EP1981636A1 - Procede et structure microfluidique dotee d'un joint elastomere permeable aux gaz - Google Patents

Procede et structure microfluidique dotee d'un joint elastomere permeable aux gaz

Info

Publication number
EP1981636A1
EP1981636A1 EP07763338A EP07763338A EP1981636A1 EP 1981636 A1 EP1981636 A1 EP 1981636A1 EP 07763338 A EP07763338 A EP 07763338A EP 07763338 A EP07763338 A EP 07763338A EP 1981636 A1 EP1981636 A1 EP 1981636A1
Authority
EP
European Patent Office
Prior art keywords
layer
fluidic structure
layers
fluidic
forming
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07763338A
Other languages
German (de)
English (en)
Other versions
EP1981636A4 (fr
Inventor
Arkadij Elizarov
James R. Heath
Hartmuth Kolb
Michael Van Dam
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
California Institute of Technology CalTech
Siemens Medical Solutions USA Inc
Original Assignee
Individual
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
Priority claimed from US11/514,396 external-priority patent/US8480053B2/en
Application filed by Individual filed Critical Individual
Publication of EP1981636A1 publication Critical patent/EP1981636A1/fr
Publication of EP1981636A4 publication Critical patent/EP1981636A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
    • F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
    • F16K7/00—Diaphragm valves or cut-off apparatus, e.g. with a member deformed, but not moved bodily, to close the passage ; Pinch valves
    • F16K7/12—Diaphragm valves or cut-off apparatus, e.g. with a member deformed, but not moved bodily, to close the passage ; Pinch valves with flat, dished, or bowl-shaped diaphragm
    • F16K7/126—Diaphragm valves or cut-off apparatus, e.g. with a member deformed, but not moved bodily, to close the passage ; Pinch valves with flat, dished, or bowl-shaped diaphragm the seat being formed on a rib perpendicular to the fluid line
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502707—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the manufacture of the container or its components
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502723—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by venting arrangements
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502738—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by integrated valves
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
    • F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
    • F16K99/00—Subject matter not provided for in other groups of this subclass
    • F16K99/0001—Microvalves
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
    • F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
    • F16K99/00—Subject matter not provided for in other groups of this subclass
    • F16K99/0001—Microvalves
    • F16K99/0003—Constructional types of microvalves; Details of the cutting-off member
    • F16K99/0015—Diaphragm or membrane valves
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
    • F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
    • F16K99/00—Subject matter not provided for in other groups of this subclass
    • F16K99/0001—Microvalves
    • F16K99/0034—Operating means specially adapted for microvalves
    • F16K99/0055—Operating means specially adapted for microvalves actuated by fluids
    • F16K99/0059—Operating means specially adapted for microvalves actuated by fluids actuated by a pilot fluid
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00783—Laminate assemblies, i.e. the reactor comprising a stack of plates
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00801—Means to assemble
    • B01J2219/0081—Plurality of modules
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/12—Specific details about manufacturing devices
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0887—Laminated structure
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/12—Specific details about materials
    • B01L2300/123—Flexible; Elastomeric
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/18—Means for temperature control
    • B01L2300/1805—Conductive heating, heat from thermostatted solids is conducted to receptacles, e.g. heating plates, blocks
    • B01L2300/1822—Conductive heating, heat from thermostatted solids is conducted to receptacles, e.g. heating plates, blocks using Peltier elements
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/18—Means for temperature control
    • B01L2300/1838—Means for temperature control using fluid heat transfer medium
    • B01L2300/1844—Means for temperature control using fluid heat transfer medium using fans
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
    • B01L2400/0478—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure pistons
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/06—Valves, specific forms thereof
    • B01L2400/0633—Valves, specific forms thereof with moving parts
    • B01L2400/0638—Valves, specific forms thereof with moving parts membrane valves, flap valves
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/06—Valves, specific forms thereof
    • B01L2400/0633—Valves, specific forms thereof with moving parts
    • B01L2400/0655—Valves, specific forms thereof with moving parts pinch valves
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
    • F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
    • F16K99/00—Subject matter not provided for in other groups of this subclass
    • F16K2099/0073—Fabrication methods specifically adapted for microvalves
    • F16K2099/0074—Fabrication methods specifically adapted for microvalves using photolithography, e.g. etching
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
    • F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
    • F16K99/00—Subject matter not provided for in other groups of this subclass
    • F16K2099/0073—Fabrication methods specifically adapted for microvalves
    • F16K2099/0078—Fabrication methods specifically adapted for microvalves using moulding or stamping
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
    • F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
    • F16K99/00—Subject matter not provided for in other groups of this subclass
    • F16K2099/0073—Fabrication methods specifically adapted for microvalves
    • F16K2099/008—Multi-layer fabrications
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
    • F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
    • F16K99/00—Subject matter not provided for in other groups of this subclass
    • F16K2099/0082—Microvalves adapted for a particular use
    • F16K2099/0084—Chemistry or biology, e.g. "lab-on-a-chip" technology
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/60—Construction of the column
    • G01N30/6052—Construction of the column body
    • G01N30/606—Construction of the column body with fluid access or exit ports
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/60—Construction of the column
    • G01N30/6095—Micromachined or nanomachined, e.g. micro- or nanosize

Definitions

  • the present disclosure relates to the fabrication and assembly of microfluidic devices.
