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WO2005070533A1 - Systeme de caracterisation d'un fluide, dispositif microfluidique de caracterisation ou d'analyse de concentrations de constituants, procede de caracterisation ou d'analyse de telles concentrations, dispositif de mesure - Google Patents

Systeme de caracterisation d'un fluide, dispositif microfluidique de caracterisation ou d'analyse de concentrations de constituants, procede de caracterisation ou d'analyse de telles concentrations, dispositif de mesure Download PDF

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Publication number
WO2005070533A1
WO2005070533A1 PCT/NL2005/000061 NL2005000061W WO2005070533A1 WO 2005070533 A1 WO2005070533 A1 WO 2005070533A1 NL 2005000061 W NL2005000061 W NL 2005000061W WO 2005070533 A1 WO2005070533 A1 WO 2005070533A1
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WO
WIPO (PCT)
Prior art keywords
fluid
microfluidic device
anyone
reaction chamber
component
Prior art date
Application number
PCT/NL2005/000061
Other languages
English (en)
Inventor
Sergi GASSÓ PONS
Michaël Franciscus Wilhelmus Cornelis MARTENS
Michaël SCHLÜTER
Leon Maria Jacobus Wilhelmus Swinkels
Anton Wilhelmus Marie Van Wijk
George Henry Parsons
Sebastian Mammitzsch
Hans Jochen Lilienhof
Franciscus Maria Anna Rosmalen
Original Assignee
Future Diagnostics B.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 Future Diagnostics B.V. filed Critical Future Diagnostics B.V.
Publication of WO2005070533A1 publication Critical patent/WO2005070533A1/fr

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502707—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the manufacture of the container or its components
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0689—Sealing
    • 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
    • B01L2300/0636—Integrated biosensor, microarrays
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0874—Three dimensional network
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0883—Serpentine channels
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0887—Laminated structure
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0433—Moving fluids with specific forces or mechanical means specific forces vibrational forces
    • B01L2400/0439—Moving fluids with specific forces or mechanical means specific forces vibrational forces ultrasonic vibrations, vibrating piezo elements
    • 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
    • B01L2400/0481—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure squeezing of channels or chambers
    • 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
    • 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
    • B01L3/50273—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 or forces applied to move the fluids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502738—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by integrated valves

Definitions

  • the present invention relates a system for characterizing a fluid, comprising a microfluidic device and a measurement device, to the microfluidic device, to the measurement device, and to the method of characterizing or analyzing a concentration of a component.
  • Analytic detection of particles, molecules and especially biomolecules, e.g., proteins, nucleic acids, hormones and the like is fundamental to diagnostics as well as to molecular biology. In many applications, it is desirable to detect the presence of at least one particular molecule in a sample. Analytic detection is also used, e.g., in disease diagnosis and drug development, to determine the presence of a particular antibody or protein, e.g., in a blood sample or large chemical library.
  • Detection of particles, molecules and biomolecules is therefore of fundamental value in, e.g., diagnostic medicine, archaeology, anthropology and criminal investigation.
  • many techniques e.g., DNA blotting, RNA blotting, protein blotting, and ELISA assays, have been developed to detect the presence of a particular molecule or fragment in the midst of a complex sample containing similar molecules.
  • US-A-6,444,461 discloses integrated systems, apparatus, software, and methods are provided for performing biochemical analyses, including DNA sequencing, genomic screening, purification of nucleic acids and other biological components and drug screening.
  • Microfluidic devices, systems and methods for using these devices and systems for performing a wide variety of fluid operations are provided.
  • the devices and systems are used in performing fluid operations that require a large number of iterative, successive or parallel fluid manipulations, in a microscale, or sealed and readily automated format.
  • US-A-6,235,175 discloses microfluidic devices that incorporate improved recess and reservoir geometries, as well as methods of using these devices in the analysis, preparation, or other manipulation of fluid borne materials, to achieve higher throughputs of such materials through these devices, with lower cost, material and/or space requirements. It is mainly aimed at improved recess and reservoir geometries. This is necessary as the dimensions are relatively small, that is in the order of l-100 ⁇ m.
  • US-A-6,479,299 discloses microfluidic devices having predisposed assay components for increased throughput and prolonged shelf life. The methods involve flowing a first component of a biochemical system in a first of the at least two intersecting recesses.
  • At least a first test compound is flowed from a second recess into the first recess whereby the test compound contacts the first component of the biochemical system. An effect of the test compound on the biochemical system is then detected. It uses electrokinetic flow.
