliters volumes. The ability to perform these processes using smaller volumes results in significant cost savings, allowing the economic operation of chemical synthesis and analysis operations. As a consequence of the reduced volume requirement, the amount of chemical waste produced during the chemical operations is correspondingly reduced.
- In microfluidic systems, regulation of minute fluid flows through a microchannel is of prime importance, as the processes performed in these systems highly depend on the delivery and movement of various liquids such as sample and reagents. A flow control device may be used to regulate the flow of liquid through a microchannel. Regulation includes control of flow rate, impeding of flow, switching of flows between various input channels and output channels as well as volumetric dosing.
- U.S. Pat. No. 6,062,681 describes a bubble valve for a liquid flow channel in which the flow of a liquid is controlled by the generation of a gas bubble in the channel using a heater placed in the liquid. As the heater is activated, a bubble is formed which can be enlarged or reduced in size by increasing or decreasing, respectively, the temperature of the heater. The described system presents a number of disadvantages, namely, the required power to operate the valve and the inherent requirement that liquid in the channel be heated upon passing the valve. Even small increases in liquid temperature, by only a couple of degrees, can have disastrous effects on the highly heat sensitive biochemical substances present in the liquids to be controlled in many microfluidic systems. In addition, the required on-chip electric circuitry for the heater increases the complexity of the described valve and consequently results in unacceptably high costs, particularly if the fluidic system employing the bubble valve only used for a single application.
- Other valves in the prior art use electrochemical means to produce a bubble in a liquid.
- The present invention provides a bubble valve for controlling, regulating or varying fluid flow through a microfluidic system. The bubble valve regulates fluid flow through a channel using an externally operated mechanical or pneumatic actuator. The actuator causes a deflection of a fluid meniscus into the interior of the channel to regulate liquid flow. The actuator may mechanically force a gas bubble into a fluid carrying microchannel to inhibit liquid flow or to cause liquid flow by applying a sufficiently high pressure to the meniscus. The bubble valve effectively controls the flow of liquids in microfluidic systems, without heating the fluid and without complex on-chip circuitry.
- The microfluidic system includes a microchannel and a sealed, gas-filled reservoir positioned adjacent to and connected to the microchannel. The gas filled reservoir has a movable wall and a meniscus formed by a liquid in the microchannel that forms an interface between the reservoir and the microchannel interior. The meniscus may form a portion of the side wall of the microchannel. An external mechanical actuator may be used to deflect the movable wall of the reservoir. As the movable wall is deflected, the volume of the reservoir decreases and the gas pressure inside the reservoir increases, causing the meniscus to deflect into the microchannel, thereby modifying the cross-sectional area of the microchannel and consequently varying the flow of liquid through the channel. The increased pressure in the reservoir pushes gas from the reservoir into the microchannel. The gas may result in a local gas bubble being forced into the microchannel from the gas-filled reservoir. The resulting gas bubble occupies a portion of the cross-section of the channel, allowing liquid flow through the channel to be effectively controlled by controlling the size of the gas bubble via the external actuator.
- The meniscus may comprise a virtual wall formed in a side wall of the microchannel. The virtual wall is a meniscus formed by a liquid in the microchannel that fills an aperture formed in the side wall of the microchannel and essentially replaces the removed portion of the side wall without affecting the properties of liquid flow through the channel. A gas bubble can be forced into the channel by applying a gas pressure at the opening using an external pneumatic actuator. The gas pressure forces the meniscus inside the channel, which varies the flow of liquid through the channel interior.
- According to one embodiment, the microchannel includes a hydrophobic patch spanning the width of the microchannel at the location where the gas bubble is introduced to enhanced on-off switching of the bubble valve. The hydrophobic patch anchors the bubble in a particular location in the microchannel. If the introduced gas bubble covers the whole area of the patch, the bubble is effectively retained by capillary forces and blocks any liquid flow up to a certain pressure difference, depending on the level of hydrophobicity of the patch.
- Alternatively or in combination with a hydrophobic patch, the microchannel can be locally shaped into a cavity for receiving and anchoring the gas bubble. By providing an appropriate cavity, the bubble can be kept in place during operation, reducing the risk that the gas bubble is carried away with the liquid.
- According to one aspect of the invention, a microfluidic device is provided. The microfluidic device comprises a microchannel having an interior bounded by a side wall and a valve for regulating the flow of fluid through the microchannel. The valve comprises a gas-filled reservoir, a fluid meniscus interfacing the reservoir and the interior and an actuator for varying the volume of the reservoir to increase an internal pressure of the reservoir to vary the flow of liquid through the channel.
- According to another aspect, a microfluidic device is provided, comprising a first plate having a groove formed therein defining a microchannel, a second plate for enclosing the microchannel and a flexible membrane. The second plate is bonded to the first plate and has an aperture adjacent to the groove sized and dimensioned to form a meniscus when the microchannel is filled with a liquid. The aperture defines a reservoir adjacent to the microchannel, wherein the meniscus forms an interface between the microchannel and the reservoir. The flexible membrane is bonded to the second plate to seal the reservoir.
- According to another aspect, a method of making a bubble valve is provided, the method comprises providing a microchannel having an interior bounded by a side wall, an aperture formed in the side wall and a valve chamber adjacent to the aperture in communication with the interior, filling the microchannel with a liquid to form a meniscus of the liquid in the aperture, whereby the step of filling traps a gas in the valve chamber and providing an actuator for increasing the pressure in the valve chamber to deflect the meniscus into the interior.
- According to yet another aspect, a method of making a bubble valve is provided. The method comprises providing a microchannel having an interior bounded by a side wall, an aperture formed in the side wall and a valve chamber adjacent to the aperture in communication with the interior, filling the microchannel with a liquid to form a meniscus of the liquid in the aperture and applying and sealing an actuator comprising a chamber to a top surface of the microchannel to form a gas-filled chamber adjacent to the meniscus. The actuator varies the pressure in the gas-filled chamber to deflect the meniscus into the interior, thereby regulating fluid flow.
- According to still another aspect, a microfluidic device is provided comprising a microchannel having an interior bounded by a side wall, a bubble valve for creating and injecting a bubble into the microchannel interior to regulate fluid flow through the microchannel and a hydrophobic patch for retaining the bubble in a predetermined position in the microchannel interior.
- According to yet another aspect a bubble valve in a particle sorting device for separating particles having a predetermined characteristic from particles not having a predetermined characteristic is provided. The bubble valve comprises a gas-filled reservoir, a side channel in communication with a channel through which a stream of particles in a carrier fluid passes, wherein the carrier fluid forms a meniscus in the side channel adjacent to the gas-filled reservoir and an actuator for deflecting the meniscus to create a pressure pulse to selectively deflect a particle having the predetermined characteristic from the stream of particles.
- According to still another aspect, a method of varying an electrical resistance in a microchannel is provided. The method comprises generating a bubble and injecting the bubble into a liquid in the microchannel, whereby the bubble varies the electrical resistance of the microchannel.
- According to yet another aspect, an electrophoretic system is provided, comprising an electrokinetically operated microchannel, a sample well for providing an sample to the microchannel, a voltage source and a bubble valve for injecting a bubble into the microchannel to vary the electrical resistance of the microchannel.
- According to a final aspect of the invention, an electrokinetic column to column switch is provided, comprising a first electrokinetically operated microchannel, a second electrokinetically operated microchannel in communication with the first electrokinetically operated microchannel and a bubble valve for selectively blocking flow from the first electrokinetically operated microchannel to the second electrokinetically operated microchannel by selectively injecting a bubble into a microchannel.
-
FIG. 1 is a schematic view of a microfluidic system suitable for implementing the illustrative embodiment of the invention. -
FIG. 2 shows an exploded view of a bubble valve according to an illustrative embodiment of the present invention. -
FIG. 3 shows an isometric view of the bubble valve ofFIG. 2 . -
FIG. 4 shows a top view of the bubble valve ofFIG. 2 . -
FIGS. 5a-c are cross-sectional views of the bubble valve ofFIG. 2 in operation. -
FIG. 6 shows an exploded view of an alternative embodiment of a bubble valve according to the present invention. -
FIG. 7 shows a top view of the bubble valve ofFIG. 6 . -
FIGS. 8a-c are cross-sectional view of the bubble valve ofFIG. 6 in operation. -
FIG. 9 shows an application of the bubble valve of an illustrative embodiment of the present invention in a microchannel. -
FIG. 10 shows a Y-intersection in a microfluidic system of an embodiment of the invention that implements a bubble valve to control liquid flow according to the teachings of the present invention. -
FIG. 11 shows a Y-intersection in a microfluidic system of another embodiment of the invention that implements a bubble valve to control liquid flow according to the teachings of the present invention. -
FIGS. 12a-c shows an electrophoresis system that implements a bubble valve to control electrical current during electrokinetic injection according to the teachings of the present invention. -
FIG. 13a shows an electrokinetic column-column switch implementing a bubble valve according to the teachings of the present invention. -
FIG. 13b shows an alternate electrokinetic column-column switch implementing a bubble valve according to another embodiment of the present invention. -
FIG. 14 shows a selective resistance circuit that employs a bubble valve to control electrical current according to the teachings of the present invention. -
FIG. 15 shows an alternative selective resistance circuit that employs a bubble valve to control electrical current according to the teachings of the present invention. -
FIG. 16 shows a particle sorting system that implements a bubble valve of the present invention to produce fluid impulses to sort particles. -
FIGS. 17a, 17b and 17c illustrate the operation of the particle sorting system ofFIG. 16 . - The present invention provides an improved bubble valve for controlling fluid flow through a microchannel in a microfluidic system. The invention further provides a method of forming the bubble valve. The bubble valve of the present invention can be applied in numerous microfluidic systems for controlling and switching fluid flows. Examples of suitable applications include, but are not limited to: flow cytometry, column switching, 2-D separations, cell or particle sorting applications on a chip, regulating pressurized fluid flows including on-off switching, regulating electrokinetic fluid flows and electrokinetically induced processes including on-off switching and electrokinetic sample injection and channel to channel switching.
-
FIG. 1 illustrates a microfluidic system suitable for implementing the illustrative embodiment of the present invention. The illustrativemicrofluidic system 100 comprises a substrate 101 having one ormore microchannels 21 disposed therein. The microchannels transport fluid through themicrofluidic system 100 for processing, handling, and/or performing any suitable operation on a liquid sample. As used herein, the term “microfluidic” refers to a system or device for handling, processing, ejecting and/or analyzing a fluid sample including at least one channel having microscale dimensions. The term “channel” as used herein refers to a pathway formed in or through a medium that allows for movement of fluids, such as liquids and gases. The term “microchannel” refers to a channel preferably formed in a microfluidic system or device having cross-sectional dimensions in the range between about 1.0 μm and about 500 μm, preferably between about 25 μm and about 250 μm and most preferably between about 50 μm and about 100 μm. One of ordinary skill in the art will be able to determine an appropriate volume and length of the microchannel. The ranges are intended to include the above-recited values as upper or lower limits. The microchannel can have any selected shape or arrangement, examples of which include a linear or non-linear configuration and a U-shaped configuration. Themicrofluidic system 100 may comprise any suitable number ofmicrochannels 21 for transporting fluids through themicrofluidic system 100. - The
microfluidic system 100 includes abubble valve FIGS. 2-8 c for controlling liquid flow through a microchannel of the system. According to the illustrative embodiment, the microchannel is defined by a side wall having any suitable shape enclosing at least a portion of the interior of the channel. The bubble valve may be formed by a gas-filled reservoir positioned adjacent to the microchannel including a meniscus that forms the interface between the reservoir and the microchannel interior. The meniscus may form a portion of the side wall of the microchannel. The bubble valve includes an actuator for modifying the pressure in the reservoir to deflect the meniscus into the channel interior, thereby modifying the cross-sectional area of the microchannel and consequently varying the flow of liquid through the channel. - According to an alternate embodiment, the bubble valve is formed by a meniscus in a separate side channel that communicates with and intersects a microchannel through which a liquid to be controlled flows. One skilled in the art will recognize that the meniscus can be located at any location relative to the microchannel through which liquid flows.