  • a method and apparatus are disclosed wherein the elastomeric layer is a gas-permeable gasket without features.
  • microfluidic device that circumvents the complicated and precise microfabrication of features in under-cured polymers as well as the task of layer-to-layer adhesion to provide a microfluidic device that is can be fabricated reproducibly and has utility amongst a range of reaction chemicals, while having a tight seal and being durable.
  • a fluidic structure comprising a first layer (30); a second layer (40) contacting said first layer, said second layer being flat, flexible, gas permeable and featureless; a third layer (60) contacting said second layer; at least one fluid channel (50), said at least one fluid channel positioned in the first layer; at least one valve pin hole (20), said at least one valve pin hole passing through the third layer and stopping at the second layer; at least one pin (10), wherein the at least one pin is activatable to actuate the second layer to occlude the at least one fluid channel.
  • a fluidic structure comprises a first layer (30); a second layer (40) contacting said first layer, said second layer being flat, flexible, gas permeable and featureless; a third layer (60) contacting said second layer; at least one fluid channel (50), said at least one fluid channel positioned in the first layer; at least one valve pin hole (20), said at least one valve pin hole passing through the third layer and stopping at the second layer; at least one pin (10), wherein the at least one pin is activatable to actuate the second layer to occlude the at least one fluid channel, and at least one mechanical means for assembling the first, second and third layers such that the first, second and third layers form a monolithic fluidic structure.
  • a method of fabricating a fluidic structure comprising the steps of forming a first layer (30); forming a second layer (40) contacting said first layer, said second layer being flat, flexible, gas permeable and featureless; forming a third layer (60) contacting said second layer; forming at least one fluid channel (50) positioned in said first layer; forming at least one valve pin hole (20); providing at least one pin (10); and providing a means of actuating the at least one pin in order to actuate the second layer to occlude the at least one fluid channel.
  • a method of fabricating a fluidic structure comprising the steps of forming a first layer (30); forming a second layer (40) contacting said first layer, said second layer being flat, flexible, gas permeable and featureless; forming a third layer (60) contacting said second layer; forming at least one fluid channel (50) positioned in said first layer; forming at least one valve pin hole (20); providing at least one pin (10); providing a means of actuating the at least one pin in order to actuate the second layer to occlude the at least one fluid channel, and providing at least one mechanical means for assembling the first, second and third layers such that the first, second and third layers form a monolithic fluidic structure.
  • Figure 1 shows a vertical cross-section of a gasket chip according to the present disclosure.
  • Figure 2 shows a top-view schematic of fluidic structure having a 6-valve pin hole (20) arranged in a symmetrical radial pattern, with 6 corresponding fluid channels (50) further comprising a vent channel (110) having an input (115) and an output (120).
  • Figures 3A-B show a "thick" pin valve in prior designs.
  • Figure 3B shows the "thin” pin valve of the present disclosure.
