WO2008132651A1 - Micromixer and/or microreactor with active flow controlling means - Google Patents

Micromixer and/or microreactor with active flow controlling means Download PDF

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Publication number
WO2008132651A1
WO2008132651A1 PCT/IB2008/051523 IB2008051523W WO2008132651A1 WO 2008132651 A1 WO2008132651 A1 WO 2008132651A1 IB 2008051523 W IB2008051523 W IB 2008051523W WO 2008132651 A1 WO2008132651 A1 WO 2008132651A1
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WO
WIPO (PCT)
Prior art keywords
controlling means
flow controlling
micromixer
active flow
present
Prior art date
Application number
PCT/IB2008/051523
Other languages
French (fr)
Inventor
Ralph Kurt
Jacob M. J. Den Toonder
Roel Penterman
Emiel Peeters
Dirk J. Broer
Original Assignee
Koninklijke Philips Electronics N.V.
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 Koninklijke Philips Electronics N.V. filed Critical Koninklijke Philips Electronics N.V.
Publication of WO2008132651A1 publication Critical patent/WO2008132651A1/en

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    • 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
    • B01J19/0046—Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F31/00—Mixers with shaking, oscillating, or vibrating mechanisms
    • B01F31/30—Mixers with shaking, oscillating, or vibrating mechanisms comprising a receptacle to only a part of which the shaking, oscillating, or vibrating movement is imparted
    • B01F31/31—Mixers with shaking, oscillating, or vibrating mechanisms comprising a receptacle to only a part of which the shaking, oscillating, or vibrating movement is imparted using receptacles with deformable parts, e.g. membranes, to which a motion is imparted
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
    • B01F33/30—Micromixers
    • 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
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    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502746—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the means for controlling flow resistance, e.g. flow controllers, baffles
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    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • 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
    • B01L2300/1827—Conductive heating, heat from thermostatted solids is conducted to receptacles, e.g. heating plates, blocks using resistive heater
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • 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

Definitions

  • Micromixer and/or microreactor with active flow controlling means are provided.
  • the present invention is directed to the field of microdevices, especially micromixers and/or microreactors.
  • Inmicro fluidic devices and systems especially those for the use of bio- molecular diagnostics chemicals have to be transported and mixed on a very small scale.
  • micromixer and/or microreactor comprising a plurality of active flow controlling means.
  • micromixer and/or microreactor in the context of the present invention especially means and/or includes a device comprising a microfluidic channel (at least one first dimension of the channel - height, thickness, width, diameter - is in the range between 5 and 5000 ⁇ m, preferably between 10 and lOOO ⁇ m, most preferably between 50 and 500 ⁇ m, and at least one other second "elongated” dimension e.g. the length of the channel is at least a factor 5, preferably a factor 10, more preferably a factor 20 larger than said first dimension), in which a fluid flows, in at least on step of use of said device, substantially in said second "elongated” dimension.
  • This "main flow” may be externally driven (external in the sense of form outside the micromixer and/or microreactor) by pumps or by capillary or osmotic, or electroosmotic pressure driven.
  • flow in the context of the present invention especially means and/ or includes that at least one component of the fluid is characterized by a velocity (or is moving) with a substantial component (which is in the context of this invention also referred as "vfl") in the direction of said channel ("elongated direction").
  • this flow is also referred to or called the main flow.
  • said micromixer causes at least parts of said flow to move in a direction with a component perpendicular to said main flow.
  • the velocity of this perpendicular flow component is in the context of this invention also (depending on the actual application) called or referred to as vpW or vpH.
  • the presence of a perpendicular flow vpW and/or vpW at a certain position of any cross segment of the channel will in most applications of the present invention usually causes a counter- flow i.e. in the opposite direction at another position of the same cross segment of the channel.
  • term "at least one component of the fluid” especially means and/or includes that the micromixer and/or microreactor may also be of use in applications such as electrophoresis, dielectrophoresis or magnetic actuation, in which only part of the fluid is moving.
  • mixing in the context of the present invention especially means and/ or includes that the distance (measured in the channel cross segment, i.e. perpendicular to the main flow direction) between at least two components of said main flow (e.g. two molecules moving in the channel) changes (by passing through said microfluidic mixer) by at least 10% preferably > 20%, more preferably >40, most preferably >60% of said first channel dimension (e.g. the width or the height). This change may be both; more apart or closer together.
  • active flow controlling means in the context of the present invention especially means and/ or includes that at least a part of the main flow and/or the flow of selected molecules in the main flow in, through and/or out of at least one selected part of the micromixer and/or microreactor may be changed. It should be noted that in the sense of the present invention, the term
  • active flow controlling means may also include that obstacles are present in the elongated direction, which is actually a preferred embodiment of the present invention.
  • obstacles may be defined as or include parts that change frequently (along the channel length) the diameter of the channel.
  • obstacles may be defined as or include parts of the cross segment of the channel where the component of the flow in the direction of the main flow is reduced (or zero) with respect to the main flow in the channel in parts where no obstacle is present.
  • active flow controlling means in the context of the present invention furthermore especially means and/ or includes that the velocity (or flow rate) of at least a part of the perpendicular flow and/or of the perpendicular flow of selected molecules in the flow in, through and/or out of at least one selected part of the micromixer and/or microreactor may be changed (i.e. increased, decreased and/or even stopped).
  • active in the context of the present invention especially means and/ or includes that the flow controlling means may change at least one physical parameter, especially including their shape, size, dimension, thickness, height, length, diameter, mobility, distance, permeability and swelling upon stimulation of at least one external activation means.
  • a micromixer and/or microreactor according to the present invention shows for most applications at least one of the following advantages:
  • micromixing and/or -reacting device setup can be made more compact for a wide range of applications within the present invention
  • the micromixing efficiency can be altered and/or tuned and the mixing may be even switched on or off (which especially does include that the perpendicular flow is zero or does not change in direction within several parts of the micromixer).
  • At least a part of the active flow controlling means are adapted to change at least one physical parameter upon stimulation of at least one external activation means so that at least the perpendicular flow in the micromixer/microreactor is changed.
  • This change may according to an embodiment of a present invention include that the velocity vpW and/or vpH is altered, alternatively and/or additionally, the direction of the perpendicular flow may be changed.
  • the plurality of active flow controlling means are adapted to shrink and/or swell upon stimulation of an external activation means.
  • the actuation means is capable of changing the swelling of at least a part of the plurality of the active flow controlling means by a factor of > 1.2, preferably by >2, more preferably >5 and most preferably >10.
  • the actuation means is capable of changing at least one of the physical properties of at least a part of the plurality of the active flow controlling means electrically and/or electrochemically.
  • the actuation means is capable of changing at least a part of the plurality of the active flow controlling means by changing at least one property/parameter out of the group comprising size, dimension, thickness, height, length, diameter, mobility, distance, permeability and swelling at least of parts of the active flow controlling means by applying an electric field.
  • the voltage applied is chosen so that no gas is generated, which will be for most applications around 2-3V.
  • the actuation means is capable of changing at least one of the physical properties of at least a part of the plurality of the active flow controlling means by changing at least one property/parameter out of the group comprising size, dimension, thickness, height, length, diameter, mobility, distance, permeability and swelling at least of parts of the active flow controlling means by electrolysis, i.e. by generating ions electrically or electrochemically.
  • the actuation means is capable of changing at least one of the physical properties at least one property/parameter out of the group comprising size, dimension, thickness, height, length, diameter, mobility, distance, permeability and swelling at least of parts of the active flow controlling means by applying an electrical current.
  • the actuation means is capable of changing at least one of the physical properties of at least one of the plurality of active flow controlling means via a change in temperature.
  • the actuation means is capable of changing at least one property/parameter out of the group size, dimension, thickness, height, length, diameter, mobility, distance, permeability and swelling at least of a part of at least one of the plurality of active flow controlling means via a change in temperature.
  • the actuation means comprises a resistive heater in the vicinity of the part of the active flow controlling means, which is able to change at least one property/parameter out of the group size, dimension, thickness, height, length, diameter, mobility, distance, permeability and swelling at least of a part of at least one of the plurality of active flow controlling means via a change in temperature.
  • the actuation means is capable of changing the size, dimension, thickness, height, length, diameter, mobility, distance, permeability and swelling by a factor >1.2, preferably >2, more preferably >5 and most preferred >10 per 0.5 0 C.
  • the actuation means is capable of changing at least one of the physical properties of at least one of the plurality of active flow controlling means via incident radiation.
  • the actuation means is capable the changing at least one property/parameter out of the group comprising size, dimension, thickness, height, length, diameter, mobility, distance, permeability and swelling at least of parts of at least one of the plurality of active flow controlling means via an incident radiation.
  • the actuation means comprises at least one resistive heater element capable of changing the temperature locally in a predefined region of at least of parts of at least one of the plurality of active flow controlling means.
