WO1999029497A1 - Fabrication of microfluidic circuits by 'printing' techniques - Google Patents

Fabrication of microfluidic circuits by 'printing' techniques Download PDF

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Publication number
WO1999029497A1
WO1999029497A1 PCT/US1998/025028 US9825028W WO9929497A1 WO 1999029497 A1 WO1999029497 A1 WO 1999029497A1 US 9825028 W US9825028 W US 9825028W WO 9929497 A1 WO9929497 A1 WO 9929497A1
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WO
WIPO (PCT)
Prior art keywords
channel
laminate
printing
planar section
charmel
Prior art date
Application number
PCT/US1998/025028
Other languages
French (fr)
Inventor
Colin Kennedy
Original Assignee
Caliper Technologies Corporation
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Caliper Technologies Corporation filed Critical Caliper Technologies Corporation
Priority to AU15347/99A priority Critical patent/AU1534799A/en
Priority to EP98959577A priority patent/EP1039995A4/en
Publication of WO1999029497A1 publication Critical patent/WO1999029497A1/en

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Classifications

    • BPERFORMING OPERATIONS; TRANSPORTING
    • B32LAYERED PRODUCTS
    • B32BLAYERED PRODUCTS, i.e. PRODUCTS BUILT-UP OF STRATA OF FLAT OR NON-FLAT, e.g. CELLULAR OR HONEYCOMB, FORM
    • B32B38/00Ancillary operations in connection with laminating processes
    • B32B38/14Printing or colouring
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027Containers 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
    • B01L3/502707Containers 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 manufacture of the container or its components
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B32LAYERED PRODUCTS
    • B32BLAYERED PRODUCTS, i.e. PRODUCTS BUILT-UP OF STRATA OF FLAT OR NON-FLAT, e.g. CELLULAR OR HONEYCOMB, FORM
    • B32B3/00Layered products comprising a layer with external or internal discontinuities or unevennesses, or a layer of non-planar form; Layered products having particular features of form
    • B32B3/26Layered products comprising a layer with external or internal discontinuities or unevennesses, or a layer of non-planar form; Layered products having particular features of form characterised by a particular shape of the outline of the cross-section of a continuous layer; characterised by a layer with cavities or internal voids ; characterised by an apertured layer
    • B32B3/30Layered products comprising a layer with external or internal discontinuities or unevennesses, or a layer of non-planar form; Layered products having particular features of form characterised by a particular shape of the outline of the cross-section of a continuous layer; characterised by a layer with cavities or internal voids ; characterised by an apertured layer characterised by a layer formed with recesses or projections, e.g. hollows, grooves, protuberances, ribs
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B41PRINTING; LINING MACHINES; TYPEWRITERS; STAMPS
    • B41MPRINTING, DUPLICATING, MARKING, OR COPYING PROCESSES; COLOUR PRINTING
    • B41M3/00Printing processes to produce particular kinds of printed work, e.g. patterns
    • B41M3/006Patterns of chemical products used for a specific purpose, e.g. pesticides, perfumes, adhesive patterns; use of microencapsulated material; Printing on smoking articles
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B81MICROSTRUCTURAL TECHNOLOGY
    • B81CPROCESSES OR APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OR TREATMENT OF MICROSTRUCTURAL DEVICES OR SYSTEMS
    • B81C1/00Manufacture or treatment of devices or systems in or on a substrate
    • B81C1/00015Manufacture or treatment of devices or systems in or on a substrate for manufacturing microsystems
    • B81C1/00023Manufacture or treatment of devices or systems in or on a substrate for manufacturing microsystems without movable or flexible elements
    • B81C1/00119Arrangement of basic structures like cavities or channels, e.g. suitable for microfluidic systems
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06Fluid handling related problems
    • B01L2200/0689Sealing
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/12Specific details about manufacturing devices
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/08Geometry, shape and general structure
    • B01L2300/0809Geometry, shape and general structure rectangular shaped
    • B01L2300/0816Cards, e.g. flat sample carriers usually with flow in two horizontal directions
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/08Geometry, shape and general structure
    • B01L2300/0887Laminated structure
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00Moving or stopping fluids
    • B01L2400/04Moving fluids with specific forces or mechanical means
    • B01L2400/0403Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0415Moving fluids with specific forces or mechanical means specific forces electrical forces, e.g. electrokinetic
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B81MICROSTRUCTURAL TECHNOLOGY
    • B81BMICROSTRUCTURAL DEVICES OR SYSTEMS, e.g. MICROMECHANICAL DEVICES
    • B81B2201/00Specific applications of microelectromechanical systems
    • B81B2201/05Microfluidics
    • B81B2201/058Microfluidics not provided for in B81B2201/051 - B81B2201/054
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B81MICROSTRUCTURAL TECHNOLOGY
    • B81CPROCESSES OR APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OR TREATMENT OF MICROSTRUCTURAL DEVICES OR SYSTEMS
    • B81C2201/00Manufacture or treatment of microstructural devices or systems
    • B81C2201/01Manufacture or treatment of microstructural devices or systems in or on a substrate
    • B81C2201/0174Manufacture or treatment of microstructural devices or systems in or on a substrate for making multi-layered devices, film deposition or growing
    • B81C2201/0183Selective deposition
    • B81C2201/0184Digital lithography, e.g. using an inkjet print-head
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B81MICROSTRUCTURAL TECHNOLOGY
    • B81CPROCESSES OR APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OR TREATMENT OF MICROSTRUCTURAL DEVICES OR SYSTEMS
    • B81C2201/00Manufacture or treatment of microstructural devices or systems
    • B81C2201/01Manufacture or treatment of microstructural devices or systems in or on a substrate
    • B81C2201/0174Manufacture or treatment of microstructural devices or systems in or on a substrate for making multi-layered devices, film deposition or growing
    • B81C2201/0183Selective deposition
    • B81C2201/0185Printing, e.g. microcontact printing
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B81MICROSTRUCTURAL TECHNOLOGY
    • B81CPROCESSES OR APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OR TREATMENT OF MICROSTRUCTURAL DEVICES OR SYSTEMS
    • B81C2201/00Manufacture or treatment of microstructural devices or systems
    • B81C2201/01Manufacture or treatment of microstructural devices or systems in or on a substrate
    • B81C2201/0174Manufacture or treatment of microstructural devices or systems in or on a substrate for making multi-layered devices, film deposition or growing
    • B81C2201/019Bonding or gluing multiple substrate layers
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00Stock material or miscellaneous articles
    • Y10T428/24Structurally defined web or sheet [e.g., overall dimension, etc.]
    • Y10T428/24744Longitudinal or transverse tubular cavity or cell
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00Stock material or miscellaneous articles
    • Y10T428/24Structurally defined web or sheet [e.g., overall dimension, etc.]
    • Y10T428/24802Discontinuous or differential coating, impregnation or bond [e.g., artwork, printing, retouched photograph, etc.]
    • Y10T428/24826Spot bonds connect components
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00Stock material or miscellaneous articles
    • Y10T428/24Structurally defined web or sheet [e.g., overall dimension, etc.]
    • Y10T428/24802Discontinuous or differential coating, impregnation or bond [e.g., artwork, printing, retouched photograph, etc.]
    • Y10T428/24851Intermediate layer is discontinuous or differential
    • Y10T428/24868Translucent outer layer
    • Y10T428/24876Intermediate layer contains particulate material [e.g., pigment, etc.]
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00Stock material or miscellaneous articles
    • Y10T428/24Structurally defined web or sheet [e.g., overall dimension, etc.]
    • Y10T428/24802Discontinuous or differential coating, impregnation or bond [e.g., artwork, printing, retouched photograph, etc.]
    • Y10T428/24893Discontinuous or differential coating, impregnation or bond [e.g., artwork, printing, retouched photograph, etc.] including particulate material
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00Stock material or miscellaneous articles
    • Y10T428/24Structurally defined web or sheet [e.g., overall dimension, etc.]
    • Y10T428/24802Discontinuous or differential coating, impregnation or bond [e.g., artwork, printing, retouched photograph, etc.]
    • Y10T428/24926Discontinuous or differential coating, impregnation or bond [e.g., artwork, printing, retouched photograph, etc.] including ceramic, glass, porcelain or quartz layer
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00Chemistry: analytical and immunological testing
    • Y10T436/25Chemistry: analytical and immunological testing including sample preparation
    • Y10T436/2575Volumetric liquid transfer