  • Figure 4 shows a "gap" valve design wherein the fluid channel comprises a raised feature (250) opposite of the valve for meeting the pin upon actuation of the second (gasket) layer (40).
  • Figure 5A shows a cross section of a gasket chip assembled by mechanical means — using, for example, screws (270).
  • Figure 5B shows a cross section of a gasket chip assembled by mechanical means — using, for example, clamps (310).
  • Figures 6A-F Figure 6A shows vent and flow layers cast on wax molds and cured to an elastomer-like state.
  • Figure 6B shows soft vent (235) and flow layers (230) removed from molds, followed by hole punching and pin insertion.
  • Figure 6C shows thin elastomeric gasket layer cast on a flat surface (215) and partially cured.
  • Figure 6D shows the flow layer placed on top of the gasket layer.
  • Figure 6E shows the molded layers after cutting the excess thin layer, two layers are pulled off the casting surface and inverted.
  • Figure 6F shows after the addition of the vent layer on top of the gasket layer, the assembly is cured to completion.
  • Figures 7A-F show the step-wise fabrication of a microfluidic device using sacrificial "inverse" molds.
  • Figures 8A-D show the step-wise fabrication of a microfluidic device using elastomeric "tub" molds.
  • a rigid microfluidic device with a thin elastomeric gasket layer allows for efficient mechanical actuation of fluid channels.
  • a thin elastomeric gasket does not absolutely require adhesion between the layers.
  • the chip acts as a monolithic device that does not allow leaks or unwanted channel connections at fluid pressures in excess of 40 psi and at elevated temperatures up to 100° C.
  • a new method is disclosed herein for fabrication of a microfluidic device that results in a sealed apparatus that is easily reproducible and durable.
  • This microfluidic device can be mechanically held together rather than chemically adhered.
  • a microfluidic device as described herein comprises a middle "gasket” layer positioned between at least two hard outer layers. This gasket layer is sufficiently deformable (e.g. flexible or elastic) to form a fluid-tight seal against the outer layers, acting essentially as an O-ring between the other two layers.
  • the method of the present disclosure involves the technology suitable for fabrication of microfluidic devices based on a reactor with mechanically-actuated valves.
  • the microfluidic device (also referred to as a "chip”) comprises at least three layers, as follows: (1) a first rigid layer (30) with the fluidic network etched or molded in it; (2) a flat second (middle) gasket layer (40) of gas-permeable elastomer without, bridging over the features of the first layer; and (3) a hard third layer (60) with vent features and sleeves for mechanical valve actuators (Figure 1).
  • the layers of a device according to the present invention can be bonded by well-known bonding methods, or held together by mechanical means as opposed to chemical means.
  • a combination of both mechanical and chemical means for layer assembly is also possible.
  • the layers can be bolted or clamped together.
  • the outer two layers should be rigid enough to transfer the mechanical clamping force to the interface between the gasket layer and each of the outer layers, and to prevent collapse of intricate channel features molded in their surfaces.
  • the gasket layer should be flat, deformable (e.g. flexible or elastic) to form a fluid-tight seal against the proximal layers, featureless and gas permeable in order to accommodate the solvent exchange requirement of the device.
  • Figure 2 contains the top view of a chip having 6 valve pin holes (20) with 6 corresponding fluid channels (50). Vent channel (110) allows for the evaporation of solvents across the second gasket layer membrane.
  • Figure 1 demonstrates the vertical cross-section of the same device taken through the middle. It illustrates that all the elastomer properties required for an operational chip can be concentrated in the single flat thin layer without any features and therefore not requiring elastomeric microfabrication (is this sentence true?).
  • the lower (first) layer (30) and the upper (third) layer (60) are hard, rigid layers.
  • the middle soft "gasket" layer is without features. Thus, all features (fluid channel, reaction area, vents, fluid reservoir, etc) are within the rigid hard layers. This design allows for the gasket layer to be without features, and thereby does not limit the necessary thickness required of the gasket layer for function.
