EP2062644A1 - Dispositif micro-fluidique doté d'un contrôle de dégazage - Google Patents

Dispositif micro-fluidique doté d'un contrôle de dégazage Download PDF

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Publication number
EP2062644A1
EP2062644A1 EP07121551A EP07121551A EP2062644A1 EP 2062644 A1 EP2062644 A1 EP 2062644A1 EP 07121551 A EP07121551 A EP 07121551A EP 07121551 A EP07121551 A EP 07121551A EP 2062644 A1 EP2062644 A1 EP 2062644A1
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Prior art keywords
micro
fluidic
electrodes
fluid
channel
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German (de)
English (en)
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Koninklijke Philips NV
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Koninklijke Philips Electronics NV
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Priority to EP07121551A priority Critical patent/EP2062644A1/fr
Priority to PCT/IB2008/054817 priority patent/WO2009069034A1/fr
Publication of EP2062644A1 publication Critical patent/EP2062644A1/fr
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502723—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by venting arrangements
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0684—Venting, avoiding backpressure, avoid gas bubbles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/14—Process control and prevention of errors
    • B01L2200/143—Quality control, feedback systems
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0627—Sensor or part of a sensor is integrated
    • B01L2300/0645—Electrodes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0681—Filter
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/12—Specific details about materials
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
    • B01L2400/0487—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics

Definitions

  • the present invention relates to micro-fluidic device and methods to fill or "de-gas" a micro-fluidic device.
  • micro-fluidic devices nowadays are becoming more important, in particular in the biotechnological field.
  • a micro-fluidic device may be used, for example, in biotechnological and pharmaceutical applications and in microchannel cooling systems in microelectronics applications.
  • a micro-fluidic device comprises components and one or more micro-fluidic channels, which are filled with a fluid, often a gas, used during the production process of the micro-fluidic device.
  • a fluid often a gas
  • the micro-fluidic device more particular the components and micro-fluidic channels, are to be filled with a fluid which is often a buffered aqueous solution.
  • micro-fluidic devices such as those required for lab-on-a-chip applications
  • One of the major issues when developing micro-fluidic devices is to ensure that micro-fluidic channels are not blocked by the presence of gas bubbles.
  • One of the known approaches is to make use of micro-fluidic channels based upon a semi-permeable material such as polydimethylsiloxane (PDMS).
  • PDMS is gas permeable and therefore if there are any gas bubbles they can be removed by applying pressure for a prolonged period of time until degassing occurs. Gas bubbles are eliminated after a period of sustained pressure. Such an approach has been confirmed as being very effective.
  • micro-fluidic device has to be sufficiently transparent to allow visual inspection, and that the device has to be repeatedly visually inspected to see if all trapped gas has been removed. This is obviously not desirable as it requires a technician to repeatedly inspect the device and will therefore result in a costly assay.
  • Another disadvantage of a visual check is that it also excludes some applications where cartridges comprising the micro-fluidic device is enclosed within a non-transparent reader device and visual access is impaired.
  • a disadvantage of this test is that one can only check the status of the process after the process has been completed.
  • a further disadvantage is that gas bubbles which are present in the micro-fluidic channel, but which are not present along the path between the two fluidic openings, might not be detected.
  • An advantage of this device can be that filling or degassing of the device can be monitored. It is an advantage of some embodiments of the present invention that the filling or degassing operation can be performed swiftly and in a short time. According to some embodiments, the degassing or filling of the micro-fluidic device may be performed, with reduced risk or even without the risk of damaging or rupturing of the micro-fluidic device. It is an advantage of some embodiments of the present invention that the filling or degassing operation can be monitored in real time.
  • the filling or degassing operation can optionally be stopped or interrupted upon measurement of too large defects, too many defects, the observation that defects are no longer present, measurement of overpressures and the like.
  • the filling or degassing of the micro-fluidic device may be controlled by a control signal provided by a controller being separate from or being part of the micro-fluidic device. This control signal may be used to e.g. interrupt or activate fluid pumping means, or e.g. to control the flow rate of the fluid pumping means. Microfluidic pumps are known. It is an advantage of some embodiments of the present invention that visual inspection of the progress of the degassing or filling process may be avoided.
  • an arrangement of a micro-fluidic device and a controller comprises at least one micro-fluidic channel for holding a fluid, the micro-fluidic channel having an interior channel wall.
  • the micro-fluidic device comprises a plurality of electrodes present at the interior channel wall.
  • the controller is adapted for measuring the value of an electrical property of the fluid between at least two electrodes of the plurality of electrodes and for generating an output signal dependent on the measured value of the electrical property indicating whether a gas volume is present between the at least two electrodes.
  • At least part of the interior channel wall may be made from semi-permeable material.
  • the part of the interior channel wall made from semi-permeable material enables gas to pass through the interior channel wall, hence enables to evacuate gas from the channel, e.g. by means of an overpressure created in the channel.
  • the micro-fluidic device may comprise a structure in which the at least one micro-fluidic channel is provided.
  • the structure may comprise a base structure, e.g. a glass or plastic substrate, onto which electrodes are placed, such as e.g. by a lithographical process.
  • the part of the wall oriented in a direction extending from this base structure, such as e.g. about perpendicular, and providing the so-called vertical walls is provided by a second, vertical, structure, e.g. formed from e.g. PDMS.