Definitions

  • Microscale devices for high throughput mixing and assaying of small fluid volumes have recently been developed.
  • USSN 08/761,575 entitled “High Throughput Screening Assay Systems in Microscale Fluidic Devices” by Parce et al. provides pioneering technology related to Microscale Fluidic devices, including electrol ⁇ netic devices.
  • the devices are generally suitable for assays relating to the interaction of biological and chemical species, including enzymes and substrates, ligands and ligand binders, receptors and ligands, antibodies and antibody ligands, as well as many other assays. Because the devices provide the ability to mix fluidic reagents and assay mixing results in a single continuous process, and because minute amounts of reagents can be assayed, these microscale devices represent a fundamental advance for laboratory science.
  • an appropriate fluid is electrokinetically flowed into and through a microchannel microfabricated (e.g., etched, milled, laser-drilled, or otherwise fabricated) in a substrate where the channel has functional groups present on its surfaces.
  • the groups ionize when the surface is contacted with an aqueous solution.
  • protons can leave the surface of the channel and enter the fluid.
  • the surface possesses a net negative charge, whereas the fluid will possess an excess of protons, or positive charge, particularly localized near the interface between the channel surface and the fluid.
  • By applying an electric field along the length of the channel cations will flow toward the negative electrode. Movement of the positively charged species in the fluid pulls the solvent with them.
  • v is the solvent velocity
  • e is the dielectric constant of the fluid
  • is the zeta potential of the surface
  • E is the electric field strength
  • is the solvent viscosity.
  • the solvent velocity is, therefore, directly proportional to the surface potential.
  • particularly preferred electroosmotic fluid direction systems include, e.g. , those described in International Patent Application No. WO 96/04547 to Ramsey et al. , as well as USSN 08/761,575 by Parce et al.
  • additional microfluidic fluid manipulation structures relying on pumps, valves, microswitches and the like are described in, e.g. , U.S. Patent Nos. 5,271,724, 5,277,556, 5, 171,132, and 5,375,979. See also, Published U.K. Patent Application No. 2 248 891 and Published European Patent Application No. 568 902.
  • a typical microscale device can have from a few to hundreds of fluidly connected channels chambers and/or wells. Improved methods of making microscale devices which provide for simplified manufacturing, more precise construction and die like are desirable. In addition, the ability to more easily control channel height to widd ratios, thereby affecting fluid flow in the channels is also desirable. This invention provides these and many other features.
  • the manufacture of microfluidic devices by machining grooves, channels or the like in various substrates can be time consuming and expensive.
  • the present invention adapts printing technologies to print channel walls, well walls, or other desired structural features on a substrate, followed by application of a material over the printed channel walls, thereby providing a laminate having an enclosed channel.
  • the invention provides a laminate having a first surface comprismg a first planar section (e.g., a sheet of glass, polymer, plastic, ceramic, metalloid, organic material, acrylic, MYLAR ,or the like, having a substantially flat region) and a second surface comprising a second planar section (the second surface can be the same as the first surface in construction, or made from a different material).
  • the first or second surface can be rigid or flexible.
  • the laminate has a first channel disposed between the first planar section and the second planar section having at least one cross-sectional diameter between about OJ ⁇ m and 500 ⁇ m.
  • the upper and lower walls of the channel are made from the upper and lower surfaces, with the channel having a first wall and a second wall in contact with the first planar section and the second planar section.
  • the walls are raised in comparison to the first or second planar surfaces, e.g., as a result of having been printed on the surface, having typical heights of between about OJ ⁇ m and 500 ⁇ m, more typically between about 1 and lOO ⁇ m.
  • the walls can be constructed from adhesive materials which bond the first and second surfaces together, such as a wax, a the ⁇ noplastic, an epoxy, a pressure sensitive material, or a photo-resistive material.
  • the walls of the channel are printed on the first and/or second surface using a printing technology such as Serigraph printing, ink jet printing, intaligo printing, offset press printing, thermal laser printing or the like.
  • the surfaces are clamped together with a clamp, e.g., with the channels being printed with a non-adhesive material.
  • Spacers are optionally used to ensure uniform distance between the sheets of material. Clamps and spacers are optionally used on applications having adhesive channel walls as well, to improve adhesion of the surfaces and to ensure uniform distance between the sheets of material. Surfaces are optionally coated to modify surface properties.
  • the channel typically has a flat top and a flat bottom.
  • One advantage of the laminate const ⁇ iction of the invention over lithographic and laser ablation or other machining methods is that the portions of the channel made up of the first or second surface have the same physicochemical properties as the rest of the surface, because the channel portion is not altered by chemical or physical processes. Thus, the properties of the channels of the invention are more predictable than prior art microfluidic device construction methods.
  • Another advantage is that the width and height of the channel walls can easily be optimized to reduce turbulence in angled portions of a channel.
  • An additional advantage of the present invention is that laminates with multiple sheets having fluidic structures between the sheets can easily be constructed by laminating multiple layers of materials. This increases the possible complexity of fluidic structures, increasing the applicable uses for the resulting mirofluidic devices.
  • Methods of forming the laminates of the invention are also provided. In the methods, first and second surfaces, each having a first planar section, are provided. A first channel having a first and a second wall is applied to the first and/or second planar section (the first and second walls are raised in comparison to the first planar surface, and have at least one cross-sectional diameter between about OJ ⁇ m and
  • the first and second planar sections are bonded.
  • the first channel is in contact with a portion of the second planar section.
  • the first channel is applied to the first or second planar section by printing the channel on the first or second planar section.
  • Preferred methods of printing include Serigraph printing, ink jet printing, intaligo printing, offset press printing, and thermal laser printing.
  • Fig. 1 shows a top view of a laminate including a microfluidic device having two wells and a single microfluidic channel.
  • Fig. 2 panels A, B and C are side views showing construction of a laminate of the invention by dropping material to form a channel wall (panel A), and clamping the laminate (panel B and panel C).
  • Fig. 3 is a side view showing constinction of a laminate using a roller method.
  • Fig. 4 is a side view showing a laminate having spacers.
  • Fig. 5 shows a top view of a laminate including a microfluidic device having multiple wells and microfluidic channels.
  • Fig. 6 is a side view of a laminate having multiple channels and channel walls.
  • Fig. 7 is a top view showing a masking procedure for making a laminate of the invention.
  • Fig. 8 panels A and B are side views showing intaligo printing to form channel walls in a microfluidic laminate.
  • Fig. 9 panels A and B are side views showing offset printing to produce a laminate of the invention.
  • Fig. 10 panels A and B show channel formation on a substrate using lithography on a Heidelberg press.
  • Fig. 11 is a side view showing a method of mal ⁇ ng a laminate of the invention by etching a deposited material on the surface of one sheet of the laminate.
  • a “laminate” is a structure having at least two layers of materials fixed, adhered or bonded together.
  • the laminate will have two or more sheets of substrates adhered, glued or clamped together, with microfluidic elements such as channels, channel walls, wells, well walls, or the like disposed between the substrates.
  • microfluidic elements such as channels, channel walls, wells, well walls, or the like disposed between the substrates.
  • at least the outlines of the microfludic elements are printed on one or both of the substrates, and the elements are fully formed by bonding the two or more substrates together.
  • the substrates take the form of sheets of material although one or both of the substrates may exist in other forms, such as a block of material with a face having a flat section.
  • a "surface” is a face of a laminate or a face of a substrate or a face of a sheet of substrate used in forming a laminate.
  • the surface ordinarily has a substantially flat region although it optionally has grooves, depressions or the like.
  • a “printed layer” is a layer of material amenable to deposition by printing. A variety of such materials are described herein.
  • the printed layer is ordinarily between about 1 and 500 ⁇ m in thickness and is ordinarily applied to a selected surface using a printing technology such as ink-jet, Serigraph, intaligo, letter press printing, or the like, although it may also be applied manually.
  • An intermediate layer such as channel wall is "bonded" to a surface when the layer is adhered to the surface in a manner which does not permit removal of the layer under assay conditions typical for the device.
  • the intermediate layer is bonded by printing the intermediate layer on a surface; alternatively, the layer can be bonded by gluing the intermediate layer to the surface, or by embedding the intermediate layer in the surface, e.g. , by partially dissolving the surface or the intermediate layer with a solvent and forcing the intermediate layer and the surface together.
  • microfluidic devices were made by removing materials from a substrate to form a structural feature such as a channel bed, depression, or the like and bonding a second substrate to provide a cover to the strtictural feature (e.g., a top surface to a channel).
  • the present invention does not rely on removing substrate materials to make microfluidic structures. Rather than removing or modifying material to create channels, wells, chambers or other structural features in a substrate, in the present invention a material is deposited on a substrate, e.g., by printing a print material on the substrate. The print material is laid down in a pattern that defines the edges of fluidic structures, such as channels, chambers, wells or the like.
  • Lamination of a substrate over the print material completes formation of the microfluidic structures outlined with the print material (e.g., by providing a top surface for a channel, well, chamber or the like).
  • the print material is deposited on any of a variety of commercially available materials such as sheet glass, or a polymer, in a pattern that defines the outer edges of fluid structures such as channels, wells or the like.
  • a variety of print materials are suitable, including inks, waxes, plastics and many others described herein.
  • the print material is used to adhere a "cover layer," or other secondaiy substrate to form the laminate.
  • the printed material forming the circuit of channel walls also serves as an adhesive to bond the sheets of the laminate together.
  • the adhesive materials can be, e.g. a printable wax (especially thermal wax-based inks), laser copier toners, sol-gels, printable thermoplastic (including PMMAs, Polycarbonates and styrenes), printable epoxy (including UV curing epoxies), a hot melt adhesive, a pressure sensitive adhesive material, a photoresistive material, or the like.
  • Particles of materials which enhance fluid flow, or control channel wall size are optionally inco orated into the print material. Bonding is performed with pressure, RF, UV, thermal or ultrasonic methods, or any combination thereof. The methods allow fabrication of channel structures of any thickness and pe ⁇ nit formation of laminates using thin polymer sheets which are laminated and die-cut. Material choices are thus not limited to those that can be processed by etching, machining, or molding. Because the laminates can be flexible, they can be manufactured in quantity and rolled. In addition, layered laminates having many layers of fluidic structures can be made, providing more options in microfluidic structure design.
  • the geometry of printed microfluidic structures made using the methods described herein can be more flexible than prior art microfluidic devices. For example, there are fewer difficulties in producing intricate channel shapes using printing technologies than in micromachining channels. Aspect ratios of microfluidic channels can easily be selected by varying the thickness of the print material which makes up a selected microfludic structure (channel, well, etc.).
  • the channel typically has a flat top and a flat bottom.
  • One important advantage of the laminate construction of the invention over etching, milling, laser drilling or other machining methods is that the portions of the channel made up of the first or second surface have the same physicochemical properties as the rest of the surface, because the channel portion is not altered by chemical or physical processes (i.e., the channel portion is not altered by etching, heat, drilling, or the like).
  • the properties of the channels of the invention are more predictable than previous construction methods.
  • Another advantage is that the width and height of the channel walls can easily be optimized to reduce hydrodynamic effects.
  • the upper and lower portions of channels are symmetrical, flow properties in the channels are more regular and predictable.
  • the preferred embodiments of the present invention include printing a material on a substrate or sheet of substrate to form the outline of microfluidic structures, such as channels, wells, or the like.
  • a variety of printing technologies are available, including ink-jet printing, laser printing, silk-screening, Serigraph, intaligo, offset printing, letter press, Heidelberg press printing and the like, all of which can be adapted for use in the present invention.
  • an "ink” or “print material” is applied to a sheet or other substrate suitable for receiving the ink, and suitable for use in a laminate of the invention.
  • the shape of desired structural features such as channels and wells is outlined with the ink material and a second sheet is layed over the printed structure to create a laminate with channels, wells and the like.
  • the ink material makes up the walls of the desired microfluidic structure.
  • ink jet printing systems are used. Again, ink jet printing is well described in the patent, engineering and scientific literature, and an introduction to Ink jet technology is found in Kirk-Otlimer, id. and the references cited therein.
  • ink jet systems there are at least two general types of ink jet systems, i.e., "continuous stream” and “drop-on-demand” or “impulse".
  • continuous stream ink jet systems ink is emitted in a continuous stream under pressure through at least one orifice or nozzle, and often through several separate orifices, e.g., where the ink jet print head has several orifices.
  • the stream is perturbed, causing it to break up into droplets at a fixed distance from the orifice.
  • the size and frequency of droplets is a function of pumping pressure, ink viscosity and nozzle size. Drops not needed for printing are electrostatically charged and deflected into a sump.
  • impulse printers generate drops in response to a specific data signal, e.g., from a microprocessor controlling the printing process.
  • the "deflection” system electrostatic deflection is used to adjust the trajectory of the ink material, permitting droplets to be targeted at a variety of angles for delivery to specific points on a substrate.
  • the "binary" system stream has only two trajectories: straight to a target on the substrate material printing the structural features of the microfluidic device (wells, channels, etc.) or into a recirculation unit such as a sump, channel or the like for re-use by the print head.
  • the deflection system is typically used for low- resolution printing, making the binary system preferred for the present invention where a continuous ink jet system is used, as microfluidic structures are best constructed with high resolution printing methods.
  • impulse systems require no ink recovery, charging, or deflection, they are much simpler than the continuous stream type.
  • the first type is a piezoelectric ink jet which propels a drop of material by flexing one or more walls in the print mechanism (often referred to as the "firing chamber") to decrease the volume of the material, causing material to be expelled from the print head.
  • the pressure pulse resulting from the volume decrease can be controlled very precisely.
  • the wall which flexes is typically a piezoelectric crystal or a pressure diapliragm driven by a piezoelectric element incorporated into the firing ch.amber.
  • the impulse system is simpler, the relatively large size of the piezoelectric transducer prevents close spacing of the ink jet nozzles, and physical limitations of the transducer results in low ink drop velocity. Low drop velocity diminishes tolerances for drop velocity variation and directionality, impacting the system's ability to produce high resolution microfluidic structures. Drop-on-demand systems which use piezoelectric devices to expel the droplets also suffer the disadvantage of a relatively slow printing speed.
  • the technology for piezoelectric ink jet printing is well developed, and can be adapted to making microfluidic structures in the present invention.
  • the second type of impulse printer is a thermal impulse ink jet which utilizes rapid bubble formation of heated ink to propel drops from the ink jet print head.
  • This system known as thermal ink jet, or bubble jet, and produces high velocity droplets allowing very close spacing of print head nozzles— and thus very high resolutions, making thermal ink jet printing preferred technology for printing fine microfluidic structures such as microchannel walls.
  • the major components of this type of drop-on-demand system are an ink-filled channel having a nozzle on one end and a heat generating resistor near the nozzle.
  • Printing signals representing digital information originate an electric current pulse in a resistive layer within each ink passageway near the orifice or nozzle causing the ink in the immediate vicinity to quickly evaporate creating a bubble in the ink.
  • the ink at the orifice is forced out as a propelled droplet as the bubble expands.
  • the process is ready to start over again.
  • a droplet ejection system based upon thermally generated bubbles commonly referred to as the "bubble jet” system
  • the drop-on-demand ink jet printers provide simple, lower cost devices than their continuous stream counterparts, and yet have substantially the same high speed printing capability.
  • a print head can incorporate from one to hundreds of ink orifices, with more orifices generally resulting in higher resolution and faster printing speeds.
  • the selection of which type of ink jet system to apply to printing microfluidic structures in the present invention varies depending on the type of material printed from the print head. For example, high surface tension for the printed material results in good droplet formation. An increase in viscosity requires an increase in the energy required to pump and eject the material. Conductivity is important for continuous stream systems because the droplets are deflected electrostatically; thus, the droplets need to be charged. In contrast, low conductivity is preferred for impulse printing, particularly for thermal printing, because excess ions cause corrosion of the print head. Thus, selection of the material for use in outlining microfluidic structures, which is determined based on the application, is one consideration in determining which printing technology to use. Selection of materials to be printed will vaiy depending on the application.
  • an aqueous material can be used to form channel structures in contact with fluid flow. Often the material will include stabilizing agents such as humectants to inhibit drying of the ink in the printing mechanism. In contrast, where aqueous solutions are to be flowed through the printed microfluidic structures, it is generally less desirable to use an aqueous material for channel printing, to prevent dissolution of the channel by the flow of aqueous solutions. Thermally stable materials are desirable where the microfluidic device operates under a range of temperature conditions (e.g., where the device is used as a thermocycler, i.e., in a polymerase chain reaction (PCR) for DNA amplification. Both aqueous and non-aqueous-solvent based "ink" materials are well
  • electrophotographic systems In another method of printing channel walls, well walls and other structural features of microfluidic devices, electrophotographic systems are used. Again, electrophotography is well described in the patent, engineering and scientific literature. An introduction to electrophotography is found in Kirk-Othmer and the references cited therein. Additional details are found in Schafert (1980) Electrophotography Focal Press Boston MA and in Schein (1993) Electrophotography and Development Physics, Springer- Ver lag, Berlin.
  • an electrophotographic system has two physicochemical elements: a photoreceptor and a toner.
  • a photoconductive photoreceptor is uniformly charged, and the photoreceptor is selectively illuminated to form a latent electrostatic image.
  • the image is then developed by applying a toner.
  • the electrostatic image (corresponding to a microfluidic structure or set of structures such as channels, channel walls, wells, etc.) is transferred to a substrate and thermal fusing of the toner on the substrate is performed to fix the image. This is typically followed by optical erasure of the residual charge and removal of residual toner.
  • the substrate on which the latent image is formed is a substrate of the invention, with the applied toner forming channel structures.
  • Lithography In another method of printing channel walls, well walls and other structural features of microfluidic devices, lithographic or "planographic" systems are used. Again, lithography is well described in the patent, engineering and scientific literature. An introduction to Lithography is found in Kirk-Othmer and the references cited therein. Additional details are found in Hird (1991) Offset Lithographic Technology, Goodheart, New York.
  • lithography is a planographic process.
  • Image, or printing areas, and non-image, or non printing reside in the same plane on a lithographic (or “offset") plate (generally made of aluminum or other metals, or of plastic) and are differentiated by the extent to which these areas accept printing ink.
  • the lithographic or offset plate has one or more layers of radiation-sensitive compound.
  • nonprinting areas are hydrophilic, accepting water and repelling ink while printing areas are oleophilic, repelling water and accepting ink.
  • Reciprocal systems in which nonprinting areas are oleophilic (or hydrophobic), repelling a water-based ink and printing areas are hydrophilic accepting a water-based ink and repelling a hydrophobic solvent are also known. Regions which accept ink are designed to transfer an ink outline of the microfluidic structure (channel, well, etc.) desired, on a substrate of choice.
  • the ink to be used to construct microfluidic structures is applied to the plate with rollers (or a "roller train”).
  • the plate is typically made from aluminum with a radiation sensitive coating, although a wide variety of metals and polymers can also be used.
  • a radiation sensitive coating There are two types of coatings, described based on their response to actinic radiation: positive coatings which degrade in response to radiation (becoming soluble in water or a solvent) and negative coatings which become less soluble in response to radiation (e.g., due to polymerization of the coating).
  • Common radiation sensitive coatings for negative plates include diazo-based coatings, sulfuric acid derived salts and hydrochloric acid-derived salts.
  • Common positive coatings include 1,2- Napthoquinone diazide sulfonic acid esters.
  • the first step in making the printed image is to contact the radiation sensitive coating with a photographic film, which is then exposed to light in a desired pattern on the plate.
  • the plate is then exposed to a solvent which removes soluble portions of the coating (defined by the image light), revealing the support surface in the selected areas.
  • the surface in the revealed areas of the plate are strongly hydrophilic, repelling oil based materials (or, as described above, are strongly hydrophobic, repelling water-based materials).
  • repelling oil based materials or, as described above, are strongly hydrophobic, repelling water-based materials.
  • the plates are primed and siliconized, with the siliconized areas typically being "ink” repellant (it will be appreciated that "ink” in this context is the material used to form microfluidic structures). Because there are no problems with solubilization of ink by water, it is possible to create sharper images, and thus finer and more regular microfluidic structures.
  • Computer to Plate lithography, which eliminates the film intermediate step is also performed.
  • thermal imaging is performed on a high speed photopolymer or silver halide is performed on diazo plates.
  • a waterless printing plate is mounted on four units of a printing press. Each unit also has a laser head that scans the width of a cylinder plate as the plate slowly turns. The laser ablates a surface layer, exposing the "ink” -receptive surface of the plate. Printing can be performed as soon as the plates are ablated and exposed to ink. Gravure
  • gravure printing processes are used. Again, gravure is well described in the patent, engineering and scientific literature. An introduction to gravure printing is found in Kirk-Othmer at volume 20, pages 99-101 and the references cited therein.
  • the gravure process which is also known as “intaligo” and as “rotogravure” utilizes a recessed image plate cylinder to transfer the image to the substrate.
  • the plate cylinder can be either chemically or mechanically etched or engraved to generate the image.
  • the volume of the engraved area determines the height of the microfluidic feature formed on a substrate.
  • the gravure process is very simple, and yields very consistent results. Although the process has fallen out of favor because it is difficult to achieve half tones when printing standard ink images, this difficulty does not generally apply to the construction of features for microfluidic devices— there is generally no need to print a halftone in generating a microfluidic structural feature. Indeed, most features will be the same height and of uniform construction to ensure that the overlay substrate will close the feature, i.e., provide a "top" to a channel.
  • a source of material to be printed on a substrate to form features of the invention is regularly contacted to a printing roll.
  • the printing roll is squeegeed to ensure an even coating of printing material on the printing roll.
  • the substrate passes between a second image roll having the structural features etched into the roll and the printing roll.
  • the image roll presses the substrate into contact with the printing roll, causing direct transfer of the image to the substrate.
  • an electrostatic assist is used to transfer the print material.
  • the print material typically dries, or sets, by evaporation.
  • Flexography In another method of printing channel walls, well walls and other structural features of microfluidic devices, flexography is used. Again, flexography is well described in the patent, engineering and scientific literature. An introduction to flexography is found in Kirk-Othmer at volume 20, pages 101-05, and the references cited therein. An advantage of flexography is the ability to print on a wide variety of substrates, including many of those useful in the present invention. For this reason, flexography is primarily used at present by industry to print on unusual surfaces such as cardboard, plastic films, foils, laminates and the like, e.g., for packaging applications. In flexographic printing, a fountain pan supplies printing material to a rubber fountain roll, which in turn supplies material to an anilox roll.
  • the anilox roll is central to the flexographic printing process, typically having a steel core, optionally coated with ceramic.
  • the roll is engraved with cells and/or pits.
  • the function of the anilox roll is to provide uniform "ink” distribution to the plate cylinder, which provides ink to a substrate.
  • a doctor blade typically removes excess ink from the surface of the anilox roll.
  • the printing material is passed between the plate cylinder and an impression cylinder, providing for transfer of the "ink” material to the substrate.
  • flexographic printing plates There are three primary types of flexographic printing plates: molded rubber, solid sheet photopolymer and liquid photopolymer. Any of these are useful for transfer of material to a substrate of the invention for formation of microfluidic structures such as channel walls and well walls.
  • Microcontact printing applicable to the present invention is described in U.S. Pat. No. 5,512,121. Letterpress In .another method of printing channel walls, well walls and other structural features of microfluidic devices, letterpress printing is optionally used.
  • Letterpress is well described in the patent, engineering and scientific literature, and has been used for several hundred years. An introduction to letter press is found in Kirk- Othmer at volume 20, page 105 and the references cited therein. Letterpress is the oldest automated printing process, and is still one of the most precise, mal ing it suitable for printing fine microfluidic structures in the present invention. Letterpress is printed directly by the relief method from cast metal or plates on which the image or printing areas are raised above the non-printing areas. Rollers apply the material to be printed to the surface of the raised areas, which transfer it directly to a substrate. Flat bed cylinder presses are useful, as are the more common rotary presses. Letterpress is less preferred than ink-jet or other methods which use much simpler printing presses.