  • US-A-6,613,581 discloses methods of detecting a component of interest, such as a protein, in a microfluidic system. The methods include the use of a component-binding moiety specific to the component of interest, such as an antibody, to detect the component of interest. Also included are microfluidic devices and integrated systems for performing such assays, including devices utilizing flowable or fixed particle sets.
  • US-A-6,644,944 discloses microfluidic fluid control devices.
  • microfluidic fluid control device can be used as a uni-directional valve within a microfluidic system.
  • Said US- A-6,644,944 also teaches a microfluidic pump mechanism having two unidirectional valves separated by an expandable reservoir.
  • Such devices may be formed in multiple layers and utilize flexible membranes.
  • US-A-6,408,878 discloses a method of fabricating an elastomeric structure, comprising: forming a first elastomeric layer on top of a first micromachined mold, the first micromachined mold having a first raised protrusion which forms a first recess extending along a bottom surface of the first elastomeric layer; forming a second elastomeric layer on top of a second micromachined mold, the second micromachined mold having a second raised protrusion which forms a second recess extending along a bottom surface of the second elastomeric layer; binding the bottom surface of the second elastomeric layer onto a top surface of the first elastomeric layer such that a control recess forms in the second recess between the first and second elastomeric layers; and positioning the first elastomeric layer on top of a planar body such that a flow recess forms in the first recess between the first elastomeric layer and the planar
  • US-A-6, 086,740 discloses multiplexed microfluidic devices including a plurality of modular microfluidic elements, all of which are attached to a common frame or body, which itself includes one or more common input elements that are connected to corresponding input elements within several or each of the microfluidic modules for use in common control and/or common detection operations for each of the modules.
  • the state of the art is aimed at very small structures (containing typically less than 10 ⁇ l fluid). Disadvantages of such small structures are that fluids tend to clog and/or that upon flow bubbles in the fluid may be formed. Furthermore the volumes of samples and /or the constituents therein are often too large to flow through the small (nanoscale) structures. Not only impurities present in the sample but also components, such as red blood cells, tend to clog the structures and/or hinder the flow severely. Furthermore, it is clear that the fabricating techniques for very small structures are quite complicated. Another disadvantage is that the body used does not comprise recesses on several of its surfaces, e.g. on both sides of a card-like body.
  • a next disadvantage is that when electrokinetic flow is applied, it will typically function sub -optimally, that is the components do not flow according as intended. Amongst others electroosmotic flow interferes with the electrokinetic flow. Another disadvantage is that the flow cannot be controlled sufficiently, especially the amount of fluid to be flown as well as the velocity of the flow. A next disadvantage is that the microfluidic devices of the state of the art are so small that they are difficult to handle.
  • a next disadvantage is that the characterisation of the components present in the microfluidic devices are difficult to be determined, as it is difficult to get access to components present and/or the measuring device to be used is not optimised for microfluidic devices.
  • Another disadvantage is that the microfluidic devices are relatively static systems. They allow for simple operations, that is typically reacting one fluid with another and typically only once.
  • Another disadvantage is that the microfluidic devices are in general not supplied with fluids, that may contain chemicals, and if so only a very limited set is present.
  • An additional disadvantage is that the microfluidic devices mentioned above are not dedicated to specific uses. For instance they do not contain a moiety to which a label or component present can be bound. Detailed description of the invention
  • the present invention relates a system for characterising a fluid, comprising a microfluidic device and a measurement device, to the microfluidic device, to the measurement device, to the method of characterising or analysing a concentration of a component.
  • a microfluidic device arrangable for use in the system of the invention which microfluidic device comprises at least one body (11), wherein the body has at least one surface, wherein the at least one surface has at least a part of the recess for containing the fluid in the microfluidic device and/or transporting the fluid in the microfluidic device through at least a part of the microfluidic device, wherein the body has at least one provision for an inlet (15) and at least one provision for an outlet (18), wherein at least a part of said recess (16) is a reaction chamber, which reaction chamber comprises a moiety that binds to the at least one component that is suspected to be present and that is to be characterised or analysed, which reaction chamber is
  • a general layout of the microfluidic device is given in figure 1. It contains several recesses (14-17) on a body (11). The recesses are formed on both sides of the body.
  • the fluid to be characterised or measured is brought into the provision for an inlet (15). Then, it flows to the reaction chamber (16). In the reaction chamber, a component that is suspected to be present can bind to a moiety, present in the reaction chamber (16).
  • component refers to a component that itself binds to a label or a moiety present in the microfluidic device, or to a chemical part of that component, of which at least one part binds to a label or a moiety present, or to a component which is labelled in the microfluidic device, which labelled component binds to the moiety present in the microfluidic device, or to a component that causes a detectable signal by itself, by a chemical reaction with another component, or by a component formed here out, whereby the detectable signal may be chemiluminescent flash or flow, colorimetric, fluorescent and time-resolved fluorescent.