- The gas-filled reservoir may be formed when filling the microchannel having an aperture in a side wall and a reservoir formed adjacent to the aperture. An empty microchannel may be filled with liquid, forming the meniscus in the aperture, which traps the gas that forms the gas bubble and forms a gas pocket in the reservoir adjacent to the meniscus. The creation of the gas pocket on filling provides a sterile gas bubble and reduces contaminants in the system. Alternatively, the air pocket may be created by introducing a gas to the reservoir after filling of the microchannel.
-
FIG. 2 shows an exploded view of an embodiment of anillustrative bubble valve 10 of the present invention. The microfluidic system may be formed by a plurality of stacked layers. As shown inFIG. 2 , the illustrativemicrofluidic system 100 includes afirst plate 20 in which a groove defining themicrochannel 21 is provided. Ahydrophobic patch 22 may be applied to an inner wall of themicrochannel 21. Asecond plate 30 for enclosing the microchannel is bonded to thefirst plate 20 and includes anaperture 31. Athird plate 40 is bonded on top ofsecond plate 30 to close and seal the stacked structure. Theaperture 31 of the intermediatesecond plate 30 defines a void in the system adjacent to themicrochannel 21. -
FIGS. 3 and 4 illustrates the assembledbubble valve 10. As shown, the stackedfirst plate 20,second plate 30 andthird plate 40 define a closed, gas filledgas reservoir 70, which can be actuated with a displacement actuator 50. According to the illustrative embodiment, theaperture 31 defining thereservoir 70 comprises a main body 31 a and a slot 31 b extending from the main body 31 a. When themicrofluidic system 10 is assembled, the slot 31 b of theaperture 31 defines a gap in the side wall of the microchannel 21 that provides access to and communicates with the interior of themicrochannel 21. - The
bubble valve 10 operates to control the flow of liquid through themicrochannel 21. A meniscus is formed in theaperture 31, which interfaces with and separates the microchannel interior from thereservoir 70. According to the embodiment shown inFIGS. 2-8 c, the meniscus is formed by a liquid filling the microchannel in the slot 31 b. One skilled in the art will recognize that other suitable devices may be used to form the meniscus. The liquid in the slot 31 b is retained in the microchannel by capillary forces. The actuator 50 deflects the upper wall of the reservoir, defined byplate 40, which decreases the volume of thereservoir 70. The actuator 50 may comprise any suitable device for deflecting the wall, such as an electromagnetic actuator or a piezoelectric element. Theplate 40 may comprises a flexible membrane. The decreased volume consequently increases the pressure of thereservoir 70 and causes themeniscus 80 to deflect into the channel interior to create a constriction in the channel, thereby impeding fluid flow or pushing fluid away from the meniscus. If a sufficient pressure is applied to the meniscus, the actuator generates and enlarges a bubble in the liquid of the microchannel, which blocks fluid flow. Thehydrophobic patch 22 provides an anchor for the bubble and retains the bubble at a selected location in the microchannel. - After the microchannel is filled with a liquid 60, the
bubble valve 10 is ready for operation.FIG. 5a-c illustrate the operation of the bubble valve according to the teachings of the invention.FIG. 5a shows the bubble valve in an ‘open’ state. According to the embodiment ofFIGS. 5a-5c , the meniscus between the reservoir and the interior of the microchannel is defined by themeniscus 80, formed by the liquid 60 in the slot 31 b in thesecond plate 30. In the ‘open’ state, liquid flows freely through themicrochannel 21 and the valve does not impose any additional flow resistance in the channel. - The slot 31 b may be sized and dimensioned to form a “virtual wall” in the microchannel. As used herein, “virtual wall” refers to the
meniscus 80 formed by the first liquid 60 in the aperture formed in the side wall of themicrochannel 20, which essentially replaces the removed portion of the side wall without affecting the properties of the microchannel. The meniscus surface can be, although not required, substantially co-planar with the wall of the microchannel in which the meniscus is formed. The word “virtual” is chosen to express the effect that the overall liquid flow through themicrochannel 21 of themicrofluidic system 100 is not influenced by the virtual wall, i.e. the flow of liquid in the microfluidic system having a virtual wall is substantially identical to the flow of liquid through an identical microfluidic system in which no virtual wall is present. One of ordinary skill will recognize that the meniscus may be convex or concave, depending on the appropriate system pressure. - When the actuator 50 is actuated, the
bubble valve 10 switches to a “pinched” state, as shown inFIG. 5b , to inhibit fluid flow through the channel interior. In the ‘pinched’ state, the actuator 50 deflects the top of thegas reservoir 70 for a certain fraction, increasing the pressure in thereservoir 70 and forcing themeniscus 80 down into thechannel 21. The deflection of the meniscus locally reduces the cross-section of thechannel 21 and introduces an additional flow resistance to the liquid flow. The degree of reduction in the liquid flow through the microchannel corresponds to the amplitude, frequency and duration of the displacement of themeniscus 80, which are controllable by the actuator 50. One skilled in the art will recognize that any suitable means for varying the pressure within thereservoir 70 may be used to deflect themeniscus 80, thereby regulating fluid flow. - When the actuator is fully actuated, the
bubble valve 10 is switched to a closed state, as illustrated inFIG. 5c . As shown, in the closed state, themeniscus 80 deflects fully to form and introduce a gas bubble 81 into themicrochannel 21. The gas bubble 81 is retained by thehydrophobic patch 22 formed in the channel wall opposite the slot 31 b. As a result, the liquid flow in the channel is substantially blocked. By reducing the pressure on themeniscus 80, thebubble valve 10 can be brought from the ‘closed’ state ofFIG. 5c via the ‘pinched’ state ofFIG. 5b back to the ‘open’ state ofFIG. 5 a. - According to one embodiment, the
bubble valve 10 may be used as a check valve for regulating pressure in the microchannel. When the pressure in the microchannel exceeds a maximum breaking pressure, the bubble collapses, opening the valve and allowing fluid to flow through the channel, thereby reducing the pressure in the microchannel. The breaking pressure depends on the hydrophobicity of thehydrophobic patch 22, as well as the geometry of the microchannel. - Alternatively or in combination with the
hydrophobic patch 22, themicrochannel 21 can be locally shaped into a cavity for receiving and anchoring the gas bubble 81. By providing an appropriate cavity, the bubble can be kept in place during operation, reducing the risk that the gas bubble is carried away with the liquid. - According to the embodiments shown in
FIGS. 2-5 c, the actuator 50 is integrated in themicrofluidic chip 100. However, one skilled in the art will recognize that an external, reusable actuator may also be used to control formation of a gas bubble in the microchannel. -
FIG. 6 shows an alternative embodiment of amicrofluidic system 100′ including abubble valve 10′ having anexternal actuator 90 according to the teachings of the invention. In the embodiment shown inFIG. 6 , themicrofluidic system 100′ includes afirst plate 200 including a groove defining themicrochannel 210 and asecond plate 300 bonded to thefirst plate 200 for enclosing themicrochannel 210 and in which a virtual wall opening 32 is formed. The virtual wall opening 32 is sized and dimensioned to form a “virtual wall” when themicrochannel 210 is filled with a liquid. - Upon filling of the microchannel 21 with a liquid, a
virtual wall 32 a is formed invirtual wall opening 32. As shown inFIGS. 7, 8 a-8 c, the microfluidic system further includes an external actuator, illustrated aspressurizer 90, pressed and sealed onto the top of thesecond plate 300 to form a tight seal. Theexternal pressurizer 90 defines a sealed pressurizingchamber 92 adjacent to thevirtual wall 32 a. The pressurizer varies the pressure within the pressurizingchamber 92 to control liquid flow through themicrochannel 210 by modifying the position of the virtual wall. The pressurizer 90 may include a source of pressurized gas (not shown) and agas inlet 91 to allow a gas pressure to be applied to thevirtual wall 32 a in order to move the virtual wall. The pressurizer may alternatively include a flexible wall that deflects to vary the volume of thechamber 92 upon activation of an actuator, such as a piezoelectric element or electromagnetic actuator. -
FIG. 8a shows a cross-section of thebubble valve 10′ ofFIGS. 6 and 7 in the ‘open’ state. As shown, when themicrochannel 210 is filled withliquid 600, avirtual wall 32 a, defined by ameniscus 800, is formed within thevirtual wall opening 32. The meniscus essentially replaces the absent portion of the side wall of the microchannel and allows liquid to flow through the channel interior unimpeded and uninfluenced by the virtual wall. -
FIG. 8b depicts the ‘pinched’ state of the bubble valve, when thepressurizer 90 is activated. As shown, activation of the pressurizer 90 increases the internal pressure within the pressurizingchamber 92. The increased pressure moves themeniscus 800 down the channel height and into the microchannel interior, thereby regulating liquid flow. The pressurized controls the level of the internal pressure in order to control the amount of deflection of the meniscus and therefore the rate of fluid flow. - To switch the valve to a ‘closed’ state, as shown in
FIG. 8c , thepressurizer 90 applies a large pressure that is sufficient to form and introduce agas bubble 810 into thechannel 210. Thehydrophobic patch 220 retains thegas bubble 810 in place. As a result, the liquid flow in the channel is blocked up to a ‘breaking pressure’, which depends on the hydrophobicity ofhydrophobic patch 220. A higher hydrophobicity results in a larger breaking pressure. By reducing the pressure on themeniscus 800 thebubble valve 10′ can be brought from the ‘closed’ state ofFIG. 8c via the ‘pinched’ state ofFIG. 8b back to the ‘open’ state ofFIG. 8 a. -
FIG. 9 shows an application of abubble valve 10 for flow regulation in amicrochannel 121 according to one embodiment of the invention. During typical operation of a microfluidic system, a pressure difference is applied over the length of amicrochannel 121. Abubble valve 10 can be employed to regulate the flow through the microchannel between zero and a maximum flow rate, depending on the applied pressure difference. -
FIG. 10 shows a portion of a microfluidic system according to an embodiment of the invention forming a Y-intersection comprising twoinlet microchannels 121 a and 121 b and anoutlet channel 121 c that combines the fluids flowing through the two inlet microchannels. The first microchannel 121 a carries a first liquid and thesecond microchannel 121 b carries a second liquid. Themicrochannels 121 a and 121 b are each controlled by a corresponding bubble valve, 10 a and 10 b, respectively, for regulating the combined composition and flow rate through theoutlet microchannel 121 c. One skilled in the art will recognize that that the number of inlet channels is not limited to two, but is presented here merely as an example. -
FIG. 11 shows a Y-intersection of a microfluidic system according to another embodiment of the invention. As shown the Y-intersection comprises an inlet microchannel 221 c and two outlet microchannels 221 a and 221 b for splitting the incoming liquid flow from the inlet microchannel 221 c. The flow of each outlet channel is regulated by a corresponding bubble valve 200 a and 200 b, respectively. The incoming liquid flow from the inlet microchannel 221 c can be split betweenmicrochannel 221 a and microchannel 221 b in any required ratio. One skilled in the art will recognize that that the number of inlet channels is not limited to two, but is presented here merely as an example. -
FIG. 12a-12c shows the implementation of an electrophoresis system 110 comprising five bubble valves, 10 a-e of the present invention, arranged with a crossed microchannel configuration. Regulation of thebubble valve 10 a regulates the electric current through the associated electrokinetically operated microchannel 115 a. The pinching of the liquid in the electrokinetically operated microchannel 115 a by a bubble valve will result in an increased electrical resistance in the microchannel 115 a. As a result, the migration of charged species and electro-osmotic flow in the electrokinetically operated microchannel 115 a can be regulated. A voltages difference for the injection of sample from a well storing a supply of asample 125 between thebubble valve 10 a and the crossing point 111 of the microchannels and consecutive separation are provided via wells V+ and V0. Electrodes are placed in the V+ and V0 wells and energized with a constant voltage difference during the operation of the electrophoresis system. - In the injection phase,