  • a top substrate, e.g. a PDMS layer which is connected to the base structures via the vertical walls, e.g. PDMS walls.
  • the term channel wall hence is to be understood as any of the walls of the channel, which are provided by different structures together providing the channel.
  • An advantage of the arrangement according to the present invention is obtained during degassing of the micro-fluidic device, i.e. during provision of a fluid, such as a buffer fluid, usually a liquid, in the micro-fluidic channel of the micro-fluidic device.
  • the values measured between pairs of the electrodes are dependent on the presence of the buffer fluid between these electrodes. If no buffer fluid is present, the electrical property of the gas present in the micro-fluidic channel is measured. When the micro-fluidic channel is completely filled with buffer fluid between the electrodes, the electric property of the buffer fluid will be measured. In case the buffer fluid holds a gas bubble between the electrodes (hence the micro-fluidic device is not yet completely degassed), the value of the electric property measured between the two electrodes will not be equal to the electric property of the buffer fluid itself.
  • the controller upon measuring preset values for the electric property between the electrodes, can be adapted to give a signal indicating the completeness of the filling or degassing operation.
  • This signal may be used to control, e.g. interrupt pumping devices providing the buffer fluid to the micro-fluidic device.
  • the electric property measured may be an impedance between the electrodes.
  • the capacitance or resistance between two electrodes may be measured and the controller may be adapted accordingly.
  • the controller may comprise a look-up table, comprising for each pair of electrodes the preset value to be measured, optionally in function of the buffer fluid.
  • the sequence of measured values between pairs of electrodes along the inner wall of the micro-fluidic channel represents the progress of the degassing or "filling". Hence the filling can be monitored.
  • the last pair of electrodes for which a value equal to the predetermined electric property of the buffer fluid is measured is an indication of where the buffer liquid has reached in the micro-fluidic channel.
  • the pairs of electrode being upstream of this last pair of electrodes for which a value equal to the electric property of the buffer fluid is measured may optionally provide a measured value different from the value equal to the electric property of the buffer fluid.
  • the buffer fluid may comprise gas bubbles.
  • the electrodes are provided along the inner channel wall of the micro-fluidic channel.
  • the plurality of electrodes may be substantially equally distributed along the inner wall of the micro-fluidic channel.
  • the electrodes may be located on the channel wall, providing zones on the micro-fluidic channel, or they may be partially or completely sunken in the channel wall.
  • the surface of the electrode used to contact the buffer fluid may be coplanar with the inner channel wall.
  • a plurality of electrodes may be provided along the complete longitudinal length of the micro-fluidic channel or micro-fluidic channels.
  • the centre-to-centre distance between adjacent electrodes is optionally in the range of 10 ⁇ m to 1000 ⁇ m. So optionally 50 electrodes per millimetre along the longitudinal direction of the micro-fluidic channel may be provided.
  • the electrodes themselves may have any suitable shape, such as being substantially rectangular or circular.
  • the electrodes may have a with of e.g. 1 ⁇ m to 1000 ⁇ m and a thickness of e.g. 10nm to 1000nm.
  • the controller may be adapted to monitor automatically the progress of the degassing or filling of the micro-fluidic channel of the micro-fluidic device.
  • the controller may optionally be adapted to generate a signal indicative for the progress of the filling or degassing, dependent upon the sequence of measured values, measured between electrodes.
  • This signal may be used to set the flow rate, the volume and/or pressure of the buffer fluid provided to the micro-fluidic device by means of e.g. pumps.
  • the flow rate can be set high at start of the filling or degassing procedure, and be gradually or stepwise reduced to a relatively low flow rate when the filling or degassing process reaches its end point.
  • the controller may give a fault signal, indicating than the filling or degassing process has not correctly proceeded at that moment.
  • the defect signal may be used to interrupt the filling or degassing process.
  • the micro-fluidic device may comprise "buffer fluid sensitive" components, i.e. components which cannot be reused once they have been in contact with buffer fluid, an early interruption of the filling or degassing process may be advantageous in case the micro-fluidic device can still be emptied and refilled, without the buffer fluid sensitive components having been in contact with buffer fluid.
  • a hybridisation spot for DNA detection being buffer fluid sensitive components, may form part of the micro-fluidic device.
  • the micro-fluidic device may comprise more than one micro-fluidic channel, which micro-fluidic channels may be linked one to the other for defining a complex labyrinth of micro-fluidic channels.
  • each of the micro-fluidic channels may be provided with a plurality of electrodes, such that for each micro-fluidic channel, the progress of the filling or degassing in this particular micro-fluidic channel may be monitored and controlled.
  • the micro-fluidic device may also comprise one or more components having a particular function when the micro-fluidic device is used as e.g. a biosensor device. Such components may be mixing chambers, reagent inlet openings, and alike.
  • the cross-flow geometries of channels may be designed or provided for exerting force on a cell to flow through the channel.
  • the device may be a device for performing RT(PCR), a matrix device for quantifying multiple individual cells, a device with electrodes for classifying cells via their electrical properties and alike.
  • the micro-fluidic device further comprises one or more fluidic openings. It is understood that the plurality of electrodes are located within the micro-fluidic channel present between these fluid openings.