  • fluid refers to liquid compositions that flow at operating pressure and temperature.
  • pump refers to a combination of an actuator, a displacement volume and at least one means for transferring the variation in pressure of the actuator towards the displacement volume.
  • the means for transferring the variation can be a membrane.
  • the displacement volume is referred to as pump chamber.
  • the pump further comprises means for controlling the actuator.
  • the pump chamber typically has a volume of 1 —1000 ⁇ l, preferably of 10-100 ⁇ l.
  • inlet as used herein refers to a provision through which a fluid or a gas may pass. The direction of the fluid or gas is intended to be from the environment to a recess.
  • outlet refers to a provision through which a fluid or a gas may pass.
  • the direction of the fluid or gas is intended to be from a recess to the environment. It typically has a volume of 1 -1000 ⁇ l, preferably from 1-10 ⁇ l.
  • fluid connection as used herein is a recess sealed by a cover layer. It is to be interpreted in a broad sense. Thus, it is not intended to be restricted to elongated configurations where the transverse or longitudinal dimension greatly exceeds the diameter or cross-sectional dimension.
  • a cavity may, for example, comprise a flow-through cell where fluid is to be continuously passed or, alternatively, a chamber for holding a specified, discrete amount of fluid for a specified amount of time.
  • a "fluid connection" may be filled or may contain internal structures comprising fluid diodes, valves or equivalent components. Its volume is from 1 to 1000 ⁇ l, preferably from 10-100 ⁇ l.
  • microfluidic as used herein is to be understood, without any restriction thereto, to refer to structures or devices through which fluid(s) are capable of being passed or directed, wherein one or more of the dimensions is less than 500 microns.
  • reces refers to a "fluid connection” type structure that is present on a surface of the body of the microfluidic device.
  • the body substantially surrounds it.
  • a recess in use is at least partly sealed by at least one cover layer, except for inlet and outlet provisions. It may also refer to part of a recess, especially in the case of chambers, meandering fluid path and fluid connection.
  • chamber refers to part of a covered recess in the body, which has a volume of 1 -1000 ⁇ l, preferably of 10-100 ⁇ l. It is capable of for instance comprising a fluid, a binding-moiety etc.
  • reaction chamber refers to a chamber used for reacting components and/or for binding at least one component to a moiety that is present in the reaction chamber. Furthermore, the reaction chamber can be arranged with the measurement device. It has a volume of 1 —1000 ⁇ l, preferably of 10-100 ⁇ l, more preferably of 10-30 ⁇ l.
  • meandering fluid path refers to part of a fluid connection. It is a channel type part of a recess, which channel forms several bends. Hereby a relatively long channel occupies only a limited amount of surface on the microfluidic device.
  • body refers to a solid material.
  • the solid material has at least one surface and can be of any shape. A preferred shape has the dimensions of a "credit-card”.
  • At least one surface of the body comprises at least a part of a recess.
  • the top and bottom side of the body comprise at least one recess.
  • the at least one recess of the topside is in fluid connection with the at least one recess of the bottom side.
  • the solid material should allow for manufacturing techniques to form recesses on the surface of the body.
  • the material preferably is stable and chemically resistant to the fluids used in the microfluidic device. It furthermore preferably has the desired physical properties, such as hydrophilicity and a smooth surface after manufacturing.
  • the material used as body is typically a polymer or silicon or glass.
  • a suitable polymer is selected from the group consisting of latex, rubber, polyesters, polycarbonates, polyalkanes, polyalkenes, polytetrafluoroethylenes, polypropylenes, polyimides, polymethylmethacrylates, silicones, polymethylmethacrylate (PMMA), PEEK, polystyrene, PDMS, and polyesters.
  • a preferred material is polymethylmethacrylate (PMMA).
  • cover layer refers to a material that is used to seal recesses from the environment. The material used as cover layer is typically a polymer or silicon or glass.
  • a suitable polymer is selected from the group consisting of latex, rubber, polyesters, polycarbonates, polyalkanes, polyalkenes, polytetrafluoroethylenes, polypropylenes, polyimides, polymethylmethacrylates, silicones, polymethylmethacrylate (PMMA), PEEK, polystyrene, PDMS, and polyesters.
  • a preferred material is polymethylmethacrylate (PMMA).
  • the moiety that binds a component is attached to the cover layer, covering the reaction chamber.
  • This has the advantage that the moiety can be deposited on the cover layer, prior to covering the reaction chamber recess with this cover.