  • Screen Printing and Stencil Processes There are two stencil processes in general use: screen printing and stencil duplicating. Screen printing typically used for art reproduction is referred to as "serigraphy" . In one method of printing channel walls, well walls and other structural features of microfluidic devices, screen printing or stencil processes printing are used. These processes are in common use and well described in the patent, engineering and scientific literature, and have been used for several hundred years. An introduction to screen printing and stencil processes is found in Kirk-Otlimer at volume 20, page 105- 106 and the references cited therein. A review of screen printing techniques is found in Appleton (1984) Screen Printing a Literature Review, Pira international, Letterhead, Surrey, U.K. In brief, screen printing is performed manually or by photomechanical means.
  • the screens typically consist of silk or nylon fabric mesh with openings of 40- 120 and often more, openings per lineal centimeter.
  • the screen material is attached to a frame and stretched to provide a smooth surface.
  • the stencil is applied to the bottom side of the screen, i.e., the side in contact with the substrate upon which microfluidic structures are to be printed.
  • the print material is painted onto the screen, and transferred by rubbing the screen (which is in contact with the substrate) with, e.g., a squeegee. Screens typically last for up to about 100,000 printings.
  • the stencil provides the outline of the portion of the microfluidic structures which are lowest, i.e., the "bottom" of a channel or well, while the unstenciled portion provides the raised areas, i.e., the channel walls.
  • Screen printing and Serigraph is also practiced by using rotary screens, made by plating a metal cylinder electrolytically on a steel cylinder, removing the cylinder after plating, applying a polymer coating to the cylinder, exposing it through a positive and a screen, developing the image and etching it.
  • the result is a cylinder having a solid metal in the areas corresponding to raised features on the substrates in the microfluidic devices of the invention, and pores in the non-raised areas.
  • Screen printing (Reviewed in Appleton, supra) is used generally in the manufacture of electrical circuit boards, and for printing textiles. Accordingly, very disparate substrates are easily printed using screen printing methods, making it applicable to the manufacture of microfluidic structures on a wide range of materials.
  • Thermal printing is a generic name for methods that mark a substrate by imagewise heating of special purpose consumable media. Common technologies include direct thermal (wax, transfer, etc.), and diffusion (dye-sublimation). Properties and preferred applications are diverse, but apparatus and processes are similar. For a review See, Kirk-Othmer, supra, at page 106-107 and the references cited therein. See also, Sturge et al. (1989) Image Processes and Materials, 8th edition, Van Nostrad Reinhold Co., Inc., New York; Komersaka and Diamond (1989) in Nonimpact Printing, Graphic Arts Foundation, Pittsburgh, Pa., and McLaughlin (1973) Proceedings of Microelectronic Symposium, San Francisco, CA.
  • Printheads are common to many thermal printing technologies.
  • the heads are typically page-wide printed circuit-like arrays of uniform resistors.
  • lasers replace printheads for precise thermal printing applications.
  • wax overlays are melted to reveal a substrate (e.g., a sheet of the laminate) below the wax.
  • This technology is suitable for making channels wells and the like on substrates having meltable overlays, i.e., the desired microfluidic structure is carved out of the overlay with heat.
  • thermal transfer imagewise transfer of wax or other material to a substrate is performed. This process is in common use for malting transparencies, signs, high quality labels and the like. This process is suitable for printing features on the substrates of the invention.
  • dye- sublimation thermal printing occurs by submilation, condensation and diffusion. See also, Kirk Oth er, supra, at page 108-109 and the references cited therein, and Hahn and Beck (1980) Proceedings of 5th International Congress on Advances in Non-Impact Printing Technologies, San Diego, CA pp. 441-448. Additional non-printing methods
  • non-printing methods are also used to form channel structures in the present invention.
  • thin films with microfluidic structures cut out of the sheet can be applied to a sheet to be laminated, films can be cut, laser etched, or the like after application to a sheet to be laminated, or the microfluidic structures can be applied by hand.
  • the film will be bonded to at least one sheet of the laminate, and often at least two sheets of the laminate.
  • screens or masks comprising microfluidic structures are applied to a sheet to be laminated and coated with an additional material. The screen is then removed, leaving an outline of the microfluidic structure in the additional material.
  • Die or laser cut films comprising microfluidic structures such as microchannels and/or wells are preferred, as are screening and masking methods.
  • the "ink” materials used in printing microfluidic structures such as channels, wells and the like are selected based upon the intended application.
  • Example materials include e.g. wax (especially thermal wax-based inks useful in all of the thermal processes described herein), laser copier toners, sol-gels, thermoplastics (including PMMAs, Polycarbonates and styrenes), epoxies (including UV curing epoxies), hot melt adhesives, pressure sensitive materials, or photoresist. Particles of materials which enhance fluid flow, or control channel wall size are optionally added.
  • the laminates of the invention comprise separate sheets which are adhered together using an adhesive.
  • the adhesive material is the "ink" which is printed on a substrate to form microfluidic strtictures such as channels and wells.
  • the adhesive can be separate from microfluidic structures, and used simply to bond two or more substrates together.
  • adhesive materials can be, e.g. wax (especially thermal wax-based inks), laser copier toners, sol-gels, thermoplastics (including PMMAs, Polycarbonates and styrenes), epoxies (including UV curing epoxies), hot melt adhesives, pressure sensitive materials, or photoresists.
  • Particles of materials which enhance fluid flow, or control channel wall size are optionally added. Bonding can be performed with pressure, RF, UV, thermal or ultrasonic methods, or any combination thereof.
  • the selection of adhesive depends on the nature of the substrate, and upon the nature of the material to which the adhesive material is to be attached. In general, glues, cements, pastes, epoxies, and the like are suitable and widely available, as are mechanical adhesives such as threads, staples and the like. Adhesives are selected based upon the intended application, and it is expected that one of skill is thoroughly familiar with available adhesives and their use. For example, where the application is subjected to water, an adhesive which is waterproof is used.
  • Adhesives are used as print materials (ink), or are applied separate from print materials to adhere sheets of laminate together.
  • wax materials useful in a wide variety of printing processes are known and discussed in the literature.
  • Insect and animal-derived waxes include beeswax and various waxes derived from animal fats.
  • Vegetable-derived waxes include candellia, ca ⁇ iuba, Japan wax, ouricury wax, Douglas-Fir bark wax, rice- bran wax, jojoba, castor wax, bayberry wax, and the like.
  • Mineral waxes include montan wax, peat waxes, ozokerite and ceresin waxes, petroleum waxes (e.g., paraffin waxes consisting primarily of normal alkanes, scale waxes, and microcrystalline waxes), and the like.
  • Synthetic waxes include polyethylene, Fischer-Tropsch (polymethylene), a wide variety of chemically modified hydrocarbon waxes, substituted amide waxes and the like.
  • Waxes have a very wide range of physical properties, with melting temperatures from room temperature to 150°C or higher, a range of viscosities, and the like. The use of waxes in thermal printing processes is well developed as described, supra, Accordingly, waxes have broad applicability as a print material for the construction of microfluidic structures in the present invention.
  • Sol-gel technologies are well known, and described, e.g., in Kirk-Otlimer, supra at volume 22 and the references cited therein.
  • Sols are dispersions of colloidal particles (nanoscaled elements) in a liquid such as water, or a solvent. Sol particles are typically small enough to remain suspended in the liquid, e.g., by Browninan motion.
  • Gels are viscoelastic bodies that have interconnected pores of submicrometeric dimensions.
  • Sol-gels are used in the preparation of glass, ceramics, composites, plastics or the like by preparation of a sol, gelation of the sol and removal of the liquid suspending the sols. This process is used in the many relatively low-temperature processes for the construction of fibers, films, aerogels, and the like.
  • sol-gels Three general processes for malting sol-gels are typically used. In the first, gelatination of a dispersion of colloidial particles is performed. In the second, hydrolysis and polycondensation of alkoxide or metal salt precursors is performed. In the third, hydrolysis and polycondensation of alkoxide precursors followed by aging and drying at room temperature is performed. For further details, see, Kirk-Othmer, id. Applied to the present invention, sols are optionally deposited by the printing technologies described supra, followed by gelatination, hydrolysis, polycondensation, or the like.
  • Resists including photoresists are described in Kirk-Othmer Chemical Technology third and fourth editions, esp. volume 17 for the third edition and volume 9 for the fourth edition, Martin Grayson, Executive Editor, Wiley-Interscience, John Wiley and Sons, NY, and in the references cited therein. Resists are often temporary, thin coatings applied to the surface of a laminate. The films act like masks that are chemically resistant to deposition of additional materials. Thus, in the context of the invention, the interior portions of microfluidic structures (channels, wells, etc.) are printed or masked on a substrate with a resistive material, and the substrate is coated with an additional material. The resist is then removed, leaving the outline of a desired structure in the additional material.
  • a resistive material can, itself, be the intermediate layer which bonds the laminate together.
  • a variety of screenable resists including inks, silk, nylon, metal screening materials and the like can be used as resists.
  • Photoresists are particularly preferred. Photoresists typically change chemically when exposed to light (typically UV), becoming more or less soluble in selected solvents. Photoresists can be used in maslting strategies in a manner similar to screenable resists, and can also be used to print microfluidic structures such as such as a channel wall by printing the structure in photoresist .and exposing the photoresist to light (in this application, the photoresist becomes less soluble upon exposure, i.e., due to polymerization).
  • the ⁇ noplastics are useful both as ink components, and as substrates upon which microfluidic structures are formed.
  • Plastics are classified as thermoplastic resins or as fhermosetting resins, depending on how the plastic is affected by heat. When heated, thermoplastic resins soften and flow as liquids; when cooled, they solidify. These changes on heating and cooling can be repeated.
  • Thermoplastics are thermally stable in their intended applications. Generally, thermoplastic products are made by melting thermoplastic compounds, and shaping and cooling the melt. When heated, theimosetting resins liquify and then solidity with continued heating due to crosslinking of the plastic during heating. Crosslinking is a permanent change; once molded, a thermoset plastic cannot be reheated and remolded.
  • thermoplastics can be reworked.
  • a general introduction to thermoplastics, and to plastics in general, is found in Kirk-Otlimer Encyclopedia of Chemical Technology third and fourth editions, esp. volume 18 and volume 23, Martin Grayson, Executive Editor, Wiley-Interscience, John Wiley and Sons, NY, and in the references cited therein.
  • thermoplastic or thermosetting resins are heated and printed on a substrate, e.g., using any of the various thermal printing methods discussed herein.
  • thermoplastics are thermoplastics. These include crystalline resins such as various polyethelenes, nylons and polyesters, and amorphous thermoplastics such as acrylo-nitrile-butadine-styrene terpolymers (ABS plastics), cellulose acetate, phenylene oxide based resins, polycarbonates, poly(methyl methacrylate) (PMMA), polystyrene, polyvinylchloride (PVC), styrene-acrylonitrile copolymers (SAN) and various urethanes.
  • ABS plastics acrylo-nitrile-butadine-styrene terpolymers
  • PMMA poly(methyl methacrylate)
  • PVC polyvinylchloride
  • SAN styrene-acrylonitrile copolymers
  • Raw resins are available from a variety of commercial sources, typically in the form of pellets.
  • thermoplastics are optionally processed into microfluidic components, or act as substrates such as sheets or panels upon which microfluidic components are printed.
  • Techniques for depositing thermoplastics include printing as discussed above, and can also include extrusion, blown film extnision, cast film extrusion, extrusion of plastic sheets, profile extrusion, extrusion coating, wire coating, injection molding, stnictural foam molding, rotational molding, thermoforming, cast acrylic sheeting, expandable polystyrene molding, foamed polystyrene sheet extrusion, calendaring, thermosetting, reaction injection molding, and the like. See, Kirk-Othmer, supra.
  • Urethane plastics are an example of useful thermoplastics for use in the present invention.
  • Urethane plastics are optionally used to form sheets, rolls, or other printable substrates, and are also useful as print materials, i.e., when urethane plastics or other thermoplastics are in solution (e.g., in a solvent) they can be sprayed through an ink-jet, or printed using the other methods herein.
  • urethane plastics or other thermoplastics are in solution (e.g., in a solvent) they can be sprayed through an ink-jet, or printed using the other methods herein.
  • the interaction of the solvent with the substrate causes the thermoplastic print material to become embedded in the thermoplastic substrate.
  • the properties and methods of malting thermoplastic and thermosetting plastics such as urethanes are known.
  • urethane polymers e.g. , at volume 23.
  • a variety of manufacturing techniques are known for both thermoplastic and thermosetting urethanes, and polyurethanes and associated solvents, reagents, catalysts and the like are commercially available from J. P. Stevens (East Hampton, MA) as well as other commercial sources such as Al zo, BASF, Dow, Mobay, Olin, Rubicon, Upjolm, Bayer, Takeda, Veba, Eastman, Sun Oil, and other manufacturers known to persons of skill. See also, Kirk Othmer, id.
  • substrates for Printing An advantage of the present invention is that it provides for a wider choice of substrate materials for use in the microfluidic devices of the invention.
  • channels, wells or the like were typically etched, machined, milled, cut, or formed in injectably molded materials.
  • any material can be used as a substrate or sheet in a laminate of the invention, provided the printed material is compatible with the substrate.
  • substrates can include thin sheets of plastics or other polymers, glass, ceramic, metal, metalloid, organic material, acrylic, MYLAR , or the like, having a substantially flat region.
  • other materials can also be used, including coated papers, or the like.
  • Substrate selection is performed by considering the environmental operating parameters of the microfluidic device (temperature, pH operation range, salt operation range, need for conductivity if the device is electrokinetic, etc.), considering the properties of the print material (whether it will adhere to the substrate, whether it is caustic, etc.) and by considering the equipment available to the person of skill (e.g., type of printer to be used in laying out microfluidic structures). Many materials suitable for use as substrates or sheets in the laminates of the invention are described, e.g., in Kirk Othmer, id., and the references cited therein.
  • a particularly preferred feature of the invention is the ability to dramatically speed and simplify manufacturing of microfluidic devices.
  • materials to be laminated such as plastic or other polymer sheets can be manufactured in large sheets, or rolls.
  • Microfluidic structures are easily printed on these sheets or rolls of material using the printing technology described, supra, and a cover sheet or roll of material can be bonded to the printed sheet as described, supra, to provide laminates having closed microfluidic structures. The sheets or rolls are then cut into smaller sections to provide individual microfluidic devices.
  • This process is optionally performed in a single continuous process, making it possible to generate large quantities of microfluidic devices. Alternatively, any of these operations can be performed separately. This is often desirable, e.g., where the sheets of the laminate are simply purchased from a commercial supplier, and printing, lamination and cutting processes are performed with the purchased sheets in a continuous process. In this regard, it will be appreciated that many polymer sheets, films and the like are widely available.
  • any of the manufacturing steps are optionally separated, i.e., the planar surface produced using a sheet manufacturing technique can be manufactured, pieces exposed to an appropriate printing technology to form a printed layer and a second sheet of material mated to the printed surface in steps of separate manufacturing processes.
  • one advantage of the present invention is that it provides for continuous manufacturing of a laminate.
  • cast film extrusion is optionally used with the printing techniques described, supra, in a single continuous process, to create a laminate.
  • sheets of planar polymer are continuously produced by the extrusion process. Following water cooling on a chill roll, the material is dried and fed past a print head or other printer as described above and a printed layer is formed on the planar surface.
  • a second sheet of material is optionally mated with the printed surface in a single continuous process to form a laminate of the invention.
  • the laminate formed by mating the second sheet of material with the printed surface is die-cut to produce a microfluidic device as described above.
  • sheet manufacture is combined with the printing technologies described herein in a single continuous process.
  • a web of molten plastic is pulled from an extruder die into the nip between two pressure rollers. At the nip, there is a very small rolling bank of melt. Pressure between the rolls is adjusted to produce a sheet of the desired thickness and surface appearance. The necessary amount of pressure depends on the viscosity of the plastic or other polymer. For a given width, thickness depends on the balance between extruder output rate and the take-off rate of pull rolls. A change in either the extruder screw speed or the pull-roll speed affects sheet thickness. A constant thickness across the sheet requires a constant thickness of melt from the die.
  • Sheet extrusion requires that the resin be of high melt viscosity to prevent excessive sag of the melt between the die and the nip.
  • the melt should reach the nip before touching any other part of the middle roll to prevent uncontrolled cooling of the resin.
  • sheet extrusion is suitable to the present invention, because the sheets used as printable surfaces have adequate structural rigidity for their use in microfluidic devices. Further details of sheet manufacturing are found in •Kirk-Otahmer, supra.
  • sheet extrusion is optionally used with the printing techniques described supra in a single continuous process to create a laminate.
  • sheets of planar polymer are continuously produced by the extrusion process.
  • the material is fed past a print head or other printer as described above and a printed layer is formed on the planar surface.
  • a second sheet of material is optionally mated with the printed surface in a single continuous process.
  • the laminate formed by mating the second sheet of material with the printed surface is die-cut (or cut by any other .known process) to produce a microfluidic device as described above.
  • any of the above continuous process steps are optionally separated, i.e., planar surfaces can be manufactured, exposed to an appropriate printing technology to form a printed layer and a second sheet of material mated to the printed surface in steps of separate manufacturing processes.
  • one advantage of the present invention is that it provides for continuous manufacturing of a laminate. Calendaring
  • calendaring processes can also be used for malting sheeting of uniform thickness from 0.75-0.05 mm after stretching.
  • a calendar has four heavy, large steel rolls, which are usually assembled in an inverted "L" configuration.
  • a two-roll mill, a Banbury mixer, or an extruder melt the resin, which is subsequently transferred to the calendar.
  • Sheet can be made up to about 2.5 m wide and production rates can be as high as 100 m/min.
  • Calendaring is followed by printing, and laminating as described above.
  • a continuous process can be used for making the laminates of the invention, i.e. , the sheets can be calendared, printed and laminated in a single continuous process.
  • a variety of mating techniques to form the laminate from commercially available sheets or those manufactured by the processes described above are appropriate, depending on the print material, and all can be used in a continuous process with the manufacture of the sheet and printing of print layers on the sheets, or can be separated from either or both operations.
  • a variety of adhesive print materials are suitable, including those described supra.
  • thermoset polymers such as amino resins, polyesters, and epoxies. Any of these materials can be printed onto a sheet (or other substrate such as glass) as described above, and used as the adhesive between sheets.
  • Treating is a term used by the lamination industry to describe application of these the ⁇ noset polymers to materials to be laminated. As discussed above, in the present invention, these materials are applied by various printing processes to form print layers which adhere sheets of a laminate together. Alternatively, or in conjunction with printing methods, portions of the sheets to be laminated next to regions comprising printed microfluidic structures can have adhesives applied to aid in lamination. In one common embodiment, the print or other adhesive material is passed through a drying oven such as an air flotation oven (see, Kirk-Othmer at pp 1078-1079) to boil off unwanted solvents.
  • a drying oven such as an air flotation oven (see, Kirk-Othmer at pp 1078-1079) to boil off unwanted solvents.
  • “Collation” is the process by which individual laminate sheets are assembled, i.e., placed in an appropriate physical relationship to each other.
  • the collated sheets are bonded by pressing into a laminate.
  • presses are known.
  • the sheet with the printed material and the second sheet are fed through a roller to apply pressure between the two sheets.
  • the print material or other adhesive adheres the sheets together.
  • this technique has the advantage of forming a laminate of a continuous and uniform thickness, thereby causing microfluidic structures such as channel walls, chambers, wells, well walls and the like to have a uniform height, and to form a good seal between the sheets of the laminate.
  • the laminate can be formed simply by laying a sheet on top of the printed layer. Variations of heat and pressure are used, depending on the print material.
  • a variety of other presses are suitable, including flatbed high and low pressure presses.
  • the sheets of the laminate are heated in the press.
  • the initial heating causes the adhesive resins (and/or the sheets of the laminate) to melt.
  • the applied heat simultaneously causes the resin to polymerize .and cross-link or gel. This is the point at which the curing process becomes dominant over the melt flow process. Dynamic mechanical and dielectric analyses are used to track this transition. With a sufficiently long press cycle, a state of complete cure is achieved. At this point, the laminate is cooled (typically in the press, under pressure, e.g., using a cooling plate).
  • Low pressure processes are especially suitable for the present invention, as microfluidic geometries can be distorted by high pressure processes. Low pressure processes are also generally of short duration, making these processes especially suitable for continuous processing (this is also an advantage in the present invention, as continuous processes are especially economical for manufacture of large numbers of components). Additional Specific Embodiments
  • Fig. 1 is a top view of first sheet 5 of a laminate of the invention comprising channel 10.
  • Channel 10 includes raised walls 15 and 20, with the charmel terminating in reservoirs 25 and 30.
  • second sheet 35 typically overlays the first sheet, thereby providing charmel 10 with a top and bottom portion.
  • a very simple charmel pattern is depicted; however it will be appreciated that many channel patterns can be produced in accordance with the present invention, including intersecting perpendicular channels, serpentine, saw tooth or any of a variety of other charmel geometries.
  • Substrates are of essentially any size, with area typical dimensions of about 0.5 cm 2 to 1000 cm 2 . Typical sizes are in the range of 0.5-10 cm 2 , e.g., about 1 to about 5 cm 2 .
  • Figs. 2A-2C show a preferred method of making charmel 10.
  • Fig. 2A shows ink jet printing head 205 spraying material 210 from nozzle 215 to fOatm raised walls 15 and 20 having a defined width a.
  • Fig. 2B shows second sheet 35 in the process of contacting lower sheet 5 to create a closed channel structure for channel 10.
  • spacer clamps 220 and 225 are used to position second sheet 35 and first sheet 5 relative to each other in a manner in which second sheet 35 contacts raised walls 15 and 20, thereby forming charmel 10.
  • first sheet 5 comprising raised walls 15 and 20 is laminated to second sheet 35 by pressing the sheets between rollers 305 and 310.
  • raised walls 15 and 20 are optionally constructed from an adhesive material which bonds sheets 5 and 35.
  • sheets 5 and 35 can be bonded by pressure, heat or a combination of pressure and heat. Sheets 5 and 35 can be fed between rollers 305 and 310 in separate sheets, or in large rolls which are subsequently cut to form individual substrates.
  • Fig. 4 shows an alternative embodiment comprising spacers 405 and 410 which keep the distance between sheets 5 and 35 constant, thereby keeping the depth of channel 10 uniform.
  • Fig. 5 shows a top view of a more complex laminate 500 having top sheet 505 laminated to bottom sheet 510.
  • the laminate includes channels 515-545 which are in fluid communication with each other and with reservoirs 550-580.
  • Fig. 6 shows a cross sectional view of laminate 600 comprising parallel sheets 605 and 610, raised walls 615-635 and channels 640-655.
  • Sheets 605 and 610 are a constant distance apart, with the distance being defined by, e.g., the viscosity of the material used to construct raised walls 615-635, the pressure used to bond sheets 605 and 610, environmental parameters such as temperature and humidity, and the like.
  • Fig. 7 shows a masking method of making a charmel on a substrate.
  • Substrate 705 is masked by screen 710 comprising mask 715 which defines charmel region 720.
  • Applicator 725 deposits adhesive material 730 onto screen 710.
  • Screen 710 prevents deposition of adhesive material 730 in channel region 720.
  • a charmel in channel region 720 results, with walls formed by deposited adhesive material 730.
  • Fig. 8 A and Fig. 8B show an etching or engraving (intaligo) method of forming charmels on a substrate.
  • Plate 805 comprising raised regions 810 and 815 is coated with material 820, resulting in deposits of material 820 in raised regions 810 and 815.
  • Substrate 825 is pressed against plate 805, for example by rollers 830 and 840, resulting in transfer of material 820 from raised regions 810 and 815 to substrate 825, thereby forming raised walls 850 and 855 defining channel 860.
  • a second substrate is laminated to substrate 825 to form a laminate of the invention.
  • Fig. 9A and Fig. 9B show a "letter press” or “offset” style of forming a channel on a substrate for making a laminate of the invention.
  • Letterpress 905 comprising material 910 presses material 910 onto substrate 915, resulting in the formation of raised charmel walls 920 and 925 which define channel 930.
  • a second substrate is laminated to substrate 915 to form a laminate of the invention.
  • Figs. 10A- 10C Show charmel formation on a substrate using lithography on a Heidelberg press.
  • lithographic plate 1005 comprising regions with deposited material 1010 and regions without deposited material 1015 is pressed against substrate 1020, resulting in the formation of raised channel walls 1025-1040 defining channels 1045-1050.
  • regions without deposited material 1015 correspond to formation of channels 1045- 1050.
  • regions of lithographic plate 1005 comprising deposited material 1010 are hydrophobic, while regions without deposited material 1015 are hydrophilic. Where deposited material 1010 is hydrophobic, it is preferentially deposited on the hydrophobic regions of lithographic plate 1005, without depositing on the hydrophilic regions.
  • regions of lithographic plate 1005 comprising deposited material 1010 are hydrophilic, while regions without deposited material 1015 are hydrophobic. Where deposited material 1010 is hydrophilic, it can be preferentially deposited on the hydrophilic regions of lithographic plate 1005, without depositing on the hydrophobic regions.
  • Fig. 11 depicts a method of making a laminate of the invention by etching a deposited material on the surface of one sheet of the laminate. Roller 1105 rolls material 1110 onto the surface of sheet 1115. Etchant 1120 is applied before or after material 1110 to sheet 1115, either preventing deposition of material 1110, or removing material 1110 after it is deposited. In operation, a second sheet is adhered to sheet 1115, thereby providing a laminate with channels in the pattern etched by etchant 1120.