valves FIG. 12b shows direction of current/sample), while bubble valve 10 e is closed. The valves are kept in this position long enough for the sample to move from the sample well 125 towards and past the central injection crossing 111. Varying the opening ratio ofvalves FIG. 12c (i.e. ‘pinched injection’). - Immediately after the injection phase, a plug of sample is injected and separated in the separation column 115 a (microchannel which runs horizontally in figure) by closing
bubble valves 10 a, 10 d and 10 c and openingvalves 10 b and 10 e. Now the total voltage difference is applied longitudinally over the separation channel, resulting in the separation of the constituents in the sample (FIG. 12c ). -
FIG. 13a illustrates another application of the bubble valve of the present invention implemented in a column-column switch 130 for electrokinetically transferring a substance from a first electrokinetically operatedmicrochannel 215 a to a second electrokinetically operated microchannel 215 b. The column-column switch 130 comprises abubble valve 10 b of the present invention that connects the first electrokinetically operatedmicrochannel 215 a to the second electrokinetically operated microchannel 215 b. Both electrokinetically operatedmicrochannel 215 a and electrokinetically operated microchannel 215 b are connected to corresponding wells well 220 a-d. In the following example, it is assumed that the substances electrokinetically move from a positive electric potential to ground and that well 120 c and well 120 b are provided with a positive potential whilst well 120 a and well 120 d are grounded. - At first, the two electrokinetically operated
microchannel 215 a and electrokinetically operated microchannel 215 b are operated independently and the connectingbubble valve 10 b is in the ‘closed’ state whilstbubble valve 10 a and bubble valve 10 c are in the ‘open’ state. To electrokinetically transfer substance from electrokinetically operatedmicrochannel 215 a to the electrokinetically operated microchannel 215 b,bubble valve 10 a and bubble valve 10 c are switched to the closed state, and the connectingbubble valve 10 b is opened momentarily to allow passage of an amount of substance from the electrokinetically operatedmicrochannel 215 a to the electrokinetically operated microchannel 215 b. The amount transferred depends directly upon thetime bubble valve 10 b is opened. After the required amount of substance is transferred, the connectingbubble valve 10 b is closed and thebubble valve 10 a andbubble valve 10 b are opened again. -
FIG. 13b illustrates the implementation of another column tocolumn switch 130′ to exchange liquid from afirst column 215 a′ selectively into a second column 215 b′. The first column and the second column are each crossed by atransfer column 250, operated by afirst bubble valve 10 a arranged on one end of thetransfer column 250 and asecond bubble valve 10 b arranged on the opposite end of thetransfer column 250. The first one of the bubble valves is attached to thefirst column 215 a′ and is actuated upon transiently by an external actuator for increasing the pressure within the bubble valve reservoir. Increasing the pressure on the bubble valve will deflect themeniscus 80, inducing a transient flow in thetransfer column 250 from thepressurized bubble valve 10 a towards thesecond bubble valve 10 b, which comprises a compressible volume of gas. This transient flow effectively transfers a liquid volume from thefirst column 215 a′ to the second column 215 b′. Upon deactivation of the external actuator, the flow in thetransfer column 250 reverses as the compressed gas volume in thesecond bubble valve 10 b exerts a pressure on the liquid in thetransfer column 250. -
FIG. 14 shows a selective resistance circuit employing a bubble valve of the present invention for selectively including a predefined electrical resistance in an electrokinetic circuit. Thecircuit 140 comprises aninlet microchannel 321, which splits into two paths. The first path 322 includes a fluidic resistor 240 a and abubble valve 10 a, the second parallel path 323 includes afluidic resistor 240 b and abubble valve 10 b. The fluidic resistors 240 a-b comprise a channel of appropriate length to results in a certain electrical resistance. Thebubble valve 10 a and thebubble valve 10 b can be switched each to either on to allow fluid flow through the associated microchannel or off to block fluid flow through the associated microchannel. As a result, the overall electrical resistance of the electrokinetic circuit can be switched between four values: infinite (bothbubble valves 10 a-b are off), the resistance of fluidic resistor 240 a (bubble valve 10 a on,bubble valve 10 b off), the resistance offluidic resistor 240 b (bubble valve 10 a off,bubble valve 10 b on) and the parallel resistance of fluidic resistor 24 a-b (bothbubble valves -
FIG. 15 shows analternative resistance circuit 150 according to another application of the invention, now for the selective application of a voltage. By opening either thebubble valve 10 a orbubble valve 10 b, the voltage imposed on anoutgoing channel 523 can be selected. Fluidic resistor 245 a and 245 b function to limit the electric current in either of the two states to a predetermined value. -
FIG. 16 illustrates another application of thebubble valve 10 of the present invention in a particle sorting application, wherein the bubble valve is positioned in a side channel that communicates with a channel through which particles in suspension flow. According to one application of the present invention, aparticle sorter 160 comprises a closed channel system of capillary size for sorting particles, such as cells. The channel system comprises afirst supply duct 162 for introducing a stream of particles and a second supply duct 164 for supplying a carrier liquid. Thefirst supply duct 162 ends in a nozzle, and a stream of particles is introduced into the flow of carrier liquid. Thefirst supply duct 162 and the second supply duct 164 enter ameasurement duct 166, which branches into a first branch 172 a and asecond branch 172 b at a branch point 171. A measurement region 182 a is defined in themeasurement duct 166 and is associated with a detector 182 b to sense a predetermined characteristic of particles in the measurement region 182 a. Twoopposed bubble valves measurement duct 166 and are spaced opposite each other. Thebubble valves measurement duct 166 through a pair of opposed side passages 174 a and 174 b, respectively. Liquid is allowed to partly fill these side passages 174 a and 174 b to form ameniscus 175 therein. Anexternal actuator 176 is also provided for actuating thebubble valves actuator 176. - In a suspension introduced by the
first supply duct 162, two types of particles can be distinguished, normal particles 180 a and particles of interest 180 b. The flow rates in bothbranches 172 a and 172 b are adjusted so that the stream of particles normally flows through thesecond branch 172 b. Upon sensing the predetermined characteristic in the particles in the measurement region 182 a, the detector 182 b raises a signal. Theexternal actuator 176 activates thebubble valves measurement duct 166 between the sideway passages 174 a, 174 b, to deflect the particle having the predetermined characteristic so that it flows down the first branch duct 172 a rather than thesecond branch duct 172 b. The detector communicates with theactuator 176, so that when the detector 182 b senses a predetermined characteristic in a particle, the actuator activates thefirst bubble valve 10 a to cause pressure variations in thereservoir 70 of the first bubble valve. The activation of the first bubble valves causes a transient pressure variation in the first side passage 174 a. The second side passage 174 b and thesecond bubble valve 10 b absorb the transient pressure variations in themeasurement duct 166 induced via theactuator 176. Basically, the reservoir 70 b of thesecond bubble valve 10 b is a chamber having a resilient wall or contains a compressible fluid such as a gas. The resilient properties allow the flow of liquid from the measurement duct into the second side passage 174 b. -
FIGS. 17a-17c illustrate the operation of theparticle sorting system 160 ofFIG. 16 . InFIG. 17a , the detector raises a signal to activate the actuator. Upon activation of the actuator, the pressure within the reservoir of thefirst bubble valve 10 a is increased, causing a transient discharge of liquid from the first side passage 174 a as indicated by the arrow. The sudden pressure increase caused at this point in the duct causes liquid to flow into the second side passage 174 b because of the resilient properties of the reservoir of thesecond bubble valve 10 b. This movement of liquid into the second side passage 174 b is indicated with an arrow. Resultingly, as can be seen in the figure, the flow through the duct is deflected causing the selected particle of interest 178 b located between the first side passage 174 a and the second side passage 174 b to be shifted perpendicular to its flow direction in the normal state. The flow resistances to themeasurement duct 166, the first branch 172 a and thesecond branch 172 b is chosen so that the preferred direction of the flow to and from the first side passage 174 a and the second side passage 174 b has an appreciable component perpendicular to the normal flow through themeasurement duct 166. This goal can for instance be reached by the first branch 172 a and thesecond branch 172 b so that their resistances to flow is large in comparison with the flow resistances of the first side passage 174 a and the second side passage 174 b. -
FIG. 17b shows theparticle sorting system 160 during the relief of the first bubble valve reservoir when the particle of interest 178 b has left the volume between the first side passage 174 a and the second side passage 174 b. Theactuator 176 is deactivated, causing the pressure inside the reservoir to return to the normal pressure. During this relief phase there is a negative pressure difference between the two reservoirs of the bubble valves, causing a liquid flow through the first side passage 174 a and the second side passage 174 b opposite to the liquid flow shown in the previous figure and is indicated by the arrows. -
FIG. 17c shows theparticle sorting system 160 after completion of the switching sequence. The pressures inside the reservoirs of the bubble valves has been equalized so the flow through themeasurement duct 166 is normalized. As the particle of interest 178 b has been displaced radially, it will flow into the first branch 172 a as was the objective of the switching operation. - According to yet another embodiment, the cross-sectional dimensions of a microchannel including a bubble valve according to the teachings of the present invention may be varied locally to affect the pressure within the microchannel interior. For example, the microchannel may be narrowed or widened at certain locations to increase or decrease the capillary forces acting on a fluid in the microchannel interior. One of ordinary skill in the art will be able to determine a suitable cross-sectional dimension to achieve a desired pressure within the microchannel interior.
- The bubble valve of the present invention may be implemented in a variety of microfluidic devices used for many applications. In a particular application, the bubble valve is implemented in a flow-cytometer based instrument for sorting or physically separating particles of interest from a sample or for measuring selected physical and chemical characteristics of cells or particles in suspension as they travel past a particular site. The bubble valve may also be employed in devices for sequencing or manipulating DNA, medical diagnostic instruments, devices for drug discovery, chemical analysis and so on.
- The present invention provides an improved system and method for regulating fluid flow in a microchannel for a variety of applications. The bubble valve of the present invention is easy to operate and control, simple to manufacture and economical. In addition, the bubble valve does not adversely affect the liquid in the microchannel. The bubble valve effectively controls the flow of liquids in microfluidic systems, without heating the fluid and without complex on-chip circuitry.
- The present invention has been described relative to an illustrative embodiment. Since certain changes may be made in the above constructions without departing from the scope of the invention, it is intended that all matter contained in the above description or shown in the accompanying drawings be interpreted as illustrative and not in a limiting sense.
- It is also to be understood that the following claims are to cover all generic and specific features of the invention described herein, and all statements of the scope of the invention which, as a matter of language, might be said to fall therebetween.