  • the cover layer (12) has an adhesive (22) to which the moiety (23) is attached.
  • the reaction chamber itself (16) is a recess in the body (11). Further, a second cover layer (13) is visible.
  • the moiety can be present in the form of magnetic and/or non-magnetic antibody coated particles.
  • the moiety that binds is chosen from the group consisting of a nuclear receptor, an intracellular receptor, a solubilized receptor, an antibody, an antigen, an enzyme, avidin, a polynucleotide and a polysaccharide.
  • the present invention has a first advantage that it can optimally use the surface of the body, e.g. both sides of a credit card shaped body, to form recesses. This makes it possible to separate various functions of the system, such as the pump function and the receiving function.
  • the energy transfer is located at one side of the body and the provision for an inlet and the reaction chamber are located on the other side.
  • the pump function generally requires a relative large amount of space, even with the micro-sized pumps that now become available.
  • the present invention is not particularly aimed at reducing the size; it rather provides a microfluidic device that is easy to operate.
  • the microfluidic device has size of that is similar to that of a credit card, e.g. 85 by 60 by 1 mm 3 .
  • the present invention further has the advantage that it provides a combination of a microfluidic device with a compatible measurement device.
  • the microfluidic device is filled with a fluid to be characterised or analysed. After the pump forces the fluid to flow from the pump chamber to the reaction chamber, the fluid can be characterised by the measuring device by arranging the microfluidic device with the measuring device.
  • microfluidic device In a preferred embodiment of the microfluidic device two cover layers form, one part, which make it easier to seal the microfluidic device. This is an advantage in the manufacture of the microfluidic device.
  • the microfluidic device it further comprises a filter in at least one provision for an inlet.
  • the filter is used to hold particles and/or components that adversely interfere in the characterisation or analyses of th.e fluid in the measurement device.
  • the filter is for instance a particle filter, such as a MilliporeTM filter with an intended hole-size, or a chemical compound that reacts or binds to undesired components, thereby immobilising these components.
  • the microfluidic device further comprises at least a part of the recess for a washing fluid and at least a part of the recess for collecting waste fluid.
  • the microfluidic device further comprises at least a part of the recess which comprises at least one label fluid, which label binds to the moiety in the reaction chamber and/or to the at least one component to be characterised or analysed.
  • FIG 3 such a layout is given. It shows a top view of the microfluidic device.
  • the bottom side of the microfluidic device comprises also a number of recesses. The bottom side is brought into an arrangement with the pump -actuator. A first glance at the figure immediately indicates the intense use of the surface of the body. Not only do reaction chamber(s) occupy space, but also the meandering fluid path type recesses do.
  • meandering fluid path type structures have the advantage that they contain a relative large volume on the side, which is combined with the possibility to flow very well controlled amounts of fluid on the other side.
  • a meandering fluid path type structure contains from 1-1000 ⁇ l of fluid.
  • a further advantage with respect to a chamber is that the meandering fluid path can be emptied almost completely, whereas a chamber always has some residual liquid. Further, the meandering fluid path has less leakage as compared to a chamber.
  • the fluid to be characterised is transferred to the provision for an inlet (15). This provision for an inlet is in fluid connection with the central reaction chamber (16). It is optional to have other reaction chambers present (16), which serve similar functions as the first chamber.
  • the provision for an inlet (15) is used to insert the fluid to be characterised or analysed.
  • Fluid connections (33-35) are used to transfer the label fluid.
  • Fluid connections (36-38) are used to transfer the wash fluid.
  • Fluid connection (39) is used to collect the waste fluid.
  • This embodiment has the advantage that it comprises all necessary fluids in one single body. Furthermore the fluid connections and the arrangement of the pump enable complicated reaction sequences, involving one or more label steps and one or more washing steps.
  • another layout is given. The dimension of this layout is 60 mm by 49 mm. The recess on the bottom surface as well as the contact area of the pump actuator is projected onto the front side.
  • Figure 4 shows a provision for an inlet (15), wherein the fluid to be characterised or analysed is injected.
  • the fluid is moved from the inlet (15) towards the reaction chamber (16) by means of a pump (17), located on the bottom side, in fluid connection with the front side.
  • the fluid diodes (40) provide for the desired flow direction of the fluids used.
  • Thereto the at least one provision for the outlet (18) is opened, in order to compensate for the volume of fluid moved.
  • the design of the provision for the inlet and the fluid connection towards the reaction chamber limit the back flow.
  • the design of the reaction chamber is such that it provides for optimal flow profiles, with minimised dead volume and optimised contact with the moiety present.