  • the device according to the present invention has the advantage that there is no longer a need for visual inspection of the degassing or filling rate, hence the filling or degassing may be automated, even without the necessity of the presence of inspection windows in the micro-fluidic device.
  • the micro-fluidic device may be mounted in cartridges that impair visual access as the present invention removes the need for visual access.
  • the semi-permeable material may be used to provide the base structure of the device.
  • the base structure may be made from polymethylsiloxane (PDMS).
  • PDMS polymethylsiloxane
  • any other gas permeable and liquid impermeable material such as various fine porous gels or polyethylene may be used.
  • Semi-permeable material is to be understood as being permeable for gasses, but impermeable for liquids, in particular the buffer liquids to be used.
  • gas bubbles may be formed in one or more of the micro-fluidic channels. These defects may be found by the measured values of the electric properties over the plurality of electrodes. As it is known that maintaining a given fluid pressure will cause the gas to dissipate though the semi-permeable material. Hence the controller, obtaining the measured values and comparing these with the predetermined values, the controller may provide a control signal to maintain the fluid pressure until e.g. the measured values meet the predetermined values and/or for preset period in time.
  • the plurality of electrodes may comprise a plurality of electrode pairs, the controller being adapted for measuring the electric property between the electrodes of each pair of electrodes.
  • Each pair may comprise a reference electrode and a probe electrode.
  • the perimeter of the micro-fluidic channel has a longitudinal direction (which is identical to the flow direction of the fluid in the micro-fluidic channel) and may have any suitable cross sectional shape in radial cross section, such as circular, oval, rectangular or square or similar.
  • the plurality of electrodes may be provided at identical or different, even opposite positions relative to a radial cross section of the micro-fluidic channel.
  • a radial cross section at a given position in longitudinal direction is to be understood as a section according to a plane being perpendicular to the longitudinal direction of the micro-fluidic channel at that given position along the longitudinal direction.
  • the at least one micro-fluidic channel may have a substantially rectangular radial cross section having two pairs of mutually opposite sides, the plurality of electrodes baing present along the same side of the radial cross sections.
  • micro-fluidic channel or micro-fluidic channels along their longitudinal direction must not be identical all along the longitudinal direction.
  • the electrodes may be provided using a large area electronics substrate, such as a low temperature poly silicon substrate (LTPS).
  • LTPS low temperature poly silicon substrate
  • the micro-fluidic device further may comprise an overpressure measuring device.
  • the overpressure measuring device may comprise at least one expansion chamber being separated from the at least one micro-fluidic channel by means of a membrane , which membrane cooperates with a sensor for generating a signal when the pressure over the membrane becomes larger than a given threshold pressure.
  • two electrodes e.g. 10 ⁇ m wide electrodes are provided, and the impedance between them is measured.
  • the two electrodes may be coupled to a resistance meter.
  • a transistor such as an ISFET e.g. provided using LTPS technology could be used.
  • the resistance transistor channel may be measured and will change when the gate comes into contact with the liquid, optionally a conductive solution.
  • the pressure of deformation should be less than the pressure required for device failure.
  • the membrane may be adapted to rupture when said threshold pressure is reached.
  • the sensor may be located within the expansion chamber. Upon rupture of the membrane, the buffer fluid will contact the sensor, which contact may cause the signal of the sensor to be generated.
  • the membrane and sensor may be in contact with each other when a fluid pressure less than the threshold pressure is applied to the membrane, the contact between the membrane and sensor being interrupted when a fluid pressure less than the threshold pressure is applied to the membrane or vice versa.
  • the interruption of the contact may cause the signal of the sensor to be generated.
  • the filling or degassing processes may be interrupted.
  • the controller may further evaluate the measured values of the plurality of electrodes to evaluate if the filling or degassing process is completed, or if the overpressure at the sensor was caused by accidental pressure build up during the process. In the later case, the controller may provide a signal indicating an incomplete, incorrect filling or degassing process.
  • micro-fluidic device comprises more than one micro-fluidic channel, optionally coupled to each other, a plurality of such overpressure measuring devices may be provided, such as at least one per micro-fluidic channel of the micro-fluidic device.
  • the at least one micro-fluidic channel may be provided using a substrate.
  • the micro-fluidic device further may comprise at least one of a valve or a pump, the at least one of a valve or a pump being integrated in the substrate.
  • a method for degassing a micro-fluidic device comprises at least one micro-fluidic channel for holding a fluid.
  • the method comprises:
  • the micro-fluidic channel may have an interior channel wall, at least part of the interior channel wall, hence at least part of the micro-fluidic device, being made from semi-permeable material.
  • the at least part of the interior channel wall which is made from semi-permeable material enables gas to be removed or evacuated from the channel by passing the gas through the semi-permeable material.
  • the micro-fluidic channel may have an interior channel wall.
  • the micro-fluidic device may comprise a plurality of electrodes present at the interior channel wall, the measuring step including measuring between at least two of the plurality of electrodes.
  • the output signal may be used to determine the end of a degassing of the micro-fluidic device.
  • the buffer fluid may be provided to the micro-fluidic device by means of a pump (1910), the output signal being used to control the pump.
  • the output signal may be used to control the flow rate of buffer fluid provided by the pump.