  • the actuation means is capable of changing at least one of the physical properties of at least one of the plurality of active flow controlling means via applying an electrical potential.
  • the device according to the invention comprises at least one electrode and/or at least one set of electrodes.
  • micromixer and/or microreactor which may also include actuating, accelerating or rejecting preselected biomolecules towards predefined locations by applying an electrical DC or AC field, i.e. by electrophoresis or dielectrophoresis.
  • At least one of the plurality of active flow controlling means is provided in close proximity to the at least one electrode and/or the at least one set of electrodes.
  • the actuation means is capable of changing at least one of the parameters including size, dimension, thickness, height, length, diameter, mobility, distance, permeability and swelling of at least one of the plurality of active flow controlling means by inducing a phase transition resulting a micro phase separation with a continuous fluid/water phase either with or in the proximity of at least one active flow controlling means.
  • the actuation means is capable of changing at least one of the parameters including size, dimension, thickness, height, length, diameter, mobility, distance, permeability and swelling of at least one of the plurality of active flow controlling means by inducing a LCST (lower critical solution temperature) phase transition in at least one active flow controlling means.
  • LCST lower critical solution temperature
  • the a plurality of active flow controlling means comprises at least one responsive layer which has at least in parts of the layer an intrinsic structural gradient in the direction of the layer thickness and/ or in a direction substantially perpendicular to the main flow.
  • the term "responsive" means and/or includes especially that at least one of the plurality of active flow controlling means is responsive in such a way that it displays a change of shape and total volume upon a change of a specific parameter.
  • a specific parameter can be a physical (temperature, pressure) or chemical property (ionic concentration, pH, analyte concentration) or biochemical property (enzymatic activity).
  • the term "in the direction of the layer thickness” does not mean that the intrinsic structural gradient is present in the direction of the layer thickness only. This may be an embodiment of the present invention, however, according to a further embodiment of the present invention (as will be described later on) there may be an intrinsic structural gradient in further directions, too.
  • vH vH
  • the actuation means is capable of changing the perpendicular flow vpH and/or vpW into and from the active flow controlling means by changing of at least one of the parameters including size, dimension, thickness, height, length, diameter, mobility, distance, permeability, porosity and swelling of at least one of the plurality of active flow controlling means.
  • At least one of the active flow controlling means comprises a layer which is responsive to at least one external stimulus, upon which the flow of at the least a predefined species of biomolecules is altered.
  • the term "external" especially means that at least one of the plurality of active flow controlling means is triggered by a means and/or stimulus provided and/or arising outside the layer, such as a change in pH or temperature, however it is clear to any skilled person in the art that this means and/or stimulus might arise from an actuation means inside the device, such as a heater, e.g. resistive heater etc.
  • the micromixer and/or microreactor comprises a plurality of passive flow controlling means.
  • the plurality of passive flow controlling means is associated with the plurality of active flow controlling means, preferably in that every passive flow controlling means is associated with at least one active flow controlling means.
  • At least one of the plurality of active flow controlling means is a polymeric material. According to an embodiment of the present invention, at least one of the plurality of active flow controlling means is a polymeric material with a conversion of >50% and ⁇ 100%.
  • the conversion especially includes, means or refers to a measurement according to the following procedure:
  • At least one of the plurality of active flow controlling means is a polymeric material with a conversion of >70% and ⁇ 95%.
  • the term "essentially” means and/or includes especially a wt-% content of >90 %, according to an embodiment >95 %, according to an embodiment >99 %.
  • the crosslink density in at least one of the plurality of active flow controlling means is >0.002 and ⁇ 1, preferably >0.05 and ⁇ 1.
  • crosslink density means or includes especially the following definition:
  • the crosslink density ⁇ x is here defined as
  • each actuation means is capable of changing at least one of the physical properties of at least one of the plurality of active flow controlling means by each actuation means differ from that which are changed by the other actuation means.
  • the plurality of active flow controlling means comprises at least one hydrogelic material.
  • At least one of the plurality of active flow controlling means comprises a hydrogelic material.
  • hydrogelic material means and/or includes especially that this material comprises polymers that in water form a water-swollen network.
  • hydrogelic material in the sense of the present invention furthermore especially means that at least a part of the hydrogelic material comprises polymers that in water form a water-swollen network and/or a network of polymer chains that are water-soluble.
  • the hydrogelic material comprises in swollen state >50% water and/or solvent, more preferably >70% and most preferred >90%, whereby preferred solvents include organic solvents, preferably organic polar solvents and most preferred alkanols such as Ethanol, Methanol and/or (Iso-) Propanol.
  • hydrogelic material means and/or includes especially that the hydrogel is responsive which means that it displays a change of shape and total volume upon a change of a specific parameter.
  • a specific parameter can be a physical (temperature, pressure) or chemical property (ionic concentration, pH, analyte concentration) or biochemical property (enzymatic activity).
  • the hydrogelic material comprises in swollen state >50% water and/or solvent, more preferably >70% and most preferred >90%, whereby preferred solvents include organic solvents, preferably organic polar solvents and most preferred alkanols such as Ethanol, Methanol and/or (Iso-) Propanol.
  • preferred solvents include organic solvents, preferably organic polar solvents and most preferred alkanols such as Ethanol, Methanol and/or (Iso-) Propanol.
  • the hydrogelic material comprises a material selected out of the group comprising poly(meth)acrylic materials, silicagel materials, substituted vinyl materials or mixture thereof.
  • the hydrogelic material comprises a substituted vinyl material, preferably vinylcaprolactam and/or substituted vinylcaprolactam.
  • the hydrogelic material comprises a poly(meth)acrylic material made out of the polymerization of at least one (meth)acrylic monomer and at least one polyfunctional (meth)acrylic monomer.
  • the (meth)acrylic monomer is chosen out of the group comprising (meth)acrylamide, acrylic esters, hydroxyethyl(meth)acrylate, ethoxyethoxyethyl(meth)acrylate or mixtures thereof.
  • (meth)acrylic monomer is a bis-(meth)acryl and/or a tri-(meth)acryl and/or a tetra- (meth)acryl and/or a penta-(meth)acryl monomer.
  • the polyfunctional (meth)acrylic monomer is chosen out of the group comprising bis(meth)acrylamide, tetraethylene glycol di(meth)acrylate, triethylene glycol di(meth)acrylate, diethylene glycol di(meth)acrylate, tripropyleneglycol di(meth)acrylates, pentaerythritol tri(meth)acrylate polyethyleneglycoldi(meth)acrylate, ethoxylated bisphenol-A- di(meth)acrylate , hexanedioldi(meth)acrylate or mixtures thereof.
  • the hydrogelic material comprises an anionic poly(meth)acrylic material, , preferably selected out of the group comprising (meth)acrylic acids, arylsulfonic acids, especially styrenesulfonic acid, itaconic acid, crotonic acid, sulfonamides or mixtures thereof, and/or a cationic poly(meth)acrylic material , preferably selected out of the group comprising vinyl pyridine, vinyl imidazole, aminoethyl (meth)acrylates or mixtures thereof, co- polymerized with at least one monomer selected out of the group neutral monomers, preferably selected out of the group vinyl acetate, hydroxy ethyl (meth)acrylate (meth)acrylamide, ethoxyethoxyethyl(meth)acrylate or mixture thereof, or mixtures thereof.
  • an anionic poly(meth)acrylic material preferably selected out of the group comprising (meth)acrylic acids, arylsulfonic acids, especially
  • At least one of the plurality of active flow controlling means comprises a hydrogelic material comprising thermo-sensitive polymers.
  • At least one of the plurality of active flow controlling means comprises a hydrogelic material comprising monomers selected out of the group comprising poly-N-isopropylamide (PNIPAAm) and copolymers thereof with monomers selected out of the group comprising polyoxyethylene, trimethylol-propane distearate, poly- ⁇ -caprolactone or mixtures thereof.
  • the hydrogelic material is based on thermo -responsive monomers selected out of the group comprising N-isopropylamide , diethylacrylamide, carboxyisopropylacrylamide, hydroxymethylpropylmethacrylamide, acryloylalkylpiperazine.
  • At least one of the plurality of active flow controlling means comprises a hydrogelic material with a swelling ratio of >1% and ⁇ 500% at 20 0 C.
  • the swelling ratio especially includes, means or refers to a measurement according to the following procedure:
  • At least one of the plurality of active flow controlling means was dried to form a film in an oven under the temperature of 50 0 C.
  • the film was immersed in an excess of deionized water to remove the residual unreacted compounds.
  • the swollen polymer film was then cut into disk forms with 8mm in diameter and dried at 50 0 C until the weight no longer changed.
  • a preweighed dried sample (Wo) was immersed in an excess of deionized water in a thermostatic water bath until the swelling equilibrium was attained.
  • the weight of the wet sample (Wi) was determined after the removal of the surface water via blotting with filter paper.