  • Fluid reservoirs (91) are also a feature of the assembled device, and are below the gasket layer (40). If the lower first layer is etched in glass or silicon, the fluids can be introduced via needles (116) that puncture the gasket. Alternatively, if the first lower layer is made of a hard polymer the fluid inlets can be formed by hollow metal pins introduced into the polymer during molding. The vent (110) in the third upper layer is separated from the reaction chamber (90) by the gas permeable membrane (gasket layer). As mentioned, given the elastomer layer has no features, this elastomer membrane can be made as thin as it can be without breaking. In other words, the gasket layer is not limited in thickness by other features contained in the layer.
  • Valves of the present invention stretch the elastomer layer over ⁇ 45 um, to close a 45 um channel, pressing it against the concave surface of the channel (less stressful geometry) (Figure 3b).
  • Lower actuation pressures, more efficient closure and lower elasticity requirements are provided by the gasket layer, valve design of the present invention. Thinner elastomer can be controlled more precisely.
  • the pin tips are rounded to accommodate the "cup" valve design.
  • This cup valve design as shown refers to a rounded pin which upon actuation, actuates the gasket layer and together the gasket layer and the pin move across the width of the fluid channel forming a seal with the opposing first layer, thereby occluding the fluid channel.
  • the fluid channel of the first layer comprises a raised feature or platform (250) which is positioned opposite the valve pin hole (20), wherein actuation of the pin (10,11) actuates the second gasket layer (40) to form a seal with the platform (250), thereby occluding the fluid channel (50).
  • This type of valve closure is referred to as a "gap" valve ( Figure 4).
  • the pins are metal wire (an example of such can be purchased from Gambit Corporation).
  • the smaller the pin the more likely it is to act as a needle and tear or prick through an elastomer layer.
  • a hollow pin e.g. a hollow metal wire
  • any shape that is not sharp it may be preferred to use.
  • a fhiidic structure of the present disclosure comprises at least one valve pin hole (20).
  • each valve pin hole corresponds to one fluid channel (50). That is, each actuated pin corresponds to a valve pin hole whereby the actuated pin in the valve pin hole occludes a corresponding fluid channel.
  • the pin can be actuated (moved) by applied pressure or by coupling the pin to a solenoid (Electromechanisms, San Dimas, CA).
  • the pin can be actuated pneumatically. This can be carried out by connecting the pin to a commercially available pneumatic cylinder (Festo, Hauppauge, N. Y). Applied pressure to actuate the pin as disclosed herein, can be applied between 0 and 45 pounds per square inch (psi).
  • the first layer (30) of the present invention can be fabricated from a variety materials provided the material is relatively rigid, is compatible with the reaction reagents, is thermally conductive, (has a low heat capacity) if the reaction to be processed requires heating and/or cooling.
  • Examples of possible materials for the first layer of the present invention include, but are not limited to: DCPD (dicyclopentadiene), glass, metal (e.g. alumunim, copper), metal coated with a protecting layer, ceramic, polycarbonate, silicon, graphite, or DCPD doped with any of the above or other components known to one of skill in the art.
  • the gasket layer (40) of the present invention can be fabricated from several materials, provided the gasket material is deformable (i.e. flexible, elastic), gas permeable, is compatible with the reaction, has enough tensile strength to withstand actuation by mechanical pins.
  • Examples of possible materials for the second gasket layer of the present invention include, but are not limited to: PDMS (polydimethylsiloxane), PFPE (perfluoropolyether), ROMP (ring- opening metathesis polymerization) polymer, various combinations of DNB (decylnorbornene), HNB (hexylnorbornene), and FNB (fluoronorbornene), or those polymers alone, PTFE (polytetrafluoroethylene), PVDF (polyvinylidene difluoride), and latex.
  • PDMS polydimethylsiloxane
  • PFPE perfluoropolyether
  • ROMP ring- opening metathesis polymerization
  • DNB decylnorbornene
  • HNB hexylnorbornene
  • FNB fluoronorbornene
  • PTFE polytetrafluoroethylene
  • PVDF polyvinylidene difluoride
  • the gasket layer if sufficiently thick — can "absorb" a slight amount of non-uniformity in the hard layers.
  • Other rigid-chip microfluidic technologies involving only glass or silicon
  • the gasket layer relaxes this requirement and allows the use of manufacturing processes such as machining and molding that may not result in ultrafiat surfaces.