Claims (10)
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US14/689,508 US9943847B2 (en) | 2002-04-17 | 2015-04-17 | Microfluidic system including a bubble valve for regulating fluid flow through a microchannel |
US15/941,793 US10427159B2 (en) | 2002-04-17 | 2018-03-30 | Microfluidic device |
US16/584,315 US11027278B2 (en) | 2002-04-17 | 2019-09-26 | Methods for controlling fluid flow in a microfluidic system |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US37325602P | 2002-04-17 | 2002-04-17 | |
US10/179,586 US6877528B2 (en) | 2002-04-17 | 2002-06-24 | Microfluidic system including a bubble valve for regulating fluid flow through a microchannel |
US11/021,251 US7069943B2 (en) | 2002-04-17 | 2004-12-21 | Microfluidic system including a bubble valve for regulating fluid flow through a microchannel |
US11/433,781 US8210209B2 (en) | 2002-04-17 | 2006-05-12 | Microfluidic system including a bubble valve for regulating fluid flow through a microchannel |
US13/527,331 US9011797B2 (en) | 2002-04-17 | 2012-06-19 | Microfluidic system including a bubble valve for regulating fluid flow through a microchannel |
US14/689,508 US9943847B2 (en) | 2002-04-17 | 2015-04-17 | Microfluidic system including a bubble valve for regulating fluid flow through a microchannel |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/527,331 Continuation US9011797B2 (en) | 2002-04-17 | 2012-06-19 | Microfluidic system including a bubble valve for regulating fluid flow through a microchannel |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/941,793 Continuation US10427159B2 (en) | 2002-04-17 | 2018-03-30 | Microfluidic device |
Publications (3)
Publication Number | Publication Date |
---|---|
US20160303564A1 US20160303564A1 (en) | 2016-10-20 |
US20170128938A9 true US20170128938A9 (en) | 2017-05-11 |
US9943847B2 US9943847B2 (en) | 2018-04-17 |
Family
ID=57129519
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/689,508 Expired - Lifetime US9943847B2 (en) | 2002-04-17 | 2015-04-17 | Microfluidic system including a bubble valve for regulating fluid flow through a microchannel |
US15/941,793 Expired - Fee Related US10427159B2 (en) | 2002-04-17 | 2018-03-30 | Microfluidic device |
US16/584,315 Expired - Lifetime US11027278B2 (en) | 2002-04-17 | 2019-09-26 | Methods for controlling fluid flow in a microfluidic system |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/941,793 Expired - Fee Related US10427159B2 (en) | 2002-04-17 | 2018-03-30 | Microfluidic device |
US16/584,315 Expired - Lifetime US11027278B2 (en) | 2002-04-17 | 2019-09-26 | Methods for controlling fluid flow in a microfluidic system |
Country Status (1)
Country | Link |
---|---|
US (3) | US9943847B2 (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10357771B2 (en) | 2017-08-22 | 2019-07-23 | 10X Genomics, Inc. | Method of producing emulsions |
US10544413B2 (en) | 2017-05-18 | 2020-01-28 | 10X Genomics, Inc. | Methods and systems for sorting droplets and beads |
US10816550B2 (en) | 2012-10-15 | 2020-10-27 | Nanocellect Biomedical, Inc. | Systems, apparatus, and methods for sorting particles |
US11660601B2 (en) | 2017-05-18 | 2023-05-30 | 10X Genomics, Inc. | Methods for sorting particles |
US11833515B2 (en) | 2017-10-26 | 2023-12-05 | 10X Genomics, Inc. | Microfluidic channel networks for partitioning |
Families Citing this family (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6976590B2 (en) | 2002-06-24 | 2005-12-20 | Cytonome, Inc. | Method and apparatus for sorting particles |
US9943847B2 (en) | 2002-04-17 | 2018-04-17 | Cytonome/St, Llc | Microfluidic system including a bubble valve for regulating fluid flow through a microchannel |
US11243494B2 (en) | 2002-07-31 | 2022-02-08 | Abs Global, Inc. | Multiple laminar flow-based particle and cellular separation with laser steering |
US9657290B2 (en) | 2012-07-03 | 2017-05-23 | The Board Of Trustees Of The Leland Stanford Junior University | Scalable bio-element analysis |
US8961904B2 (en) | 2013-07-16 | 2015-02-24 | Premium Genetics (Uk) Ltd. | Microfluidic chip |
US11796449B2 (en) | 2013-10-30 | 2023-10-24 | Abs Global, Inc. | Microfluidic system and method with focused energy apparatus |
SG11201706777QA (en) | 2015-02-19 | 2017-09-28 | Premium Genetics (Uk) Ltd | Scanning infrared measurement system |
JP6920997B2 (en) | 2015-02-22 | 2021-08-18 | ザ ボード オブ トラスティーズ オブ ザ レランド スタンフォード ジュニア ユニバーシティー | Microscreening equipment, processes, and products |
CN110198786A (en) * | 2016-11-14 | 2019-09-03 | 浩康生物系统公司 | Method and apparatus for sorting target particles |
US11441701B2 (en) * | 2017-07-14 | 2022-09-13 | Hewlett-Packard Development Company, L.P. | Microfluidic valve |
EP3796998A1 (en) | 2018-05-23 | 2021-03-31 | ABS Global, Inc. | Systems and methods for particle focusing in microchannels |
FR3082440B1 (en) * | 2018-06-14 | 2020-12-11 | Paris Sciences Lettres Quartier Latin | MATERIAL TRANSFER METHOD IN A MICROFLUIDIC OR MILLIFLUIDIC DEVICE |
GB2578528B (en) | 2018-12-04 | 2021-02-24 | Omniome Inc | Mixed-phase fluids for nucleic acid sequencing and other analytical assays |
BR112021020390A2 (en) | 2019-04-18 | 2022-01-18 | Abs Global Inc | Cryoprotectant delivery system, cryopreservation system for delivering a cryoprotectant to a biological specimen, method for delivering a cryoprotectant to a biological specimen, delivery system, and method for preparing a biological specimen for cryopreservation |
CN110605148A (en) * | 2019-10-18 | 2019-12-24 | 广东工业大学 | Micro-channel structure, micro-fluidic chip and quantitative heterogeneous reaction method |
US11628439B2 (en) | 2020-01-13 | 2023-04-18 | Abs Global, Inc. | Single-sheath microfluidic chip |
US20220236165A1 (en) * | 2021-01-27 | 2022-07-28 | Becton, Dickinson And Company | Flow cytometers including fiber optic light collectors, and methods of use thereof |
CN113101846B (en) * | 2021-05-10 | 2022-03-29 | 浙江师范大学 | Active-passive combined piezoelectric gas micro mixer |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6033191A (en) * | 1997-05-16 | 2000-03-07 | Institut Fur Mikrotechnik Mainz Gmbh | Micromembrane pump |
Family Cites Families (336)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US350864A (en) | 1886-10-12 | Umax butler | ||
US2015522A (en) | 1931-12-16 | 1935-09-24 | Alfred O Hoffman | Riffle trough |
US2646882A (en) | 1950-08-02 | 1953-07-28 | Jr Hildreth Frost | Flotation machine |
US2787453A (en) | 1953-11-30 | 1957-04-02 | Exxon Research Engineering Co | Fractionating tower utilizing directional upflow means in conjunction with slanted trays |
US2850940A (en) | 1955-04-28 | 1958-09-09 | Perkin Elmer Corp | Device to measure refractive index gradient |
US2923410A (en) | 1957-04-29 | 1960-02-02 | Tschmelitsch Florian | Portable flexible sluice box |
US3362421A (en) | 1963-05-28 | 1968-01-09 | Ibm | Bounded free jet fluid amplifier with turbulent attachment |
US3289687A (en) | 1964-02-13 | 1966-12-06 | J C Dunaway | Actuator for pure fluid amplifier |
US3380584A (en) | 1965-06-04 | 1968-04-30 | Atomic Energy Commission Usa | Particle separator |
US3560754A (en) | 1965-11-17 | 1971-02-02 | Ibm | Photoelectric particle separator using time delay |
US3370538A (en) | 1966-02-11 | 1968-02-27 | E W Hines And Associates | Fluid pumps energized by magnetostrictive action |
CH441233A (en) | 1966-08-31 | 1967-08-15 | Ibm | Separation device for suspended particles |
US3506654A (en) | 1966-09-15 | 1970-04-14 | Syntex Corp | Benzylidene derivatives of chromene,thiochromene,quinoline,and n-alkyl quinoline and corresponding benzyl tertiary carbinol intermediates |
US3508655A (en) | 1967-02-03 | 1970-04-28 | Ibm | Cell extraction and collection apparatus |
US3785390A (en) | 1967-03-09 | 1974-01-15 | Powers Regulator Co | Pure fluid amplifier |
US3495253A (en) | 1967-06-26 | 1970-02-10 | George B Richards | Planar fluid amplifier |
US3574309A (en) | 1968-06-28 | 1971-04-13 | Foxboro Co | Chambered fluidic amplifier |
JPS4946274A (en) | 1972-09-12 | 1974-05-02 | ||
US3827555A (en) | 1973-03-05 | 1974-08-06 | Bio Physics Systems Inc | Particle sorter with segregation indicator |
US3791517A (en) | 1973-03-05 | 1974-02-12 | Bio Physics Systems Inc | Digital fluidic amplifier particle sorter |
US3984307A (en) | 1973-03-05 | 1976-10-05 | Bio/Physics Systems, Inc. | Combined particle sorter and segregation indicator |
US3906415A (en) | 1974-06-14 | 1975-09-16 | Massachusetts Inst Technology | Apparatus wherein a segmented fluid stream performs electrical switching functions and the like |
US4004150A (en) | 1975-05-01 | 1977-01-18 | Samuel Natelson | Analytical multiple component readout system |
US3984621A (en) | 1975-09-15 | 1976-10-05 | Merritt Foods Company | Electrically wired floor construction |
US4050851A (en) | 1975-11-10 | 1977-09-27 | The Nash Engineering Company | Liquid ring pumps and compressors using a ferrofluidic ring liquid |
US4148585A (en) | 1977-02-11 | 1979-04-10 | The United States Of America As Represented By The Department Of Health, Education & Welfare | Three dimensional laser Doppler velocimeter |
DE2716095A1 (en) | 1977-04-12 | 1978-10-19 | Zoeld Tibor Dr Phys | GAS CONTROLLED PROCESS FOR SORTING PARTICLES SUSPENDED IN AN ELECTROLYTE AND DEVICE FOR CARRYING OUT THE PROCESS |
US4147621A (en) | 1977-06-28 | 1979-04-03 | University Of Utah | Method and apparatus for flow field-flow fractionation |
US4195811A (en) | 1977-08-22 | 1980-04-01 | EMX Controls Inc. | Electronic valve control means |
CA1127227A (en) | 1977-10-03 | 1982-07-06 | Ichiro Endo | Liquid jet recording process and apparatus therefor |
US4153855A (en) | 1977-12-16 | 1979-05-08 | The United States Of America As Represented By The Secretary Of The Army | Method of making a plate having a pattern of microchannels |
US4284499A (en) | 1978-04-19 | 1981-08-18 | Occidental Research Corporation | Apparatus for the float concentration of ore |
US4279345A (en) | 1979-08-03 | 1981-07-21 | Allred John C | High speed particle sorter using a field emission electrode |
US4318483A (en) | 1979-08-20 | 1982-03-09 | Ortho Diagnostics, Inc. | Automatic relative droplet charging time delay system for an electrostatic particle sorting system using a relatively moveable stream surface sensing system |
US4361400A (en) | 1980-11-26 | 1982-11-30 | The United States Of America As Represented By The United States Department Of Energy | Fluidic assembly for an ultra-high-speed chromosome flow sorter |
US4426451A (en) | 1981-01-28 | 1984-01-17 | Eastman Kodak Company | Multi-zoned reaction vessel having pressure-actuatable control means between zones |
JPS57132038A (en) | 1981-02-10 | 1982-08-16 | Olympus Optical Co Ltd | Photometric device |
US4344844A (en) | 1981-03-17 | 1982-08-17 | Townley J O | Inclined static deoiler and conditioner for treating ore |
US4498782A (en) | 1981-05-29 | 1985-02-12 | Science Research Center, Inc. | Assembly for determining light transmissiveness of a fluid |