  • At least one of the plurality of active flow controlling means comprises a hydrogelic material with a swelling ratio of >3% and ⁇ 200% at 20 0 C.
  • At least one of the plurality of active flow controlling means comprises a hydrogelic material with a swelling ratio of >5% and ⁇ 100% at 20 0 C.
  • At least one of the plurality of active flow controlling means comprises a hydrogelic material with a swelling of>l% and ⁇ 30% at 20°C. According to an embodiment of the present invention, at least one of the plurality of active flow controlling means comprises a hydrogelic material with a swelling ratio of >1% and ⁇ 25% at 20 0 C.
  • At least one of the plurality of active flow controlling means comprises a hydrogelic material with a swelling of >1% and ⁇ 20% at 20 0 C.
  • At least part of the plurality of active flow controlling means comprise a hydrogelic material with a structural gradient.
  • the structural gradient comprises a gradient in at least one or more of the following features: cross-link density, composition, porosity, ordering parameter, LCST (lower critical solution temperature).
  • At least one part of the plurality of active flow controlling means comprises a semi-permeable elastic sheet.
  • Said semi-permeable elastic sheet or layer is preferably an elastic rubber material such as polydimethylsiloxane (PDMS) or other silicon rubbers, siloxanes etc.
  • PDMS polydimethylsiloxane
  • the channel in which the fluid flows is separated from an actuation medium (such as responsive polymeric material, or pressure/hydrostatic driven via an actuation fluid (gas or second liquid) with external or internal pump), by at least one, preferably thin, elastic sheet, such as polydimethylsiloxane (PDMS) or other silicon rubbers, polypropylene (PP), polyimide, siloxanes etc.
  • an actuation medium such as responsive polymeric material, or pressure/hydrostatic driven via an actuation fluid (gas or second liquid) with external or internal pump
  • PDMS polydimethylsiloxane
  • PP polypropylene
  • siloxanes siloxanes etc.
  • Said elastic sheet is preferably non-permeable for said actuation medium and preferably also not permeable for at least predefined components of the main flow in the channel.
  • said elastic sheet is permeable for a first component of the flow e.g. water or some ions, whereas it is non permeable for a second component of the flow e.g. bioanalyte to be mixed in said micromixer.
  • the term "responsive polymeric material" includes especially that the material is responsive in such a way that it displays a change of shape and total volume upon a change of a specific parameter.
  • An example of a change is melting, which may happen if a wax- like material is heated.
  • polymeric material is used that swells upon a temperature increase such as low melting point polymers including wax or polyethyleneglycol PEG.
  • said responsive polymeric material undergoes a phase transition including from solid to liquid, from liquid to gas, and preferably from crystalline to amorphous and/or liquid.
  • the plurality of active flow controlling means are divided in segments of correlated active flow controlling means.
  • each of the segments of correlated active flow controlling means comprise >2- ⁇ 50, preferably >4- ⁇ 20, most preferably >6- ⁇ 20 or about 10 flow controlling means.
  • said number of flow controlling means per segment are substantially identical in their shape and effect on the perpendicular flow component.
  • one parameter such as the height, length dimension etc. of said elements changes gradually within one segment.
  • US patent 6,852,287 which is incorporated by reference in total, proposes embodiments of a method to control a number N of independently controllable components with smaller number of control terminals.
  • both the use of multiplexing techniques or passive matrix techniques is proposed.
  • the matrix technique is extremely attractive, as this allows for the maximum number of components to be controlled with the minimum number of control terminals.
  • one specific heater element in a passive matrix is activated also a number of other heater elements will be activated unintentionally.
  • Co-pending application IB2006/053434 discloses a micro-fluidic device, e.g. a biochip, fabricated on a substrate based upon active matrix principles.
  • the device is preferably fabricated from one of the well known large area electronics technologies, such as amorphous silicon (a-Si), low temperature polycrystalline silicon (LTPS) or organic transistor technologies.
  • a-Si amorphous silicon
  • LTPS low temperature polycrystalline silicon
  • the active matrix makes it possible to independently control a larger number of components on the device with a smaller number of control terminals.
  • This device enables accurate and localized control of temperature in an active matrix set up, without the need for a large device periphery to locate the I/O pins.
  • the first electronic components preferably comprise at least one heater element.
  • the micro-fluidic device comprises further first electronic components for sensing properties of the fluid such as the fluid flow or the mixing actuation etc.
  • the device comprises at least two, even more preferred a multiplicity of heater elements.
  • Such a device is referred to as a thermal processing array.
  • These heater elements are suitable for heating fluid that may be present in cells or compartments of the microfluidic device.
  • the thermal processing array can be used to either maintain a constant temperature across the entire compartment area, or alternatively to create a defined time- dependent temperature profile if the reaction compartment is also configured in the form of an array and different portions of the reaction chamber require different temperatures.
  • the thermal processing array comprises a multiplicity of individually addressable and drivable heating elements, and may preferably comprise additional elements such as temperature sensors and fluid-mixing or fluid- pumping elements or a combination thereof.
  • At least one of the electronic components of the active matrix comprises thin film transistors having gate, source and drain electrodes.
  • the active matrix includes a set of select lines and a set of control lines such that each individual component may be controlled by one select line and one control line and the gate electrode of each thin film transistor is connected to a select line.
  • a memory device for storing a control signal supplied to the control terminal.
  • the second electronic components are formed by thin film diodes, e.g. metal-insulator-metal (MIM) diodes. It is preferred that a MIM diode connects a first electrode of each first electronic component to a control line, and a second electrode of each first electronic component is connected to a select line.
  • MIM metal-insulator-metal
  • the thin film diodes are PIN or Schottky diodes, wherein a first diode connects a first electrode of each component to a control line, wherein a second diode connects the first electrode of each component to a common rest line and wherein a second electrode of each component is connected to a select line.
  • the first diode is replaced by a pair of diodes connected in parallel and the second diode as well is replaced by a pair of diodes connected in parallel.
  • the first diode is replaced by a pair of diodes connected in series, and also the second diode is replaced by a pair of diodes connected in series.
  • the second electronic components comprise circuitry based on transistors or diodes or passive components (such as resistors and capacitors) or combinations thereof.
  • a micromixer and/or microreactor and/or a method according to the present invention may be of use in a broad variety of systems and/or applications, amongst them one or more of the following: biomicromixer and/or microreactors used for molecular diagnostics rapid and sensitive detection of proteins and nucleic acids in complex biological mixtures and body fluids such as e.g. blood, urine or saliva - high throughput screening devices for chemistry, pharmaceuticals or molecular biology testing devices e.g. for DNA or proteins e.g. in criminology, for on-site testing (in a hospital), for diagnostics in centralized laboratories or in scientific research - tools for DNA or protein diagnostics for cardiology, infectious disease and oncology, food, and environmental diagnostics tools for combinatorial chemistry analysis devices
  • biomicromixer and/or microreactors used for molecular diagnostics rapid and sensitive detection of proteins and nucleic acids in complex biological mixtures and body fluids such as e.g. blood, urine or saliva - high throughput screening devices for
  • Fig. 1 shows a very schematically partial top view of a micromixer and/or microreactor according to a first embodiment of the present invention
  • Fig. 2 shows a very schematically cross-cut view of the microreactor of
  • Fig. 1 approximately along line H-II in Fig. 1 in a first condition of the active flow controlling means
  • Fig. 3 shows the view of Fig. 2 in a second (swollen) condition of the active flow controlling means.
  • Fig. 4 shows a very schematic partial top view of a micromixer and/or microreactor according to a second embodiment of the present invention
  • Fig. 5 shows a very schematic partial top view of a micromixer and/or microreactor according to a third embodiment of the present invention
  • Fig. 6 shows a very schematically cross-cut partial view of a micromixer and/or microreactor according to a fourth embodiment of the present invention employing active and passive flow controlling means.
  • Fig. 7 shows the view of Fig. 6 with the active flow controlling means in swollen state
  • Fig. 8 shows (as an alternative to Fig. 8) the view of Fig. 6 with the active flow controlling means in shrunken state.
  • Fig. 9 shows a very schematically cross-cut partial view of a micromixer and/or microreactor according to a fifth embodiment of the present invention employing active and passive flow controlling means and an elastic sheet.
  • Fig.10 shows the embodiment of Fig. 9 with the active flow controlling means in shrunken state
  • Fig. 1 shows a very schematic partial top view of a micromixer and/or microreactor 1 according to a first embodiment of the present invention.
  • the micromixer and/or microreactor according to this embodiments comprises a plurality of segments Ll, L2 etc, which itself comprise several active flow controlling means 10 (for sake of brevity and visibility only one active flow controlling means is referred to as 10).
  • vfl main flow
  • vpW perpendicular flow
  • vpW perpendicular flow direction
  • vpH perpendicular flow direction
  • Said active flow controlling means 10 are positioned differently in Ll and L2 segments with respect to the channel or channel wall (right and left). But there are also other variations possible (in height, in width, in angle of the bars with respect to the main flow etc.).