  • a controller for controlling a micro-fluidic device comprises at least one micro-fluidic channel for holding a fluid.
  • the controller comprises:
  • the micro-fluidic channel may have an interior channel wall, at least part of the interior channel wall, hence at least part of the micro-fluidic device being made from semi-permeable material.
  • the at least part of the interior channel wall which is made from semi-permeable material enables gas to be removed or evacuated from the channel by passing the gas through the semi-permeable material.
  • a micro-fluidic device may be used in biotechnological or biomedical applications such as biosensors, rapid DNA separation and sizing, cell manipulation and sorting, or in pharmaceutical applications, in particular high-throughput combinatorial testing.
  • a micro-fluidic device may also be used in microchannel cooling systems in microelectronics applications.
  • an element described herein of an apparatus embodiment is an example of a means for carrying out the function performed by the element for the purpose of carrying out the invention.
  • Semi-permeable material is to be understood as a liquid permeable and gas impermeable material, i.e. being permeable for gasses, but impermeable for liquids, in particular the buffer liquids to be used.
  • Substantially planar is to be understood as lying in the same plane, within deviations, which are in typical tolerances applicable for the related technical field.
  • substantially rectangular or circular is to be understood as being rectangular or circular, within deviations, which are in typical tolerances applicable for the related technical field.
  • substantially equal distances is to be understood as distances being equal, plus or minus deviations which are in typical tolerances applicable for the related technical field. Typical deviations may be less than or equal to 30 ⁇ m, even less than or equal to 20 ⁇ m, even less than 10 ⁇ m such as in the range of 5 ⁇ m to 10 ⁇ m.
  • a micro-fluidic device 100 according to a first embodiment of the present invention is shown schematically in Figure 1 .
  • the micro-fluidic device 100 comprises a structure 110.
  • the structure comprises at least one, and in this particular case a plurality of micro-fluidic channels 120 for holding and/or transporting a fluid, e.g. a gas or a liquid.
  • the micro-fluidic device 100 further comprises a plurality of fluidic openings 130, of which two are shown in Figure 1 .
  • the micro-fluidic channels 120 visible in Figure 1 show two gas volumes or gas bubbles 200.
  • the micro-fluidic device is further filled with a buffer liquid 210.
  • the device 100 with the plurality of fluidic openings 130 in figure 1 is purely given as an example of a micro fluidic device.
  • This buffer fluid is typically a buffer liquid.
  • the liquid can be either an aqueous liquid or an oily liquid, e.g. an oil. If aqueous then it may be a buffered saline solution.
  • PBS phosphate buffered saline
  • SSC sodium chloride and sodium citrate
  • zwitterionic buffers such as HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), HEPPS (3-[4-(2-hydroxyethyl)-1-piperazinyl]propanesulfonic acid), Bis-Tris (1,3-bis(tris(hydroxymethyl)methylamino)propane), MOPS (3-N-(morpholino)-propanesulfonic acid), and electrophoresis Tris (tris(hydroxymethyl)-aminomethane) buffers, such as Tris acetate EDTA (ethylenediamine tetraacetic acid), TBE (Tris base, boric
  • the aqueous solution may also contain e.g. BCS (Bovine Calf Serum), BSA protein, (growth factors such as VEGF).
  • BCS Bovine Calf Serum
  • BSA protein BSA protein
  • growth factors such as VEGF
  • a detail "A" of the micro-fluidic device 100 of Figure 1 is shown in Figure 2 .
  • the micro-fluidic channel 120 in which one of the gas bubbles 200 is present, is shown in detail in Figure 2 .
  • the micro-fluidic channel 120 has an interior channel wall 121.
  • the micro-fluidic device 100 comprises a plurality of electrodes 300, present at the interior channel wall 121.
  • the micro-fluidic device 100 further comprises a controller 400 for measuring the value of an electrical property of the fluid 500, being either the gas 200 or the buffer liquid 210, between at least two electrodes of the plurality of electrodes 300 and for generating an output signal dependent on the measured value of the electrical property.
  • the controller can be a separate item from the micro-fluidic device or may be incorporated in it.
  • the channel with its channel wall may be provided by the additional of several layers constituting the structure 110.
  • a base structure e.g. a glass or plastic substrate is provided, onto which electrodes are provided.
  • the vertical structures that may be formed from e.g. PDMS, may provide the vertical walls of the channel.
  • a top substrate e.g. a PDMS layer which is connected to the base structures via the vertical walls, e.g. PDMS walls.
  • the term channel wall hence is to be understood as any of the walls of the channel, which may be provided by different structure parts together providing the structure 110.
  • the base structure may be made from polymethylsiloxane (PDMS).
  • PDMS polymethylsiloxane
  • the plurality of electrodes 300 comprises a plurality of electrode pairs 310, each pair comprising a reference electrode 311 and a probe electrode 312.
  • the controller 400 is adapted to measure an electrical property of the fluid 500, which is present between the reference electrode 311 and the probe electrode 312.
  • the controller 400 is adapted to monitor e.g. the impedance between the electrodes 311 and 312 of each pair of electrodes 310 within the micro-fluidic device 100. Depending on the frequency of the probe signal the impedance can be dominated by either a capacitive contribution or a resistive contribution.