US4365719A (en) | 1981-07-06 | 1982-12-28 | Leonard Kelly | Radiometric ore sorting method and apparatus |
JPS5857560A (en) | 1981-09-30 | 1983-04-05 | Fuji Heavy Ind Ltd | Air breather mechanism for oil seal |
GB2116740B (en) | 1982-02-27 | 1985-08-29 | Bergstroem Arne | Objectives comprising pinhole aperture and image intensifier |
DK148334C (en) | 1982-04-07 | 1985-11-04 | Risoe Forsoegsanlaeg | PROCEDURE FOR MEASURING SPEED GRADIENTS IN A FLOWING MEDIUM AND APPARATUS FOR IMPLEMENTING THE PROCEDURE |
US4541429A (en) | 1982-05-10 | 1985-09-17 | Prosl Frank R | Implantable magnetically-actuated valve |
US4501144A (en) | 1982-09-30 | 1985-02-26 | Honeywell Inc. | Flow sensor |
US4478076A (en) | 1982-09-30 | 1984-10-23 | Honeywell Inc. | Flow sensor |
US4478077A (en) | 1982-09-30 | 1984-10-23 | Honeywell Inc. | Flow sensor |
US4651564A (en) | 1982-09-30 | 1987-03-24 | Honeywell Inc. | Semiconductor device |
US4445696A (en) | 1983-02-22 | 1984-05-01 | Ferrofluidics Corporation | Nonbursting magnetic liquid seals for high vacuum applications |
US4526276A (en) | 1983-04-28 | 1985-07-02 | Becton, Dickinson And Company | Apparatus and method for sorting particles by gas actuation |
GB2140128A (en) | 1983-05-19 | 1984-11-21 | Emi Ltd | Gas valve |
US4579173A (en) | 1983-09-30 | 1986-04-01 | Exxon Research And Engineering Co. | Magnetized drive fluids |
US4554427A (en) | 1983-12-19 | 1985-11-19 | Westinghouse Electric Corp. | Molded case circuit breaker with movable lower electrical contact |
JPS60153023A (en) | 1984-01-23 | 1985-08-12 | Toshiba Corp | Beam splitter device for high output laser |
US4581624A (en) | 1984-03-01 | 1986-04-08 | Allied Corporation | Microminiature semiconductor valve |
ATE48477T1 (en) | 1984-09-11 | 1989-12-15 | Partec Ag | METHOD AND DEVICE FOR SORTING MICROSCOPIC PARTICLES. |
US4676274A (en) * | 1985-02-28 | 1987-06-30 | Brown James F | Capillary flow control |
US4636149A (en) | 1985-05-13 | 1987-01-13 | Cordis Corporation | Differential thermal expansion driven pump |
US4797696A (en) | 1985-07-24 | 1989-01-10 | Ateq Corporation | Beam splitting apparatus |
US4963498A (en) | 1985-08-05 | 1990-10-16 | Biotrack | Capillary flow device |
NZ216327A (en) | 1986-05-28 | 1989-04-26 | Lindsay Guy Herron | Hollow, perforated riffle bar and apparatus using a set of bars |
EP0286088B1 (en) | 1987-04-08 | 1994-09-14 | Hitachi, Ltd. | A sheath flow type flow-cell device |
JPS63259466A (en) | 1987-04-16 | 1988-10-26 | Hitachi Ltd | Cell analyzer |
US4939081A (en) | 1987-05-27 | 1990-07-03 | The Netherlands Cancer Institute | Cell-separation |
US4808079A (en) | 1987-06-08 | 1989-02-28 | Crowley Christopher J | Magnetic pump for ferrofluids |
US5053344A (en) | 1987-08-04 | 1991-10-01 | Cleveland Clinic Foundation | Magnetic field separation and analysis system |
US5040890A (en) | 1987-11-25 | 1991-08-20 | Becton, Dickinson And Company | Sheathed particle flow controlled by differential pressure |
US4936465A (en) | 1987-12-07 | 1990-06-26 | Zoeld Tibor | Method and apparatus for fast, reliable, and environmentally safe dispensing of fluids, gases and individual particles of a suspension through pressure control at well defined parts of a closed flow-through system |
JPH01170853A (en) | 1987-12-25 | 1989-07-05 | Hitachi Ltd | Cell screening device |
US5005639A (en) | 1988-03-24 | 1991-04-09 | The United States Of America As Represented By The Secretary Of The Air Force | Ferrofluid piston pump for use with heat pipes or the like |
US5065978A (en) | 1988-04-27 | 1991-11-19 | Dragerwerk Aktiengesellschaft | Valve arrangement of microstructured components |
US4908112A (en) | 1988-06-16 | 1990-03-13 | E. I. Du Pont De Nemours & Co. | Silicon semiconductor wafer for analyzing micronic biological samples |
DE3831630A1 (en) | 1988-09-17 | 1990-03-22 | Ulrich M Landwehr | METHOD AND DEVICE FOR DETERMINING THE DIMENSIONS OF AN OBJECT BY PHOTOGRAPHIC WAY |
CA1328861C (en) | 1988-09-30 | 1994-04-26 | Occam Marine Technologies Ltd. | Low speed particle concentrator |
HU203288B (en) | 1989-04-01 | 1991-07-29 | Mta Mueszaki Kemiai Kutato Int | Apparatus for carrying out biocatalytic processes by means of biocatalyzer of solid phase |
US4954715A (en) | 1989-06-26 | 1990-09-04 | Zoeld Tibor | Method and apparatus for an optimized multiparameter flow-through particle and cell analyzer |
US5238223A (en) | 1989-08-11 | 1993-08-24 | Robert Bosch Gmbh | Method of making a microvalve |
US5030002A (en) | 1989-08-11 | 1991-07-09 | Becton, Dickinson And Company | Method and apparatus for sorting particles with a moving catcher tube |
US5275787A (en) | 1989-10-04 | 1994-01-04 | Canon Kabushiki Kaisha | Apparatus for separating or measuring particles to be examined in a sample fluid |
US5101978A (en) | 1989-11-27 | 1992-04-07 | The United States Of America As Represented By The Secretary Of The Army | Fluidic sorting device for two or more materials suspended in a fluid |
US5193688A (en) | 1989-12-08 | 1993-03-16 | University Of Utah | Method and apparatus for hydrodynamic relaxation and sample concentration NIN field-flow fraction using permeable wall elements |
US5082242A (en) | 1989-12-27 | 1992-01-21 | Ulrich Bonne | Electronic microvalve apparatus and fabrication |
US5171132A (en) | 1989-12-27 | 1992-12-15 | Seiko Epson Corporation | Two-valve thin plate micropump |
US5244537A (en) | 1989-12-27 | 1993-09-14 | Honeywell, Inc. | Fabrication of an electronic microvalve apparatus |
US5050429A (en) | 1990-02-22 | 1991-09-24 | Yamatake-Honeywell Co., Ltd. | Microbridge flow sensor |
GB9008044D0 (en) | 1990-04-09 | 1990-06-06 | Hatfield Polytechnic Higher Ed | Microfabricated device for biological cell sorting |
DE69107813T2 (en) | 1990-07-10 | 1995-11-09 | Westonbridge Int Ltd | Valve, method of making this valve and micropump equipped with this valve. |
US5092972A (en) | 1990-07-12 | 1992-03-03 | Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College | Field-effect electroosmosis |
DE69111591T2 (en) | 1990-08-31 | 1996-02-29 | Westonbridge Int Ltd | VALVE WITH POSITION DETECTOR AND MICROPUMP WITH IT. |
US5204884A (en) | 1991-03-18 | 1993-04-20 | University Of Rochester | System for high-speed measurement and sorting of particles |
US5541072A (en) | 1994-04-18 | 1996-07-30 | Immunivest Corporation | Method for magnetic separation featuring magnetic particles in a multi-phase system |
US5622831A (en) | 1990-09-26 | 1997-04-22 | Immunivest Corporation | Methods and devices for manipulation of magnetically collected material |
FI86340C (en) | 1990-10-31 | 1992-08-10 | Labsystems Oy | Procedure for conducting light |
US5108623A (en) | 1990-11-19 | 1992-04-28 | Gould Inc. | Moving web filter assembly |
US5199576A (en) | 1991-04-05 | 1993-04-06 | University Of Rochester | System for flexibly sorting particles |
US5176358A (en) | 1991-08-08 | 1993-01-05 | Honeywell Inc. | Microstructure gas valve control |
US5627040A (en) | 1991-08-28 | 1997-05-06 | Becton Dickinson And Company | Flow cytometric method for autoclustering cells |
US5265327A (en) | 1991-09-13 | 1993-11-30 | Faris Sadeg M | Microchannel plate technology |
JPH05157684A (en) | 1991-12-02 | 1993-06-25 | Seikagaku Kogyo Co Ltd | Absorptionmeter |
US5213479A (en) | 1992-04-09 | 1993-05-25 | The Nash Engineering Company | Liquid ring pumps with improved housing shapes |
US5498392A (en) | 1992-05-01 | 1996-03-12 | Trustees Of The University Of Pennsylvania | Mesoscale polynucleotide amplification device and method |
US5486335A (en) | 1992-05-01 | 1996-01-23 | Trustees Of The University Of Pennsylvania | Analysis based on flow restriction |
US5726026A (en) | 1992-05-01 | 1998-03-10 | Trustees Of The University Of Pennsylvania | Mesoscale sample preparation device and systems for determination and processing of analytes |
US5466572A (en) | 1992-09-03 | 1995-11-14 | Systemix, Inc. | High speed flow cytometric separation of viable cells |
EP0591989B1 (en) | 1992-10-09 | 2000-01-26 | Canon Kabushiki Kaisha | Ink jet printing head and printing apparatus using same |
US5489506A (en) | 1992-10-26 | 1996-02-06 | Biolife Systems, Inc. | Dielectrophoretic cell stream sorter |
US6152181A (en) | 1992-11-16 | 2000-11-28 | The United States Of America As Represented By The Secretary Of The Air Force | Microdevices based on surface tension and wettability that function as sensors, actuators, and other devices |
US5789045A (en) | 1994-04-15 | 1998-08-04 | The United States Of America As Represented By The Secretary Of The Air Force | Microtubes devices based on surface tension and wettability |
US5441597A (en) | 1992-12-01 | 1995-08-15 | Honeywell Inc. | Microstructure gas valve control forming method |
US5395588A (en) | 1992-12-14 | 1995-03-07 | Becton Dickinson And Company | Control of flow cytometer having vacuum fluidics |
SE508435C2 (en) | 1993-02-23 | 1998-10-05 | Erik Stemme | Diaphragm pump type pump |
SE501713C2 (en) | 1993-09-06 | 1995-05-02 | Pharmacia Biosensor Ab | Diaphragm-type valve, especially for liquid handling blocks with micro-flow channels |
US5637496A (en) | 1993-07-02 | 1997-06-10 | B. Braun Biotech International Mbh | Device and method for conveying and separating a suspension with biological cells or micro-organisms |
US5483469A (en) | 1993-08-02 | 1996-01-09 | The Regents Of The University Of California | Multiple sort flow cytometer |
US5464581A (en) | 1993-08-02 | 1995-11-07 | The Regents Of The University Of California | Flow cytometer |
DE69424236T2 (en) | 1993-09-16 | 2000-11-30 | Owens Brockway Glass Container | Testing transparent containers |
JP2948069B2 (en) | 1993-09-20 | 1999-09-13 | 株式会社日立製作所 | Chemical analyzer |
US5544756A (en) | 1994-03-14 | 1996-08-13 | Peter Abt | Dynamic mining system comprsing hydrated multiple recovery sites and related methods |
GB9406551D0 (en) | 1994-03-31 | 1994-05-25 | Hjelm Nils M | Chromatography system and methodology |
JPH07286953A (en) | 1994-04-19 | 1995-10-31 | Toa Medical Electronics Co Ltd | Imaging flow sight meter |
US5632935A (en) | 1994-04-28 | 1997-05-27 | Koch Engineering Company, Inc. | Vapor-liquid contact tray and downcomer assembly and method employing same |
US6001229A (en) | 1994-08-01 | 1999-12-14 | Lockheed Martin Energy Systems, Inc. | Apparatus and method for performing microfluidic manipulations for chemical analysis |
WO1996012171A2 (en) | 1994-10-14 | 1996-04-25 | University Of Washington | High speed flow cytometer droplet formation system |
US5602039A (en) | 1994-10-14 | 1997-02-11 | The University Of Washington | Flow cytometer jet monitor system |
ATE269160T1 (en) | 1994-11-14 | 2004-07-15 | Univ Pennsylvania | MINIATURIZED SAMPLE PREPARATION DEVICES AND SYSTEMS FOR DETECTING AND TREATING ANALYTES |
US5876187A (en) | 1995-03-09 | 1999-03-02 | University Of Washington | Micropumps with fixed valves |