  • W2 is typically bigger than the half of Wl.
  • the width of the active flow controlling means W2 is preferably between >30 and ⁇ 90% of the channel width Wl, more preferably between >40 and ⁇ 80%, and most preferably between >50 and ⁇ 70%.
  • Fig. 4 shows a very schematic partial top view of a micromixer and/or microreactor according to a second embodiment of the present invention
  • the angle of said flow controlling means with respect to the main flow preferably between >20 and ⁇ 160 degree; according to one embodiment between >30 and ⁇ 60, according to a further embodiment between >120 and ⁇ 150.
  • Said active flow controlling means may according to further embodiments (not shown in the figs) also have bar-like, sinus-shape, saw tooth shape, fishbone or other suitable configurations, involving different or multiple angles.
  • a number of flow controlling means per segment there are a number of flow controlling means per segment, this number ranges from 2-50, preferably 4-20, most preferably 6-20 (or about 10).
  • said number of flow controlling means per segment are substantially identical in their shape and effect on the perpendicular flow component.
  • one parameter such as the height, length dimension etc. of said elements changes gradually within one segment.
  • the microfluidic mixing device comprises 4-50 segments, more preferably 8-20 segments.
  • the function of said segments is according to an embodiment of the present invention and within a wide range of applications basically to force the flow to change of direction of perpendicular flow, e.g. changing from a perpendicular component to the right to another one to the left resulting e.g. in a change from a clockwise rotation of the fluid (along an axis in the main flow direction) into a counterclockwise rotation of the fluid.)
  • the segments are typically arranged alternating, i.e. L1-L2-L1-L2 etc., but there might also be cases where L1-L2-L3-L4-L1.. or other arrangements are chosen (not shown in the figs).
  • Fig. 2 shows a very schematically cross-cut view of the microreactor of Fig. 1 approximately along line H-II in Fig. 1 in a first condition of the active flow controlling means
  • Fig. 3 shows the view of Fig. 2 in a second (swollen) condition of the active flow controlling means.
  • the height of the active flow controlling means H2 and/or H3 is preferably in the range between >5 and ⁇ 50% of the channel height Hl, more preferably between >10 and ⁇ 40%, and most preferably between >20 and ⁇ 30%; this goes for the "non-swollen"-state as well as for the "swollen state”.
  • the height H2 and/or H3 are especially chosen such that that the perpendicular component of the flow, i.e. vpW and/or vpH is > 2%, preferably > 5%, more preferably > 10 of the main flow vfl.
  • the length of one segment Ll is preferably in the range >1 and ⁇ 5000 ⁇ m, more preferably between >10 and ⁇ 2000 ⁇ m, most preferably between >100 and ⁇ lOOO ⁇ m.
  • the length of one segment Ll is preferably a factor >1 to ⁇ 100 larger than said first dimension of the channel (the diameter, height H lor width Wl) preferably a factor 5-20, most preferably a factor of about 10. It should be noted that in Figs. 2 and 3 there is also shown a "third flow"
  • vH in into the flow controlling means
  • vH out out of the flow controlling means
  • the active flow controlling means may be coated with an elastic material (such as silicon rubber, such as PDMS etc.) so that there will be no flow "vHin” or "vHout”.
  • Fig. 5 shows a very schematic partial top view of a micromixer and/or microreactor according to a second embodiment of the present invention.
  • several hydrogelic material "segments" 50a, 50b are placed in the flow.
  • the segments 50a, 50b differ from each other that they are sensible to different stimuli, i.e. it is possible e.g. to shrink and swell the segments 50a and 50b independent from each other.
  • Fig. 6 shows a very schematically cross-cut partial view of a micromixer and/or microreactor according to a fourth embodiment of the present invention employing active and passive flow controlling means
  • Fig. 7 and 8 show the same view with the active flow controlling means 10 in swollen and shrunken state, respectively.
  • micromixer and/or microreactor of Figs. 6 to 8 differs to the previous ones in that several passive flow controlling means 20 are present in addition to the active flow controlling means 10.
  • every passive flow controlling means 20 is associated with at least one active flow controlling means 10, however, it is apparent to any skilled person in the art that this need not be the case for every embodiment within the present invention.
  • the passive flow controlling means 20 may be made of a material which is "harder” or less elastic than the material of the active flow controlling means 10, in order to adapt to applications where different conditions (e.g. a faster flow) is needed.
  • Fig. 6 shows a very schematically cross-cut partial view of a micromixer and/or microreactor according to a fifth embodiment of the present invention. This embodiment differs from the embodiment of Figs. 6 to 8 in that besides employing active 10 and passive 20 flow controlling means, also an elastic sheet 30 is used (as described above). By doing so, a flow in and from the active and/or passive flow controlling means may be greatly or fully prevented, which has shown to be advantageous for a wide range of applications within the present invention.
  • Fig.10 shows the embodiment of Fig. 9 with the active flow controlling means 10 in shrunken state. It should be noted and is clear to any skilled person in the art that the Figs. 9 and 10 are for illustrative purposes only and the actual dimensions (including the thickness of the elastic sheet 30) may for actual embodiments and applications of the inventions very different from those indicated in the figures.

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Abstract

The invention relates to a micromixer and/or microreactor with a plurality of active flow controlling means (10). These active flow controlling means allow to set up the micromixer more compact with no constant flow needed.

Description

Micromixer and/or microreactor with active flow controlling means
The present invention is directed to the field of microdevices, especially micromixers and/or microreactors.
Inmicro fluidic devices and systems, especially those for the use of bio- molecular diagnostics chemicals have to be transported and mixed on a very small scale.
However, downscaling of the processes in these systems is very attractive for a variety of reasons, including the high price of the biochemicals or sometimes even the fact that those biochemicals can only be provided in minute amounts. This means that the architecture of fluidic devices asks for new fluid transport and mixing mechanisms.
It is challenging to mix solutions in tiny micro channels. Under typical operating conditions, flows in these channels are laminar - the spontaneous fluctuations of velocity that tend to homogenize fluids in turbulent flows are absent, and molecular diffusion across the channels is slow.
Abraham D. Stroock et al. present in "Chaotic Mixer for Microchannels" Science, Vol. 295, 25 January 2002, p.647, which is hereby fully incorporated by reference a passive method for mixing streams of steady pressure- driven flows in micro channels at low Reynolds number. Using this method, the length of the channel required for mixing grows only logarithmically with the Peclet number, and hydrodynamic dispersion along the channel is reduced relative to that in a simple, smooth channel. This method uses bas-relief structures on the floor of the channel that are easily fabricated with commonly used methods of planar lithography.
However, this solution usually requires a constant flow and cannot be controlled easily.
It is therefore an object of the present invention to provide a biochemical micromixer and/or microreactor which is at least partly overcome the above-mentioned drawbacks and allows for satisfactory mixing under controlled conditions for a variety of embodiments and applications.
This object is solved by a micromixer and/or microreactor according to claim 1 of the present invention. Accordingly, a micromixer and/or microreactor is provided, comprising a plurality of active flow controlling means.
The term "micromixer and/or microreactor" in the context of the present invention especially means and/or includes a device comprising a microfluidic channel (at least one first dimension of the channel - height, thickness, width, diameter - is in the range between 5 and 5000μm, preferably between 10 and lOOOμm, most preferably between 50 and 500μm, and at least one other second "elongated" dimension e.g. the length of the channel is at least a factor 5, preferably a factor 10, more preferably a factor 20 larger than said first dimension), in which a fluid flows, in at least on step of use of said device, substantially in said second "elongated" dimension. This "main flow" may be externally driven (external in the sense of form outside the micromixer and/or microreactor) by pumps or by capillary or osmotic, or electroosmotic pressure driven.
The term "flow" in the context of the present invention especially means and/ or includes that at least one component of the fluid is characterized by a velocity (or is moving) with a substantial component (which is in the context of this invention also referred as "vfl") in the direction of said channel ("elongated direction"). In the context of this invention, this flow is also referred to or called the main flow. It is especially preferred for the invention that said micromixer causes at least parts of said flow to move in a direction with a component perpendicular to said main flow. The velocity of this perpendicular flow component is in the context of this invention also (depending on the actual application) called or referred to as vpW or vpH.
It should be mentioned that the presence of a perpendicular flow vpW and/or vpW at a certain position of any cross segment of the channel will in most applications of the present invention usually causes a counter- flow i.e. in the opposite direction at another position of the same cross segment of the channel. It should be noted that term "at least one component of the fluid" especially means and/or includes that the micromixer and/or microreactor may also be of use in applications such as electrophoresis, dielectrophoresis or magnetic actuation, in which only part of the fluid is moving.