  • the gasket thickness can be designed to make it impossible that the channels in each hard layer be occluded, even if substantial mechanical pressure is applied to the chip.
  • the third layer (60) of the present invention can be fabricated from a variety of materials, provided the layer material is relatively rigid (can withstand force up to 80 psi), and is preferably transparent, though transparency is not absolutely necessary. This third layer does not have to be compatible with the reaction given all species reaching thislayer are removed by applied vacuum through the vent (110).
  • Examples of possible materials for the second gasket layer of the present invention include, but are not limited to: DCPD, glass, polycarbonate, and quartz.
  • valves of the microfluidic device of the present invention require a means of actuation.
  • the valves are actuated by mechanical means. That is, an object transfers force onto the second gasket layer, which is then actuated to occlude the fluid channel.
  • An example of such an object is a pin.
  • the pin can be a hollow metal pin (117) placed into a valve pin hole (20).
  • the valve pin hole serves to guide the pin to avoid misdirection.
  • the layers (30, 40, 60) of the microfiuidic device can be assembled together via chemical adhesion or mechanical means.
  • FIG. 5A shows a cross section of a gasket chip assembled using screws, wherein two screws (270) are provided into two screw holes (280), wherein the two screw holes transverse the three layers thereby forming a monolithic microfiuidic device.
  • Figure 5B at least one clamp (310) is used for mechanically assembly of the microfiuidic structure.
  • Adhesion-less assembly also allows for the possibility of more than three layers.
  • a 5-layer chip with the following layers (from top to bottom): (i) thick, rigid valve-guiding layer; (ii) thin flexible gasket layer to act as valve membranes; (iii) thin, rigid layer containing flow channels; (iv) thin flexible gasket layer to act as gas exchange membrane; (v) thick, rigid layer containing vacuum vent channels.
  • This architecture has the advantage of separating the requirements of the gasket material: the top gasket must be tough and flexible but need not be gas permeable while the bottom gasket must be permeable but need not be flexible or tough. This further expands the range of suitable materials for device fabrication.
  • under-cured soft-gelled gasket layers must be supported by a substrate during handling to prevent wrinkling and damage.
  • a thicker layer is first stacked on the gelled layer and bonded to it.
  • Adhesion-less chips allow the use of fully-cured gasket layers which have sufficient strength/toughness to be handled on their own (e.g. with tweezers) and lack much of the stickiness/tackiness often associated with undercured materials that makes them difficult to handle.
  • the mechanical assembly is self-aligning.
  • the rigid first and third layers are fabricated on a CNC (computer numerical control) device, the screw holes are placed in these layers in precise locations allowing the chip to fit together only one possible way.
  • CNC computer numerical control
  • the seal was sufficient to hold at least 45 psi of fluid pressure, tested by injecting acetonitrile into the flow channels.
  • Valves in the chip functioned correctly and operated under similar conditions as needed to actuate valves in chips fabricated by adhesion methods. [045] The chip was exposed to high temperatures (100 "C) for long periods of time (2 hours) with trapped acetonitrile (liquid and vapor) and no leaks were observed, despite a slight softening of the DCPD.
  • the microfluidic structure comprising at least three layers as described herein is assembled using screws (270)( Figure 5A).
  • the microfluidic structure comprising at least three layers as described herein is assembled using at least one clamp (310) ( Figure 5B).
  • the thick layers (the first and third layer, for example) can be fabricated via molding as described below and shown in Figures 6-8, or by other techniques such as hot-embossing, injection-molding, conventional machining, etc.
  • the gasket layers can similarly be fabricated by a variety of techniques such as spin coating, casting, injection molding, etc. Bonding methods are known in the art (see, for example, U.S. Patent No. 7,040,338; US Application No. 11/297,651).
  • Figures 6A-6F shows the stepwise method of forming features such as fluid channels and reaction area into the first layer and forming vent channels in the first layer and providing pin valve holes through all three layers with the gasket layer in between the first and third hard layers.
  • Some hard materials have an intermediate state in their curing profile which resembles an elastomer in its properties.
  • the hard layers are cast on the corresponding molds and cured to an intermediate (elastomer-like) state without pins and sleeves.