Abstract

Laminates (600) having microfluidic structures (615-635) disposed between sheets (605-610) of the laminate (600) are provided. The microfluidic structures (615-635) are raised on a sheet (605, 610) of the laminate (600), typically by printing the structure (615-635) on the sheet (605, 610). Printing methods include Serigraph, ink-jet, intaligo, offset printing and thermal laser printing.

Description

FABRICATION OF MICROFLUIDIC CIRCUITS BY "PRINTING" TECHNIQUES
BACKGROUND OF THE INVENTION Microscale devices for high throughput mixing and assaying of small fluid volumes have recently been developed. For example, USSN 08/761,575 entitled "High Throughput Screening Assay Systems in Microscale Fluidic Devices" by Parce et al. provides pioneering technology related to Microscale Fluidic devices, including electrolάnetic devices. The devices are generally suitable for assays relating to the interaction of biological and chemical species, including enzymes and substrates, ligands and ligand binders, receptors and ligands, antibodies and antibody ligands, as well as many other assays. Because the devices provide the ability to mix fluidic reagents and assay mixing results in a single continuous process, and because minute amounts of reagents can be assayed, these microscale devices represent a fundamental advance for laboratory science.
In the electrOakinetic microscale devices provided by Parce et al. above, an appropriate fluid is electrokinetically flowed into and through a microchannel microfabricated (e.g., etched, milled, laser-drilled, or otherwise fabricated) in a substrate where the channel has functional groups present on its surfaces. The groups ionize when the surface is contacted with an aqueous solution. For example, where the surface of the channel includes hydroxyl functional groups at the surface, protons can leave the surface of the channel and enter the fluid. Under such conditions, the surface possesses a net negative charge, whereas the fluid will possess an excess of protons, or positive charge, particularly localized near the interface between the channel surface and the fluid. By applying an electric field along the length of the channel, cations will flow toward the negative electrode. Movement of the positively charged species in the fluid pulls the solvent with them. The steady state velocity of this fluid movement is generally given by the equation: v= e£E
where v is the solvent velocity, e is the dielectric constant of the fluid, ξ is the zeta potential of the surface, E is the electric field strength, and η is the solvent viscosity. The solvent velocity is, therefore, directly proportional to the surface potential. Examples of particularly preferred electroosmotic fluid direction systems include, e.g. , those described in International Patent Application No. WO 96/04547 to Ramsey et al. , as well as USSN 08/761,575 by Parce et al. Examples of additional microfluidic fluid manipulation structures relying on pumps, valves, microswitches and the like are described in, e.g. , U.S. Patent Nos. 5,271,724, 5,277,556, 5, 171,132, and 5,375,979. See also, Published U.K. Patent Application No. 2 248 891 and Published European Patent Application No. 568 902.
A typical microscale device can have from a few to hundreds of fluidly connected channels chambers and/or wells. Improved methods of making microscale devices which provide for simplified manufacturing, more precise construction and die like are desirable. In addition, the ability to more easily control channel height to widd ratios, thereby affecting fluid flow in the channels is also desirable. This invention provides these and many other features.
SUMMARY OF THE INVENTION The manufacture of microfluidic devices by machining grooves, channels or the like in various substrates (glass, plastics, metals, metalloids, ceramics, polymers, organics, etc.) can be time consuming and expensive. To overcome these problems, the present invention adapts printing technologies to print channel walls, well walls, or other desired structural features on a substrate, followed by application of a material over the printed channel walls, thereby providing a laminate having an enclosed channel.
In one embodiment, the invention provides a laminate having a first surface comprismg a first planar section (e.g., a sheet of glass, polymer, plastic, ceramic, metalloid, organic material, acrylic, MYLAR ,or the like, having a substantially flat region) and a second surface comprising a second planar section (the second surface can be the same as the first surface in construction, or made from a different material). The first or second surface can be rigid or flexible. The laminate has a first channel disposed between the first planar section and the second planar section having at least one cross-sectional diameter between about OJμm and 500μm. The upper and lower walls of the channel are made from the upper and lower surfaces, with the channel having a first wall and a second wall in contact with the first planar section and the second planar section. The walls are raised in comparison to the first or second planar surfaces, e.g., as a result of having been printed on the surface, having typical heights of between about OJμm and 500μm, more typically between about 1 and lOOμm. The walls can be constructed from adhesive materials which bond the first and second surfaces together, such as a wax, a theπnoplastic, an epoxy, a pressure sensitive material, or a photo-resistive material. In typical embodiments, the walls of the channel are printed on the first and/or second surface using a printing technology such as Serigraph printing, ink jet printing, intaligo printing, offset press printing, thermal laser printing or the like. In an alternate embodiment, the surfaces are clamped together with a clamp, e.g., with the channels being printed with a non-adhesive material. Spacers are optionally used to ensure uniform distance between the sheets of material. Clamps and spacers are optionally used on applications having adhesive channel walls as well, to improve adhesion of the surfaces and to ensure uniform distance between the sheets of material. Surfaces are optionally coated to modify surface properties.
Because the upper and lower portions of the channel are made from the first and second surfaces, the channel typically has a flat top and a flat bottom. One advantage of the laminate constπiction of the invention over lithographic and laser ablation or other machining methods is that the portions of the channel made up of the first or second surface have the same physicochemical properties as the rest of the surface, because the channel portion is not altered by chemical or physical processes. Thus, the properties of the channels of the invention are more predictable than prior art microfluidic device construction methods. Another advantage is that the width and height of the channel walls can easily be optimized to reduce turbulence in angled portions of a channel.
An additional advantage of the present invention is that laminates with multiple sheets having fluidic structures between the sheets can easily be constructed by laminating multiple layers of materials. This increases the possible complexity of fluidic structures, increasing the applicable uses for the resulting mirofluidic devices. Methods of forming the laminates of the invention are also provided. In the methods, first and second surfaces, each having a first planar section, are provided. A first channel having a first and a second wall is applied to the first and/or second planar section (the first and second walls are raised in comparison to the first planar surface, and have at least one cross-sectional diameter between about OJμm and
500μm), and the first and second planar sections are bonded. The first channel is in contact with a portion of the second planar section. The first channel is applied to the first or second planar section by printing the channel on the first or second planar section. Preferred methods of printing include Serigraph printing, ink jet printing, intaligo printing, offset press printing, and thermal laser printing.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 shows a top view of a laminate including a microfluidic device having two wells and a single microfluidic channel. Fig. 2 panels A, B and C are side views showing construction of a laminate of the invention by dropping material to form a channel wall (panel A), and clamping the laminate (panel B and panel C).
Fig. 3 is a side view showing constinction of a laminate using a roller method. Fig. 4 is a side view showing a laminate having spacers.
Fig. 5 shows a top view of a laminate including a microfluidic device having multiple wells and microfluidic channels.
Fig. 6 is a side view of a laminate having multiple channels and channel walls. Fig. 7 is a top view showing a masking procedure for making a laminate of the invention.
Fig. 8 panels A and B are side views showing intaligo printing to form channel walls in a microfluidic laminate.
Fig. 9 panels A and B are side views showing offset printing to produce a laminate of the invention.
Fig. 10, panels A and B show channel formation on a substrate using lithography on a Heidelberg press. Fig. 11 is a side view showing a method of malάng a laminate of the invention by etching a deposited material on the surface of one sheet of the laminate.
DEFINITIONS A "laminate" is a structure having at least two layers of materials fixed, adhered or bonded together. Typically, in the present invention, the laminate will have two or more sheets of substrates adhered, glued or clamped together, with microfluidic elements such as channels, channel walls, wells, well walls, or the like disposed between the substrates. Ordinarily, at least the outlines of the microfludic elements are printed on one or both of the substrates, and the elements are fully formed by bonding the two or more substrates together. Ordinarily, the substrates take the form of sheets of material although one or both of the substrates may exist in other forms, such as a block of material with a face having a flat section.
In reference to a laminate, a "surface" is a face of a laminate or a face of a substrate or a face of a sheet of substrate used in forming a laminate. The surface ordinarily has a substantially flat region although it optionally has grooves, depressions or the like.
A "printed layer" is a layer of material amenable to deposition by printing. A variety of such materials are described herein. The printed layer is ordinarily between about 1 and 500 μm in thickness and is ordinarily applied to a selected surface using a printing technology such as ink-jet, Serigraph, intaligo, letter press printing, or the like, although it may also be applied manually.
An intermediate layer such as channel wall is "bonded" to a surface when the layer is adhered to the surface in a manner which does not permit removal of the layer under assay conditions typical for the device. Most typically, the intermediate layer is bonded by printing the intermediate layer on a surface; alternatively, the layer can be bonded by gluing the intermediate layer to the surface, or by embedding the intermediate layer in the surface, e.g. , by partially dissolving the surface or the intermediate layer with a solvent and forcing the intermediate layer and the surface together. DESCRIPTION OF THE PREFERRED EMBODIMENT In previous embodiments, microfluidic devices were made by removing materials from a substrate to form a structural feature such as a channel bed, depression, or the like and bonding a second substrate to provide a cover to the strtictural feature (e.g., a top surface to a channel). In contrast, the present invention does not rely on removing substrate materials to make microfluidic structures. Rather than removing or modifying material to create channels, wells, chambers or other structural features in a substrate, in the present invention a material is deposited on a substrate, e.g., by printing a print material on the substrate. The print material is laid down in a pattern that defines the edges of fluidic structures, such as channels, chambers, wells or the like.
Lamination of a substrate over the print material completes formation of the microfluidic structures outlined with the print material (e.g., by providing a top surface for a channel, well, chamber or the like).
The print material is deposited on any of a variety of commercially available materials such as sheet glass, or a polymer, in a pattern that defines the outer edges of fluid structures such as channels, wells or the like. A variety of print materials are suitable, including inks, waxes, plastics and many others described herein.
In one embodiment, the print material is used to adhere a "cover layer," or other secondaiy substrate to form the laminate. In this embodiment, the printed material forming the circuit of channel walls also serves as an adhesive to bond the sheets of the laminate together. The adhesive materials can be, e.g. a printable wax (especially thermal wax-based inks), laser copier toners, sol-gels, printable thermoplastic (including PMMAs, Polycarbonates and styrenes), printable epoxy (including UV curing epoxies), a hot melt adhesive, a pressure sensitive adhesive material, a photoresistive material, or the like.
Particles of materials which enhance fluid flow, or control channel wall size are optionally inco orated into the print material. Bonding is performed with pressure, RF, UV, thermal or ultrasonic methods, or any combination thereof. The methods allow fabrication of channel structures of any thickness and peπnit formation of laminates using thin polymer sheets which are laminated and die-cut. Material choices are thus not limited to those that can be processed by etching, machining, or molding. Because the laminates can be flexible, they can be manufactured in quantity and rolled. In addition, layered laminates having many layers of fluidic structures can be made, providing more options in microfluidic structure design.
Similarly, the geometry of printed microfluidic structures made using the methods described herein can be more flexible than prior art microfluidic devices. For example, there are fewer difficulties in producing intricate channel shapes using printing technologies than in micromachining channels. Aspect ratios of microfluidic channels can easily be selected by varying the thickness of the print material which makes up a selected microfludic structure (channel, well, etc.).
As described, because the upper and lower portions of the channel are made from the first and second surfaces, the channel typically has a flat top and a flat bottom. One important advantage of the laminate construction of the invention over etching, milling, laser drilling or other machining methods is that the portions of the channel made up of the first or second surface have the same physicochemical properties as the rest of the surface, because the channel portion is not altered by chemical or physical processes (i.e., the channel portion is not altered by etching, heat, drilling, or the like). Thus, the properties of the channels of the invention are more predictable than previous construction methods. Another advantage is that the width and height of the channel walls can easily be optimized to reduce hydrodynamic effects. In addition, because the upper and lower portions of channels are symmetrical, flow properties in the channels are more regular and predictable.
The preferred embodiments of the present invention include printing a material on a substrate or sheet of substrate to form the outline of microfluidic structures, such as channels, wells, or the like. A variety of printing technologies are available, including ink-jet printing, laser printing, silk-screening, Serigraph, intaligo, offset printing, letter press, Heidelberg press printing and the like, all of which can be adapted for use in the present invention.
For use in making a laminate of the invention, an "ink" or "print material" is applied to a sheet or other substrate suitable for receiving the ink, and suitable for use in a laminate of the invention. The shape of desired structural features such as channels and wells is outlined with the ink material and a second sheet is layed over the printed structure to create a laminate with channels, wells and the like. The ink material makes up the walls of the desired microfluidic structure. A wide variety of printing methods useful for applying materials suitable for channel wall formation are known, and can be adapted to use in the present invention. Printing technologies are well illustrated in the scientific, patent and engineering literature, and many commercial embodiments are available; accordingly, no attempt is made to describe these processes in detail.
An introduction to printing methods is found in Kirk-Othmer Encyclopedia of Chemical Technology third and fourth editions, esp. volume 20, Martin Grayson, Executive Editor, Wiley-Interscience, Jolin Wiley and Sons, NY, and in the references cited therein ("Kirk-Oώmer"). Common printing methods include lithography, flexography, intaligo, letterpress, screen processes, thermal printing, electrophotography, and ink jet printing.
Ink Jet Printing of Microfluidic Structures
In one preferred method of printing channel walls, well walls and other structural features of microfluidic devices, ink jet printing systems are used. Again, ink jet printing is well described in the patent, engineering and scientific literature, and an introduction to Ink jet technology is found in Kirk-Otlimer, id. and the references cited therein.
In brief, there are at least two general types of ink jet systems, i.e., "continuous stream" and "drop-on-demand" or "impulse". In continuous stream ink jet systems, ink is emitted in a continuous stream under pressure through at least one orifice or nozzle, and often through several separate orifices, e.g., where the ink jet print head has several orifices. The stream is perturbed, causing it to break up into droplets at a fixed distance from the orifice. The size and frequency of droplets is a function of pumping pressure, ink viscosity and nozzle size. Drops not needed for printing are electrostatically charged and deflected into a sump. In contrast, impulse printers generate drops in response to a specific data signal, e.g., from a microprocessor controlling the printing process.
There are two modes for continuous ink jet systems. In the "deflection" system, electrostatic deflection is used to adjust the trajectory of the ink material, permitting droplets to be targeted at a variety of angles for delivery to specific points on a substrate. In contrast, the "binary" system stream has only two trajectories: straight to a target on the substrate material printing the structural features of the microfluidic device (wells, channels, etc.) or into a recirculation unit such as a sump, channel or the like for re-use by the print head. The deflection system is typically used for low- resolution printing, making the binary system preferred for the present invention where a continuous ink jet system is used, as microfluidic structures are best constructed with high resolution printing methods. Since impulse systems require no ink recovery, charging, or deflection, they are much simpler than the continuous stream type. There are also two types of impulse printers. The first type is a piezoelectric ink jet which propels a drop of material by flexing one or more walls in the print mechanism (often referred to as the "firing chamber") to decrease the volume of the material, causing material to be expelled from the print head. The pressure pulse resulting from the volume decrease can be controlled very precisely. The wall which flexes is typically a piezoelectric crystal or a pressure diapliragm driven by a piezoelectric element incorporated into the firing ch.amber.
Although the impulse system is simpler, the relatively large size of the piezoelectric transducer prevents close spacing of the ink jet nozzles, and physical limitations of the transducer results in low ink drop velocity. Low drop velocity diminishes tolerances for drop velocity variation and directionality, impacting the system's ability to produce high resolution microfluidic structures. Drop-on-demand systems which use piezoelectric devices to expel the droplets also suffer the disadvantage of a relatively slow printing speed. However, the technology for piezoelectric ink jet printing is well developed, and can be adapted to making microfluidic structures in the present invention.
The second type of impulse printer is a thermal impulse ink jet which utilizes rapid bubble formation of heated ink to propel drops from the ink jet print head. This system known as thermal ink jet, or bubble jet, and produces high velocity droplets allowing very close spacing of print head nozzles— and thus very high resolutions, making thermal ink jet printing preferred technology for printing fine microfluidic structures such as microchannel walls. The major components of this type of drop-on-demand system are an ink-filled channel having a nozzle on one end and a heat generating resistor near the nozzle. Printing signals representing digital information originate an electric current pulse in a resistive layer within each ink passageway near the orifice or nozzle causing the ink in the immediate vicinity to quickly evaporate creating a bubble in the ink. The ink at the orifice is forced out as a propelled droplet as the bubble expands. When the hydrodynamic motion of the ink stops, the process is ready to start over again. With the introduction of a droplet ejection system based upon thermally generated bubbles, commonly referred to as the "bubble jet" system, the drop-on-demand ink jet printers provide simple, lower cost devices than their continuous stream counterparts, and yet have substantially the same high speed printing capability. In both impulse and continuous stream systems, a print head can incorporate from one to hundreds of ink orifices, with more orifices generally resulting in higher resolution and faster printing speeds.
The selection of which type of ink jet system to apply to printing microfluidic structures in the present invention varies depending on the type of material printed from the print head. For example, high surface tension for the printed material results in good droplet formation. An increase in viscosity requires an increase in the energy required to pump and eject the material. Conductivity is important for continuous stream systems because the droplets are deflected electrostatically; thus, the droplets need to be charged. In contrast, low conductivity is preferred for impulse printing, particularly for thermal printing, because excess ions cause corrosion of the print head. Thus, selection of the material for use in outlining microfluidic structures, which is determined based on the application, is one consideration in determining which printing technology to use. Selection of materials to be printed will vaiy depending on the application.
Where non-aqueous solvents are to be flowed through the microfluidic device, an aqueous material can be used to form channel structures in contact with fluid flow. Often the material will include stabilizing agents such as humectants to inhibit drying of the ink in the printing mechanism. In contrast, where aqueous solutions are to be flowed through the printed microfluidic structures, it is generally less desirable to use an aqueous material for channel printing, to prevent dissolution of the channel by the flow of aqueous solutions. Thermally stable materials are desirable where the microfluidic device operates under a range of temperature conditions (e.g., where the device is used as a thermocycler, i.e., in a polymerase chain reaction (PCR) for DNA amplification. Both aqueous and non-aqueous-solvent based "ink" materials are well
.known. Indeed, ink jet technology has been used to deposit a variety of materials, including liquid metals, fluxes, photoresists, epoxies, UV cured materials, alcohol, acetones, aliphatics, aromatics, dipolar solvents, DNA solutions, antibody solutions, buffers, sol-gels, thermoplastics, particle laden fluids, latex beads, metal particles and the like. See, e.g., Wallace (1996) Laboratory Automation News 1(5): 6-9 and the references therein, where ink-jet based fluid microdispensing in Biochemical Applications is further described. Electrophotography
In another method of printing channel walls, well walls and other structural features of microfluidic devices, electrophotographic systems are used. Again, electrophotography is well described in the patent, engineering and scientific literature. An introduction to electrophotography is found in Kirk-Othmer and the references cited therein. Additional details are found in Schafert (1980) Electrophotography Focal Press Boston MA and in Schein (1993) Electrophotography and Development Physics, Springer- Ver lag, Berlin.
In brief, an electrophotographic system has two physicochemical elements: a photoreceptor and a toner. In the process, a photoconductive photoreceptor is uniformly charged, and the photoreceptor is selectively illuminated to form a latent electrostatic image. The image is then developed by applying a toner. Commonly, the electrostatic image (corresponding to a microfluidic structure or set of structures such as channels, channel walls, wells, etc.) is transferred to a substrate and thermal fusing of the toner on the substrate is performed to fix the image. This is typically followed by optical erasure of the residual charge and removal of residual toner. In application to the invention, the substrate on which the latent image is formed is a substrate of the invention, with the applied toner forming channel structures. One common example of an electrophotographic system is the ubiquitous office copier. Lithography In another method of printing channel walls, well walls and other structural features of microfluidic devices, lithographic or "planographic" systems are used. Again, lithography is well described in the patent, engineering and scientific literature. An introduction to Lithography is found in Kirk-Othmer and the references cited therein. Additional details are found in Hird (1991) Offset Lithographic Technology, Goodheart, New York.
In brief, lithography is a planographic process. Image, or printing areas, and non-image, or non printing reside in the same plane on a lithographic (or "offset") plate (generally made of aluminum or other metals, or of plastic) and are differentiated by the extent to which these areas accept printing ink. The lithographic or offset plate has one or more layers of radiation-sensitive compound. Typically, nonprinting areas are hydrophilic, accepting water and repelling ink while printing areas are oleophilic, repelling water and accepting ink. Reciprocal systems in which nonprinting areas are oleophilic (or hydrophobic), repelling a water-based ink and printing areas are hydrophilic accepting a water-based ink and repelling a hydrophobic solvent are also known. Regions which accept ink are designed to transfer an ink outline of the microfluidic structure (channel, well, etc.) desired, on a substrate of choice.
In the typical lithographic arrangement, water is applied to the surface of the printing plate (generally with various surfactants; the resulting mixture is known as a "fountain" solution) and the ink to be used to construct microfluidic structures is applied to the plate with rollers (or a "roller train"). The plate is typically made from aluminum with a radiation sensitive coating, although a wide variety of metals and polymers can also be used. There are two types of coatings, described based on their response to actinic radiation: positive coatings which degrade in response to radiation (becoming soluble in water or a solvent) and negative coatings which become less soluble in response to radiation (e.g., due to polymerization of the coating). Common radiation sensitive coatings for negative plates include diazo-based coatings, sulfuric acid derived salts and hydrochloric acid-derived salts. Common positive coatings include 1,2- Napthoquinone diazide sulfonic acid esters.
The first step in making the printed image is to contact the radiation sensitive coating with a photographic film, which is then exposed to light in a desired pattern on the plate. The plate is then exposed to a solvent which removes soluble portions of the coating (defined by the image light), revealing the support surface in the selected areas. The surface in the revealed areas of the plate are strongly hydrophilic, repelling oil based materials (or, as described above, are strongly hydrophobic, repelling water-based materials). In the case of a "positive" working plate, it is the unexposed areas that provide the final image; in the case of a "negative" working plate the exposed areas provide the final image. "Waterless" lithography is also useful. In this embodiment, the plates are primed and siliconized, with the siliconized areas typically being "ink" repellant (it will be appreciated that "ink" in this context is the material used to form microfluidic structures). Because there are no problems with solubilization of ink by water, it is possible to create sharper images, and thus finer and more regular microfluidic structures.
"Computer to Plate" lithography, which eliminates the film intermediate step is also performed. In this embodiment, thermal imaging is performed on a high speed photopolymer or silver halide is performed on diazo plates.
"Direct to press" lithography is preformed on a Heidelberg press. In this embodiment, printing plates are directly exposed to the substrate. A waterless printing plate is mounted on four units of a printing press. Each unit also has a laser head that scans the width of a cylinder plate as the plate slowly turns. The laser ablates a surface layer, exposing the "ink" -receptive surface of the plate. Printing can be performed as soon as the plates are ablated and exposed to ink. Gravure
In another method of printing channel walls, well walls and other structural features of microfluidic devices, gravure printing processes are used. Again, gravure is well described in the patent, engineering and scientific literature. An introduction to gravure printing is found in Kirk-Othmer at volume 20, pages 99-101 and the references cited therein.
In brief, in the gravure process, which is also known as "intaligo" and as "rotogravure" utilizes a recessed image plate cylinder to transfer the image to the substrate. The plate cylinder can be either chemically or mechanically etched or engraved to generate the image. The volume of the engraved area determines the height of the microfluidic feature formed on a substrate. The gravure process is very simple, and yields very consistent results. Although the process has fallen out of favor because it is difficult to achieve half tones when printing standard ink images, this difficulty does not generally apply to the construction of features for microfluidic devices— there is generally no need to print a halftone in generating a microfluidic structural feature. Indeed, most features will be the same height and of uniform construction to ensure that the overlay substrate will close the feature, i.e., provide a "top" to a channel.
In the gravure system, a source of material to be printed on a substrate to form features of the invention is regularly contacted to a printing roll. Often the printing roll is squeegeed to ensure an even coating of printing material on the printing roll. The substrate passes between a second image roll having the structural features etched into the roll and the printing roll. The image roll presses the substrate into contact with the printing roll, causing direct transfer of the image to the substrate. Often, an electrostatic assist is used to transfer the print material. The print material typically dries, or sets, by evaporation.
Flexography In another method of printing channel walls, well walls and other structural features of microfluidic devices, flexography is used. Again, flexography is well described in the patent, engineering and scientific literature. An introduction to flexography is found in Kirk-Othmer at volume 20, pages 101-05, and the references cited therein. An advantage of flexography is the ability to print on a wide variety of substrates, including many of those useful in the present invention. For this reason, flexography is primarily used at present by industry to print on unusual surfaces such as cardboard, plastic films, foils, laminates and the like, e.g., for packaging applications. In flexographic printing, a fountain pan supplies printing material to a rubber fountain roll, which in turn supplies material to an anilox roll. The anilox roll is central to the flexographic printing process, typically having a steel core, optionally coated with ceramic. The roll is engraved with cells and/or pits. The function of the anilox roll is to provide uniform "ink" distribution to the plate cylinder, which provides ink to a substrate. A doctor blade typically removes excess ink from the surface of the anilox roll. The printing material is passed between the plate cylinder and an impression cylinder, providing for transfer of the "ink" material to the substrate. There are three primary types of flexographic printing plates: molded rubber, solid sheet photopolymer and liquid photopolymer. Any of these are useful for transfer of material to a substrate of the invention for formation of microfluidic structures such as channel walls and well walls.
"Microcontact" printing, applicable to the present invention is described in U.S. Pat. No. 5,512,121. Letterpress In .another method of printing channel walls, well walls and other structural features of microfluidic devices, letterpress printing is optionally used.
Letterpress is well described in the patent, engineering and scientific literature, and has been used for several hundred years. An introduction to letter press is found in Kirk- Othmer at volume 20, page 105 and the references cited therein. Letterpress is the oldest automated printing process, and is still one of the most precise, mal ing it suitable for printing fine microfluidic structures in the present invention. Letterpress is printed directly by the relief method from cast metal or plates on which the image or printing areas are raised above the non-printing areas. Rollers apply the material to be printed to the surface of the raised areas, which transfer it directly to a substrate. Flat bed cylinder presses are useful, as are the more common rotary presses. Letterpress is less preferred than ink-jet or other methods which use much simpler printing presses.