The term "mixing" in the context of the present invention especially means and/ or includes that the distance (measured in the channel cross segment, i.e. perpendicular to the main flow direction) between at least two components of said main flow (e.g. two molecules moving in the channel) changes (by passing through said microfluidic mixer) by at least 10% preferably > 20%, more preferably >40, most preferably >60% of said first channel dimension (e.g. the width or the height). This change may be both; more apart or closer together.
The term "active flow controlling means" in the context of the present invention especially means and/ or includes that at least a part of the main flow and/or the flow of selected molecules in the main flow in, through and/or out of at least one selected part of the micromixer and/or microreactor may be changed. It should be noted that in the sense of the present invention, the term
"active flow controlling means" may also include that obstacles are present in the elongated direction, which is actually a preferred embodiment of the present invention. In the context of this invention, obstacles may be defined as or include parts that change frequently (along the channel length) the diameter of the channel. Alternatively or additionally obstacles may be defined as or include parts of the cross segment of the channel where the component of the flow in the direction of the main flow is reduced (or zero) with respect to the main flow in the channel in parts where no obstacle is present.
The term "active flow controlling means" in the context of the present invention furthermore especially means and/ or includes that the velocity (or flow rate) of at least a part of the perpendicular flow and/or of the perpendicular flow of selected molecules in the flow in, through and/or out of at least one selected part of the micromixer and/or microreactor may be changed (i.e. increased, decreased and/or even stopped).
The term "active" in the context of the present invention especially means and/ or includes that the flow controlling means may change at least one physical parameter, especially including their shape, size, dimension, thickness, height, length, diameter, mobility, distance, permeability and swelling upon stimulation of at least one external activation means.
A micromixer and/or microreactor according to the present invention shows for most applications at least one of the following advantages:
The control over the micromixing process can be effected easily for a wide range of applications within the present invention
Other than passive micromixers known in the art, for a wide range of applications within the present invention no constant or essentially constant flow is needed. - The micromixing and/or -reacting device setup can be made more compact for a wide range of applications within the present invention
The micromixing efficiency can be altered and/or tuned and the mixing may be even switched on or off (which especially does include that the perpendicular flow is zero or does not change in direction within several parts of the micromixer).
According to an embodiment of the present invention, at least a part of the active flow controlling means are adapted to change at least one physical parameter upon stimulation of at least one external activation means so that at least the perpendicular flow in the micromixer/microreactor is changed. This change may according to an embodiment of a present invention include that the velocity vpW and/or vpH is altered, alternatively and/or additionally, the direction of the perpendicular flow may be changed.
According to an embodiment of the present invention, the plurality of active flow controlling means are adapted to shrink and/or swell upon stimulation of an external activation means.
According to an embodiment of the present invention, the actuation means is capable of changing the swelling of at least a part of the plurality of the active flow controlling means by a factor of > 1.2, preferably by >2, more preferably >5 and most preferably >10. According to an embodiment of the present invention, the actuation means is capable of changing at least one of the physical properties of at least a part of the plurality of the active flow controlling means electrically and/or electrochemically.
According to an embodiment of the present invention, the actuation means is capable of changing at least a part of the plurality of the active flow controlling means by changing at least one property/parameter out of the group comprising size, dimension, thickness, height, length, diameter, mobility, distance, permeability and swelling at least of parts of the active flow controlling means by applying an electric field. In this context, according to a further embodiment, the voltage applied is chosen so that no gas is generated, which will be for most applications around 2-3V. According to an embodiment of the present invention, the actuation means is capable of changing at least one of the physical properties of at least a part of the plurality of the active flow controlling means by changing at least one property/parameter out of the group comprising size, dimension, thickness, height, length, diameter, mobility, distance, permeability and swelling at least of parts of the active flow controlling means by electrolysis, i.e. by generating ions electrically or electrochemically.
According to an embodiment of the present invention, the actuation means is capable of changing at least one of the physical properties at least one property/parameter out of the group comprising size, dimension, thickness, height, length, diameter, mobility, distance, permeability and swelling at least of parts of the active flow controlling means by applying an electrical current.
According to an embodiment of the present invention, the actuation means is capable of changing at least one of the physical properties of at least one of the plurality of active flow controlling means via a change in temperature. According to an embodiment of the present invention, the actuation means is capable of changing at least one property/parameter out of the group size, dimension, thickness, height, length, diameter, mobility, distance, permeability and swelling at least of a part of at least one of the plurality of active flow controlling means via a change in temperature. According to an embodiment of the present invention, the actuation means comprises a resistive heater in the vicinity of the part of the active flow controlling means, which is able to change at least one property/parameter out of the group size, dimension, thickness, height, length, diameter, mobility, distance, permeability and swelling at least of a part of at least one of the plurality of active flow controlling means via a change in temperature.
According to an embodiment of the present invention, the actuation means is capable of changing the size, dimension, thickness, height, length, diameter, mobility, distance, permeability and swelling by a factor >1.2, preferably >2, more preferably >5 and most preferred >10 per 0.50C. According to an embodiment of the present invention, the actuation means is capable of changing at least one of the physical properties of at least one of the plurality of active flow controlling means via incident radiation.
According to an embodiment of the present invention, the actuation means is capable the changing at least one property/parameter out of the group comprising size, dimension, thickness, height, length, diameter, mobility, distance, permeability and swelling at least of parts of at least one of the plurality of active flow controlling means via an incident radiation.
According to an embodiment of the present invention, the actuation means comprises at least one resistive heater element capable of changing the temperature locally in a predefined region of at least of parts of at least one of the plurality of active flow controlling means.
According to an embodiment of the present invention, the actuation means is capable of changing at least one of the physical properties of at least one of the plurality of active flow controlling means via applying an electrical potential. To this end, according to an embodiment of the present invention, the device according to the invention comprises at least one electrode and/or at least one set of electrodes.
By doing so, it is for a wide range of applications within the present invention possible even to control the flow inside the micromixer and/or microreactor, which may also include actuating, accelerating or rejecting preselected biomolecules towards predefined locations by applying an electrical DC or AC field, i.e. by electrophoresis or dielectrophoresis.
According to an embodiment of the present invention, at least one of the plurality of active flow controlling means is provided in close proximity to the at least one electrode and/or the at least one set of electrodes.
According to an embodiment of the present invention, the actuation means is capable of changing at least one of the parameters including size, dimension, thickness, height, length, diameter, mobility, distance, permeability and swelling of at least one of the plurality of active flow controlling means by inducing a phase transition resulting a micro phase separation with a continuous fluid/water phase either with or in the proximity of at least one active flow controlling means.
According to an embodiment of the present invention, the actuation means is capable of changing at least one of the parameters including size, dimension, thickness, height, length, diameter, mobility, distance, permeability and swelling of at least one of the plurality of active flow controlling means by inducing a LCST (lower critical solution temperature) phase transition in at least one active flow controlling means.
According to a preferred embodiment of the present invention, the a plurality of active flow controlling means comprises at least one responsive layer which has at least in parts of the layer an intrinsic structural gradient in the direction of the layer thickness and/ or in a direction substantially perpendicular to the main flow.
In the sense of the present invention, the term "responsive" means and/or includes especially that at least one of the plurality of active flow controlling means is responsive in such a way that it displays a change of shape and total volume upon a change of a specific parameter. Such parameter can be a physical (temperature, pressure) or chemical property (ionic concentration, pH, analyte concentration) or biochemical property (enzymatic activity).
The term "in the direction of the layer thickness" does not mean that the intrinsic structural gradient is present in the direction of the layer thickness only. This may be an embodiment of the present invention, however, according to a further embodiment of the present invention (as will be described later on) there may be an intrinsic structural gradient in further directions, too.
According to a preferred embodiment of the present invention, there is a flow into and from the active flow controlling means. The velocity of this flow in the context of this invention may be called or referred to as vH.
According to a preferred embodiment, the actuation means is capable of changing the perpendicular flow vpH and/or vpW into and from the active flow controlling means by changing of at least one of the parameters including size, dimension, thickness, height, length, diameter, mobility, distance, permeability, porosity and swelling of at least one of the plurality of active flow controlling means.
According to an embodiment of the present invention, at least one of the active flow controlling means comprises a layer which is responsive to at least one external stimulus, upon which the flow of at the least a predefined species of biomolecules is altered. The term "external" especially means that at least one of the plurality of active flow controlling means is triggered by a means and/or stimulus provided and/or arising outside the layer, such as a change in pH or temperature, however it is clear to any skilled person in the art that this means and/or stimulus might arise from an actuation means inside the device, such as a heater, e.g. resistive heater etc. According to an embodiment of the present invention, the micromixer and/or microreactor comprises a plurality of passive flow controlling means.
By doing so, it has been shown in many applications within the present invention, that an adaptation to further conditions (e.g. when a higher flow is needed etc.) is possible. According to an embodiment of the present invention, the plurality of passive flow controlling means is associated with the plurality of active flow controlling means, preferably in that every passive flow controlling means is associated with at least one active flow controlling means.