  • the gasket layer is cast or spin-coated on a flat surface (215) such as that of a Si wafer.
  • the hard layers are removed from molds (if the latter are wax molds, the wax can be washed out at this point), and have holes for fluid inlets and outlet (I/O) ports (25) and pin holes (20) punched in them. Then they are assembled with metal pins for fluid delivery and actuator pins.
  • vent (235) and flow (230) layers cast on wax molds are cured to an elastomer-like state ( Figure 6A).
  • Soft vent and flow layers are removed from molds, followed by hole-punching and pin insertion (Figure 6B).
  • Thin elastomeric gasket layer is then cast on a flat surface and cured partially just past a gel state ( Figure 6C).
  • the first lower flow layer (30) is then dropped on top of the gasket layer (40).
  • Minimal tackiness at this step needs to be stronger between the flow layer and the gasket layer than between the gasket layer and the bottom flat surface (215) ( Figure 6D).
  • FIGs 7A, 7B Sacrificial wax molds for both fluid (230) and vent (235) layers.
  • these molds are printed on Si wafers (215) by a 3-D printer.
  • these wax molds can be made from an elastomeric "inverse mold" on a Si-wafer or another substrate that the wax can weakly adhere to. The bond has to be strong enough to hold the wax in place, but yet weak enough to allow the wax to be released into the molded part when the substrate is removed. Such conditions can be optimized by one of skill in the art.
  • FIG. 1C The next step after preparation of the inverse mold, is to create borders (240) around the molds that would (a) hold the pre-polymer in a confined space and (b) hold the I/O ports (25) in the case of fluid layer.
  • borders can once again be made of an elastomer that seals well to the substrate and does not absorb the hard pre-polymer or react with it.
  • the height of these borders determines the thickness of the layers made in the next step.
  • the top layer needs pin sleeves (for the valves) (20) to be attached to the mold so that they are locked in place when the hard polymer cures. These are attached to the wax expansions and stand vertically, and are held in place by a rigid "guide” (260) from above.
  • the same connection is made for the vent I/O ports.
  • the first lower (fluid) layer connections are made through the sides of the mold with pins held by the elastomer border and connected to the wax expansions at the ends of the fluid channel features.
  • Figure 7D Next the assemblies of Figure 7C are filled with hard pre-polymer, which is allowed to cure in them ( Figure 7D).
  • the pre-polymer is covered with a glass cover slip (300) to preserve the flat nature of the surface which will have to be in contact with the heating element in the final device.
  • Figure 7E The hard polymer is cured to the earliest gel stage that allows unsupported structures to hold their shape and preserve the features. Then the borders (240), glass cover slip (300), and the substrates (215) are removed leaving the polymer with wax and pins (Figure 7E). Hard layers removed from the molds. The first (fluid) layer is depicted turned over.
  • Figure 7F Spacer features (45) are placed on the fluid layer (after turning it over) to control the thickness of the elastomer layer (40).
  • the elastomer pre-polymer is poured on top of the fluid layer with spacer features, which is immediately covered with the top (vent) layer (60) that rests on the supports.
  • the entire assembly is then cured to completion ( Figure 7F).
  • the final step involves the removal of sacrificial wax by melting and rinsing the chip with organic solvents. Once the wax is removed, it yields a chip with all the architecture necessary for multi-step synthesis ( Figure 1). It is made of materials that are inert to chemical reactions.
  • the valves have thin membranes that can deflect with minimum pin pressure and the reactor is separated from the vacuum vent by a thin gas permeable membrane allowing efficient evaporations and solvent exchange.
  • FIG. 8A Elastomer "tub” mold.
  • the elastomer should form a tub that will be filled by the hard layer precursor.
  • the height of the walls of this tub determines the resulting layer thickness.
  • the fluid I/O ports (25) (hollow metal pins) are inserted through the sides of the "tub” mold and connect to the reservoirs at the ends of fluid channels.
  • the reasons for making this mold from an elastomer are (a) the ease of removal of a hard part with dense features from a soft mold and (b) the I/O port connections will have to break the mold as the part is removed.