US5608519A (en) | 1995-03-20 | 1997-03-04 | Gourley; Paul L. | Laser apparatus and method for microscopic and spectroscopic analysis and processing of biological cells |
DE19520298A1 (en) | 1995-06-02 | 1996-12-05 | Bayer Ag | Sorting device for biological cells or viruses |
US5758823A (en) | 1995-06-12 | 1998-06-02 | Georgia Tech Research Corporation | Synthetic jet actuator and applications thereof |
US5716852A (en) | 1996-03-29 | 1998-02-10 | University Of Washington | Microfabricated diffusion-based chemical sensor |
US5932100A (en) | 1995-06-16 | 1999-08-03 | University Of Washington | Microfabricated differential extraction device and method |
US5922210A (en) | 1995-06-16 | 1999-07-13 | University Of Washington | Tangential flow planar microfabricated fluid filter and method of using thereof |
US5856174A (en) | 1995-06-29 | 1999-01-05 | Affymetrix, Inc. | Integrated nucleic acid diagnostic device |
US6048734A (en) | 1995-09-15 | 2000-04-11 | The Regents Of The University Of Michigan | Thermal microvalves in a fluid flow method |
JP3515646B2 (en) | 1995-09-18 | 2004-04-05 | 大塚電子株式会社 | Multi-capillary electrophoresis device |
US5726751A (en) | 1995-09-27 | 1998-03-10 | University Of Washington | Silicon microchannel optical flow cytometer |
US5803270A (en) | 1995-10-31 | 1998-09-08 | Institute Of Paper Science & Technology, Inc. | Methods and apparatus for acoustic fiber fractionation |
JP3226012B2 (en) | 1995-11-17 | 2001-11-05 | 矢崎総業株式会社 | Equipment for separating microscopic substances in culture solution |
US6068751A (en) | 1995-12-18 | 2000-05-30 | Neukermans; Armand P. | Microfluidic valve and integrated microfluidic system |
JP3308441B2 (en) | 1995-12-19 | 2002-07-29 | シスメックス株式会社 | Urine particle analyzer |
US5863502A (en) | 1996-01-24 | 1999-01-26 | Sarnoff Corporation | Parallel reaction cassette and associated devices |
US5851488A (en) | 1996-02-29 | 1998-12-22 | Biocircuits Corporation | Apparatus for automatic electro-optical chemical assay determination |
US5783446A (en) | 1996-03-04 | 1998-07-21 | Biocircuits Corporation | Particle assay using fluid velocity gradients |
US5948684A (en) | 1997-03-31 | 1999-09-07 | University Of Washington | Simultaneous analyte determination and reference balancing in reference T-sensor devices |
US5942443A (en) | 1996-06-28 | 1999-08-24 | Caliper Technologies Corporation | High throughput screening assay systems in microscale fluidic devices |
US5885470A (en) | 1997-04-14 | 1999-03-23 | Caliper Technologies Corporation | Controlled fluid transport in microfabricated polymeric substrates |
US6196525B1 (en) | 1996-05-13 | 2001-03-06 | Universidad De Sevilla | Device and method for fluid aeration via gas forced through a liquid within an orifice of a pressure chamber |
US5726404A (en) | 1996-05-31 | 1998-03-10 | University Of Washington | Valveless liquid microswitch |
US6361672B1 (en) | 1996-06-10 | 2002-03-26 | Transgenomic, Inc. | Multiple laser diode electromagnetic radiation source in multiple electrophoresis channel systems |
US5699462A (en) | 1996-06-14 | 1997-12-16 | Hewlett-Packard Company | Total internal reflection optical switches employing thermal activation |
JP2000512541A (en) | 1996-06-14 | 2000-09-26 | ユニバーシティ オブ ワシントン | Difference extraction device with improved absorption |
WO1997049925A1 (en) | 1996-06-27 | 1997-12-31 | Weyerhaeuser Company | Fluid switch |
US5764674A (en) | 1996-06-28 | 1998-06-09 | Honeywell Inc. | Current confinement for a vertical cavity surface emitting laser |
AU726987B2 (en) | 1996-06-28 | 2000-11-30 | Caliper Life Sciences, Inc. | Electropipettor and compensation means for electrophoretic bias |
NZ333346A (en) | 1996-06-28 | 2000-03-27 | Caliper Techn Corp | High-throughput screening assay systems in microscale fluidic devices |
US5699157A (en) | 1996-07-16 | 1997-12-16 | Caliper Technologies Corp. | Fourier detection of species migrating in a microchannel |
US5799030A (en) | 1996-07-26 | 1998-08-25 | Honeywell Inc. | Semiconductor device with a laser and a photodetector in a common container |
US6280967B1 (en) | 1996-08-02 | 2001-08-28 | Axiom Biotechnologies, Inc. | Cell flow apparatus and method for real-time of cellular responses |
US6136212A (en) | 1996-08-12 | 2000-10-24 | The Regents Of The University Of Michigan | Polymer-based micromachining for microfluidic devices |
JP2002503334A (en) | 1996-09-04 | 2002-01-29 | テクニカル ユニバーシティ オブ デンマーク | Microflow system for particle separation and analysis |
US6221654B1 (en) | 1996-09-25 | 2001-04-24 | California Institute Of Technology | Method and apparatus for analysis and sorting of polynucleotides based on size |
US5858187A (en) | 1996-09-26 | 1999-01-12 | Lockheed Martin Energy Systems, Inc. | Apparatus and method for performing electrodynamic focusing on a microchip |
US6120666A (en) | 1996-09-26 | 2000-09-19 | Ut-Battelle, Llc | Microfabricated device and method for multiplexed electrokinetic focusing of fluid streams and a transport cytometry method using same |
AU5442198A (en) | 1996-11-13 | 1998-06-03 | Q.B.I. Enterprises Ltd. | Gene identification method |
US5971355A (en) | 1996-11-27 | 1999-10-26 | Xerox Corporation | Microdevice valve structures to fluid control |
US5683159A (en) | 1997-01-03 | 1997-11-04 | Johnson; Greg P. | Hardware mounting rail |
US6445448B1 (en) | 1997-03-12 | 2002-09-03 | Corning Applied Technologies, Corp. | System and method for molecular sample measurement |
US6252715B1 (en) | 1997-03-13 | 2001-06-26 | T. Squared G, Inc. | Beam pattern contractor and focus element, method and apparatus |
WO1998049548A1 (en) | 1997-04-25 | 1998-11-05 | Caliper Technologies Corporation | Microfluidic devices incorporating improved channel geometries |
US5976336A (en) | 1997-04-25 | 1999-11-02 | Caliper Technologies Corp. | Microfluidic devices incorporating improved channel geometries |
WO1998052691A1 (en) | 1997-05-16 | 1998-11-26 | Alberta Research Council | Microfluidic system and methods of use |
US6613512B1 (en) | 1997-06-09 | 2003-09-02 | Caliper Technologies Corp. | Apparatus and method for correcting for variable velocity in microfluidic systems |
US5974867A (en) | 1997-06-13 | 1999-11-02 | University Of Washington | Method for determining concentration of a laminar sample stream |
DE19725050C2 (en) | 1997-06-13 | 1999-06-24 | Fraunhofer Ges Forschung | Arrangement for the detection of biochemical or chemical substances by means of fluorescent light excitation and method for their production |
US6001231A (en) | 1997-07-15 | 1999-12-14 | Caliper Technologies Corp. | Methods and systems for monitoring and controlling fluid flow rates in microfluidic systems |
US5876266A (en) | 1997-07-15 | 1999-03-02 | International Business Machines Corporation | Polishing pad with controlled release of desired micro-encapsulated polishing agents |
US6082185A (en) | 1997-07-25 | 2000-07-04 | Research International, Inc. | Disposable fluidic circuit cards |
WO1999009042A2 (en) | 1997-08-13 | 1999-02-25 | Cepheid | Microstructures for the manipulation of fluid samples |
US6540895B1 (en) | 1997-09-23 | 2003-04-01 | California Institute Of Technology | Microfabricated cell sorter for chemical and biological materials |
US7214298B2 (en) | 1997-09-23 | 2007-05-08 | California Institute Of Technology | Microfabricated cell sorter |
US6007775A (en) | 1997-09-26 | 1999-12-28 | University Of Washington | Multiple analyte diffusion based chemical sensor |
JPH11108838A (en) | 1997-10-06 | 1999-04-23 | Horiba Ltd | Method and device for measuring turbidity |
US5822170A (en) | 1997-10-09 | 1998-10-13 | Honeywell Inc. | Hydrophobic coating for reducing humidity effect in electrostatic actuators |
US5836750A (en) | 1997-10-09 | 1998-11-17 | Honeywell Inc. | Electrostatically actuated mesopump having a plurality of elementary cells |
EP1032824A4 (en) | 1997-10-15 | 2003-07-23 | Aclara Biosciences Inc | Laminate microstructure device and method for making same |
IT1295939B1 (en) | 1997-10-31 | 1999-05-28 | Giammaria Sitar | DEVICE AND METHOD FOR THE SEPARATION OF HUMAN OR ANIMAL CELLS WITH DIFFERENT DENSITIES FROM CELL DISPERSIONS THAT CONTAIN THEM |
US5992820A (en) | 1997-11-19 | 1999-11-30 | Sarnoff Corporation | Flow control in microfluidics devices by controlled bubble formation |
DE19754482A1 (en) | 1997-11-27 | 1999-07-01 | Epigenomics Gmbh | Process for making complex DNA methylation fingerprints |
AU758407B2 (en) | 1997-12-24 | 2003-03-20 | Cepheid | Integrated fluid manipulation cartridge |
US6273553B1 (en) | 1998-01-23 | 2001-08-14 | Chang-Jin Kim | Apparatus for using bubbles as virtual valve in microinjector to eject fluid |
HUP0101628A3 (en) | 1998-01-23 | 2002-07-29 | Acer Comm & Multimedia Inc | Apparatus and method for using bubble as virtual valve in microinjector to eject fluid |
US6048328A (en) | 1998-02-02 | 2000-04-11 | Medtronic, Inc. | Implantable drug infusion device having an improved valve |
ATE344322T1 (en) | 1998-02-13 | 2006-11-15 | Koester Hubert | USE OF RIBOZYMES TO DETERMINE THE FUNCTION OF GENES |
US6251343B1 (en) | 1998-02-24 | 2001-06-26 | Caliper Technologies Corp. | Microfluidic devices and systems incorporating cover layers |
US6756019B1 (en) | 1998-02-24 | 2004-06-29 | Caliper Technologies Corp. | Microfluidic devices and systems incorporating cover layers |
US6100541A (en) | 1998-02-24 | 2000-08-08 | Caliper Technologies Corporation | Microfluidic devices and systems incorporating integrated optical elements |
US6318970B1 (en) | 1998-03-12 | 2001-11-20 | Micralyne Inc. | Fluidic devices |
DE69903800T2 (en) | 1998-03-18 | 2003-10-02 | Massachusetts Inst Technology | VASCULARIZED PERFUNDED ARRANGEMENTS FOR MICRO TISSUE AND MICROORGANES |
US6719868B1 (en) | 1998-03-23 | 2004-04-13 | President And Fellows Of Harvard College | Methods for fabricating microfluidic structures |
EP1046032A4 (en) | 1998-05-18 | 2002-05-29 | Univ Washington | Liquid analysis cartridge |
JP3522535B2 (en) | 1998-05-29 | 2004-04-26 | 忠弘 大見 | Gas supply equipment equipped with pressure type flow controller |
US6062681A (en) | 1998-07-14 | 2000-05-16 | Hewlett-Packard Company | Bubble valve and bubble valve-based pressure regulator |
AU5311699A (en) | 1998-07-28 | 2000-02-21 | Ce Resources Pte Ltd | Optical detection system |
JP2002524134A (en) | 1998-09-02 | 2002-08-06 | ランゲルハンス・アンパルトセルスカブ | Particle separation device |
US6103199A (en) | 1998-09-15 | 2000-08-15 | Aclara Biosciences, Inc. | Capillary electroflow apparatus and method |
US6086740A (en) | 1998-10-29 | 2000-07-11 | Caliper Technologies Corp. | Multiplexed microfluidic devices and systems |
JP3349965B2 (en) | 1998-11-05 | 2002-11-25 | 松下電器産業株式会社 | Fine particle classification method and apparatus |
MXPA01006046A (en) | 1998-12-15 | 2002-03-27 | Union Biometrica Inc | Axial pattern analysis and sorting instrument for multicellular organisms employing improved light scatter trigger. |