According to an embodiment of the present invention, at least one of the plurality of active flow controlling means is a polymeric material. According to an embodiment of the present invention, at least one of the plurality of active flow controlling means is a polymeric material with a conversion of >50% and <100%.
In the sense of the present invention, the conversion especially includes, means or refers to a measurement according to the following procedure:
After the polymerization of at least one of the plurality of active flow controlling means, a quantitative amount of inhibitor was introduced into a sample of at least one of the plurality of active flow controlling means and the sample was quickly quenched in an ice bath. For the removal of remaining monomers and initiators, the sample as washed with deionized water several times. After that, the sample was dried in vacuum oven at 700C until there was no change in weight anymore. The conversion was calculated as follows: conversion = P/Mo * 100 % where P is the weight of the dry copolymer composite network obtained from the sample and M0 is the weight of the monomers in the feed.
According to an embodiment of the present invention, at least one of the plurality of active flow controlling means is a polymeric material with a conversion of >70% and <95%.
The term "essentially" means and/or includes especially a wt-% content of >90 %, according to an embodiment >95 %, according to an embodiment >99 %. According to an embodiment of the present invention, the crosslink density in at least one of the plurality of active flow controlling means is >0.002 and <1, preferably >0.05 and <1.
In the sense of the present invention, the term "crosslink density" means or includes especially the following definition: The crosslink density δx is here defined as
δ „ = where X is the mole fraction of polyfunctional monomers and L the mole x L + X fraction of linear chain (= non polyfunctional) forming monomers. In a linear polymer δx = 0 , in a fully crosslinked system δx = 1 .
According to a further embodiment of the present invention, there are more than one actuation means whereby each actuation means is capable of changing at least one of the physical properties of at least one of the plurality of active flow controlling means by each actuation means differ from that which are changed by the other actuation means. According to a preferred embodiment of the present invention, the plurality of active flow controlling means comprises at least one hydrogelic material.
According to an embodiment of the present invention, at least one of the plurality of active flow controlling means comprises a hydrogelic material.
In the sense of the present invention, the term "hydrogelic material" means and/or includes especially that this material comprises polymers that in water form a water-swollen network.
The term "hydrogelic material" in the sense of the present invention furthermore especially means that at least a part of the hydrogelic material comprises polymers that in water form a water-swollen network and/or a network of polymer chains that are water-soluble. Preferably the hydrogelic material comprises in swollen state >50% water and/or solvent, more preferably >70% and most preferred >90%, whereby preferred solvents include organic solvents, preferably organic polar solvents and most preferred alkanols such as Ethanol, Methanol and/or (Iso-) Propanol.
In the sense of the present invention, the term "hydrogelic material" means and/or includes especially that the hydrogel is responsive which means that it displays a change of shape and total volume upon a change of a specific parameter. Such parameter can be a physical (temperature, pressure) or chemical property (ionic concentration, pH, analyte concentration) or biochemical property (enzymatic activity).
Preferably the hydrogelic material comprises in swollen state >50% water and/or solvent, more preferably >70% and most preferred >90%, whereby preferred solvents include organic solvents, preferably organic polar solvents and most preferred alkanols such as Ethanol, Methanol and/or (Iso-) Propanol.
According to an embodiment of the present invention, the hydrogelic material comprises a material selected out of the group comprising poly(meth)acrylic materials, silicagel materials, substituted vinyl materials or mixture thereof. According to an embodiment of the present invention, the hydrogelic material comprises a substituted vinyl material, preferably vinylcaprolactam and/or substituted vinylcaprolactam.
According to an embodiment of the present invention, the hydrogelic material comprises a poly(meth)acrylic material made out of the polymerization of at least one (meth)acrylic monomer and at least one polyfunctional (meth)acrylic monomer.
According to an embodiment of the present invention, the (meth)acrylic monomer is chosen out of the group comprising (meth)acrylamide, acrylic esters, hydroxyethyl(meth)acrylate, ethoxyethoxyethyl(meth)acrylate or mixtures thereof. According to an embodiment of the present invention, the polyfunctional
(meth)acrylic monomer is a bis-(meth)acryl and/or a tri-(meth)acryl and/or a tetra- (meth)acryl and/or a penta-(meth)acryl monomer.
According to an embodiment of the present invention, the polyfunctional (meth)acrylic monomer is chosen out of the group comprising bis(meth)acrylamide, tetraethylene glycol di(meth)acrylate, triethylene glycol di(meth)acrylate, diethylene glycol di(meth)acrylate, tripropyleneglycol di(meth)acrylates, pentaerythritol tri(meth)acrylate polyethyleneglycoldi(meth)acrylate, ethoxylated bisphenol-A- di(meth)acrylate , hexanedioldi(meth)acrylate or mixtures thereof.
According to an embodiment of the present invention, the hydrogelic material comprises an anionic poly(meth)acrylic material, , preferably selected out of the group comprising (meth)acrylic acids, arylsulfonic acids, especially styrenesulfonic acid, itaconic acid, crotonic acid, sulfonamides or mixtures thereof, and/or a cationic poly(meth)acrylic material , preferably selected out of the group comprising vinyl pyridine, vinyl imidazole, aminoethyl (meth)acrylates or mixtures thereof, co- polymerized with at least one monomer selected out of the group neutral monomers, preferably selected out of the group vinyl acetate, hydroxy ethyl (meth)acrylate (meth)acrylamide, ethoxyethoxyethyl(meth)acrylate or mixture thereof, or mixtures thereof. These co-polymers change their shape as a function of pH and can respond to an applied electrical field and/or current by as well. Therefore these materials may be of use for a wide range of applications within the present invention. According to an embodiment of the present invention, at least one of the plurality of active flow controlling means comprises a hydrogelic material comprising thermo-sensitive polymers.
According to an embodiment of the present invention, at least one of the plurality of active flow controlling means comprises a hydrogelic material comprising monomers selected out of the group comprising poly-N-isopropylamide (PNIPAAm) and copolymers thereof with monomers selected out of the group comprising polyoxyethylene, trimethylol-propane distearate, poly-ε-caprolactone or mixtures thereof. According to an embodiment of the present invention, the hydrogelic material is based on thermo -responsive monomers selected out of the group comprising N-isopropylamide , diethylacrylamide, carboxyisopropylacrylamide, hydroxymethylpropylmethacrylamide, acryloylalkylpiperazine. and copolymers thereof with monomers selected out of the group hydrophilic monomers, comprising hydroxyethyl(meth)acrylate, (meth)acrylic acid, acrylamide, polyethyleneglycol(meth)acrylate or mixtures thereof, and/or co -polymerized with monomers selected out of the group hydrophobic monomers, comprising (iso)butyl(meth)acrylate, methylmethacrylate, isobornyl(meth)acrylate or mixtures thereof. These co-polymers are known to be thermo -responsive and therefore may be of use for a wide range of applications within the present invention.
According to an embodiment of the present invention, at least one of the plurality of active flow controlling means comprises a hydrogelic material with a swelling ratio of >1% and <500% at 200C.
In the sense of the present invention, the swelling ratio especially includes, means or refers to a measurement according to the following procedure:
At least one of the plurality of active flow controlling means was dried to form a film in an oven under the temperature of 500C. The film was immersed in an excess of deionized water to remove the residual unreacted compounds. The swollen polymer film was then cut into disk forms with 8mm in diameter and dried at 500C until the weight no longer changed. A preweighed dried sample (Wo) was immersed in an excess of deionized water in a thermostatic water bath until the swelling equilibrium was attained. The weight of the wet sample (Wi) was determined after the removal of the surface water via blotting with filter paper. The equilibrium swelling ration was calculated with the following formula swelling ratio = (Wi - W0) / W0
According to an embodiment of the present invention, at least one of the plurality of active flow controlling means comprises a hydrogelic material with a swelling ratio of >3% and <200% at 200C.
According to an embodiment of the present invention, at least one of the plurality of active flow controlling means comprises a hydrogelic material with a swelling ratio of >5% and <100% at 200C.
According to an embodiment of the present invention, at least one of the plurality of active flow controlling means comprises a hydrogelic material with a swelling of>l% and ≤30% at 20°C. According to an embodiment of the present invention, at least one of the plurality of active flow controlling means comprises a hydrogelic material with a swelling ratio of >1% and <25% at 200C.
According to an embodiment of the present invention, at least one of the plurality of active flow controlling means comprises a hydrogelic material with a swelling of >1% and <20% at 200C.
According to a preferred embodiment of the present invention, at least part of the plurality of active flow controlling means comprise a hydrogelic material with a structural gradient.
According to a preferred embodiment of the present invention, the structural gradient comprises a gradient in at least one or more of the following features: cross-link density, composition, porosity, ordering parameter, LCST (lower critical solution temperature).