  • the controller may include means or may control means for measuring impedance between the electrodes 311 and 312. By measuring the impedance between alternate electrodes the presence (or absence) of trapped gas can be sensed, as gas, e.g. air, has typically a higher resistance than the buffer fluid, e.g. saline water.
  • the resistance R G measured over electrode pair 313 will be relatively high, since the resistance is determined by the electrical resistance of the gas 200.
  • the resistance R L measured over electrode pair 314 will be low because the resistance is determined by the fluid 210, e.g. a liquid that can be an electrolyte.
  • the controller 400 can be adapted to compare the impedances, e.g. resistances or capacitances measured at each of the pairs of electrodes with a preset or predetermined value indicating the presence of buffer fluid between the reference electrode 311 and probe electrode 312. In response to the comparison the controller 400 can be adapted to monitor where gas is present along the longitudinal direction 122 of the micro-fluidic channel 120.
  • the impedances e.g. resistances or capacitances measured at each of the pairs of electrodes with a preset or predetermined value indicating the presence of buffer fluid between the reference electrode 311 and probe electrode 312.
  • the controller 400 can be adapted to monitor where gas is present along the longitudinal direction 122 of the micro-fluidic channel 120.
  • the controller 400 can also be adapted to determine how much gas 200 remains in the micro-fluidic device, and therefore how much additional fluid 210 is required to just fill the micro-fluidic device and hence complete the degassing. This can be achieved by summing all the locations where gas has been detected, i.e. the controller may include a means for summing all the locations where measurements between the electrode pairs indicate gas and not liquid. With this information, pumping devices coupled to one of the fluidic openings 130 can be programmed to only deliver the required amount of additional fluid, hence reducing the chances of rupturing the micro-fluidic channels 120. The controller 400 may be adapted to control the pumping devices to only deliver the required amount of additional fluid.
  • An embodiment of the present invention for realizing the plurality of electrodes in the micro-fluidic channels and monitoring the impedance between the electrodes is to use a large area electronics substrate with electrodes positioned in the branches, for example use of low temperature polysilicon (LTPS) substrates, large area amorphous silicon substrates, microcrystalline substrates with electrodes positioned in the branches.
  • LTPS low temperature polysilicon
  • monocrystalline substrates need not be used.
  • the micro-fluidic channels 120 of the micro-fluidic device 100 may have an average radial cross section area in the range of e.g. 90 ⁇ m height and 150 ⁇ m width, or e.g. 10 ⁇ m height and 10 ⁇ m width, or e.g. up to 300 ⁇ m height and up to e.g. 1000 ⁇ m width.
  • the centre-to-centre distance D between adjacent electrodes is optionally in the range of 10 ⁇ m to 1000 ⁇ m, such as e.g. 20 ⁇ m. So optionally 50 electrodes per millimetre along the longitudinal direction of the micro-fluidic channel may be provided.
  • the electrodes themselves may have any suitable shape, such as being substantially rectangular or circular.
  • the width W of the electrodes may be e.g. 1 ⁇ m to 1000 ⁇ m, e.g. 10 ⁇ m.
  • the plurality of electrodes 300 as shown in Figure 2 are located on the inner channel wall 121, so they provide zones on the inner channel wall 121 having a minor thickness, e.g. of about 100 nm to 200 nm thickness.
  • the electrodes may be situated on the top and bottom of the wall.
  • the channel with its channel wall may be provided by the additional of several layers.
  • a base structure e.g. a glass or plastic substrate is provided, onto which electrodes are placed.
  • the vertical structures that may be formed from e.g. PDMS, may provide the vertical walls of the channel.
  • a top substrate, e.g. a PDMS layer which is connected to the base structures via the vertical walls, e.g. PDMS walls.
  • channel wall hence is to be understood as any of the walls of the channel, which may be provided by different structures together providing the channel.
  • the PDMS wall and/or the PDMS layer can be a semi-permeable material, hence providing at least a part of the interior channel wall being provided from semi-permeable material.
  • the reference electrodes 311 and the probe electrodes 312 of the pairs of electrodes 310 are sunk into the wall 121 of the micro-fluidic channel.
  • the micro-fluidic channel 120 in this particular example has a perimeter having a substantially rectangular radial cross section.
  • the electrodes 311 may extend along the full width of the channel 120, as shown in Figure 3 .
  • the electrodes 311 and 312 have their surface 320 substantially coplanar with the inner channel wall 121.
  • the electrodes are positioned at identical positions relative to the radial cross section.
  • the rectangular cross section has two pairs of mutually opposed sides, being a first pair of mutually opposed sides 710 and 711, and a second pair of mutually opposed sides 720 and 721.
  • the electrodes 311 and 312 are all located at the same side, in this embodiment side 711.
  • the reference electrodes 311 and the probe electrodes 312 of the pairs of electrodes 310 are sunk into the wall 121 of the micro-fluidic channel.
  • the micro-fluidic channel 120 in this particular example, has a perimeter having a substantially rectangular radial cross section.
  • the electrodes 311 and 312 have their surface 320 substantially coplanar with the inner channel wall 121.
  • the electrodes are positioned at opposite positions relative to the radial cross section, at opposite sides of the rectangular perimeter.
  • the reference electrode 311 and the probe electrode 312 of each pair of electrodes 310 are mounted face to face along the longitudinal direction 122 of the micro-fluidic channel 120.