  • Figure 8B Hard Layer Casting. Deposit catalyzed pre-polymer into the "tub" and cover with a glass cover slip to form a flat surface will be in contact with a heating element in the final device ( Figure 8B).
  • Figure 8C Gelled Hard Layer. Cure the hard polymer to a "gel” state (just rigid enough to be removed from the mold, but only partially cured). Remove the cover slip and the mold and inverted the part (Figure 8C).
  • Figure 8D Injection of wax into the gelled mold with an elastomer seal. Fill the fluidic network with the sacrificial wax by either adding melted wax onto the surface and removing excess with a razor blade-like tool, or by covering the mold with a flat piece of elastomer sealing (290) at contact surfaces and filling the hot wax through the I/O ports ( Figure 8D). Upon cooling, the wax solidifies producing the fabrication intermediates shown in the previous mold methods of Figures 6 and 7.
  • the present disclosure comprises a first layer; a second layer contacting said first layer, said second layer being a flexible layer; a third layer contacting said second layer; at least one fluid channel, said at least one fluid channel positioned proximal to the second layer; at least one valve pin hole, said at least one valve pin hole passing through the third layer and stopping at the second layer; at least one pin, wherein the at least one pin is activatable to actuate the second layer, thereby occluding the at least one fluid channel; wherein the above together forms an integrated fluidic device.
  • the fluidic structure of the present invention can have many orientations.
  • the first layer can a lower layer, in which case, the second layer is a middle layer overlying the first, layer, and the third layer is an upper layer, overlying the second middle layer.
  • the first layer is an upper layer, wherein the second layer is a middle layer underlying the first layer, and the third layer is a lower layer, underlying the second middle layer.
  • the first layer is a right layer positioned to the right of the second layer which is positioned to the right of the third layer, which is the left most layer.
  • the first layer is a left layer positioned to the left of the second middle layer, wherein the middle layer is positioned to the left of the third layer, wherein the third layer is the layer on the right of the middle layer.
  • the size and scale of the fluidic structure of the present disclosure and the corresponding channel and pin sizes can vary as needed for a given application. It is apparent to one of skill in the art that there are advantages and disadvantages at both the micron (small) size and millimeter (larger) size. Thus, one of skill in the art can optimize the scale of the fluidic structure that will work best for a given application.
  • the fluidic structure of the present disclosure can comprise channels which range in size from 10 ⁇ m to lmm in diameter having pins ranging in size from 0.25 inches to 12 inches or more in length and 100 ⁇ m to 1 millimeter in diameter.
  • the fluidic structure of the present disclosure can be combined with a temperature control device such as a heat sink (e.g. Peltier device) and a fan.
  • a fluidic structures can have an attached heat sink positioned below the synthesis chip (215).
  • An array of temperature control devices can be coupled with the present disclosure as needed for a particular fluidic reaction.
  • One of skill in the art can provide a temperature control device to the fluidic structure of the present disclosure.
  • a fluidic structure, and more specifically, a synthesis chip of the present disclosure comprising a reactor area also comprises at least one vent channel.
  • a vent channel (110) ( Figure 5) can be one of a variety of formations, as long as it facilitates the evaporation of solvent from the reactor area and enables reduction of reactor area pressure.
  • the vent channel in Figure 5 forms a serpentine pattern proximal to the reactor area.
  • This vent channel has an input (115) and output (120), one of which is plugged and the other connected to a vacuum.
  • Another possible vent channel pattern is a right-angled U-shape directly above the reactor area in the second flexible layer allowing for evaporation through this layer above the reactor area.
  • a vent channel is preferably in contact with the third layer and positioned proximal to the reactor area.
  • the fluidic structure is used to control fluid flow in an integrated fluidic device.
  • the fluid flow in the fluid channel can be any reactant fluid.
  • the resulting process could be the synthesis of a compound.
  • the resulting fluidic compound could be the result of a solvent exchange, wherein a first fluid reactant is fed through a fluid channel, and a solute is trapped (this application would further comprise a selective membrane in a fluid output channel for trapping the solute) and a subsequent second fluid reactant is fed through the same fluid channel, whereby the solute is suspended in the second fluid reactant.
  • the fluidic structure of the present disclosure would provide a new method for solvent exchange.