Screen Printing and Stencil Processes There are two stencil processes in general use: screen printing and stencil duplicating. Screen printing typically used for art reproduction is referred to as "serigraphy" . In one method of printing channel walls, well walls and other structural features of microfluidic devices, screen printing or stencil processes printing are used. These processes are in common use and well described in the patent, engineering and scientific literature, and have been used for several hundred years. An introduction to screen printing and stencil processes is found in Kirk-Otlimer at volume 20, page 105- 106 and the references cited therein. A review of screen printing techniques is found in Appleton (1984) Screen Printing a Literature Review, Pira international, Letterhead, Surrey, U.K. In brief, screen printing is performed manually or by photomechanical means. The screens typically consist of silk or nylon fabric mesh with openings of 40- 120 and often more, openings per lineal centimeter. The screen material is attached to a frame and stretched to provide a smooth surface. The stencil is applied to the bottom side of the screen, i.e., the side in contact with the substrate upon which microfluidic structures are to be printed. The print material is painted onto the screen, and transferred by rubbing the screen (which is in contact with the substrate) with, e.g., a squeegee. Screens typically last for up to about 100,000 printings. Note that in this embodiment, the stencil provides the outline of the portion of the microfluidic structures which are lowest, i.e., the "bottom" of a channel or well, while the unstenciled portion provides the raised areas, i.e., the channel walls. Typically, this results in a channel or well appearing against a background of a solid block of printed material, rather than the well or channel wall having discreet inner and outer walls. Screen printing and Serigraph is also practiced by using rotary screens, made by plating a metal cylinder electrolytically on a steel cylinder, removing the cylinder after plating, applying a polymer coating to the cylinder, exposing it through a positive and a screen, developing the image and etching it. The result is a cylinder having a solid metal in the areas corresponding to raised features on the substrates in the microfluidic devices of the invention, and pores in the non-raised areas. Screen printing (Reviewed in Appleton, supra) is used generally in the manufacture of electrical circuit boards, and for printing textiles. Accordingly, very disparate substrates are easily printed using screen printing methods, making it applicable to the manufacture of microfluidic structures on a wide range of materials.
Thermal Printing
Thermal printing is a generic name for methods that mark a substrate by imagewise heating of special purpose consumable media. Common technologies include direct thermal (wax, transfer, etc.), and diffusion (dye-sublimation). Properties and preferred applications are diverse, but apparatus and processes are similar. For a review See, Kirk-Othmer, supra, at page 106-107 and the references cited therein. See also, Sturge et al. (1989) Image Processes and Materials, 8th edition, Van Nostrad Reinhold Co., Inc., New York; Komersaka and Diamond (1989) in Nonimpact Printing, Graphic Arts Foundation, Pittsburgh, Pa., and McLaughlin (1973) Proceedings of Microelectronic Symposium, San Francisco, CA.
Printheads are common to many thermal printing technologies. The heads are typically page-wide printed circuit-like arrays of uniform resistors. Alternatively, lasers replace printheads for precise thermal printing applications. In "direct" thermal printing, wax overlays are melted to reveal a substrate (e.g., a sheet of the laminate) below the wax. This technology is suitable for making channels wells and the like on substrates having meltable overlays, i.e., the desired microfluidic structure is carved out of the overlay with heat. In "thermal transfer" printing, imagewise transfer of wax or other material to a substrate is performed. This process is in common use for malting transparencies, signs, high quality labels and the like. This process is suitable for printing features on the substrates of the invention. An alternative embodiment, dye- sublimation thermal printing, occurs by submilation, condensation and diffusion. See also, Kirk Oth er, supra, at page 108-109 and the references cited therein, and Hahn and Beck (1980) Proceedings of 5th International Congress on Advances in Non-Impact Printing Technologies, San Diego, CA pp. 441-448. Additional non-printing methods
In addition to the printing methods described above, non-printing methods are also used to form channel structures in the present invention. In particular, thin films with microfluidic structures cut out of the sheet can be applied to a sheet to be laminated, films can be cut, laser etched, or the like after application to a sheet to be laminated, or the microfluidic structures can be applied by hand. Ordinarily, the film will be bonded to at least one sheet of the laminate, and often at least two sheets of the laminate. Similarly, screens or masks comprising microfluidic structures are applied to a sheet to be laminated and coated with an additional material. The screen is then removed, leaving an outline of the microfluidic structure in the additional material. Die or laser cut films comprising microfluidic structures such as microchannels and/or wells are preferred, as are screening and masking methods. Ink Materials
The "ink" materials used in printing microfluidic structures such as channels, wells and the like are selected based upon the intended application. Example materials include e.g. wax (especially thermal wax-based inks useful in all of the thermal processes described herein), laser copier toners, sol-gels, thermoplastics (including PMMAs, Polycarbonates and styrenes), epoxies (including UV curing epoxies), hot melt adhesives, pressure sensitive materials, or photoresist. Particles of materials which enhance fluid flow, or control channel wall size are optionally added.
In certain embodiments, the laminates of the invention comprise separate sheets which are adhered together using an adhesive. As discussed, in preferred embodiments, the adhesive material is the "ink" which is printed on a substrate to form microfluidic strtictures such as channels and wells. In an alternate embodiment, the adhesive can be separate from microfluidic structures, and used simply to bond two or more substrates together. As discussed, adhesive materials can be, e.g. wax (especially thermal wax-based inks), laser copier toners, sol-gels, thermoplastics (including PMMAs, Polycarbonates and styrenes), epoxies (including UV curing epoxies), hot melt adhesives, pressure sensitive materials, or photoresists. Particles of materials which enhance fluid flow, or control channel wall size are optionally added. Bonding can be performed with pressure, RF, UV, thermal or ultrasonic methods, or any combination thereof. The selection of adhesive depends on the nature of the substrate, and upon the nature of the material to which the adhesive material is to be attached. In general, glues, cements, pastes, epoxies, and the like are suitable and widely available, as are mechanical adhesives such as threads, staples and the like. Adhesives are selected based upon the intended application, and it is expected that one of skill is thoroughly familiar with available adhesives and their use. For example, where the application is subjected to water, an adhesive which is waterproof is used. For a discussion of adhesives in particular applications, see, the Adhesives Red Book published by Argus Business, a division of Argus, Inc. Adhesive materials are used as print materials (ink), or are applied separate from print materials to adhere sheets of laminate together.
A wide variety of wax materials, useful in a wide variety of printing processes are known and discussed in the literature. For a brief introduction to waxes, see, Kirk-Otlimer, volume 24 and the references cited therein. Insect and animal-derived waxes include beeswax and various waxes derived from animal fats. Vegetable-derived waxes include candellia, caπiuba, Japan wax, ouricury wax, Douglas-Fir bark wax, rice- bran wax, jojoba, castor wax, bayberry wax, and the like. Mineral waxes include montan wax, peat waxes, ozokerite and ceresin waxes, petroleum waxes (e.g., paraffin waxes consisting primarily of normal alkanes, scale waxes, and microcrystalline waxes), and the like. Synthetic waxes include polyethylene, Fischer-Tropsch (polymethylene), a wide variety of chemically modified hydrocarbon waxes, substituted amide waxes and the like. Waxes have a very wide range of physical properties, with melting temperatures from room temperature to 150°C or higher, a range of viscosities, and the like. The use of waxes in thermal printing processes is well developed as described, supra, Accordingly, waxes have broad applicability as a print material for the construction of microfluidic structures in the present invention.
Sol-gel technologies are well known, and described, e.g., in Kirk-Otlimer, supra at volume 22 and the references cited therein. Sols are dispersions of colloidal particles (nanoscaled elements) in a liquid such as water, or a solvent. Sol particles are typically small enough to remain suspended in the liquid, e.g., by Browninan motion. Gels are viscoelastic bodies that have interconnected pores of submicrometeric dimensions. Sol-gels are used in the preparation of glass, ceramics, composites, plastics or the like by preparation of a sol, gelation of the sol and removal of the liquid suspending the sols. This process is used in the many relatively low-temperature processes for the construction of fibers, films, aerogels, and the like. Three general processes for malting sol-gels are typically used. In the first, gelatination of a dispersion of colloidial particles is performed. In the second, hydrolysis and polycondensation of alkoxide or metal salt precursors is performed. In the third, hydrolysis and polycondensation of alkoxide precursors followed by aging and drying at room temperature is performed. For further details, see, Kirk-Othmer, id. Applied to the present invention, sols are optionally deposited by the printing technologies described supra, followed by gelatination, hydrolysis, polycondensation, or the like.
Resists including photoresists .are described in Kirk-Othmer Chemical Technology third and fourth editions, esp. volume 17 for the third edition and volume 9 for the fourth edition, Martin Grayson, Executive Editor, Wiley-Interscience, John Wiley and Sons, NY, and in the references cited therein. Resists are often temporary, thin coatings applied to the surface of a laminate. The films act like masks that are chemically resistant to deposition of additional materials. Thus, in the context of the invention, the interior portions of microfluidic structures (channels, wells, etc.) are printed or masked on a substrate with a resistive material, and the substrate is coated with an additional material. The resist is then removed, leaving the outline of a desired structure in the additional material. Alternatively, a resistive material can, itself, be the intermediate layer which bonds the laminate together. A variety of screenable resists, including inks, silk, nylon, metal screening materials and the like can be used as resists. Photoresists are particularly preferred. Photoresists typically change chemically when exposed to light (typically UV), becoming more or less soluble in selected solvents. Photoresists can be used in maslting strategies in a manner similar to screenable resists, and can also be used to print microfluidic structures such as such as a channel wall by printing the structure in photoresist .and exposing the photoresist to light (in this application, the photoresist becomes less soluble upon exposure, i.e., due to polymerization).
Theπnoplastics are useful both as ink components, and as substrates upon which microfluidic structures are formed. Plastics are classified as thermoplastic resins or as fhermosetting resins, depending on how the plastic is affected by heat. When heated, thermoplastic resins soften and flow as liquids; when cooled, they solidify. These changes on heating and cooling can be repeated. Thermoplastics are thermally stable in their intended applications. Generally, thermoplastic products are made by melting thermoplastic compounds, and shaping and cooling the melt. When heated, theimosetting resins liquify and then solidity with continued heating due to crosslinking of the plastic during heating. Crosslinking is a permanent change; once molded, a thermoset plastic cannot be reheated and remolded. In contrast, thermoplastics can be reworked. A general introduction to thermoplastics, and to plastics in general, is found in Kirk-Otlimer Encyclopedia of Chemical Technology third and fourth editions, esp. volume 18 and volume 23, Martin Grayson, Executive Editor, Wiley-Interscience, John Wiley and Sons, NY, and in the references cited therein. In the present application, thermoplastic or thermosetting resins are heated and printed on a substrate, e.g., using any of the various thermal printing methods discussed herein.
Many of the resins commonly used as commercial or industrial building materials are thermoplastics. These include crystalline resins such as various polyethelenes, nylons and polyesters, and amorphous thermoplastics such as acrylo-nitrile-butadine-styrene terpolymers (ABS plastics), cellulose acetate, phenylene oxide based resins, polycarbonates, poly(methyl methacrylate) (PMMA), polystyrene, polyvinylchloride (PVC), styrene-acrylonitrile copolymers (SAN) and various urethanes. Raw resins are available from a variety of commercial sources, typically in the form of pellets. Thermoplastics are optionally processed into microfluidic components, or act as substrates such as sheets or panels upon which microfluidic components are printed. Techniques for depositing thermoplastics include printing as discussed above, and can also include extrusion, blown film extnision, cast film extrusion, extrusion of plastic sheets, profile extrusion, extrusion coating, wire coating, injection molding, stnictural foam molding, rotational molding, thermoforming, cast acrylic sheeting, expandable polystyrene molding, foamed polystyrene sheet extrusion, calendaring, thermosetting, reaction injection molding, and the like. See, Kirk-Othmer, supra.
Urethane plastics are an example of useful thermoplastics for use in the present invention. Urethane plastics are optionally used to form sheets, rolls, or other printable substrates, and are also useful as print materials, i.e., when urethane plastics or other thermoplastics are in solution (e.g., in a solvent) they can be sprayed through an ink-jet, or printed using the other methods herein. When printed on a thermoplastic substrate, the interaction of the solvent with the substrate causes the thermoplastic print material to become embedded in the thermoplastic substrate. The properties and methods of malting thermoplastic and thermosetting plastics such as urethanes are known. aKirk-Otahmer and the references cited therein provide a discussion of urethane polymers, e.g. , at volume 23. A variety of manufacturing techniques are known for both thermoplastic and thermosetting urethanes, and polyurethanes and associated solvents, reagents, catalysts and the like are commercially available from J. P. Stevens (East Hampton, MA) as well as other commercial sources such as Al zo, BASF, Dow, Mobay, Olin, Rubicon, Upjolm, Bayer, Takeda, Veba, Eastman, Sun Oil, and other manufacturers known to persons of skill. See also, Kirk Othmer, id. Substrates for Printing An advantage of the present invention is that it provides for a wider choice of substrate materials for use in the microfluidic devices of the invention. In prior art microfluidic devices, channels, wells or the like were typically etched, machined, milled, cut, or formed in injectably molded materials. In contrast, in the present invention, any material can be used as a substrate or sheet in a laminate of the invention, provided the printed material is compatible with the substrate. Typically, substrates can include thin sheets of plastics or other polymers, glass, ceramic, metal, metalloid, organic material, acrylic, MYLAR , or the like, having a substantially flat region. However, it will be appreciated that other materials can also be used, including coated papers, or the like. One of skill will perceive many suitable substrates depending on the application. Substrate selection is performed by considering the environmental operating parameters of the microfluidic device (temperature, pH operation range, salt operation range, need for conductivity if the device is electrokinetic, etc.), considering the properties of the print material (whether it will adhere to the substrate, whether it is caustic, etc.) and by considering the equipment available to the person of skill (e.g., type of printer to be used in laying out microfluidic structures). Many materials suitable for use as substrates or sheets in the laminates of the invention are described, e.g., in Kirk Othmer, id., and the references cited therein. It should be noted that many substrates are made suitable for use in a microfluidic device by applying a coating of material such as was, plastic, silicon, or the like to the surface of the substrate. Continuous Manufacture of Laminates with Printed Layers A particularly preferred feature of the invention is the ability to dramatically speed and simplify manufacturing of microfluidic devices. In particular, materials to be laminated such as plastic or other polymer sheets can be manufactured in large sheets, or rolls. Microfluidic structures are easily printed on these sheets or rolls of material using the printing technology described, supra, and a cover sheet or roll of material can be bonded to the printed sheet as described, supra, to provide laminates having closed microfluidic structures. The sheets or rolls are then cut into smaller sections to provide individual microfluidic devices. This process is optionally performed in a single continuous process, making it possible to generate large quantities of microfluidic devices. Alternatively, any of these operations can be performed separately. This is often desirable, e.g., where the sheets of the laminate are simply purchased from a commercial supplier, and printing, lamination and cutting processes are performed with the purchased sheets in a continuous process. In this regard, it will be appreciated that many polymer sheets, films and the like are widely available.
It will also be appreciated that the continuous manufacture of many polymer sheets and methods of laminating the sheets are well .known, and can be combined with printing, lamination and cutting processes to provide microfluidic devices in a single continuous process. A wide variety of polymer sheet manufacturing techniques are known for producing sheets of polymer material including, e.g., various forms of extrusion, cast film, sheet, and the like. See, e.g., Kirk-Othmer (1996) at volume 19 and the references cited therein for details on these manufacturing techniques. The sheets are optionally laminated by any of a variety of heat, pressure, and adhesive techniques, as described supra and as further described, e.g., in Kirk-Othmer at Volume 14.
Although optionally performed in a single process, it will be appreciated that any of the manufacturing steps are optionally separated, i.e., the planar surface produced using a sheet manufacturing technique can be manufactured, pieces exposed to an appropriate printing technology to form a printed layer and a second sheet of material mated to the printed surface in steps of separate manufacturing processes. However, one advantage of the present invention is that it provides for continuous manufacturing of a laminate.
Cast Film
In operation, cast film extrusion is optionally used with the printing techniques described, supra, in a single continuous process, to create a laminate. In particular, sheets of planar polymer are continuously produced by the extrusion process. Following water cooling on a chill roll, the material is dried and fed past a print head or other printer as described above and a printed layer is formed on the planar surface. A second sheet of material is optionally mated with the printed surface in a single continuous process to form a laminate of the invention. Optionally, the laminate formed by mating the second sheet of material with the printed surface is die-cut to produce a microfluidic device as described above. Sheet
In one embodiment, sheet manufacture is combined with the printing technologies described herein in a single continuous process. In sheet manufacturing, a web of molten plastic is pulled from an extruder die into the nip between two pressure rollers. At the nip, there is a very small rolling bank of melt. Pressure between the rolls is adjusted to produce a sheet of the desired thickness and surface appearance. The necessary amount of pressure depends on the viscosity of the plastic or other polymer. For a given width, thickness depends on the balance between extruder output rate and the take-off rate of pull rolls. A change in either the extruder screw speed or the pull-roll speed affects sheet thickness. A constant thickness across the sheet requires a constant thickness of melt from the die. Sheet extrusion requires that the resin be of high melt viscosity to prevent excessive sag of the melt between the die and the nip. The melt should reach the nip before touching any other part of the middle roll to prevent uncontrolled cooling of the resin. There usually is no need for a high melt temperature to obtain flow through a sheeting die, because die openings are large. Cooling of the sheet is slow because sheeting is thick. Thus, sheet extrusion is suitable to the present invention, because the sheets used as printable surfaces have adequate structural rigidity for their use in microfluidic devices. Further details of sheet manufacturing are found in •Kirk-Otahmer, supra.
In operation, sheet extrusion is optionally used with the printing techniques described supra in a single continuous process to create a laminate. In particular, sheets of planar polymer are continuously produced by the extrusion process. Following cooling, the material is fed past a print head or other printer as described above and a printed layer is formed on the planar surface. A second sheet of material is optionally mated with the printed surface in a single continuous process. Optionally, the laminate formed by mating the second sheet of material with the printed surface is die-cut (or cut by any other .known process) to produce a microfluidic device as described above.
Although described as single processes, it will be appreciated that any of the above continuous process steps are optionally separated, i.e., planar surfaces can be manufactured, exposed to an appropriate printing technology to form a printed layer and a second sheet of material mated to the printed surface in steps of separate manufacturing processes. However, one advantage of the present invention is that it provides for continuous manufacturing of a laminate. Calendaring
In addition to extrusion methods of making sheets for use in the laminates of the invention, calendaring processes can also be used for malting sheeting of uniform thickness from 0.75-0.05 mm after stretching. A calendar has four heavy, large steel rolls, which are usually assembled in an inverted "L" configuration. A two-roll mill, a Banbury mixer, or an extruder melt the resin, which is subsequently transferred to the calendar. Sheet can be made up to about 2.5 m wide and production rates can be as high as 100 m/min. Calendaring is followed by printing, and laminating as described above. As described for other manufacturing methods, a continuous process can be used for making the laminates of the invention, i.e. , the sheets can be calendared, printed and laminated in a single continuous process. Lamination
A variety of mating techniques to form the laminate from commercially available sheets or those manufactured by the processes described above are appropriate, depending on the print material, and all can be used in a continuous process with the manufacture of the sheet and printing of print layers on the sheets, or can be separated from either or both operations. As described supra, a variety of adhesive print materials are suitable, including those described supra.
Additional methods of lamination of two sheets (of polymer, glass or the like) are described in Kirk-Othmer at volume 14. Common types of adhesives used in continuous processes include thermoset polymers such as amino resins, polyesters, and epoxies. Any of these materials can be printed onto a sheet (or other substrate such as glass) as described above, and used as the adhesive between sheets.
"Treating" is a term used by the lamination industry to describe application of these theπnoset polymers to materials to be laminated. As discussed above, in the present invention, these materials are applied by various printing processes to form print layers which adhere sheets of a laminate together. Alternatively, or in conjunction with printing methods, portions of the sheets to be laminated next to regions comprising printed microfluidic structures can have adhesives applied to aid in lamination. In one common embodiment, the print or other adhesive material is passed through a drying oven such as an air flotation oven (see, Kirk-Othmer at pp 1078-1079) to boil off unwanted solvents.
"Collation" is the process by which individual laminate sheets are assembled, i.e., placed in an appropriate physical relationship to each other. In many high-speed processes, the collated sheets are bonded by pressing into a laminate. A variety of presses are known. In one simple embodiment, the sheet with the printed material and the second sheet are fed through a roller to apply pressure between the two sheets. The print material or other adhesive adheres the sheets together. It will be appreciated that this technique has the advantage of forming a laminate of a continuous and uniform thickness, thereby causing microfluidic structures such as channel walls, chambers, wells, well walls and the like to have a uniform height, and to form a good seal between the sheets of the laminate. Similarly, the laminate can be formed simply by laying a sheet on top of the printed layer. Variations of heat and pressure are used, depending on the print material. A variety of other presses are suitable, including flatbed high and low pressure presses.
In a typical embodiment, the sheets of the laminate are heated in the press. The initial heating causes the adhesive resins (and/or the sheets of the laminate) to melt. The applied heat simultaneously causes the resin to polymerize .and cross-link or gel. This is the point at which the curing process becomes dominant over the melt flow process. Dynamic mechanical and dielectric analyses are used to track this transition. With a sufficiently long press cycle, a state of complete cure is achieved. At this point, the laminate is cooled (typically in the press, under pressure, e.g., using a cooling plate). Low pressure processes are especially suitable for the present invention, as microfluidic geometries can be distorted by high pressure processes. Low pressure processes are also generally of short duration, making these processes especially suitable for continuous processing (this is also an advantage in the present invention, as continuous processes are especially economical for manufacture of large numbers of components). Additional Specific Embodiments
The present invention is further illustrated by consideration of the figures. The embodiments exemplified in the figures are provided by way of illustration and not by way of limitation. Those of skill will readily recognize a variety of noncritical parameters which could be changed or modified to yield essentially similar results.
Fig. 1 is a top view of first sheet 5 of a laminate of the invention comprising channel 10. Channel 10 includes raised walls 15 and 20, with the charmel terminating in reservoirs 25 and 30. In operation, second sheet 35 typically overlays the first sheet, thereby providing charmel 10 with a top and bottom portion. For simplicity of illustration, a very simple charmel pattern is depicted; however it will be appreciated that many channel patterns can be produced in accordance with the present invention, including intersecting perpendicular channels, serpentine, saw tooth or any of a variety of other charmel geometries. Substrates are of essentially any size, with area typical dimensions of about 0.5 cm2 to 1000 cm2. Typical sizes are in the range of 0.5-10 cm2, e.g., about 1 to about 5 cm2.
Figs. 2A-2C show a preferred method of making charmel 10. In particular, Fig. 2A shows ink jet printing head 205 spraying material 210 from nozzle 215 to fOatm raised walls 15 and 20 having a defined width a. Fig. 2B shows second sheet 35 in the process of contacting lower sheet 5 to create a closed channel structure for channel 10. In one embodiment depicted in Fig. 2C, spacer clamps 220 and 225 are used to position second sheet 35 and first sheet 5 relative to each other in a manner in which second sheet 35 contacts raised walls 15 and 20, thereby forming charmel 10. Fig. 3 shows an alternative embodiment, in which first sheet 5 comprising raised walls 15 and 20 is laminated to second sheet 35 by pressing the sheets between rollers 305 and 310. In this embodiment, raised walls 15 and 20 are optionally constructed from an adhesive material which bonds sheets 5 and 35. Alternatively, sheets 5 and 35 can be bonded by pressure, heat or a combination of pressure and heat. Sheets 5 and 35 can be fed between rollers 305 and 310 in separate sheets, or in large rolls which are subsequently cut to form individual substrates.
Fig. 4 shows an alternative embodiment comprising spacers 405 and 410 which keep the distance between sheets 5 and 35 constant, thereby keeping the depth of channel 10 uniform. Many additional spacer embodiments .are also appropriate; for example, beads can be incorporated into the material printed onto a substrate. Typical bead spacers range from l-100μm in size, e.g., about 10 μM. Fig. 5 shows a top view of a more complex laminate 500 having top sheet 505 laminated to bottom sheet 510. The laminate includes channels 515-545 which are in fluid communication with each other and with reservoirs 550-580.
Fig. 6 shows a cross sectional view of laminate 600 comprising parallel sheets 605 and 610, raised walls 615-635 and channels 640-655. Sheets 605 and 610 are a constant distance apart, with the distance being defined by, e.g., the viscosity of the material used to construct raised walls 615-635, the pressure used to bond sheets 605 and 610, environmental parameters such as temperature and humidity, and the like.
Fig. 7 shows a masking method of making a charmel on a substrate. Substrate 705 is masked by screen 710 comprising mask 715 which defines charmel region 720. Applicator 725 deposits adhesive material 730 onto screen 710. Screen 710 prevents deposition of adhesive material 730 in channel region 720. After mask 715 is removed from channel region 720, a charmel in channel region 720 results, with walls formed by deposited adhesive material 730. Fig. 8 A and Fig. 8B show an etching or engraving (intaligo) method of forming charmels on a substrate. Plate 805 comprising raised regions 810 and 815 is coated with material 820, resulting in deposits of material 820 in raised regions 810 and 815. Substrate 825 is pressed against plate 805, for example by rollers 830 and 840, resulting in transfer of material 820 from raised regions 810 and 815 to substrate 825, thereby forming raised walls 850 and 855 defining channel 860. In subsequent procedures, a second substrate is laminated to substrate 825 to form a laminate of the invention.
Fig. 9A and Fig. 9B show a "letter press" or "offset" style of forming a channel on a substrate for making a laminate of the invention. Letterpress 905 comprising material 910 presses material 910 onto substrate 915, resulting in the formation of raised charmel walls 920 and 925 which define channel 930. In subsequent procedures, a second substrate is laminated to substrate 915 to form a laminate of the invention.
Figs. 10A- 10C Show charmel formation on a substrate using lithography on a Heidelberg press. In brief, lithographic plate 1005 comprising regions with deposited material 1010 and regions without deposited material 1015 is pressed against substrate 1020, resulting in the formation of raised channel walls 1025-1040 defining channels 1045-1050. As depicted, regions without deposited material 1015 correspond to formation of channels 1045- 1050. In one embodiment, regions of lithographic plate 1005 comprising deposited material 1010 are hydrophobic, while regions without deposited material 1015 are hydrophilic. Where deposited material 1010 is hydrophobic, it is preferentially deposited on the hydrophobic regions of lithographic plate 1005, without depositing on the hydrophilic regions. In a similar variation, regions of lithographic plate 1005 comprising deposited material 1010 are hydrophilic, while regions without deposited material 1015 are hydrophobic. Where deposited material 1010 is hydrophilic, it can be preferentially deposited on the hydrophilic regions of lithographic plate 1005, without depositing on the hydrophobic regions. Fig. 11 depicts a method of making a laminate of the invention by etching a deposited material on the surface of one sheet of the laminate. Roller 1105 rolls material 1110 onto the surface of sheet 1115. Etchant 1120 is applied before or after material 1110 to sheet 1115, either preventing deposition of material 1110, or removing material 1110 after it is deposited. In operation, a second sheet is adhered to sheet 1115, thereby providing a laminate with channels in the pattern etched by etchant 1120.
The present invention is illustrated by the foregoing embodiments, although one of skill will recognize many modifications which fall within the scope of the following claims. All publications and patent applications cited herein are incorporated by reference in their entirety for all purposes, as if each were specifically indicated to be incorporated by reference.