  • the reference electrodes 311 and the probe electrodes 312 of the pairs of electrodes 310 are mounted on the wall 121 of the micro-fluidic channel.
  • the micro-fluidic channel 120 in this particular example, has a perimeter having a substantially circular radial cross section.
  • the electrodes are positioned at different positions relative to the radial cross section.
  • the adjacent electrodes are provided at a distance D in longitudinal direction.
  • the micro-fluidic channel may be provided with N reference electrodes, distributed along the channel wall, and a M probe electrodes, M being larger than N.
  • Each probe electrode may form a pair with one of the N reference electrodes or more.
  • one common reference electrode may exist at e.g. the liquid inlet where it is always in contact with the liquid. The resistance of every other probe electrode could be measured with respect to this common reference.
  • FIG. 6 An exemplary circuitry for the detection of a gas bubble using several electrodes as used in Figure 2 is shown in detail in Figure 6 .
  • the circuit relies upon the fact that the resistance between two neighbouring electrodes of a pair of electrodes 310, being a reference electrode 311 and a probe electrode 312, is higher if the bubble is situated between those electrodes i.e. it changes from R F (low resistance fluid) to R G (high resistance gas).
  • FIG. 6 shows a example of such circuitry.
  • a voltage +V is applied to a reference electrode 311.
  • the probe electrode 312 is connected to a voltage -V via a resistor R, chosen between R F (low resistance fluid) and R G (high resistance).
  • the fluid resistance R F and resistor R determine the voltage at the probe electrode 312. If the probe electrode 312 is surrounded by fluid, the probe electrode will be at around +V. If the probe electrode 312 is surrounded by gas, the probe electrode will be at around -V.
  • the voltage of the probe electrode 312 forms the input for a comparator 330, which determines whether the probe electrode is surrounded by gas or fluid.
  • the comparator 330 will provide an output value Vx which will be used by the controller 400 to determine if buffer fluid or gas is present at the position of the pair of electrodes 310.
  • the comparator can easily be constructed using standard techniques.
  • a technique that can be used in LTPS circuitry is to use an inverter, as is also shown in figure 6 .
  • each of the micro-fluidic channels 120 of the micro-fluidic device 100 may be provided with an overpressure measuring device 600.
  • the overpressure measuring device 600 can comprise at least one expansion chamber 610 being separated from the at least one micro-fluidic channel by means of a membrane 620.
  • the membrane 620 which can be in the form of a thin flexible section of PDMS wall, cooperates with a sensor 630 for generating a signal when the pressure of the fluid 500, such as the buffer fluid 210, over the membrane 620 becomes larger than a given threshold pressure.
  • the membrane 620 will rupture when subjected to pressures more than the threshold pressure.
  • the pressure over the membrane 620 is less than the threshold pressure.
  • the membrane 620 remains uninterrupted.
  • the sensor 630 which is now in contact with the fluid, e.g. the buffer fluid 210, may generate a signal, which is provided to the controller 400.
  • the controller obtaining the signal of sensor 630, may provide an output signal for e.g. deactivating the pumping device providing buffer fluid to the micro-fluidic device 100.
  • FIG. 8a and Figure 8b An alternative is shown in Figure 8a and Figure 8b , the membrane 620 will expand when subjected to pressures more than the threshold pressure.
  • the pressure over the membrane 620 is less than the threshold pressure.
  • the membrane 620 remains in contact with the sensor 630.
  • the sensor 630 which is now no longer in contact with the membrane 620 but which is completely covered with fluid 210, generates a signal, which is provided to the controller 400.
  • the controller obtaining the signal of sensor 630, may provide an output signal for e.g. deactivating the pumping device providing buffer fluid to the micro-fluidic device 100.
  • the membrane 620 is in its rest position not in contact with the sensor 630. When the fluid pressure rises above the threshold pressure, the contact between the sensor 630 and the membrane 620 is made and the sensor provides a signal indicative of an overpressure.
  • a further advantage is that some part of the fluid may enter into the expansion chamber, thereby again reducing the fluid pressure in the micro-fluidic channel, whereby other components of the micro-fluidic device is protected from further over pressure.
  • the membrane may be a piece of flexible wall, e.g. flexible PDMS wall, covering a sensor chamber.
  • the strength of the membrane may be tuned by changing or selecting its thickness, since making the membrane thinner weakens the membrane. It is also possible to photolithographically create a small metal area under a section of wall. This results in a decrease in the adherence of the PDMS at this point and allows it to be pushed back via pressure. This is in particular useful for providing a reversible sensor.
  • the membrane does not have to make a good seal as there is no vent in the chamber containing the sensor. The liquid cannot enter the chamber unless the pressure is sufficient to compress the gas.
  • the sensor may e.g. be two electrodes of e.g. 10 ⁇ m width.
  • the volume behind the membrane is dry but when the pressure increases the membrane deforms and allows liquid to flow over the sensor. By measuring the impedance between the sensor electrodes the presence of liquid and hence over pressure is detected.
  • Volume of sensor chamber may be e.g. 50 by 50 by 50 ⁇ m but may be tuned depending on time needed to switch off the liquid flow.