  • the fluidic structure as disclosed can be used in applications including, but not limited to: biopolymer synthesis, cell sorting, DNA sorting, chemical synthesis, therapeutic synthesis, optofluidics, and semiconductor processing.
  • a microfluidic structure and method are disclosed, where the structure comprises a featureless gasket layer allowing for efficient and reproducible structure production and assembly. Layering methods allow for the use of a variety of device materials and easy assembly. [075] While illustrative embodiments have been shown and described in the above description, numerous variations and alternative embodiments will occur to those skilled in the art. Such variations and alternative embodiments are contemplated, and can be made without departing from the scope of the invention as defined in the appended claims.

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Abstract

L'invention concerne une structure et un procédé microfluidiques, où la structure comprend une couche de joint sans relief qui permet une production et un assemblage efficaces et reproductibles de la structure. Les procédés de stratification permettent son utilisation dans une diversité de matériaux de dispositifs et un assemblage facile.
EP07763338A 2006-02-03 2007-02-02 Procede et structure microfluidique dotee d'un joint elastomere permeable aux gaz Withdrawn EP1981636A4 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US76515006P 2006-02-03 2006-02-03
US79177806P 2006-04-13 2006-04-13
US11/514,396 US8480053B2 (en) 2005-09-02 2006-08-30 Method and apparatus for the mechanical actuation of valves in fluidic devices
PCT/US2006/034083 WO2007027928A1 (fr) 2005-09-02 2006-08-30 Methode et appareil pour un actionnement mecanique de soupapes dans des dispositifs fluidiques
PCT/US2007/003208 WO2007092472A1 (fr) 2006-02-03 2007-02-02 Procede et structure microfluidique dotee d'un joint elastomere permeable aux gaz

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EP1981636A4 EP1981636A4 (fr) 2010-06-09

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ES2379921T3 (es) 2005-09-29 2012-05-07 Siemens Medical Solutions Usa, Inc. Chip microfluídico que puede sintetizar moléculas marcadas radiactivamente en una escala adecuada para la obtención de imágenes en seres humanos con tomografía por emisión de positrones
WO2008091694A2 (fr) * 2007-01-23 2008-07-31 Siemens Medical Solutions Usa, Inc. Système microfluidique entièrement automatisé pour réaliser la synthèse de biomarqueurs radiomarqués pour tomographie par émission de positons
CN102083525A (zh) * 2007-04-12 2011-06-01 美国西门子医疗解决公司 用于正电子发射断层摄影术生物标记物的微流体放射合成系统
US8071035B2 (en) 2007-04-12 2011-12-06 Siemens Medical Solutions Usa, Inc. Microfluidic radiosynthesis system for positron emission tomography biomarkers
ITBO20090152A1 (it) * 2009-03-17 2010-09-18 Silicon Biosystems Spa Dispositivo microfluidico
JP5438351B2 (ja) * 2009-03-30 2014-03-12 Ｊｆｅテクノス株式会社 マイクロチップを用いたｐｅｔ用標識化合物の調剤方法及び装置
DE102009023430B4 (de) * 2009-05-29 2013-07-25 Siemens Aktiengesellschaft Vorrichtung und Verfahren zum Steuern von Fluidströmen in Lab-on-a-Chip-Systemen sowie Verfahren zum Herstellen der Vorrichtung
ITBO20100502A1 (it) * 2010-08-04 2012-02-05 Silicon Biosystems Spa Sistema microfluidico
GB201119002D0 (en) * 2011-11-03 2011-12-14 Givaudan Sa Valve
ES2459269B1 (es) * 2012-10-04 2015-03-24 Universidad De Zaragoza Dispositivo y método de encapsulado de sistemas microfluídicos
ES2614252B1 (es) * 2015-10-27 2018-03-12 Universidad De Zaragoza Chip microfluídico, dispositivo microfluídico, procedimientos y usos asociados
GB201913529D0 (en) * 2019-09-19 2019-11-06 Tanriverdi Ugur Method And Apparatus

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US6830729B1 (en) * 1998-05-18 2004-12-14 University Of Washington Sample analysis instrument
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JP2009525443A (ja) 2009-07-09

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