Claims

WHAT IS CLAIMED IS: 1. A laminate comprising: a first surface comprising a first planar section; a second surface comprising a second planar section; and, a first microscale channel disposed between the first planar section and the second planar section, said first channel comprising at least one cross-sectional dimension between about J╬╝m and 500╬╝m, which first channel further comprises a first wall and a second wall in contact with the first planar section and the second planar section, which first and second walls are raised in comparison to the first or second planar surfaces, wherein the first or second wall is bonded to the first or second surface.
2. The laminate of claim 1, wherein the walls are formed from an intermediate printed layer.
3. The laminate of claim 1, wherein the first surface comprises a first coating over a portion of the surface of the first planar section, wherein the first channel is formed in the coating.
4. A laminate comprising: a first surface comprising a first planar section; a second surface comprising a second planar section; an intermediate printed layer on at least one of the first and second planar sections, the intermediate printed layer disposed between the first and second planar sections, the intermediate printed layer defining first and second walls of at least a first microscale charmel, the channel comprising the walls formed by the intermediate printed layer, a portion of the first planar section and a portion of the second planar section.
5. The laminate of claim 1 or 4, wherein the first or second surface is rigid.
6. The laminate of claim 1 or 4, wherein the first or second surface is flexible.
7. The laminate of claim 1 or 4, wherein the first or second wall is between about . l╬╝m and 500╬╝m in height.
8. The laminate of claim 1 or 4, wherein the first or second wall is between about l╬╝m and lOO╬╝m in height.
9. The laminate of claim 1 or 4, wherein the first charmel is a flat- bottomed channel.
10. The laminate of claim 1 or 4, wherein the first channel comprises a top region along a portion of the second planar section, a bottom region portion along a portion of the first planar section, and wherein the bottom region has the same physicochemical properties as the first planar section, and wherein the top portion has the same physicochemical properties as the second planar section.
11. The laminate of claim 1 or 4, wherein the first charmel comprises an angled section and wherein the width of the first channel and the height of the first channel walls in the angled section is optimized to reduce turbulence of a liquid in the channel.
12. The laminate of claim 1 or 4, wherein the first wall and the second wall comprise an adhesive material which bonds the first planar surface and the second planar surface together.
13. The laminate of claim 12, wherein the adhesive material is selected from the group consisting of a wax, a theimoplastic, an epoxy, a pressure sensitive material, and a photoresistive material.
14. The laminate of claim 12, wherein the first channel is formed by printing an adhesive material to form the first and second adhesive walls.
15. The laminate of claim 1 or 4, wherein the first surface and second surface are independently selected from the group consisting of a glass, a polymer, a ceramic, a metalloid, and an organic material.
16. The laminate of claim 1 or 4, wherein the first surface and second surface are independently selected from the group consisting of an acrylic and MYLAR®.
17. The laminate of claim 1 or 4, further comprising a spacer between the first and second surfaces, which spacer provides a uniform separation between the first and second surfaces.
18. The laminate of claim 1 or 4, further comprising an adhesive material which bonds the first and second surfaces together.
19. The laminate of claim 1 or 4, further comprising a clamp which bonds the first and second surfaces together.
20. The laminate of claim 1 or 4, further comprising a second charmel having at least an electrokinetic fluid direction means for moving fluid from the second channel to the first channel.
21. The laminate of claim 1 or 4, fuither comprising a second channel having at least one cross sectional dimension between about . l╬╝m and 500╬╝m, which second charmel intersects with said first channel.
22. The laminate of claim 1 or 4, further comprising a third surface laminated to the second surface and a second channel located between the second surface and the third surface.
23. A method of forming a channel between two surfaces comprising providing a first surface comprising a first planar section; providing a second surface comprising a second planar section; applying a first charmel comprising a first and a second wall to the first or second planar section, wherein the first and second walls are raised in comparison to the first or second planar surfaces, and wherein the first channel comprises at least one cross-sectional diameter between about . l╬╝m and 500╬╝m; and, bonding the first and second planar sections, wherein the first channel is in contact with a portion of the first planar section and a portion of the second planar section.
24. The method of claim 23, wherein the steps of the method are performed in a single continuous process.
25. The method of claim 23, wherein the first channel is applied to the first or second planar section by printing the channel on the first or second planar section.
26. The method of claim 25, wherein an outline of the channel is printed on the first planar section.
27. The method of claim 25, wherein the channel is printed by printing an area to include the channel, and etching the channel out of the printed area.
28. The method of claim 25, wherein the printing method is selected from the group consisting of Serigraph printing, ink jet printing, intaligo printing, offset press printing, and thermal laser printing.
29. The method of claim 23, wherein the first charmel is made by applying a mask comprising a shape corresponding to the first charmel on the first planar section, applying a first coating over the first planar section, and removing the mask, thereby providing the first channel.
30. The method of claim 23, wherein the first charmel is made by applying a first coating over the first planar section, applying a mask onto the first coating, thereby exposing a shape corresponding to the first charmel on the first coating, etching the first channel out of the first coating and removing the mask to provide the first charmel.
31. The method of claim 23, further comprising clamping the first and second surfaces together.
32. The method of claim 23, further comprising providing a spacer between the first and second surfaces to provide a uniform distance between the first and second sections on the first and second surfaces.
33. The method of claim 23, wherein the charmel is applied by printing the channel using a print material selected from the group consisting of a wax, a thermoplastic, an epoxy, a pressure sensitive material, and a photo-resistive material.
34. The method of claim 23, wherein the charmel is laminated between the first and second surfaces.
35. The method of claim 23, wherein the method fuither comprises die cutting the first and second surfaces.
36. The method of claim 23, wherein the method comprises printing the channel on the first or second surface, lamination of the first and second surfaces, thereby providing a laminate with the charmel disposed between the first and second surfaces.
37. The method of claim 23, wherein the method comprises printing the charmel on the first or second surface, lamination of the first and second surfaces, thereby providing a laminate with the channel disposed between the first and second surfaces, and cutting the laminate into at least two pieces, thereby producing two laminates.
PCT/US1998/025028 1997-12-10 1998-11-23 Fabrication of microfluidic circuits by 'printing' techniques WO1999029497A1 (en)

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Cited By (54)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6068752A (en) * 1997-04-25 2000-05-30 Caliper Technologies Corp. Microfluidic devices incorporating improved channel geometries
US6156181A (en) * 1996-04-16 2000-12-05 Caliper Technologies, Corp. Controlled fluid transport microfabricated polymeric substrates
GB2351245A (en) * 1999-06-21 2000-12-27 Univ Hull Chemical apparatus; Electro-osmosis; Preparing solutions
WO2001025137A1 (en) * 1999-10-04 2001-04-12 Nanostream, Inc. Modular microfluidic devices comprising layered circuit board-type substrates
WO2001025138A1 (en) * 1999-10-04 2001-04-12 Nanostream, Inc. Modular microfluidic devices comprising sandwiched stencils
WO2001026812A1 (en) * 1999-10-14 2001-04-19 Ce Resources Pte Ltd Microfluidic structures and methods of fabrication
US6251343B1 (en) 1998-02-24 2001-06-26 Caliper Technologies Corp. Microfluidic devices and systems incorporating cover layers
US6303343B1 (en) 1999-04-06 2001-10-16 Caliper Technologies Corp. Inefficient fast PCR
US6306590B1 (en) 1998-06-08 2001-10-23 Caliper Technologies Corp. Microfluidic matrix localization apparatus and methods
US6306659B1 (en) 1996-06-28 2001-10-23 Caliper Technologies Corp. High throughput screening assay systems in microscale fluidic devices
US6326083B1 (en) 1999-03-08 2001-12-04 Calipher Technologies Corp. Surface coating for microfluidic devices that incorporate a biopolymer resistant moiety
US6447661B1 (en) 1998-10-14 2002-09-10 Caliper Technologies Corp. External material accession systems and methods
US6458259B1 (en) 1999-05-11 2002-10-01 Caliper Technologies Corp. Prevention of surface adsorption in microchannels by application of electric current during pressure-induced flow
US6468761B2 (en) 2000-01-07 2002-10-22 Caliper Technologies, Corp. Microfluidic in-line labeling method for continuous-flow protease inhibition analysis
US6506609B1 (en) 1999-05-17 2003-01-14 Caliper Technologies Corp. Focusing of microparticles in microfluidic systems
US6524790B1 (en) 1997-06-09 2003-02-25 Caliper Technologies Corp. Apparatus and methods for correcting for variable velocity in microfluidic systems
US6537771B1 (en) 1999-10-08 2003-03-25 Caliper Technologies Corp. Use of nernstein voltage sensitive dyes in measuring transmembrane voltage
US6551836B1 (en) 1998-06-08 2003-04-22 Caliper Technologies Corp. Microfluidic devices, systems and methods for performing integrated reactions and separations
US6561208B1 (en) 2000-04-14 2003-05-13 Nanostream, Inc. Fluidic impedances in microfluidic system
US6592821B1 (en) 1999-05-17 2003-07-15 Caliper Technologies Corp. Focusing of microparticles in microfluidic systems
US6613513B1 (en) 1999-02-23 2003-09-02 Caliper Technologies Corp. Sequencing by incorporation
US6613581B1 (en) 1999-08-26 2003-09-02 Caliper Technologies Corp. Microfluidic analytic detection assays, devices, and integrated systems
US6613580B1 (en) 1999-07-06 2003-09-02 Caliper Technologies Corp. Microfluidic systems and methods for determining modulator kinetics
US6649358B1 (en) 1999-06-01 2003-11-18 Caliper Technologies Corp. Microscale assays and microfluidic devices for transporter, gradient induced, and binding activities
US6669831B2 (en) 2000-05-11 2003-12-30 Caliper Technologies Corp. Microfluidic devices and methods to regulate hydrodynamic and electrical resistance utilizing bulk viscosity enhancers
US6733645B1 (en) 2000-04-18 2004-05-11 Caliper Technologies Corp. Total analyte quantitation
US6756019B1 (en) 1998-02-24 2004-06-29 Caliper Technologies Corp. Microfluidic devices and systems incorporating cover layers
US6777184B2 (en) 2000-05-12 2004-08-17 Caliper Life Sciences, Inc. Detection of nucleic acid hybridization by fluorescence polarization
US6814938B2 (en) 2001-05-23 2004-11-09 Nanostream, Inc. Non-planar microfluidic devices and methods for their manufacture
US6827831B1 (en) 1997-08-29 2004-12-07 Callper Life Sciences, Inc. Controller/detector interfaces for microfluidic systems
US6858185B1 (en) 1999-08-25 2005-02-22 Caliper Life Sciences, Inc. Dilutions in high throughput systems with a single vacuum source
US6877892B2 (en) 2002-01-11 2005-04-12 Nanostream, Inc. Multi-stream microfluidic aperture mixers
US6890093B2 (en) 2000-08-07 2005-05-10 Nanostream, Inc. Multi-stream microfludic mixers
US6918309B2 (en) * 2001-01-17 2005-07-19 Irm Llc Sample deposition method and system
US6923907B2 (en) 2002-02-13 2005-08-02 Nanostream, Inc. Separation column devices and fabrication methods
US6935772B2 (en) 2000-08-07 2005-08-30 Nanostream, Inc. Fluidic mixer in microfluidic system
US6981522B2 (en) 2001-06-07 2006-01-03 Nanostream, Inc. Microfluidic devices with distributing inputs
US7033474B1 (en) 1997-04-25 2006-04-25 Caliper Life Sciences, Inc. Microfluidic devices incorporating improved channel geometries
US7037416B2 (en) 2000-01-14 2006-05-02 Caliper Life Sciences, Inc. Method for monitoring flow rate using fluorescent markers
US7192559B2 (en) 2000-08-03 2007-03-20 Caliper Life Sciences, Inc. Methods and devices for high throughput fluid delivery
US7261812B1 (en) 2002-02-13 2007-08-28 Nanostream, Inc. Multi-column separation devices and methods
FR2905690A1 (en) * 2006-09-12 2008-03-14 Saint Gobain METHOD FOR MANUFACTURING MICROFLUIDIC DEVICE
EP1910688A2 (en) * 2005-08-04 2008-04-16 Helicos Biosciences Corporation Multi-channel flow cells
WO2008063124A1 (en) * 2006-11-21 2008-05-29 Gyros Patent Ab Method of bonding a micrifluidic device and a microfluidic device
US7497994B2 (en) 1998-02-24 2009-03-03 Khushroo Gandhi Microfluidic devices and systems incorporating cover layers
US7521186B2 (en) 2000-03-20 2009-04-21 Caliper Lifesciences Inc. PCR compatible nucleic acid sieving matrix
US7723123B1 (en) 2001-06-05 2010-05-25 Caliper Life Sciences, Inc. Western blot by incorporating an affinity purification zone
WO2011009422A1 (en) * 2009-07-21 2011-01-27 Heiko Schwertner Method using non-impact printing processes together with printing fluids that contain active biological molecules to produce sensors and complex analytical systems
FR2954305A1 (en) * 2009-12-21 2011-06-24 Saint Gobain Manufacturing microfluidic device comprising substrate and microstructure, comprises depositing glass frit on first substrate having predefined patterns, and optionally subjecting substrate to heat treatment at temperature of given range
EP2051147A3 (en) * 2007-10-18 2011-06-29 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Method of producing functional service areas on a flat substrate
EP1975120A3 (en) * 2007-03-29 2013-08-21 FUJIFILM Corporation Microchemical chip and method for fabricating the same
EP3677336A1 (en) 2007-09-05 2020-07-08 Caliper Life Sciences Inc. Microfluidic method and system for enzyme inhibition activity screening
WO2021039740A1 (en) * 2019-08-29 2021-03-04 キヤノン株式会社 Microchannel device manufacturing method
US11369968B2 (en) 2017-04-21 2022-06-28 Essenlix Corporation Molecular manipulation and assay with controlled temperature (II)