  • a large volume with a plurality of sensors may provide a larger expansion volume. The sensitivity to overflow remains, but the larger expansion volume provides more time to switch off the liquid displacement means such as a pump.
  • a micro-fluidic device 1000 comprises a structure 1110, in this embodiment comprising a base structure being a PDMS semi-permeable base structure, having at least one micro-fluidic channel 1120 for holding a fluid.
  • the micro-fluidic channel 1120 has an interior channel wall 1121.
  • the micro-fluidic device comprises a plurality of electrodes 1300 present at the interior channel wall 1121.
  • the micro-fluidic device comprises a controller 1400 for measuring the value of an electrical property of the fluid 1500 between at least two electrodes 1300 of the plurality of electrodes and for generating an output signal dependent on the measured value of the electrical property.
  • the controller may be separate from or integrated in the micro-fluidic device.
  • the micro-fluidic device 1000 comprises two fluidic openings, one opening 1131 being the opening via which buffer fluid 1210 is provided to the micro-fluidic channel 1120.
  • the other opening 1132 is the fluid outlet.
  • the buffer fluid 1210 preferably a degassed liquid, is provided to the micro-fluidic channel 1120 by means of a pump 1910.
  • the micro-fluidic channel 1120 Prior to the filling and degassing process, the micro-fluidic channel 1120 is filled with gas 1200.
  • the plurality of electrodes comprises a plurality of electrode pairs 1310. Each pair of electrodes 1310 comprises a reference electrode 1311 and a probe electrode 1312, between which an electrical property of the fluid 1500 is measured, e.g.
  • the micro-fluidic channel 1120 further comprises an overpressure measuring device 1600.
  • the overpressure measuring device 1600 can comprise at least one expansion chamber 1610 being separated from the at least one micro-fluidic channel by means of a membrane 1620.
  • the membrane 1620 cooperates with a sensor 1630 for generating a signal when the pressure of the fluid 1500, such as the buffer fluid 1210, over the membrane 1620 becomes larger than a given threshold pressure.
  • the micro-fluidic channel 1120 is filled with gas and is to be filled or "degassed".
  • a buffer fluid 1210 is provided to the micro-fluidic channel 1120 of the micro-fluidic device 1000. This is done by activating a fluid displacement means, e.g. the pump 1910. As the fluid leading edge 1224 moves along the micro-fluidic channel 1120 in longitudinal direction, some pairs 1381 of electrodes will generate and communicate a measured value, i.e. an impedance such as a resistance or a capacitance, to the controller 1400, which matches a predetermined value indicating the electrodes to be contacted by buffer fluid 1210. Other pairs 1382 of electrodes will generate and communicate a measured value, i.e.
  • a measured value i.e. an impedance such as a resistance or a capacitance
  • the controller 1400 which does not match the predetermined value indicating the electrodes to be contacted by buffer fluid 1210.
  • the controller is able to identify the progress of the filling of the micro-fluidic channel 1120, as the fluid leading edge is situated between the last pair 1381 of electrodes measuring the predetermined value and the first pair 1382 of electrodes not measuring the predetermined value.
  • a gas bubble 1201 develops, as shown in Figure 9c , at least one of the pairs of electrodes, here referred to as pair 1383, will provide a measured value for the electric property to the controller 1400, which does not or does no longer match the predetermined value, whereas downstream in the micro-fluidic channel 1120, there are pairs 1381 which when measured provide the predetermined value.
  • the controller 1400 may thus determine the presence of a gas bubble 1201, and by determining the size of the measured value, e.g. comparing with one of a number of reference values, it may determine a value relating to the dimension of the bubble 1201 as well.
  • the flow into the micro-fluidic device 1000 can be either increased or released accordingly in response to the monitoring, e.g. by using a control signal of the controller 1400 to adjust the flow of the fluid displacement means or pumping device, such as pump 1910. Due to the real time measurement of the impedance such as the resistance, it becomes possible to vary the flow rate during the filling procedure, i.e. the controller may be adapted to control pumping devices such that the flow rate can be high in the beginning of the procedure and slow when filling is almost complete.
  • the controller may switch off the pump 1910, or in case there are electrodes, such as pair of electrodes 1383, measuring a value not matching the predetermined value, the controller may reduce the flow of the pump 1910.
  • the pressure of the fluid may be kept substantially constant as long as there are gas bubbles 1201 present and detected.
  • the gas of the gas bubble 1201 will gradually dissipate through the semi-permeable basic structure 1110.
  • the fluid pressure may suddenly raise, since there is no gas volume anymore, which can be compressed.
  • This pressure pulse may be sufficient to cause the overpressure measuring device 1600 to generate a signal by means of the sensor 1630, as shown in Figure 9e .
  • the controller 1400 can be adapted to switch off the pump 1910 immediately. Because all pairs of electrodes now provide the predetermined value, the controller may generate a control signal indicating that the micro-fluidic device 1000 is filled and degassed completely according to the required procedure.
  • the micro-fluidic channel may be provided with one reference electrode located at the entrance of the channel, and a plurality of probe electrodes along the channel. Each probe electrode may form a pair with the reference electrode. The resistance of every other probe electrode could be measured with respect to this common reference.
  • the controller may identify the progress of the filling, and the presence of gas volumes or gas bubbles, similar as described in relation to the previous example.