According to a preferred embodiment of the present invention, at least one part of the plurality of active flow controlling means comprises a semi-permeable elastic sheet. Said semi-permeable elastic sheet or layer is preferably an elastic rubber material such as polydimethylsiloxane (PDMS) or other silicon rubbers, siloxanes etc.
In a preferred embodiment the channel in which the fluid flows is separated from an actuation medium (such as responsive polymeric material, or pressure/hydrostatic driven via an actuation fluid (gas or second liquid) with external or internal pump), by at least one, preferably thin, elastic sheet, such as polydimethylsiloxane (PDMS) or other silicon rubbers, polypropylene (PP), polyimide, siloxanes etc.
Said elastic sheet is preferably non-permeable for said actuation medium and preferably also not permeable for at least predefined components of the main flow in the channel.
However according to an embodiment of the present invention said elastic sheet is permeable for a first component of the flow e.g. water or some ions, whereas it is non permeable for a second component of the flow e.g. bioanalyte to be mixed in said micromixer. In the context of the present invention, the term "responsive polymeric material" includes especially that the material is responsive in such a way that it displays a change of shape and total volume upon a change of a specific parameter. An example of a change is melting, which may happen if a wax- like material is heated. In another embodiment polymeric material is used that swells upon a temperature increase such as low melting point polymers including wax or polyethyleneglycol PEG. Preferably said responsive polymeric material undergoes a phase transition including from solid to liquid, from liquid to gas, and preferably from crystalline to amorphous and/or liquid.
According to a preferred embodiment of the present invention, the plurality of active flow controlling means are divided in segments of correlated active flow controlling means.
According to a preferred embodiment of the present invention, each of the segments of correlated active flow controlling means comprise >2-<50, preferably >4-<20, most preferably >6-<20 or about 10 flow controlling means.
In a preferred embodiment said number of flow controlling means per segment are substantially identical in their shape and effect on the perpendicular flow component.
In another preferred embodiment one parameter such as the height, length dimension etc. of said elements changes gradually within one segment.
In order to avoid a large number of control terminals, US patent 6,852,287, which is incorporated by reference in total, proposes embodiments of a method to control a number N of independently controllable components with smaller number of control terminals. In order to achieve this, both the use of multiplexing techniques or passive matrix techniques is proposed. In particular, the matrix technique is extremely attractive, as this allows for the maximum number of components to be controlled with the minimum number of control terminals. Conceptually, if one specific heater element in a passive matrix is activated also a number of other heater elements will be activated unintentionally. As a result, heat will be generated where it is not required, and the heat generated at the intended heater element will be different than required as either some of the applied current has traveled through alternative paths, or the applied voltage is dropped along the rows and columns before reaching the heater element intended to be activated.
Co-pending application IB2006/053434 discloses a micro-fluidic device, e.g. a biochip, fabricated on a substrate based upon active matrix principles. The device is preferably fabricated from one of the well known large area electronics technologies, such as amorphous silicon (a-Si), low temperature polycrystalline silicon (LTPS) or organic transistor technologies. The active matrix makes it possible to independently control a larger number of components on the device with a smaller number of control terminals. This device enables accurate and localized control of temperature in an active matrix set up, without the need for a large device periphery to locate the I/O pins. To enable control over the temperature at specific positions in the device, the first electronic components preferably comprise at least one heater element.
Optionally the micro-fluidic device comprises further first electronic components for sensing properties of the fluid such as the fluid flow or the mixing actuation etc. In a preferred embodiment, the device comprises at least two, even more preferred a multiplicity of heater elements. Such a device is referred to as a thermal processing array. These heater elements are suitable for heating fluid that may be present in cells or compartments of the microfluidic device.
The thermal processing array can be used to either maintain a constant temperature across the entire compartment area, or alternatively to create a defined time- dependent temperature profile if the reaction compartment is also configured in the form of an array and different portions of the reaction chamber require different temperatures. In a most preferred embodiment, the thermal processing array comprises a multiplicity of individually addressable and drivable heating elements, and may preferably comprise additional elements such as temperature sensors and fluid-mixing or fluid- pumping elements or a combination thereof.
In one advantageous embodiment of the invention at least one of the electronic components of the active matrix comprises thin film transistors having gate, source and drain electrodes. In this case the active matrix includes a set of select lines and a set of control lines such that each individual component may be controlled by one select line and one control line and the gate electrode of each thin film transistor is connected to a select line.
In another advantageous embodiment of the invention a memory device is provided for storing a control signal supplied to the control terminal. In an alternative embodiment of the invention the second electronic components are formed by thin film diodes, e.g. metal-insulator-metal (MIM) diodes. It is preferred that a MIM diode connects a first electrode of each first electronic component to a control line, and a second electrode of each first electronic component is connected to a select line. In another advantageous embodiment of the invention the thin film diodes are PIN or Schottky diodes, wherein a first diode connects a first electrode of each component to a control line, wherein a second diode connects the first electrode of each component to a common rest line and wherein a second electrode of each component is connected to a select line. In an advantageous development of the invention the first diode is replaced by a pair of diodes connected in parallel and the second diode as well is replaced by a pair of diodes connected in parallel.
In yet another advantageous development the first diode is replaced by a pair of diodes connected in series, and also the second diode is replaced by a pair of diodes connected in series.
In another advantageous embodiment of the invention the second electronic components comprise circuitry based on transistors or diodes or passive components (such as resistors and capacitors) or combinations thereof.
A micromixer and/or microreactor and/or a method according to the present invention may be of use in a broad variety of systems and/or applications, amongst them one or more of the following: biomicromixer and/or microreactors used for molecular diagnostics rapid and sensitive detection of proteins and nucleic acids in complex biological mixtures and body fluids such as e.g. blood, urine or saliva - high throughput screening devices for chemistry, pharmaceuticals or molecular biology testing devices e.g. for DNA or proteins e.g. in criminology, for on-site testing (in a hospital), for diagnostics in centralized laboratories or in scientific research - tools for DNA or protein diagnostics for cardiology, infectious disease and oncology, food, and environmental diagnostics tools for combinatorial chemistry analysis devices
The aforementioned components, as well as the claimed components and the components to be used in accordance with the invention in the described embodiments, are not subject to any special exceptions with respect to their size, shape, material selection and technical concept such that the selection criteria known in the pertinent field can be applied without limitations. Additional details, features, characteristics and advantages of the object of the invention are disclosed in the subclaims, the figures and the following description of the respective figure and examples, which — in an exemplary fashion — show several preferred embodiments of a micromixer and/or microreactor according to the invention.
Fig. 1 shows a very schematically partial top view of a micromixer and/or microreactor according to a first embodiment of the present invention;
Fig. 2 shows a very schematically cross-cut view of the microreactor of
Fig. 1 approximately along line H-II in Fig. 1 in a first condition of the active flow controlling means
Fig. 3 shows the view of Fig. 2 in a second (swollen) condition of the active flow controlling means.
Fig. 4 shows a very schematic partial top view of a micromixer and/or microreactor according to a second embodiment of the present invention; Fig. 5 shows a very schematic partial top view of a micromixer and/or microreactor according to a third embodiment of the present invention;
Fig. 6 shows a very schematically cross-cut partial view of a micromixer and/or microreactor according to a fourth embodiment of the present invention employing active and passive flow controlling means. Fig. 7 shows the view of Fig. 6 with the active flow controlling means in swollen state
Fig. 8 shows (as an alternative to Fig. 8) the view of Fig. 6 with the active flow controlling means in shrunken state.
Fig. 9 shows a very schematically cross-cut partial view of a micromixer and/or microreactor according to a fifth embodiment of the present invention employing active and passive flow controlling means and an elastic sheet.
Fig.10 shows the embodiment of Fig. 9 with the active flow controlling means in shrunken state Fig. 1 shows a very schematic partial top view of a micromixer and/or microreactor 1 according to a first embodiment of the present invention. The micromixer and/or microreactor according to this embodiments comprises a plurality of segments Ll, L2 etc, which itself comprise several active flow controlling means 10 (for sake of brevity and visibility only one active flow controlling means is referred to as 10).
As indicated in Fig. 1 , in the micromixer and/or microreactor, there are several flow components, including a main flow (which velocity is referred to as "vfl") and at least one perpendicular flow (which velocity is referred to as "vpW").
Between segments the component in the perpendicular flow direction vpW (or vpH) changes in direction, which is realized in this embodiment by changing the symmetry (or asymmetry) in the cross segment of the channel. Said active flow controlling means 10 are positioned differently in Ll and L2 segments with respect to the channel or channel wall (right and left). But there are also other variations possible (in height, in width, in angle of the bars with respect to the main flow etc.). According to a preferred embodiment of the invention, there is an asymmetry in the configuration of said flow controlling means in each segment, which means in this embodiment that W2 is typically bigger than the half of Wl.
According to a preferred embodiment, the width of the active flow controlling means W2 is preferably between >30 and <90% of the channel width Wl, more preferably between >40 and <80%, and most preferably between >50 and <70%.