US6455280B1 (en) | 1998-12-22 | 2002-09-24 | Genset S.A. | Methods and compositions for inhibiting neoplastic cell growth |
US6360775B1 (en) | 1998-12-23 | 2002-03-26 | Agilent Technologies, Inc. | Capillary fluid switch with asymmetric bubble chamber |
US6496260B1 (en) | 1998-12-23 | 2002-12-17 | Molecular Devices Corp. | Vertical-beam photometer for determination of light absorption pathlength |
US6887693B2 (en) | 1998-12-24 | 2005-05-03 | Cepheid | Device and method for lysing cells, spores, or microorganisms |
US6608682B2 (en) | 1999-01-25 | 2003-08-19 | Amnis Corporation | Imaging and analyzing parameters of small moving objects such as cells |
EP1163052B1 (en) | 1999-02-23 | 2010-06-02 | Caliper Life Sciences, Inc. | Manipulation of microparticles in microfluidic systems |
US6097485A (en) | 1999-03-08 | 2000-08-01 | Integrated Waveguides, Inc. | Microchip optical transport technology for use in a personal flow cytometer |
US20020177135A1 (en) | 1999-07-27 | 2002-11-28 | Doung Hau H. | Devices and methods for biochip multiplexing |
US6592821B1 (en) | 1999-05-17 | 2003-07-15 | Caliper Technologies Corp. | Focusing of microparticles in microfluidic systems |
AU770678B2 (en) | 1999-05-17 | 2004-02-26 | Caliper Life Sciences, Inc. | Focusing of microparticles in microfluidic systems |
CA2721172C (en) | 1999-06-28 | 2012-04-10 | California Institute Of Technology | Microfabricated elastomeric valve and pump systems |
US6193471B1 (en) | 1999-06-30 | 2001-02-27 | Perseptive Biosystems, Inc. | Pneumatic control of formation and transport of small volume liquid samples |
US6353475B1 (en) | 1999-07-12 | 2002-03-05 | Caliper Technologies Corp. | Light source power modulation for use with chemical and biochemical analysis |
EP1204859B1 (en) | 1999-07-16 | 2006-11-22 | The Board Of Regents, The University Of Texas System | Method and apparatus for the delivery of samples to a chemical sensor array |
WO2001009598A1 (en) | 1999-07-28 | 2001-02-08 | University Of Washington | Fluidic interconnect, interconnect manifold and microfluidic devices for internal delivery of gases and application of vacuum |
WO2001026813A2 (en) | 1999-10-08 | 2001-04-19 | Micronics, Inc. | Microfluidics without electrically of mechanically operated pumps |
CA2364381C (en) | 1999-12-22 | 2009-03-10 | Gene Logic, Inc. | Flow-thru chip cartridge, chip holder, system and method thereof |
WO2001055702A1 (en) | 2000-01-31 | 2001-08-02 | Board Of Regents, The University Of Texas System | Portable sensor array system |
US6325114B1 (en) | 2000-02-01 | 2001-12-04 | Incyte Genomics, Inc. | Pipetting station apparatus |
US6482652B2 (en) | 2000-03-23 | 2002-11-19 | The Board Of Trustees Of The Leland Stanford Junior University | Biological particle sorter |
US6481453B1 (en) | 2000-04-14 | 2002-11-19 | Nanostream, Inc. | Microfluidic branch metering systems and methods |
US6431212B1 (en) | 2000-05-24 | 2002-08-13 | Jon W. Hayenga | Valve for use in microfluidic structures |
US6597438B1 (en) | 2000-08-02 | 2003-07-22 | Honeywell International Inc. | Portable flow cytometry |
US7242474B2 (en) | 2004-07-27 | 2007-07-10 | Cox James A | Cytometer having fluid core stream position control |
US7641856B2 (en) | 2004-05-14 | 2010-01-05 | Honeywell International Inc. | Portable sample analyzer with removable cartridge |
US7351376B1 (en) | 2000-06-05 | 2008-04-01 | California Institute Of Technology | Integrated active flux microfluidic devices and methods |
US6632400B1 (en) | 2000-06-22 | 2003-10-14 | Agilent Technologies, Inc. | Integrated microfluidic and electronic components |
WO2002001081A2 (en) | 2000-06-23 | 2002-01-03 | Micronics, Inc. | Valve for use in microfluidic structures |
US6686193B2 (en) | 2000-07-10 | 2004-02-03 | Vertex Pharmaceuticals, Inc. | High throughput method and system for screening candidate compounds for activity against target ion channels |
FR2811683B1 (en) | 2000-07-12 | 2002-08-30 | Ugine Savoie Imphy | FERRITIC STAINLESS STEEL FOR USE IN FERROMAGNETIC PARTS |
US6567163B1 (en) | 2000-08-17 | 2003-05-20 | Able Signal Company Llc | Microarray detector and synthesizer |
WO2002017219A1 (en) | 2000-08-25 | 2002-02-28 | Amnis Corporation | Measuring the velocity of small moving objects such as cells |
EP1334347A1 (en) | 2000-09-15 | 2003-08-13 | California Institute Of Technology | Microfabricated crossflow devices and methods |
US7258774B2 (en) | 2000-10-03 | 2007-08-21 | California Institute Of Technology | Microfluidic devices and methods of use |
US6827095B2 (en) | 2000-10-12 | 2004-12-07 | Nanostream, Inc. | Modular microfluidic systems |
AU2002230592A1 (en) | 2000-10-27 | 2002-05-06 | Molecular Devices Corporation | Light detection device |
WO2002055198A2 (en) | 2000-11-06 | 2002-07-18 | Nanostream Inc | Microfluidic flow control devices |
US6744038B2 (en) | 2000-11-13 | 2004-06-01 | Genoptix, Inc. | Methods of separating particles using an optical gradient |
US6824024B2 (en) | 2000-11-17 | 2004-11-30 | Tecan Trading Ag | Device for the take-up and/or release of liquid samples |
WO2002044689A2 (en) | 2000-11-28 | 2002-06-06 | The Regents Of The University Of California | Storing microparticles in optical switch which is transported by micro-fluidic device |
US7024281B1 (en) | 2000-12-11 | 2006-04-04 | Callper Life Sciences, Inc. | Software for the controlled sampling of arrayed materials |
EP1221581A1 (en) | 2001-01-04 | 2002-07-10 | Universität Stuttgart | Interferometer |
AU2002239823B2 (en) | 2001-01-08 | 2008-01-17 | President And Fellows Of Harvard College | Valves and pumps for microfluidic systems and method for making microfluidic systems |
JP4862108B2 (en) | 2001-02-02 | 2012-01-25 | 株式会社森精機製作所 | Light emitting / receiving composite unit and displacement detection device using the same |
JP4148778B2 (en) | 2001-03-09 | 2008-09-10 | バイオミクロ システムズ インコーポレイティッド | Microfluidic interface equipment with arrays |
DE10111457B4 (en) | 2001-03-09 | 2006-12-14 | Siemens Ag | diagnostic device |
US7010391B2 (en) | 2001-03-28 | 2006-03-07 | Handylab, Inc. | Methods and systems for control of microfluidic devices |
US8895311B1 (en) | 2001-03-28 | 2014-11-25 | Handylab, Inc. | Methods and systems for control of general purpose microfluidic devices |
US20020159920A1 (en) | 2001-04-03 | 2002-10-31 | Weigl Bernhard H. | Multiple redundant microfluidic structures cross reference to related applications |
US6802342B2 (en) | 2001-04-06 | 2004-10-12 | Fluidigm Corporation | Microfabricated fluidic circuit elements and applications |
US6629820B2 (en) | 2001-06-26 | 2003-10-07 | Micralyne Inc. | Microfluidic flow control device |
US20030027225A1 (en) | 2001-07-13 | 2003-02-06 | Caliper Technologies Corp. | Microfluidic devices and systems for separating components of a mixture |
US7338760B2 (en) | 2001-10-26 | 2008-03-04 | Ntu Ventures Private Limited | Sample preparation integrated chip |
WO2003046256A1 (en) | 2001-11-28 | 2003-06-05 | The Research Foundation Of State University Of New York | Electrochemically driven monolithic microfluidic systems |
EP1463796B1 (en) | 2001-11-30 | 2013-01-09 | Fluidigm Corporation | Microfluidic device and methods of using same |
AU2002353107A1 (en) | 2001-12-11 | 2003-07-09 | Sau Lan Tang Staats | Microfluidic devices and methods for two-dimensional separations |
US6739576B2 (en) | 2001-12-20 | 2004-05-25 | Nanostream, Inc. | Microfluidic flow control device with floating element |
WO2003060486A1 (en) | 2002-01-10 | 2003-07-24 | Board Of Regents, The University Of Texas System | Flow sorting system and methods regarding same |
US6799681B1 (en) | 2002-02-05 | 2004-10-05 | Albert J. Warren | Portable hydraulic classifier |
US6561224B1 (en) | 2002-02-14 | 2003-05-13 | Abbott Laboratories | Microfluidic valve and system therefor |
US7303727B1 (en) | 2002-03-06 | 2007-12-04 | Caliper Life Sciences, Inc | Microfluidic sample delivery devices, systems, and methods |
US7312085B2 (en) | 2002-04-01 | 2007-12-25 | Fluidigm Corporation | Microfluidic particle-analysis systems |
CA2480200A1 (en) | 2002-04-02 | 2003-10-16 | Caliper Life Sciences, Inc. | Methods and apparatus for separation and isolation of components from a biological sample |
WO2004016729A2 (en) | 2002-08-19 | 2004-02-26 | Bioprocessors Corporation | SYSTEMS AND METHODS FOR CONTROL OF pH AND OTHER REACTOR ENVIRONMENTAL CONDITIONS |
US6808075B2 (en) | 2002-04-17 | 2004-10-26 | Cytonome, Inc. | Method and apparatus for sorting particles |
US6976590B2 (en) | 2002-06-24 | 2005-12-20 | Cytonome, Inc. | Method and apparatus for sorting particles |
AU2003228630B2 (en) | 2002-04-17 | 2009-10-22 | Cytonome/St, Llc | Method and apparatus for sorting particles |
US9943847B2 (en) * | 2002-04-17 | 2018-04-17 | Cytonome/St, Llc | Microfluidic system including a bubble valve for regulating fluid flow through a microchannel |
US20070065808A1 (en) | 2002-04-17 | 2007-03-22 | Cytonome, Inc. | Method and apparatus for sorting particles |
US6877528B2 (en) | 2002-04-17 | 2005-04-12 | Cytonome, Inc. | Microfluidic system including a bubble valve for regulating fluid flow through a microchannel |
US7157274B2 (en) | 2002-06-24 | 2007-01-02 | Cytonome, Inc. | Method and apparatus for sorting particles |
US6883957B2 (en) | 2002-05-08 | 2005-04-26 | Cytonome, Inc. | On chip dilution system |
CA2489177C (en) | 2002-06-11 | 2013-08-13 | Chempaq A/S | A disposable cartridge for characterizing particles suspended in a liquid |
JP4704036B2 (en) | 2002-06-11 | 2011-06-15 | ケムパック エイ/エス | Disposable cartridge for characterizing particles suspended in liquid |
US7220594B2 (en) | 2002-07-08 | 2007-05-22 | Innovative Micro Technology | Method and apparatus for sorting particles with a MEMS device |
US6838056B2 (en) | 2002-07-08 | 2005-01-04 | Innovative Micro Technology | Method and apparatus for sorting biological cells with a MEMS device |
US20040011650A1 (en) | 2002-07-22 | 2004-01-22 | Frederic Zenhausern | Method and apparatus for manipulating polarizable analytes via dielectrophoresis |
US20040017570A1 (en) | 2002-07-23 | 2004-01-29 | Bhairavi Parikh | Device and system for the quantification of breath gases |
KR100463171B1 (en) | 2002-08-13 | 2004-12-23 | 주식회사 엘지화학 | Rubber-modified styrene resin composition |
US20040086872A1 (en) | 2002-10-31 | 2004-05-06 | Childers Winthrop D. | Microfluidic system for analysis of nucleic acids |
US7476363B2 (en) | 2003-04-03 | 2009-01-13 | Fluidigm Corporation | Microfluidic devices and methods of using same |
TW577855B (en) | 2003-05-21 | 2004-03-01 | Univ Nat Cheng Kung | Chip-type micro-fluid particle 3-D focusing and detection device |
US7298478B2 (en) | 2003-08-14 | 2007-11-20 | Cytonome, Inc. | Optical detector for a particle sorting system |
US7157275B2 (en) | 2003-08-15 | 2007-01-02 | Becton, Dickinson And Company | Peptides for enhanced cell attachment and growth |