  • the controller 1400 may be adapted to stop the pump 1910, and indicate that the process has been completed without defects. It is also understood that, after the overpressure measuring device 1600 gave a signal, and the controller still obtains measured values from one or more pairs of electrodes that do not match the predetermined value, the controller 1400 may give a control signal indicating then an incorrect filling and degassing process has been performed.
  • controller may comprise a look-up table with predetermined values for each pair of electrodes.
  • the predetermined values may differ from each other, e.g. due to the geometrical dimensions of the micro-fluidic channel at the location of the pair of electrodes.
  • the micro-fluidic device may further comprise numerous components, such as electrodes for heating the liquid, either uniformly for PCR reactions or for not uniformally for creating flows, electrodes for creating flow via, electrothermal, electroosmosis, magnetohydrodynamic or any other electrokinetic principle, integrated photodiodes or other optical detectors, electrode geometries for bio particle manipulation, e.g. electrophoresis, cell lysis, DNA extraction cell separation, bacteria separation. Also functional microfluidics for particle separation via flow separation or mechanical cell lysis may be provided.
  • micro-fluidic device suitable for its particular use as e.g. biosensors, in rapid DNA separation and sizing, cell manipulation and sorting, or in pharmaceutical applications, in particular high-throughput combinatorial testing where local mixing is essential.
  • the micro-fluidic device according to embodiments of the present invention may also be used in microchannel cooling systems in microelectronics applications.
  • the present invention also provides the controller 1400 for use in micro-fluidic device 1000 for measuring the value of an electrical property of the fluid 1500 between at least two electrodes 1300 of the plurality of electrodes and for generating an output signal dependent on the measured value of the electrical property and optionally for controlled driving of the fluid in the micro-fluidic device 1000 according to embodiments of the present invention.
  • the controller as described above may include a computing device, e.g. microprocessor, for instance it may be a micro-controller.
  • a programmable controller for instance a programmable digital logic device such as a Programmable Array Logic (PAL), a Programmable Logic Array, a Programmable Gate Array, especially a Field Programmable Gate Array (FPGA).
  • PAL Programmable Array Logic
  • FPGA Field Programmable Gate Array
  • the controller may be operated in accordance with settable parameters, such as driving parameters, for example, threshold values of impedance when a bubble is present or liquid is present.
  • the processing system in the controller may include at least one customisable or programmable processor coupled to a memory subsystem that includes at least one form of memory, e.g., RAM, ROM, and so forth.
  • the processor or processors may be a general purpose, or a special purpose processor, and may be for inclusion in a device, e.g., a chip that has other components that perform other functions.
  • a storage subsystem that has at least one solid state memory, or disk drive and/or CD-ROM drive and/or DVD drive.
  • a display system, a keyboard, and a pointing device may be included as part of a user interface subsystem to provide for a user to manually input information, such as parameter values. Ports for inputting and outputting data, e.g. desired or obtained flow rate, also may be included. More elements such as network connections, interfaces to various devices, and so forth, may be included.
  • the various elements of the processing system may be coupled in various ways, including via a bus subsystem for simplicity as a single bus, but will be understood to those in the art to include a system of at least one bus.
  • the memory of the memory subsystem may at some time hold part or all of a set of instructions that when executed on the processing system implement the steps of the method embodiments described herein.
  • the present invention also includes a computer program product which provides the functionality of any of the methods according to the present invention when executed on a computing device.
  • Such computer program product can be tangibly embodied in a carrier medium carrying machine-readable code for execution by a programmable processor.
  • the present invention thus relates to a carrier medium carrying a computer program product that, when executed on computing means, provides instructions for executing any of the methods as described above.
  • carrier medium refers to any medium that participates in providing instructions to a processor for execution. Such a medium may take many forms, including but not limited to, non-volatile media, and transmission media.
  • Non-volatile media includes, for example, optical or magnetic disks, such as a storage device which is part of mass storage.
  • Computer readable media include, a CD-ROM, a DVD, a flexible disk or floppy disk, a tape, a memory chip or cartridge or any other medium from which a computer can read.
  • Various forms of computer readable media may be involved in carrying one or more sequences of one or more instructions to a processor for execution.
  • the computer program product can also be transmitted via a carrier wave in a network, such as a LAN, a WAN or the Internet.
  • Transmission media can take the form of acoustic or light waves, such as those generated during radio wave and infrared data communications. Transmission media include coaxial cables, copper wire and fibre optics, including the wires that comprise a bus within a computer.
EP07121551A 2007-11-26 2007-11-26 Dispositif micro-fluidique doté d'un contrôle de dégazage Ceased EP2062644A1 (fr)

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PCT/IB2008/054817 WO2009069034A1 (fr) 2007-11-26 2008-11-17 Dispositif microfluide à contrôle du dégazage

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WO2015195636A1 (fr) * 2014-06-16 2015-12-23 Siemens Healthcare Diagnostics Inc. Dispositif fluidique et procédé de dégazage
CN110264961A (zh) * 2019-04-04 2019-09-20 上海中航光电子有限公司 驱动电路及其驱动方法、面板及其驱动方法
CN112530374A (zh) * 2019-04-04 2021-03-19 上海中航光电子有限公司 驱动电路及其驱动方法、面板及其驱动方法
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