Families Citing this family (291)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5593852A (en) 1993-12-02 1997-01-14 Heller; Adam Subcutaneous glucose electrode
US6485625B1 (en) * 1995-05-09 2002-11-26 Curagen Corporation Apparatus and method for the generation, separation, detection, and recognition of biopolymer fragments
US6048734A (en) 1995-09-15 2000-04-11 The Regents Of The University Of Michigan Thermal microvalves in a fluid flow method
WO1998045481A1 (en) 1997-04-04 1998-10-15 Caliper Technologies Corporation Closed-loop biochemical analyzers
US6134461A (en) 1998-03-04 2000-10-17 E. Heller & Company Electrochemical analyte
US6103033A (en) 1998-03-04 2000-08-15 Therasense, Inc. Process for producing an electrochemical biosensor
US8974386B2 (en) 1998-04-30 2015-03-10 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US6175752B1 (en) 1998-04-30 2001-01-16 Therasense, Inc. Analyte monitoring device and methods of use
US8465425B2 (en) 1998-04-30 2013-06-18 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8346337B2 (en) 1998-04-30 2013-01-01 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US6949816B2 (en) 2003-04-21 2005-09-27 Motorola, Inc. Semiconductor component having first surface area for electrically coupling to a semiconductor chip and second surface area for electrically coupling to a substrate, and method of manufacturing same
US9066695B2 (en) 1998-04-30 2015-06-30 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8688188B2 (en) 1998-04-30 2014-04-01 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8480580B2 (en) 1998-04-30 2013-07-09 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US6794197B1 (en) * 1998-07-14 2004-09-21 Zyomyx, Inc. Microdevice and method for detecting a characteristic of a fluid
US7640083B2 (en) * 2002-11-22 2009-12-29 Monroe David A Record and playback system for aircraft
US6585939B1 (en) * 1999-02-26 2003-07-01 Orchid Biosciences, Inc. Microstructures for use in biological assays and reactions
US6749814B1 (en) 1999-03-03 2004-06-15 Symyx Technologies, Inc. Chemical processing microsystems comprising parallel flow microreactors and methods for using same
US6624273B1 (en) * 1999-03-19 2003-09-23 3M Innovative Properties Company Plasticized acrylics for pressure sensitive adhesive applications
JP2001033427A (en) * 1999-07-16 2001-02-09 Hitachi Software Eng Co Ltd Electrophoresis method and device
AU6117700A (en) * 1999-07-23 2001-02-13 Board Of Trustees Of The University Of Illinois, The Microfabricated devices and method of manufacturing the same
US20020112961A1 (en) * 1999-12-02 2002-08-22 Nanostream, Inc. Multi-layer microfluidic device fabrication
US7485454B1 (en) * 2000-03-10 2009-02-03 Bioprocessors Corp. Microreactor
US6481453B1 (en) 2000-04-14 2002-11-19 Nanostream, Inc. Microfluidic branch metering systems and methods
US20030054140A1 (en) * 2000-05-18 2003-03-20 Keizaburo Matsumoto Printed matter, its application and production method therefor
WO2002009483A1 (en) * 2000-07-26 2002-01-31 The Regents Of The University Of California Manipulation of live cells and inorganic objects with optical micro beam arrays
US7027683B2 (en) 2000-08-15 2006-04-11 Nanostream, Inc. Optical devices with fluidic systems
DE60103415D1 (en) 2000-09-29 2004-06-24 Nanostream Inc MICROFLUIDIC DEVICE FOR HEAT TRANSFER
US6827095B2 (en) * 2000-10-12 2004-12-07 Nanostream, Inc. Modular microfluidic systems
US6536477B1 (en) 2000-10-12 2003-03-25 Nanostream, Inc. Fluidic couplers and modular microfluidic systems
US20030057092A1 (en) * 2000-10-31 2003-03-27 Caliper Technologies Corp. Microfluidic methods, devices and systems for in situ material concentration
US20050011761A1 (en) * 2000-10-31 2005-01-20 Caliper Technologies Corp. Microfluidic methods, devices and systems for in situ material concentration
EP1334279A1 (en) 2000-11-06 2003-08-13 Nanostream, Inc. Uni-directional flow microfluidic components
EP1331997B1 (en) 2000-11-06 2004-06-16 Nanostream, Inc. Microfluidic flow control devices
DE10055374B4 (en) * 2000-11-08 2006-03-02 Bartels Mikrotechnik Gmbh Distributor plate for liquids and gases
US20020079220A1 (en) * 2000-11-09 2002-06-27 Pawliszyn Janusz B. Micromachining using printing technology
US6778724B2 (en) * 2000-11-28 2004-08-17 The Regents Of The University Of California Optical switching and sorting of biological samples and microparticles transported in a micro-fluidic device, including integrated bio-chip devices
US6560471B1 (en) 2001-01-02 2003-05-06 Therasense, Inc. Analyte monitoring device and methods of use
US20020108860A1 (en) * 2001-01-15 2002-08-15 Staats Sau Lan Tang Fabrication of polymeric microfluidic devices
US6681788B2 (en) 2001-01-29 2004-01-27 Caliper Technologies Corp. Non-mechanical valves for fluidic systems
US20020100714A1 (en) * 2001-01-31 2002-08-01 Sau Lan Tang Staats Microfluidic devices
US6692700B2 (en) 2001-02-14 2004-02-17 Handylab, Inc. Heat-reduction methods and systems related to microfluidic devices
WO2002103323A2 (en) * 2001-02-15 2002-12-27 Caliper Technologies Corp. Microfluidic systems with enhanced detection systems
US7670559B2 (en) * 2001-02-15 2010-03-02 Caliper Life Sciences, Inc. Microfluidic systems with enhanced detection systems
US6720148B1 (en) 2001-02-22 2004-04-13 Caliper Life Sciences, Inc. Methods and systems for identifying nucleotides by primer extension
US7867776B2 (en) * 2001-03-02 2011-01-11 Caliper Life Sciences, Inc. Priming module for microfluidic chips
US7150999B1 (en) 2001-03-09 2006-12-19 Califer Life Sciences, Inc. Process for filling microfluidic channels
WO2002072264A1 (en) * 2001-03-09 2002-09-19 Biomicro Systems, Inc. Method and system for microfluidic interfacing to arrays
US8895311B1 (en) 2001-03-28 2014-11-25 Handylab, Inc. Methods and systems for control of general purpose microfluidic devices
US6852287B2 (en) 2001-09-12 2005-02-08 Handylab, Inc. Microfluidic devices having a reduced number of input and output connections
US7323140B2 (en) 2001-03-28 2008-01-29 Handylab, Inc. Moving microdroplets in a microfluidic device
US7829025B2 (en) 2001-03-28 2010-11-09 Venture Lending & Leasing Iv, Inc. Systems and methods for thermal actuation of microfluidic devices
US7010391B2 (en) 2001-03-28 2006-03-07 Handylab, Inc. Methods and systems for control of microfluidic devices
US20040132166A1 (en) * 2001-04-10 2004-07-08 Bioprocessors Corp. Determination and/or control of reactor environmental conditions
US20040058437A1 (en) * 2001-04-10 2004-03-25 Rodgers Seth T. Materials and reactor systems having humidity and gas control
US20050032204A1 (en) * 2001-04-10 2005-02-10 Bioprocessors Corp. Microreactor architecture and methods
US20040058407A1 (en) * 2001-04-10 2004-03-25 Miller Scott E. Reactor systems having a light-interacting component
US6418968B1 (en) 2001-04-20 2002-07-16 Nanostream, Inc. Porous microfluidic valves
US7318912B2 (en) * 2001-06-07 2008-01-15 Nanostream, Inc. Microfluidic systems and methods for combining discrete fluid volumes
US6919046B2 (en) * 2001-06-07 2005-07-19 Nanostream, Inc. Microfluidic analytical devices and methods
US6729352B2 (en) 2001-06-07 2004-05-04 Nanostream, Inc. Microfluidic synthesis devices and methods
US20020187557A1 (en) * 2001-06-07 2002-12-12 Hobbs Steven E. Systems and methods for introducing samples into microfluidic devices
US6811695B2 (en) * 2001-06-07 2004-11-02 Nanostream, Inc. Microfluidic filter
US20020186263A1 (en) * 2001-06-07 2002-12-12 Nanostream, Inc. Microfluidic fraction collectors
US20020187564A1 (en) * 2001-06-08 2002-12-12 Caliper Technologies Corp. Microfluidic library analysis
US6977163B1 (en) 2001-06-13 2005-12-20 Caliper Life Sciences, Inc. Methods and systems for performing multiple reactions by interfacial mixing
US7077152B2 (en) * 2001-07-07 2006-07-18 Nanostream, Inc. Microfluidic metering systems and methods
ATE465811T1 (en) * 2001-07-13 2010-05-15 Caliper Life Sciences Inc METHOD FOR SEPARATING COMPONENTS OF A MIXTURE
US6825127B2 (en) 2001-07-24 2004-11-30 Zarlink Semiconductor Inc. Micro-fluidic devices
US6977138B2 (en) 2001-07-24 2005-12-20 Massachusetts Institute Of Technology Reactive polymer coatings
US7060171B1 (en) 2001-07-31 2006-06-13 Caliper Life Sciences, Inc. Methods and systems for reducing background signal in assays
WO2003020946A2 (en) * 2001-08-14 2003-03-13 The Penn State Research Foundation Fabrication of molecular scale devices using fluidic assembly
US20030040129A1 (en) * 2001-08-20 2003-02-27 Shah Haresh P. Binding assays using magnetically immobilized arrays
US20030087198A1 (en) * 2001-09-19 2003-05-08 Dharmatilleke Saman Mangala Three-dimensional polymer nano/micro molding by sacrificial layer technique
EP1296133A1 (en) * 2001-09-21 2003-03-26 Jean Brunner Miniature device for transport and analysis of a liquid sample and fabrication method therefor
US7524528B2 (en) * 2001-10-05 2009-04-28 Cabot Corporation Precursor compositions and methods for the deposition of passive electrical components on a substrate
KR20040077655A (en) * 2001-10-19 2004-09-06 슈페리어 마이크로파우더스 엘엘씨 Tape compositions for the deposition of electronic features
US6663697B1 (en) * 2001-11-02 2003-12-16 Sandia Corporation Microfabricated packed gas chromatographic column
US7553512B2 (en) * 2001-11-02 2009-06-30 Cabot Corporation Method for fabricating an inorganic resistor
US7247274B1 (en) 2001-11-13 2007-07-24 Caliper Technologies Corp. Prevention of precipitate blockage in microfluidic channels
US7069952B1 (en) * 2001-11-14 2006-07-04 Caliper Life Sciences, Inc. Microfluidic devices and methods of their manufacture
US20030098661A1 (en) * 2001-11-29 2003-05-29 Ken Stewart-Smith Control system for vehicle seats
WO2003050035A2 (en) * 2001-12-06 2003-06-19 Nanostream, Inc. Adhesiveless microfluidic device fabrication
CA2468537C (en) * 2001-12-11 2008-09-16 The Procter & Gamble Company Process for making pre-formed objects
US20030113730A1 (en) * 2001-12-18 2003-06-19 Daquino Lawrence J. Pulse jet print head having multiple printhead dies and methods for use in the manufacture of biopolymeric arrays
US6739576B2 (en) 2001-12-20 2004-05-25 Nanostream, Inc. Microfluidic flow control device with floating element
US7244393B2 (en) 2001-12-21 2007-07-17 Kimberly-Clark Worldwide, Inc. Diagnostic device and system
US8367013B2 (en) * 2001-12-24 2013-02-05 Kimberly-Clark Worldwide, Inc. Reading device, method, and system for conducting lateral flow assays
KR100855884B1 (en) * 2001-12-24 2008-09-03 엘지디스플레이 주식회사 Align Key for Liquid Crystal Display Device
US20030119203A1 (en) * 2001-12-24 2003-06-26 Kimberly-Clark Worldwide, Inc. Lateral flow assay devices and methods for conducting assays
US20040109793A1 (en) * 2002-02-07 2004-06-10 Mcneely Michael R Three-dimensional microfluidics incorporating passive fluid control structures
US6814859B2 (en) * 2002-02-13 2004-11-09 Nanostream, Inc. Frit material and bonding method for microfluidic separation devices
AU2003215340A1 (en) * 2002-02-22 2003-09-09 Nanostream, Inc. Ratiometric dilution devices and methods
US6845787B2 (en) * 2002-02-23 2005-01-25 Nanostream, Inc. Microfluidic multi-splitter
US7459127B2 (en) * 2002-02-26 2008-12-02 Siemens Healthcare Diagnostics Inc. Method and apparatus for precise transfer and manipulation of fluids by centrifugal and/or capillary forces
EP1483577B1 (en) * 2002-03-05 2015-01-07 Siemens Healthcare Diagnostics Inc. Absorbing organic reagents into diagnostic test devices by formation of amine salt complexes
CA2477702A1 (en) * 2002-03-05 2003-09-18 Caliper Life Sciences, Inc. Mixed mode microfluidic systems abstract of the disclosure
US20040017078A1 (en) * 2002-04-02 2004-01-29 Karp Christoph D. Connectors for microfluidic devices
US7419784B2 (en) * 2002-04-02 2008-09-02 Dubrow Robert S Methods, systems and apparatus for separation and isolation of one or more sample components of a sample biological material
US20050026134A1 (en) * 2002-04-10 2005-02-03 Bioprocessors Corp. Systems and methods for control of pH and other reactor environment conditions
US8383342B2 (en) 2002-04-24 2013-02-26 The University Of North Carolina At Greensboro Compositions, products, methods and systems to monitor water and other ecosystems
US8048623B1 (en) 2002-04-24 2011-11-01 The University Of North Carolina At Greensboro Compositions, products, methods and systems to monitor water and other ecosystems
US9126165B1 (en) 2002-04-24 2015-09-08 The University Of North Carolina At Greensboro Nucleic acid arrays to monitor water and other ecosystems
US6996932B2 (en) * 2002-05-17 2006-02-14 Kruer Thomas R Unitized mat to facilitate growing plants
JP2006501860A (en) 2002-05-22 2006-01-19 プラティパス テクノロジーズ エルエルシー Substrates, devices and methods for assaying cells
US20030223913A1 (en) * 2002-06-03 2003-12-04 Nanostream, Inc. Microfluidic separation devices and methods
US20050106714A1 (en) * 2002-06-05 2005-05-19 Zarur Andrey J. Rotatable reactor systems and methods
US7161356B1 (en) 2002-06-05 2007-01-09 Caliper Life Sciences, Inc. Voltage/current testing equipment for microfluidic devices
US20040005247A1 (en) * 2002-07-03 2004-01-08 Nanostream, Inc. Microfluidic closed-end metering systems and methods
US7517440B2 (en) 2002-07-17 2009-04-14 Eksigent Technologies Llc Electrokinetic delivery systems, devices and methods
US7235164B2 (en) * 2002-10-18 2007-06-26 Eksigent Technologies, Llc Electrokinetic pump having capacitive electrodes
US7364647B2 (en) * 2002-07-17 2008-04-29 Eksigent Technologies Llc Laminated flow device
EP1546026A4 (en) * 2002-07-19 2006-11-15 Univ Colorado Fabrication of 3d photopolymeric devices
US20040018115A1 (en) * 2002-07-29 2004-01-29 Nanostream, Inc. Fault tolerant detection regions in microfluidic systems
JP2004075567A (en) * 2002-08-12 2004-03-11 Idemitsu Kosan Co Ltd Oligoarylene derivative and organic electroluminescent element using the same
US7432105B2 (en) * 2002-08-27 2008-10-07 Kimberly-Clark Worldwide, Inc. Self-calibration system for a magnetic binding assay
US7285424B2 (en) 2002-08-27 2007-10-23 Kimberly-Clark Worldwide, Inc. Membrane-based assay devices
US20040053237A1 (en) * 2002-09-13 2004-03-18 Yingjie Liu Microfluidic channels with attached biomolecules
TW590982B (en) * 2002-09-27 2004-06-11 Agnitio Science & Technology I Micro-fluid driving device
US7135728B2 (en) * 2002-09-30 2006-11-14 Nanosys, Inc. Large-area nanoenabled macroelectronic substrates and uses therefor
AU2003283973B2 (en) 2002-09-30 2008-10-30 Oned Material Llc Large-area nanoenabled macroelectronic substrates and uses therefor
US20040072334A1 (en) * 2002-10-15 2004-04-15 The Regents Of The University Of California Thermal cycler
US20090209030A1 (en) * 2002-10-15 2009-08-20 Benett William J Thermal Cycler
US20040082058A1 (en) * 2002-10-29 2004-04-29 Arthur Schleifer Array hybridization apparatus and method for making uniform sample volumes
US7010964B2 (en) * 2002-10-31 2006-03-14 Nanostream, Inc. Pressurized microfluidic devices with optical detection regions
AU2003287449A1 (en) * 2002-10-31 2004-05-25 Nanostream, Inc. Parallel detection chromatography systems
US6936167B2 (en) * 2002-10-31 2005-08-30 Nanostream, Inc. System and method for performing multiple parallel chromatographic separations
GB2395196B (en) * 2002-11-14 2006-12-27 Univ Cardiff Microfluidic device and methods for construction and application
US20040106190A1 (en) * 2002-12-03 2004-06-03 Kimberly-Clark Worldwide, Inc. Flow-through assay devices
US7147695B2 (en) * 2002-12-13 2006-12-12 New Jersey Institute Of Technology Microfabricated microconcentrator for sensors and gas chromatography
US6875553B2 (en) * 2002-12-18 2005-04-05 Xerox Corporation Method of casting photoresist onto substrates
US20040120836A1 (en) * 2002-12-18 2004-06-24 Xunhu Dai Passive membrane microvalves
US7247500B2 (en) * 2002-12-19 2007-07-24 Kimberly-Clark Worldwide, Inc. Reduction of the hook effect in membrane-based assay devices
US7125711B2 (en) * 2002-12-19 2006-10-24 Bayer Healthcare Llc Method and apparatus for splitting of specimens into multiple channels of a microfluidic device
US7094354B2 (en) * 2002-12-19 2006-08-22 Bayer Healthcare Llc Method and apparatus for separation of particles in a microfluidic device
CN100439515C (en) * 2003-03-03 2008-12-03 清华大学 Laboratory nucleic acid analyzing chip system and its application
US20040179972A1 (en) * 2003-03-14 2004-09-16 Nanostream, Inc. Systems and methods for detecting manufacturing defects in microfluidic devices
US7041481B2 (en) 2003-03-14 2006-05-09 The Regents Of The University Of California Chemical amplification based on fluid partitioning
US7851209B2 (en) 2003-04-03 2010-12-14 Kimberly-Clark Worldwide, Inc. Reduction of the hook effect in assay devices
US20040197819A1 (en) * 2003-04-03 2004-10-07 Kimberly-Clark Worldwide, Inc. Assay devices that utilize hollow particles
US20040214310A1 (en) * 2003-04-25 2004-10-28 Parker Russell A. Apparatus and method for array alignment
CN1280428C (en) * 2003-05-19 2006-10-18 清华大学 Biochip system based on minute particle and its application
US7435381B2 (en) * 2003-05-29 2008-10-14 Siemens Healthcare Diagnostics Inc. Packaging of microfluidic devices
EP1628748A2 (en) * 2003-06-05 2006-03-01 Bioprocessors Corporation Reactor with memory component
US20040265172A1 (en) * 2003-06-27 2004-12-30 Pugia Michael J. Method and apparatus for entry and storage of specimens into a microfluidic device
US20080257754A1 (en) * 2003-06-27 2008-10-23 Pugia Michael J Method and apparatus for entry of specimens into a microfluidic device
US20040265171A1 (en) * 2003-06-27 2004-12-30 Pugia Michael J. Method for uniform application of fluid into a reactive reagent area
EP1654066B1 (en) 2003-07-31 2014-11-12 Handylab, Inc. Processing particle-containing samples
US7028536B2 (en) * 2004-06-29 2006-04-18 Nanostream, Inc. Sealing interface for microfluidic device
US20050032238A1 (en) * 2003-08-07 2005-02-10 Nanostream, Inc. Vented microfluidic separation devices and methods
US7347617B2 (en) * 2003-08-19 2008-03-25 Siemens Healthcare Diagnostics Inc. Mixing in microfluidic devices
JP2005077284A (en) * 2003-09-01 2005-03-24 Seiko Epson Corp Manufacturing device and method for particle array, and method of detecting target substance
US20050069462A1 (en) * 2003-09-30 2005-03-31 International Business Machines Corporation Microfluidics Packaging
US20050069949A1 (en) * 2003-09-30 2005-03-31 International Business Machines Corporation Microfabricated Fluidic Structures
US20050112703A1 (en) 2003-11-21 2005-05-26 Kimberly-Clark Worldwide, Inc. Membrane-based lateral flow assay devices that utilize phosphorescent detection
US7943395B2 (en) * 2003-11-21 2011-05-17 Kimberly-Clark Worldwide, Inc. Extension of the dynamic detection range of assay devices
US7713748B2 (en) * 2003-11-21 2010-05-11 Kimberly-Clark Worldwide, Inc. Method of reducing the sensitivity of assay devices
US20050136550A1 (en) * 2003-12-19 2005-06-23 Kimberly-Clark Worldwide, Inc. Flow control of electrochemical-based assay devices
US7943089B2 (en) * 2003-12-19 2011-05-17 Kimberly-Clark Worldwide, Inc. Laminated assay devices
US20050196761A1 (en) * 2004-03-08 2005-09-08 Thompson Allen C. Array hybridization apparatus and method
US20050202445A1 (en) * 2004-03-09 2005-09-15 Thompson Allen C. Thermoplastic array hybridization apparatus and method
US7559356B2 (en) * 2004-04-19 2009-07-14 Eksident Technologies, Inc. Electrokinetic pump driven heat transfer system
US7815854B2 (en) * 2004-04-30 2010-10-19 Kimberly-Clark Worldwide, Inc. Electroluminescent illumination source for optical detection systems
US20060019265A1 (en) * 2004-04-30 2006-01-26 Kimberly-Clark Worldwide, Inc. Transmission-based luminescent detection systems
US7796266B2 (en) * 2004-04-30 2010-09-14 Kimberly-Clark Worldwide, Inc. Optical detection system using electromagnetic radiation to detect presence or quantity of analyte
US20050244953A1 (en) * 2004-04-30 2005-11-03 Kimberly-Clark Worldwide, Inc. Techniques for controlling the optical properties of assay devices
AU2005241080B2 (en) 2004-05-03 2011-08-11 Handylab, Inc. Processing polynucleotide-containing samples
US8852862B2 (en) 2004-05-03 2014-10-07 Handylab, Inc. Method for processing polynucleotide-containing samples
US7758814B2 (en) * 2004-06-05 2010-07-20 Freeslate, Inc. Microfluidic fluid distribution manifold for use with multi-channel reactor systems
EP1758674A2 (en) * 2004-06-07 2007-03-07 Bioprocessors Corporation Creation of shear in a reactor
WO2005120698A2 (en) * 2004-06-07 2005-12-22 Bioprocessors Corp. Control of reactor environmental conditions
WO2005120691A1 (en) * 2004-06-07 2005-12-22 Bioprocessors Corp. Reactor mixing
WO2005121307A2 (en) * 2004-06-07 2005-12-22 Bioprocessor Corp. Gas control in a microreactor
US7521226B2 (en) * 2004-06-30 2009-04-21 Kimberly-Clark Worldwide, Inc. One-step enzymatic and amine detection technique
US7837821B2 (en) 2004-10-13 2010-11-23 Rheonix, Inc. Laminated microfluidic structures and method for making
US7608160B2 (en) * 2004-10-13 2009-10-27 Rheonix, Inc. Laminated microfluidic structures and method for making
EP1706467B1 (en) * 2004-10-13 2011-08-24 Rheonix, Inc. Laminated microfluidic structures and method for making
US8695355B2 (en) 2004-12-08 2014-04-15 California Institute Of Technology Thermal management techniques, apparatus and methods for use in microfluidic devices
US20070012891A1 (en) * 2004-12-08 2007-01-18 George Maltezos Prototyping methods and devices for microfluidic components
US20070121113A1 (en) * 2004-12-22 2007-05-31 Cohen David S Transmission-based optical detection systems
US7682817B2 (en) * 2004-12-23 2010-03-23 Kimberly-Clark Worldwide, Inc. Microfluidic assay devices
WO2006072167A1 (en) * 2005-01-03 2006-07-13 Questair Technologies Inc. Method for making parallel passage contactors
US7736592B2 (en) * 2005-01-10 2010-06-15 Ohmcraft, Inc. Microfluidic devices fabricated by direct thick film writing and methods thereof
US8334464B2 (en) 2005-01-14 2012-12-18 Cabot Corporation Optimized multi-layer printing of electronics and displays
WO2006076609A2 (en) 2005-01-14 2006-07-20 Cabot Corporation Printable electronic features on non-uniform substrate and processes for making same
US8383014B2 (en) 2010-06-15 2013-02-26 Cabot Corporation Metal nanoparticle compositions
US7824466B2 (en) 2005-01-14 2010-11-02 Cabot Corporation Production of metal nanoparticles
TW200640596A (en) * 2005-01-14 2006-12-01 Cabot Corp Production of metal nanoparticles
US8529738B2 (en) * 2005-02-08 2013-09-10 The Trustees Of Columbia University In The City Of New York In situ plating and etching of materials covered with a surface film
US8496799B2 (en) * 2005-02-08 2013-07-30 The Trustees Of Columbia University In The City Of New York Systems and methods for in situ annealing of electro- and electroless platings during deposition
US7670882B2 (en) * 2005-04-05 2010-03-02 Hewlett-Packard Development Company, L.P. Electronic device fabrication
KR20080005947A (en) * 2005-04-08 2008-01-15 더 트러스티스 오브 콜롬비아 유니버시티 인 더 시티 오브 뉴욕 Systems and methods for monitoring plating and etching baths
US7658470B1 (en) 2005-04-28 2010-02-09 Hewlett-Packard Development Company, L.P. Method of using a flexible circuit
US20100261286A1 (en) * 2005-07-14 2010-10-14 Young Hoon Kim Microfluidic devices and methods of preparing and using the same
WO2007027907A2 (en) * 2005-09-02 2007-03-08 The Trustees Of Columbia University In The City Of New York A system and method for obtaining anisotropic etching of patterned substrates
WO2007062182A2 (en) * 2005-11-23 2007-05-31 Eksigent Technologies, Llp Electrokinetic pump designs and drug delivery systems
JP2009524170A (en) 2006-01-24 2009-06-25 マイクロラボ ピーティーワイ エルティーディー Method for producing complex layered materials and devices at low cost
US8883490B2 (en) 2006-03-24 2014-11-11 Handylab, Inc. Fluorescence detector for microfluidic diagnostic system
WO2007112114A2 (en) 2006-03-24 2007-10-04 Handylab, Inc. Integrated system for processing microfluidic samples, and method of using same
US7998708B2 (en) 2006-03-24 2011-08-16 Handylab, Inc. Microfluidic system for amplifying and detecting polynucleotides in parallel
US10900066B2 (en) 2006-03-24 2021-01-26 Handylab, Inc. Microfluidic system for amplifying and detecting polynucleotides in parallel
US7909928B2 (en) * 2006-03-24 2011-03-22 The Regents Of The University Of Michigan Reactive coatings for regioselective surface modification
US11806718B2 (en) 2006-03-24 2023-11-07 Handylab, Inc. Fluorescence detector for microfluidic diagnostic system
US8137626B2 (en) * 2006-05-19 2012-03-20 California Institute Of Technology Fluorescence detector, filter device and related methods
US7947148B2 (en) * 2006-06-01 2011-05-24 The Regents Of The University Of Michigan Dry adhesion bonding
US20080003696A1 (en) * 2006-06-30 2008-01-03 Andrew Rae Embossed reagent card
WO2008014825A1 (en) * 2006-08-03 2008-02-07 Agilent Technologies, Inc. Channelless fluidic sample transport medium
EP2057277B1 (en) 2006-08-07 2018-06-13 Platypus Technologies, LLC Substrates, devices, and methods for cellular assays
US8497308B2 (en) 2006-09-05 2013-07-30 Velocys, Inc. Integrated microchannel synthesis and separation
US7820725B2 (en) * 2006-09-05 2010-10-26 Velocys, Inc. Integrated microchannel synthesis and separation
WO2008036614A1 (en) * 2006-09-18 2008-03-27 California Institute Of Technology Apparatus for detecting target molecules and related methods
US7814928B2 (en) * 2006-10-10 2010-10-19 California Institute Of Technology Microfluidic devices and related methods and systems
KR101611240B1 (en) 2006-10-25 2016-04-11 프로테우스 디지털 헬스, 인코포레이티드 Controlled activation ingestible identifier
WO2008061165A2 (en) 2006-11-14 2008-05-22 Handylab, Inc. Microfluidic cartridge and method of making same
US20080131590A1 (en) * 2006-12-04 2008-06-05 Illinois Tool Works Inc. Method for printing electrically conductive circuits
JP5185948B2 (en) * 2006-12-06 2013-04-17 ザ トラスティーズ オブ コロンビア ユニヴァーシティ イン ザ シティ オブ ニューヨーク Microfluidic system and method for screening plating and etching bath compositions
US7867592B2 (en) 2007-01-30 2011-01-11 Eksigent Technologies, Inc. Methods, compositions and devices, including electroosmotic pumps, comprising coated porous surfaces
US7799656B2 (en) 2007-03-15 2010-09-21 Dalsa Semiconductor Inc. Microchannels for BioMEMS devices
US8399047B2 (en) * 2007-03-22 2013-03-19 The Regents Of The Univeristy Of Michigan Multifunctional CVD coatings
US9186677B2 (en) 2007-07-13 2015-11-17 Handylab, Inc. Integrated apparatus for performing nucleic acid extraction and diagnostic testing on multiple biological samples
USD621060S1 (en) 2008-07-14 2010-08-03 Handylab, Inc. Microfluidic cartridge
US8182763B2 (en) 2007-07-13 2012-05-22 Handylab, Inc. Rack for sample tubes and reagent holders
US8133671B2 (en) 2007-07-13 2012-03-13 Handylab, Inc. Integrated apparatus for performing nucleic acid extraction and diagnostic testing on multiple biological samples
US20090136385A1 (en) 2007-07-13 2009-05-28 Handylab, Inc. Reagent Tube
US8105783B2 (en) 2007-07-13 2012-01-31 Handylab, Inc. Microfluidic cartridge
US8324372B2 (en) 2007-07-13 2012-12-04 Handylab, Inc. Polynucleotide capture materials, and methods of using same
US8287820B2 (en) 2007-07-13 2012-10-16 Handylab, Inc. Automated pipetting apparatus having a combined liquid pump and pipette head system
US9618139B2 (en) 2007-07-13 2017-04-11 Handylab, Inc. Integrated heater and magnetic separator
US8016260B2 (en) 2007-07-19 2011-09-13 Formulatrix, Inc. Metering assembly and method of dispensing fluid
WO2009076134A1 (en) * 2007-12-11 2009-06-18 Eksigent Technologies, Llc Electrokinetic pump with fixed stroke volume
US8039817B2 (en) 2008-05-05 2011-10-18 Illumina, Inc. Compensator for multiple surface imaging
USD618820S1 (en) 2008-07-11 2010-06-29 Handylab, Inc. Reagent holder
USD787087S1 (en) 2008-07-14 2017-05-16 Handylab, Inc. Housing
US9156010B2 (en) 2008-09-23 2015-10-13 Bio-Rad Laboratories, Inc. Droplet-based assay system
US11130128B2 (en) 2008-09-23 2021-09-28 Bio-Rad Laboratories, Inc. Detection method for a target nucleic acid
US8633015B2 (en) * 2008-09-23 2014-01-21 Bio-Rad Laboratories, Inc. Flow-based thermocycling system with thermoelectric cooler
US9598725B2 (en) 2010-03-02 2017-03-21 Bio-Rad Laboratories, Inc. Emulsion chemistry for encapsulated droplets
US9764322B2 (en) 2008-09-23 2017-09-19 Bio-Rad Laboratories, Inc. System for generating droplets with pressure monitoring
US10512910B2 (en) 2008-09-23 2019-12-24 Bio-Rad Laboratories, Inc. Droplet-based analysis method
US9417190B2 (en) 2008-09-23 2016-08-16 Bio-Rad Laboratories, Inc. Calibrations and controls for droplet-based assays
US8951939B2 (en) 2011-07-12 2015-02-10 Bio-Rad Laboratories, Inc. Digital assays with multiplexed detection of two or more targets in the same optical channel
US9492797B2 (en) 2008-09-23 2016-11-15 Bio-Rad Laboratories, Inc. System for detection of spaced droplets
US9132394B2 (en) 2008-09-23 2015-09-15 Bio-Rad Laboratories, Inc. System for detection of spaced droplets
US8663920B2 (en) 2011-07-29 2014-03-04 Bio-Rad Laboratories, Inc. Library characterization by digital assay
US8709762B2 (en) 2010-03-02 2014-04-29 Bio-Rad Laboratories, Inc. System for hot-start amplification via a multiple emulsion
US7927904B2 (en) 2009-01-05 2011-04-19 Dalsa Semiconductor Inc. Method of making BIOMEMS devices
US8100293B2 (en) 2009-01-23 2012-01-24 Formulatrix, Inc. Microfluidic dispensing assembly
WO2011019516A2 (en) * 2009-08-11 2011-02-17 Baril Corporation Microfluidic diagnostic device
EP2473618B1 (en) 2009-09-02 2015-03-04 Bio-Rad Laboratories, Inc. System for mixing fluids by coalescence of multiple emulsions
US8507037B2 (en) * 2009-10-29 2013-08-13 Eastman Kodak Company Digital manufacture of an gas or liquid separation device
US8985050B2 (en) * 2009-11-05 2015-03-24 The Trustees Of Columbia University In The City Of New York Substrate laser oxide removal process followed by electro or immersion plating
FI20096334A0 (en) 2009-12-15 2009-12-15 Valtion Teknillinen Process for preparing liquid flow controlling structure layers in porous substrate films
CA2767113A1 (en) 2010-03-25 2011-09-29 Bio-Rad Laboratories, Inc. Detection system for droplet-based assays
JP2013524171A (en) 2010-03-25 2013-06-17 クァンタライフ・インコーポレーテッド Droplet generation for drop-based assays
EP2556170A4 (en) 2010-03-25 2014-01-01 Quantalife Inc Droplet transport system for detection
US10232374B2 (en) 2010-05-05 2019-03-19 Miroculus Inc. Method of processing dried samples using digital microfluidic device
EP4016086A1 (en) 2010-11-01 2022-06-22 Bio-Rad Laboratories, Inc. System for forming emulsions
WO2012129187A1 (en) 2011-03-18 2012-09-27 Bio-Rad Laboratories, Inc. Multiplexed digital assays with combinatorial use of signals
WO2012142516A1 (en) 2011-04-15 2012-10-18 Becton, Dickinson And Company Scanning real-time microfluidic thermo-cycler and methods for synchronized thermocycling and scanning optical detection
JP2014512826A (en) 2011-04-25 2014-05-29 バイオ−ラド ラボラトリーズ インコーポレイテッド Methods and compositions for nucleic acid analysis
CA2834708A1 (en) 2011-05-05 2012-11-08 Eksigent Technologies, Llc Gel coupling for electrokinetic delivery systems
DE102011107046B4 (en) * 2011-07-11 2016-03-24 Friedrich-Schiller-Universität Jena micropump
AU2012315595B2 (en) 2011-09-30 2015-10-22 Becton, Dickinson And Company Unitized reagent strip
USD692162S1 (en) 2011-09-30 2013-10-22 Becton, Dickinson And Company Single piece reagent holder
CN104040238B (en) 2011-11-04 2017-06-27 汉迪拉布公司 Polynucleotides sample preparation apparatus
BR112014018995B1 (en) 2012-02-03 2021-01-19 Becton, Dickson And Company systems to perform automated testing
WO2013155531A2 (en) 2012-04-13 2013-10-17 Bio-Rad Laboratories, Inc. Sample holder with a well having a wicking promoter
US9080941B2 (en) 2012-04-27 2015-07-14 General Electric Company Microfluidic flow cell assemblies for imaging and method of use
US9150907B2 (en) 2012-04-27 2015-10-06 General Electric Company Microfluidic flow cell assemblies and method of use
US8900529B2 (en) 2012-04-27 2014-12-02 General Electric Company Microfluidic chamber device and fabrication
CH708028A2 (en) * 2013-05-02 2014-11-14 Weidmann Medical Technology Ag Containers for laboratories and processes for the identification of such a container.
US9352315B2 (en) 2013-09-27 2016-05-31 Taiwan Semiconductor Manufacturing Company, Ltd. Method to produce chemical pattern in micro-fluidic structure
EP3071329B1 (en) 2013-11-22 2019-11-06 Rheonix, Inc. Channel-less pump, methods, and applications thereof
US9415349B2 (en) 2014-02-28 2016-08-16 General Electric Company Porous membrane patterning technique
SG11201702556TA (en) * 2014-10-14 2017-04-27 Heptagon Micro Optics Pte Ltd Optical element stack assemblies
WO2016197106A1 (en) 2015-06-05 2016-12-08 Miroculus Inc. Evaporation management in digital microfluidic devices
EP3303547A4 (en) 2015-06-05 2018-12-19 Miroculus Inc. Air-matrix digital microfluidics apparatuses and methods for limiting evaporation and surface fouling
US10940428B2 (en) * 2016-03-25 2021-03-09 The Regents Of The University Of California Portable micro-preconcentrator to facilitate chemical sampling and subsequent analysis
CN109715781A (en) 2016-08-22 2019-05-03 米罗库鲁斯公司 Feedback system for the parallel drop control in digital microcurrent-controlled equipment
CN110383061A (en) 2016-12-28 2019-10-25 米罗库鲁斯公司 Digital microcurrent-controlled device and method
CN111194409A (en) * 2017-02-15 2020-05-22 Essenlix公司 Determination by rapid temperature change
US11623219B2 (en) 2017-04-04 2023-04-11 Miroculus Inc. Digital microfluidics apparatuses and methods for manipulating and processing encapsulated droplets
JP6966860B2 (en) * 2017-04-07 2021-11-17 リンテック株式会社 Manufacturing method of inspection cover film, inspection member, and inspection cover film
US11413617B2 (en) 2017-07-24 2022-08-16 Miroculus Inc. Digital microfluidics systems and methods with integrated plasma collection device
CA3073058A1 (en) 2017-09-01 2019-03-07 Miroculus Inc. Digital microfluidics devices and methods of using them
WO2020079708A1 (en) * 2018-10-17 2020-04-23 INDIAN INSTITUTE OF TECHNOLOGY MADRAS (IIT Madras) A method for fabricating microfluidic devices on porous substrate
WO2020210292A1 (en) 2019-04-08 2020-10-15 Miroculus Inc. Multi-cartridge digital microfluidics apparatuses and methods of use
WO2021016614A1 (en) 2019-07-25 2021-01-28 Miroculus Inc. Digital microfluidics devices and methods of use thereof
WO2021178376A1 (en) * 2020-03-03 2021-09-10 University Of Kansas Methods for inkjet printing objects for microfluidic devices
WO2022055530A1 (en) 2020-09-10 2022-03-17 Regents Of The University Of Minnesota Additively manufactured self-supporting microfluidics
US11772093B2 (en) 2022-01-12 2023-10-03 Miroculus Inc. Methods of mechanical microfluidic manipulation