CA2479452C (en) | 2003-08-30 | 2008-11-04 | F.Hoffmann-La Roche Ag | Method and device for determining analytes in a liquid |
FR2865145B1 (en) | 2004-01-19 | 2006-02-24 | Commissariat Energie Atomique | DEVICE FOR DISPENSING MICROFLUIDIC DROPLETS, IN PARTICULAR FOR CYTOMETRY. |
US7389879B2 (en) | 2004-01-21 | 2008-06-24 | Hewlett-Packard Development Company, L.P. | Sorting particles |
EP1735428A4 (en) | 2004-04-12 | 2010-11-10 | Univ California | Optoelectronic tweezers for microparticle and cell manipulation |
WO2005108963A1 (en) | 2004-05-06 | 2005-11-17 | Nanyang Technological University | Microfluidic cell sorter system |
US7612871B2 (en) | 2004-09-01 | 2009-11-03 | Honeywell International Inc | Frequency-multiplexed detection of multiple wavelength light for flow cytometry |
JP4462058B2 (en) | 2004-09-22 | 2010-05-12 | 富士ゼロックス株式会社 | Fine particle classification method and fine particle classification device |
DE102004047953A1 (en) | 2004-10-01 | 2006-04-20 | Rudolf Rigler | Selection of particle possessing predetermined property from population encompassing multiplicity of different particles, comprises providing population of different particles, and labeling particles which possess predetermined property |
US7075652B1 (en) | 2004-11-12 | 2006-07-11 | Ibet, Inc. | Apparatus and method for measuring temperature dependent properties of liquid |
WO2006060783A2 (en) | 2004-12-03 | 2006-06-08 | Cytonome, Inc. | Unitary cartridge for particle processing |
US9260693B2 (en) | 2004-12-03 | 2016-02-16 | Cytonome/St, Llc | Actuation of parallel microfluidic arrays |
US7355696B2 (en) | 2005-02-01 | 2008-04-08 | Arryx, Inc | Method and apparatus for sorting cells |
JP4047336B2 (en) | 2005-02-08 | 2008-02-13 | 独立行政法人科学技術振興機構 | Cell sorter chip with gel electrode |
US7080664B1 (en) | 2005-05-20 | 2006-07-25 | Crystal Fountains Inc. | Fluid amplifier with media isolation control valve |
JP4512698B2 (en) | 2005-08-30 | 2010-07-28 | ナノフォトン株式会社 | Laser microscope |
US7964078B2 (en) | 2005-11-07 | 2011-06-21 | The Regents Of The University Of California | Microfluidic device for cell and particle separation |
DE102005054923B3 (en) | 2005-11-17 | 2007-04-12 | Siemens Ag | Device for preparing a sample used in biotechnology stores the working reagents in dry form embedded in a biologically degradable medium which is water-tight in the non-degraded state |
US8609039B2 (en) | 2006-01-19 | 2013-12-17 | Rheonix, Inc. | Microfluidic systems and control methods |
CA2651250C (en) | 2006-05-05 | 2016-06-28 | Cytonome, Inc. | Actuation of parallel microfluidic arrays |
US20080070311A1 (en) | 2006-09-19 | 2008-03-20 | Vanderbilt University | Microfluidic flow cytometer and applications of same |
US7807454B2 (en) | 2006-10-18 | 2010-10-05 | The Regents Of The University Of California | Microfluidic magnetophoretic device and methods for using the same |
US8931644B2 (en) | 2006-11-30 | 2015-01-13 | Palo Alto Research Center Incorporated | Method and apparatus for splitting fluid flow in a membraneless particle separation system |
US7863035B2 (en) | 2007-02-15 | 2011-01-04 | Osmetech Technology Inc. | Fluidics devices |
US8691164B2 (en) | 2007-04-20 | 2014-04-08 | Celula, Inc. | Cell sorting system and methods |
CN103969464B (en) | 2008-03-24 | 2017-08-15 | 日本电气株式会社 | Microchip |
US8122901B2 (en) | 2008-06-30 | 2012-02-28 | Canon U.S. Life Sciences, Inc. | System and method for microfluidic flow control |
US8672532B2 (en) | 2008-12-31 | 2014-03-18 | Integenx Inc. | Microfluidic methods |
US9645010B2 (en) | 2009-03-10 | 2017-05-09 | The Regents Of The University Of California | Fluidic flow cytometry devices and methods |
DE102009034417A1 (en) | 2009-07-23 | 2011-01-27 | Airbus Operations Gmbh | Fluid actuator for generating a pulsed outlet flow in the flow around an aerodynamic body, a blowout device with such a fluid actuator and such an aerodynamic body |
US9364831B2 (en) | 2009-08-08 | 2016-06-14 | The Regents Of The University Of California | Pulsed laser triggered high speed microfluidic switch and applications in fluorescent activated cell sorting |
US8678192B1 (en) | 2010-10-27 | 2014-03-25 | Michael Pung | Gold cube |
JP5720233B2 (en) | 2010-12-17 | 2015-05-20 | ソニー株式会社 | Microchip and fine particle sorting device |
US20120258488A1 (en) | 2011-04-11 | 2012-10-11 | The Regents Of The University Of California | Systems and Methods for Electrophysiological Activated Cell Sorting and Cytometry |
US9074978B2 (en) | 2011-07-12 | 2015-07-07 | The Regents Of The University Of California | Optical space-time coding technique in microfluidic devices |
US8723140B2 (en) | 2011-08-09 | 2014-05-13 | Palo Alto Research Center Incorporated | Particle analyzer with spatial modulation and long lifetime bioprobes |
US9149806B2 (en) | 2012-01-10 | 2015-10-06 | Biopico Systems Inc | Microfluidic devices and methods for cell sorting, cell culture and cells based diagnostics and therapeutics |
EP2876427B1 (en) | 2012-07-18 | 2019-09-04 | Sony Corporation | Microparticle isolation device and microparticle isolation method |
US9194786B2 (en) | 2012-08-01 | 2015-11-24 | Owl biomedical, Inc. | Particle manipulation system with cytometric capability |
WO2014062719A2 (en) | 2012-10-15 | 2014-04-24 | Nanocellect Biomedical, Inc. | Systems, apparatus, and methods for sorting particles |
US10583439B2 (en) | 2013-03-14 | 2020-03-10 | Cytonome/St, Llc | Hydrodynamic focusing apparatus and methods |
US10190960B2 (en) | 2013-03-14 | 2019-01-29 | Cytonome/St, Llc | Micro-lens systems for particle processing systems |
US9757726B2 (en) | 2013-03-14 | 2017-09-12 | Inguran, Llc | System for high throughput sperm sorting |
US10386377B2 (en) | 2013-05-07 | 2019-08-20 | Micronics, Inc. | Microfluidic devices and methods for performing serum separation and blood cross-matching |
US10960396B2 (en) | 2014-05-16 | 2021-03-30 | Cytonome/St, Llc | Thermal activated microfluidic switching |
-
2015
- 2015-04-17 US US14/689,508 patent/US9943847B2/en not_active Expired - Lifetime
-
2018
- 2018-03-30 US US15/941,793 patent/US10427159B2/en not_active Expired - Fee Related
-
2019
- 2019-09-26 US US16/584,315 patent/US11027278B2/en not_active Expired - Lifetime
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6033191A (en) * | 1997-05-16 | 2000-03-07 | Institut Fur Mikrotechnik Mainz Gmbh | Micromembrane pump |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10816550B2 (en) | 2012-10-15 | 2020-10-27 | Nanocellect Biomedical, Inc. | Systems, apparatus, and methods for sorting particles |
US10544413B2 (en) | 2017-05-18 | 2020-01-28 | 10X Genomics, Inc. | Methods and systems for sorting droplets and beads |
US11660601B2 (en) | 2017-05-18 | 2023-05-30 | 10X Genomics, Inc. | Methods for sorting particles |
US10357771B2 (en) | 2017-08-22 | 2019-07-23 | 10X Genomics, Inc. | Method of producing emulsions |
US10549279B2 (en) | 2017-08-22 | 2020-02-04 | 10X Genomics, Inc. | Devices having a plurality of droplet formation regions |
US10583440B2 (en) | 2017-08-22 | 2020-03-10 | 10X Genomics, Inc. | Method of producing emulsions |
US10610865B2 (en) | 2017-08-22 | 2020-04-07 | 10X Genomics, Inc. | Droplet forming devices and system with differential surface properties |
US10766032B2 (en) | 2017-08-22 | 2020-09-08 | 10X Genomics, Inc. | Devices having a plurality of droplet formation regions |
US10821442B2 (en) | 2017-08-22 | 2020-11-03 | 10X Genomics, Inc. | Devices, systems, and kits for forming droplets |
US10898900B2 (en) | 2017-08-22 | 2021-01-26 | 10X Genomics, Inc. | Method of producing emulsions |
US11565263B2 (en) | 2017-08-22 | 2023-01-31 | 10X Genomics, Inc. | Droplet forming devices and system with differential surface properties |
US11833515B2 (en) | 2017-10-26 | 2023-12-05 | 10X Genomics, Inc. | Microfluidic channel networks for partitioning |
Also Published As
Publication number | Publication date |
---|---|
US20160303564A1 (en) | 2016-10-20 |
US10427159B2 (en) | 2019-10-01 |
US11027278B2 (en) | 2021-06-08 |
US20200086319A1 (en) | 2020-03-19 |
US9943847B2 (en) | 2018-04-17 |
US20180221879A1 (en) | 2018-08-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11027278B2 (en) | Methods for controlling fluid flow in a microfluidic system | |
US8623295B2 (en) | Microfluidic system including a bubble valve for regulating fluid flow through a microchannel | |
US6681788B2 (en) | Non-mechanical valves for fluidic systems | |
EP0901578B1 (en) | Valveless liquid microswitch and method | |
NL1024013C2 (en) | Cascading (cascade) hydrodynamic aiming in microfluidic channels. | |
EP3641937B1 (en) | Droplet dispensing systems | |
ZA200408705B (en) | Method and apparatus for sorting particles | |
Tangen et al. | On demand nanoliter-scale microfluidic droplet generation, injection, and mixing using a passive microfluidic device | |
US6833068B2 (en) | Passive injection control for microfluidic systems | |
US20030057092A1 (en) | Microfluidic methods, devices and systems for in situ material concentration | |
US20020110926A1 (en) | Emulator device | |
US20050011761A1 (en) | Microfluidic methods, devices and systems for in situ material concentration | |
GB2578206A (en) | Droplet dispensing systems | |
CN113661007A (en) | System and device for injecting droplets in a microfluidic system |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: CYTONOME/ST, LLC, MASSACHUSETTS Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:CYTONOME, INC.;REEL/FRAME:035469/0789 Effective date: 20091020 Owner name: TERAGENICS, INC., MASSACHUSETTS Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:COVENTOR, INC.;REEL/FRAME:035469/0065 Effective date: 20061108 Owner name: COVENTOR, INC., NORTH CAROLINA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:GILBERT, JOHN R.;BOEHM, SEBASTIAN;DESHPANDE, MANISH;SIGNING DATES FROM 20030325 TO 20030418;REEL/FRAME:035468/0352 Owner name: CYTONOME, INC., MASSACHUSETTS Free format text: CHANGE OF NAME;ASSIGNOR:TERAGENICS, INC.;REEL/FRAME:035476/0941 Effective date: 20030630 |
|
AS | Assignment |
Owner name: COMPASS BANK, TEXAS Free format text: SECURITY INTEREST;ASSIGNOR:CYTONOME/ST, LLC;REEL/FRAME:036154/0928 Effective date: 20150721 |
|
STCF | Information on status: patent grant |
Free format text: PATENTED CASE |
|
AS | Assignment |
Owner name: CYTONOME/ST, LLC, MASSACHUSETTS Free format text: RELEASE BY SECURED PARTY;ASSIGNOR:BBVA USA, FORMERLY KNOWN AS COMPASS BANK;REEL/FRAME:055640/0422 Effective date: 20210205 |
|
AS | Assignment |
Owner name: BANK OF AMERICA, N.A., AS ADMINISTRATIVE AGENT, TEXAS Free format text: SECURITY INTEREST;ASSIGNOR:CYTONOME/ST, LLC;REEL/FRAME:055791/0578 Effective date: 20210305 |
|
MAFP | Maintenance fee payment |
Free format text: PAYMENT OF MAINTENANCE FEE, 4TH YEAR, LARGE ENTITY (ORIGINAL EVENT CODE: M1551); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY Year of fee payment: 4 |