It goes without saying that there are for the skilled person in the art several possibilities for alternating configurations of the flow controlling means, which are all part of this invention. E.g. a further arrangement is shown in Fig. 4 (which is merely to be taken as an example), which shows a very schematic partial top view of a micromixer and/or microreactor according to a second embodiment of the present invention
The angle of said flow controlling means with respect to the main flow preferably between >20 and <160 degree; according to one embodiment between >30 and <60, according to a further embodiment between >120 and <150. Said active flow controlling means may according to further embodiments (not shown in the figs) also have bar-like, sinus-shape, saw tooth shape, fishbone or other suitable configurations, involving different or multiple angles.
According to a preferred embodiment of the invention there are a number of flow controlling means per segment, this number ranges from 2-50, preferably 4-20, most preferably 6-20 (or about 10). In a preferred embodiment said number of flow controlling means per segment are substantially identical in their shape and effect on the perpendicular flow component.
It has been shown advantageous to introduce such segments into the microreactor/micromixer for a wide range of applications within the present invention, since by doing so it is usually possible to change the direction of the perpendicular flow vPW easily.
In another preferred embodiment one parameter such as the height, length dimension etc. of said elements changes gradually within one segment.
The microfluidic mixing device according to a preferred embodiment of the invention comprises 4-50 segments, more preferably 8-20 segments.
The function of said segments is according to an embodiment of the present invention and within a wide range of applications basically to force the flow to change of direction of perpendicular flow, e.g. changing from a perpendicular component to the right to another one to the left resulting e.g. in a change from a clockwise rotation of the fluid (along an axis in the main flow direction) into a counterclockwise rotation of the fluid.)
The segments are typically arranged alternating, i.e. L1-L2-L1-L2 etc., but there might also be cases where L1-L2-L3-L4-L1.. or other arrangements are chosen (not shown in the figs). Pl is the length after which periodicity is obtained, typically Pl = L1+L2.
Fig. 2 shows a very schematically cross-cut view of the microreactor of Fig. 1 approximately along line H-II in Fig. 1 in a first condition of the active flow controlling means, Fig. 3 shows the view of Fig. 2 in a second (swollen) condition of the active flow controlling means. By doing so, especially the perpendicular flow may be altered, thus causing mixing inside the microreactor/micromixer. It should be noted that according to an embodiment, the height of the active flow controlling means H2 and/or H3 is preferably in the range between >5 and <50% of the channel height Hl, more preferably between >10 and <40%, and most preferably between >20 and <30%; this goes for the "non-swollen"-state as well as for the "swollen state".
Preferably the height H2 and/or H3 are especially chosen such that that the perpendicular component of the flow, i.e. vpW and/or vpH is > 2%, preferably > 5%, more preferably > 10 of the main flow vfl.
The length of one segment Ll is preferably in the range >1 and <5000μm, more preferably between >10 and <2000μm, most preferably between >100 and ≤lOOOμm.
The length of one segment Ll is preferably a factor >1 to <100 larger than said first dimension of the channel (the diameter, height H lor width Wl) preferably a factor 5-20, most preferably a factor of about 10. It should be noted that in Figs. 2 and 3 there is also shown a "third flow"
(which velocity is vH, cf. described above). Said third flow can realize or accelerate swelling, deswelling and also mixing if only parts of said first flow are up taken temporarily and rejected later in time. This flow is referred to as "vH in" (= into the flow controlling means) and "vH out" (= out of the flow controlling means). However, there are also further embodiments within the present invention that the active flow controlling means may be coated with an elastic material (such as silicon rubber, such as PDMS etc.) so that there will be no flow "vHin" or "vHout".
Fig. 5 shows a very schematic partial top view of a micromixer and/or microreactor according to a second embodiment of the present invention. In this embodiment, several hydrogelic material "segments" 50a, 50b are placed in the flow. The segments 50a, 50b differ from each other that they are sensible to different stimuli, i.e. it is possible e.g. to shrink and swell the segments 50a and 50b independent from each other.
By doing so, an efficient mixing is reached on a small scale for a wide range of applications within the present invention. It goes without saying that the elements of the embodiment of Figs. 1 to 4 and of that of Fig. 5 might also be combined.
Fig. 6 shows a very schematically cross-cut partial view of a micromixer and/or microreactor according to a fourth embodiment of the present invention employing active and passive flow controlling means, Fig. 7 and 8 show the same view with the active flow controlling means 10 in swollen and shrunken state, respectively.
The micromixer and/or microreactor of Figs. 6 to 8 differs to the previous ones in that several passive flow controlling means 20 are present in addition to the active flow controlling means 10. In the Figs, it is evident that every passive flow controlling means 20 is associated with at least one active flow controlling means 10, however, it is apparent to any skilled person in the art that this need not be the case for every embodiment within the present invention.
The passive flow controlling means 20 may be made of a material which is "harder" or less elastic than the material of the active flow controlling means 10, in order to adapt to applications where different conditions (e.g. a faster flow) is needed.
In Fig. 6, the width Bl of every passive flow controlling means 20 is preferably >10 to <50 of the combined width B2 of the passive flow controlling means 20 and the active flow controlling means 10 associated with it. This has been shown to be advantageous for a wide range of applications. Fig. 9 shows a very schematically cross-cut partial view of a micromixer and/or microreactor according to a fifth embodiment of the present invention. This embodiment differs from the embodiment of Figs. 6 to 8 in that besides employing active 10 and passive 20 flow controlling means, also an elastic sheet 30 is used (as described above). By doing so, a flow in and from the active and/or passive flow controlling means may be greatly or fully prevented, which has shown to be advantageous for a wide range of applications within the present invention.
Fig.10 shows the embodiment of Fig. 9 with the active flow controlling means 10 in shrunken state. It should be noted and is clear to any skilled person in the art that the Figs. 9 and 10 are for illustrative purposes only and the actual dimensions (including the thickness of the elastic sheet 30) may for actual embodiments and applications of the inventions very different from those indicated in the figures.
The particular combinations of elements and features in the above detailed embodiments are exemplary only; the interchanging and substitution of these teachings with other teachings in this and the patents/applications incorporated by reference are also expressly contemplated. As those skilled in the art will recognize, variations, modifications, and other implementations of what is described herein can occur to those of ordinary skill in the art without departing from the spirit and the scope of the invention as claimed. Accordingly, the foregoing description is by way of example only and is not intended as limiting. The invention's scope is defined in the following claims and the equivalents thereto. Furthermore, reference signs used in the description and claims do not limit the scope of the invention as claimed.

Claims

CLAIMS:
1. A micromixer and/or microreactor comprising a plurality of active flow controlling means.
2. The micromixer and/or microreactor according to claim 1, whereby at least a part of the active flow controlling means are adapted to change at least one physical parameter upon stimulation of at least one external activation means so that at least the perpendicular flow in the micromixer/microreactor is changed.
3. The micromixer and/or microreactor according to claim 1 or 2, whereby the plurality of active flow controlling means are adapted to shrink and/or swell upon stimulation of at least one external activation means.
4. The micromixer and/or microreactor according to claim 1 or 3, whereby the plurality of active flow controlling means is located in a preferred flow direction
5. The micromixer and/or microreactor according to any of the claims 1 to 4, whereby there is a changing direction, essentially in which the change of at least one of the plurality of active flow controlling means in response to the actuation means occurs and which is essentially perpendicular to a preferred flow direction.
6. The micromixer and/or microreactor according to any of the claims 1 to 5 whereby at least part of the plurality of active flow controlling means comprise a hydrogelic material.
7. The micromixer and/or microreactor according to any of the claims 1 to 6 whereby the a plurality of active flow controlling means comprises at least one responsive hydrogelic material
8. The micromixer and/or microreactor according to any of the claims 1 to 7 whereby the plurality of active flow controlling means are divided in segments of correlated active flow controlling means.
9. The micromixer and/or microreactor according to any of the claims 1 to 8, whereby each of the segments of correlated active flow controlling means comprise >2-<50, preferably >4-<20, most preferably >6-<20 or about 10 flow controlling means.
10. A system incorporating a micromixer and/or microreactor according to any of the Claims 1 to 9 and being used in one or more of the following applications: biomicromixer and/or microreactors used for molecular diagnostics rapid and sensitive detection of proteins and nucleic acids in complex biological mixtures such as e.g. blood or saliva high throughput screening devices for chemistry, pharmaceuticals or molecular biology testing devices e.g. for DNA or proteins e.g. in criminology, for on-site testing (in a hospital), for diagnostics in centralized laboratories or in scientific research tools for DNA or protein diagnostics for cardiology, infectious disease and oncology, food, and environmental diagnostics tools for combinatorial chemistry analysis devices
PCT/IB2008/051523 2007-04-26 2008-04-21 Micromixer and/or microreactor with active flow controlling means WO2008132651A1 (en)

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