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5075152A (en) * 1988-09-07 1991-12-24 Tonen Sekiyukagaku K.K. Polyethylene composite film and label
US5376252A (en) * 1990-05-10 1994-12-27 Pharmacia Biosensor Ab Microfluidic structure and process for its manufacture
US5750240A (en) * 1994-05-17 1998-05-12 Technoflex Innovations Limited Coating of surfaces of articles

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR910012538A (en) * 1989-12-27 1991-08-08 야마무라 가쯔미 Micro pump and its manufacturing method
ES2069896T3 (en) * 1990-07-10 1995-05-16 Westonbridge Int Ltd VALVE, METHOD TO PRODUCE SUCH VALVE AND MICROPUMP THAT INCORPORATES SUCH VALVE.
DE69111591T2 (en) * 1990-08-31 1996-02-29 Westonbridge Int Ltd VALVE WITH POSITION DETECTOR AND MICROPUMP WITH IT.
GB2248891A (en) * 1990-10-18 1992-04-22 Westonbridge Int Ltd Membrane micropump
JPH05216624A (en) * 1992-02-03 1993-08-27 Mitsubishi Electric Corp Arithmetic unit
GB2266751A (en) * 1992-05-02 1993-11-10 Westonbridge Int Ltd Piezoelectric micropump excitation voltage control.
US6001229A (en) * 1994-08-01 1999-12-14 Lockheed Martin Energy Systems, Inc. Apparatus and method for performing microfluidic manipulations for chemical analysis
GB9416002D0 (en) * 1994-08-08 1994-09-28 Univ Cranfield Fluid transport device
US5824204A (en) * 1996-06-27 1998-10-20 Ic Sensors, Inc. Micromachined capillary electrophoresis device
US6128027A (en) * 1997-06-03 2000-10-03 Eastman Kodak Company Continuous tone microfluidic printing

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5075152A (en) * 1988-09-07 1991-12-24 Tonen Sekiyukagaku K.K. Polyethylene composite film and label
US5376252A (en) * 1990-05-10 1994-12-27 Pharmacia Biosensor Ab Microfluidic structure and process for its manufacture
US5750240A (en) * 1994-05-17 1998-05-12 Technoflex Innovations Limited Coating of surfaces of articles

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1039995A4 *

Cited By (89)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6156181A (en) * 1996-04-16 2000-12-05 Caliper Technologies, Corp. Controlled fluid transport microfabricated polymeric substrates
US6787088B2 (en) 1996-04-16 2004-09-07 Caliper Life Science, Inc. Controlled fluid transport in microfabricated polymeric substrates
US6514399B1 (en) 1996-04-16 2003-02-04 Caliper Technologies Corp. Controlled fluid transport in microfabricated polymeric substrates
US6409900B1 (en) 1996-04-16 2002-06-25 Caliper Technologies Corp. Controlled fluid transport in microfabricated polymeric substrates
US6238538B1 (en) 1996-04-16 2001-05-29 Caliper Technologies, Corp. Controlled fluid transport in microfabricated polymeric substrates
US6306659B1 (en) 1996-06-28 2001-10-23 Caliper Technologies Corp. High throughput screening assay systems in microscale fluidic devices
US6153073A (en) * 1997-04-25 2000-11-28 Caliper Technologies Corp. Microfluidic devices incorporating improved channel geometries
US6068752A (en) * 1997-04-25 2000-05-30 Caliper Technologies Corp. Microfluidic devices incorporating improved channel geometries
US7033474B1 (en) 1997-04-25 2006-04-25 Caliper Life Sciences, Inc. Microfluidic devices incorporating improved channel geometries
US6524790B1 (en) 1997-06-09 2003-02-25 Caliper Technologies Corp. Apparatus and methods for correcting for variable velocity in microfluidic systems
US6703205B2 (en) 1997-06-09 2004-03-09 Caliper Technologies Corp. Apparatus and methods for correcting for variable velocity in microfluidic systems
US6613512B1 (en) 1997-06-09 2003-09-02 Caliper Technologies Corp. Apparatus and method for correcting for variable velocity in microfluidic systems
US6827831B1 (en) 1997-08-29 2004-12-07 Callper Life Sciences, Inc. Controller/detector interfaces for microfluidic systems
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
US7497994B2 (en) 1998-02-24 2009-03-03 Khushroo Gandhi Microfluidic devices and systems incorporating cover layers
US6488897B2 (en) 1998-02-24 2002-12-03 Caliper Technologies Corp. Microfluidic devices and systems incorporating cover layers
US6306590B1 (en) 1998-06-08 2001-10-23 Caliper Technologies Corp. Microfluidic matrix localization apparatus and methods
US7156969B2 (en) 1998-06-08 2007-01-02 Caliper Life Sciences, Inc. Microfluidic matrix localization apparatus and methods
US6551836B1 (en) 1998-06-08 2003-04-22 Caliper Technologies Corp. Microfluidic devices, systems and methods for performing integrated reactions and separations
US6447661B1 (en) 1998-10-14 2002-09-10 Caliper Technologies Corp. External material accession systems and methods
US7344865B2 (en) 1999-02-23 2008-03-18 Caliper Life Sciences, Inc. Sequencing by incorporation
US7105300B2 (en) 1999-02-23 2006-09-12 Caliper Life Sciences, Inc. Sequencing by incorporation
US9101928B2 (en) 1999-02-23 2015-08-11 Caliper Life Sciences, Inc. Manipulation of microparticles in microfluidic systems
US6632655B1 (en) 1999-02-23 2003-10-14 Caliper Technologies Corp. Manipulation of microparticles in microfluidic systems
US6613513B1 (en) 1999-02-23 2003-09-02 Caliper Technologies Corp. Sequencing by incorporation
US7566538B2 (en) 1999-02-23 2009-07-28 Caliper Lifesciences Inc. Sequencing by incorporation
US6326083B1 (en) 1999-03-08 2001-12-04 Calipher Technologies Corp. Surface coating for microfluidic devices that incorporate a biopolymer resistant moiety
US6660367B1 (en) 1999-03-08 2003-12-09 Caliper Technologies Corp. Surface coating for microfluidic devices that incorporate a biopolymer resistant moiety
US6509059B2 (en) 1999-03-08 2003-01-21 Caliper Technologies Corp. Surface coating for microfluidic devices that incorporate a biopolymer resistant moiety
US6841193B1 (en) 1999-03-08 2005-01-11 Caliper Life Sciences, Inc. Surface coating for microfluidic devices that incorporate a biopolymer resistant moiety
US6303343B1 (en) 1999-04-06 2001-10-16 Caliper Technologies Corp. Inefficient fast PCR
US6524830B2 (en) 1999-04-06 2003-02-25 Caliper Technologies Corp. Microfluidic devices and systems for performing inefficient fast PCR
US6458259B1 (en) 1999-05-11 2002-10-01 Caliper Technologies Corp. Prevention of surface adsorption in microchannels by application of electric current during pressure-induced flow
US7150814B1 (en) 1999-05-11 2006-12-19 Callper Life Sciences, Inc. Prevention of surface adsorption in microchannels by application of electric current during pressure-induced flow
US6592821B1 (en) 1999-05-17 2003-07-15 Caliper Technologies Corp. Focusing of microparticles in microfluidic systems
US6506609B1 (en) 1999-05-17 2003-01-14 Caliper Technologies Corp. Focusing of microparticles in microfluidic systems
US6649358B1 (en) 1999-06-01 2003-11-18 Caliper Technologies Corp. Microscale assays and microfluidic devices for transporter, gradient induced, and binding activities
US6344120B1 (en) 1999-06-21 2002-02-05 The University Of Hull Method for controlling liquid movement in a chemical device
EP1063204A3 (en) * 1999-06-21 2002-08-21 Micro Chemical Systems Limited Chemical devices, methods of manufacturing and of using chemical devices
GB2351245B (en) * 1999-06-21 2003-07-16 Univ Hull Method of controlling liquid movement in a chemical device
EP1063204A2 (en) * 1999-06-21 2000-12-27 The University of Hull Chemical devices, methods of manufacturing and of using chemical devices
GB2351245A (en) * 1999-06-21 2000-12-27 Univ Hull Chemical apparatus; Electro-osmosis; Preparing solutions
US6613580B1 (en) 1999-07-06 2003-09-02 Caliper Technologies Corp. Microfluidic systems and methods for determining modulator kinetics
US6858185B1 (en) 1999-08-25 2005-02-22 Caliper Life Sciences, Inc. Dilutions in high throughput systems with a single vacuum source
US6613581B1 (en) 1999-08-26 2003-09-02 Caliper Technologies Corp. Microfluidic analytic detection assays, devices, and integrated systems
WO2001025137A1 (en) * 1999-10-04 2001-04-12 Nanostream, Inc. Modular microfluidic devices comprising layered circuit board-type substrates
WO2001025138A1 (en) * 1999-10-04 2001-04-12 Nanostream, Inc. Modular microfluidic devices comprising sandwiched stencils
US6759191B2 (en) 1999-10-08 2004-07-06 Caliper Life Sciences, Inc. Use of nernstein voltage sensitive dyes in measuring transmembrane voltage
US6537771B1 (en) 1999-10-08 2003-03-25 Caliper Technologies Corp. Use of nernstein voltage sensitive dyes in measuring transmembrane voltage
US6979553B2 (en) 1999-10-08 2005-12-27 Caliper Life Sciences, Inc. Use of Nernstein voltage sensitive dyes in measuring transmembrane voltage
WO2001026812A1 (en) * 1999-10-14 2001-04-19 Ce Resources Pte Ltd Microfluidic structures and methods of fabrication
US6468761B2 (en) 2000-01-07 2002-10-22 Caliper Technologies, Corp. Microfluidic in-line labeling method for continuous-flow protease inhibition analysis
US6632629B2 (en) 2000-01-07 2003-10-14 Caliper Technologies Corp. Microfluidic in-line labeling method of continuous-flow protease inhibition analysis
US7037416B2 (en) 2000-01-14 2006-05-02 Caliper Life Sciences, Inc. Method for monitoring flow rate using fluorescent markers
US7521186B2 (en) 2000-03-20 2009-04-21 Caliper Lifesciences Inc. PCR compatible nucleic acid sieving matrix
US6561208B1 (en) 2000-04-14 2003-05-13 Nanostream, Inc. Fluidic impedances in microfluidic system
US6755211B1 (en) 2000-04-14 2004-06-29 Nanostream, Inc. Microfluidic systems with inter-channel impedances
US6733645B1 (en) 2000-04-18 2004-05-11 Caliper Technologies Corp. Total analyte quantitation
US7264702B1 (en) 2000-04-18 2007-09-04 Caliper Life Sciences, Inc. Total analyte quantitation
US6669831B2 (en) 2000-05-11 2003-12-30 Caliper Technologies Corp. Microfluidic devices and methods to regulate hydrodynamic and electrical resistance utilizing bulk viscosity enhancers
US6777184B2 (en) 2000-05-12 2004-08-17 Caliper Life Sciences, Inc. Detection of nucleic acid hybridization by fluorescence polarization
US7192559B2 (en) 2000-08-03 2007-03-20 Caliper Life Sciences, Inc. Methods and devices for high throughput fluid delivery
US6935772B2 (en) 2000-08-07 2005-08-30 Nanostream, Inc. Fluidic mixer in microfluidic system
US6890093B2 (en) 2000-08-07 2005-05-10 Nanostream, Inc. Multi-stream microfludic mixers
US7578206B2 (en) 2001-01-17 2009-08-25 Irm Llc Sample deposition method and system
US6918309B2 (en) * 2001-01-17 2005-07-19 Irm Llc Sample deposition method and system
US6814938B2 (en) 2001-05-23 2004-11-09 Nanostream, Inc. Non-planar microfluidic devices and methods for their manufacture
US8007738B2 (en) 2001-06-05 2011-08-30 Caliper Life Sciences, Inc. Western blot by incorporating an affinity purification zone
US8592141B2 (en) 2001-06-05 2013-11-26 Caliper Life Sciences, Inc. Western blot by incorporating an affinity purification zone
US7723123B1 (en) 2001-06-05 2010-05-25 Caliper Life Sciences, Inc. Western blot by incorporating an affinity purification zone
US6981522B2 (en) 2001-06-07 2006-01-03 Nanostream, Inc. Microfluidic devices with distributing inputs
US6877892B2 (en) 2002-01-11 2005-04-12 Nanostream, Inc. Multi-stream microfluidic aperture mixers
US6923907B2 (en) 2002-02-13 2005-08-02 Nanostream, Inc. Separation column devices and fabrication methods
US7261812B1 (en) 2002-02-13 2007-08-28 Nanostream, Inc. Multi-column separation devices and methods
EP1910688A2 (en) * 2005-08-04 2008-04-16 Helicos Biosciences Corporation Multi-channel flow cells
EP1910688A4 (en) * 2005-08-04 2010-03-03 Helicos Biosciences Corp Multi-channel flow cells
WO2008031968A1 (en) * 2006-09-12 2008-03-20 Saint-Gobain Glass France Process for fabricating a microfluidic device
FR2905690A1 (en) * 2006-09-12 2008-03-14 Saint Gobain METHOD FOR MANUFACTURING MICROFLUIDIC DEVICE
WO2008063124A1 (en) * 2006-11-21 2008-05-29 Gyros Patent Ab Method of bonding a micrifluidic device and a microfluidic device
EP1975120A3 (en) * 2007-03-29 2013-08-21 FUJIFILM Corporation Microchemical chip and method for fabricating the same
EP3677336A1 (en) 2007-09-05 2020-07-08 Caliper Life Sciences Inc. Microfluidic method and system for enzyme inhibition activity screening
EP2051147A3 (en) * 2007-10-18 2011-06-29 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Method of producing functional service areas on a flat substrate
WO2011009422A1 (en) * 2009-07-21 2011-01-27 Heiko Schwertner Method using non-impact printing processes together with printing fluids that contain active biological molecules to produce sensors and complex analytical systems
FR2954305A1 (en) * 2009-12-21 2011-06-24 Saint Gobain Manufacturing microfluidic device comprising substrate and microstructure, comprises depositing glass frit on first substrate having predefined patterns, and optionally subjecting substrate to heat treatment at temperature of given range
US11369968B2 (en) 2017-04-21 2022-06-28 Essenlix Corporation Molecular manipulation and assay with controlled temperature (II)
WO2021039740A1 (en) * 2019-08-29 2021-03-04 キヤノン株式会社 Microchannel device manufacturing method
US20220177300A1 (en) * 2019-08-29 2022-06-09 Canon Kabushiki Kaisha Method for producing microchannel device
EP4023589A4 (en) * 2019-08-29 2023-09-20 Canon Kabushiki Kaisha Microchannel device manufacturing method

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EP1039995A4 (en) 2006-04-26
US6074725A (en) 2000-06-13
AU1534799A (en) 1999-06-28
EP1039995A1 (en) 2000-10-04

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