  • label refers to a compound that can be detected directly or indirectly by the measuring the device. So it can also be a particle containing a label, such as a 3-dimensional structure with a label inside. Or it may be an enzyme that first may react with another component present. It also can form a bond with the moiety and/or at least one of the components present in the fluid. Preferred one or more of the following typically characterizes labels: high sensitivity, high stability, causing a low background signal upon detection, low environmental sensitivity and high specificity in labelling.
  • a preferred embodiment of the microfluidic device further comprises at least one provision for an inlet (15) which is arranged to receive the fluid, said inlet being sealed by a seal from the environment, which seal is to be removed upon use, thereby opening at least one entrance to the at least one provision for an inlet and/or which comprises at least one provision for an outlet (18) that is prior to use sealed from the environment by a seal, which seal is to be removed upon use.
  • This has the advantage that the microfluidic device has a prolonged shelf life.
  • the at least one provision for an outlet and the least one provision for an inlet will also be opened prior to use, the first to enable a fluid to flow, the latter to enable a sample to be inserted into the microfluidic device.
  • a preferred embodiment of the microfluidic device further comprises at least one soft seal that closes at least a part of the recess.
  • the term "soft seal” as used herein refers to a seal that closes a part of the recess, thereby preventing liquid and/or gas to flow from this apart to another part. The soft seal is broken upon applying a limited amount of force, such as the pressure or energy transferred by a pump. Typically the soft seal is selected from the group of fluids with relatively high viscosity. Soft seal material can e.g.
  • a preferred embodiment of the microfluidic device characterized in that at least one of the fluid connection(s) is equipped with fluid diodes for resisting a flow of the fluid through the fluid connections in one direction.
  • This fluid diodes (40) are also shown if figure 3.
  • a clear advantage of the use of such diodes it that it directs the flow of fluids in a desired direction, whereas it reduces the flow in the other direction significantly. This has the further advantage that it enables the performance of more complicated reaction programs.
  • fluid diode refers to a structure within a recess, which is characterized in that the resistance to a fluid flow is significantly larger in one direction compared to the other and which has no moving parts. In other words, the resistance towards a fluid flow changes significantly with change in the direction of the flow.
  • FIG. 5 shows top view of a preferred embodiment of a fluid diode in a body (11).
  • the recess (14) contains brush like structures (51), which act as a resistance to the flow in one direction.
  • the arrow (53) indicates the flow direction that is not hindered. In that case, the fluid enters the fluid diode indicated with (52).
  • the fluid diode has a width of 1 mm.
  • the brushes are 0,5 mm long and 70 ⁇ m wide.
  • the microfluidic device further comprises further elements for directing the fluid. Such elements are for instance valves. This has the advantage that even more complex pumping operations and reaction sequences can be performed.
  • the microfluidic device further comprises a readable information carrier.
  • the readable information carrier is an optically or electrically readable information carrier, most preferably it is an electrically readable information carrier.
  • the information carrier may be detachable from the microfluidic device. As for example in emergency situations a measurement would be performed, thereby using a microfluidic device according to the invention. The result of the measurement may need to be logged into a central computer; therefore the results need to be transferred from the microfluidic device to the computer.
  • the device itself may be contaminated and therefore needs to be disposed.
  • a detachable information carrier thus allows for the desired transfer.
  • the readable information carrier contains data that is for instance relating to the microfluidic device and/or relating to a method of operating the microfluidic device and/or the system for characterising a fluid. It further provides operating instructions, such as pump frequencies. These instructions optimise the use of materials contained in the device, the time necessary to label the components of interest, the accuracy of the result obtained. It also provides measurement instructions, such as a pump times, intervals etc. It also contains data relevant to the device, such as intended use, and it contains data relevant to the measurement, such as type of device and calibration curve respectively. In another embodiment the information carrier just provides the measurement system with the intended use.
  • the microfluidic device further comprises labels.
  • these labels are selected from fluorescent labels, chemiluminescent labels and colorimetric labels.
  • the present invention relates to a system for characterising or analysing a fluid, which fluid is suspected to comprise at least one component to be characterised or analysed, comprising a microfluidic device, at least one pump which is arranged to perform pumping cycles, for transporting the fluid and a measurement device which is arranged to characterise or analyse the fluid in use present in the microfluidic device, which microfluidic device comprises at least one body (11), wherein the body has at least one surface, wherein the at least one surface has at least a part of the recess for containing the fluid in the microfluidic device and/or transporting the fluid in the microfluidic device through at least a part of the microfluidic device, wherein the body has at least one provision for an inlet (15) and at least one provision for an outlet (18), wherein at least a part of said recess (16) is a reaction chamber, which reaction chamber comprises a moiety that binds to the at least one component that is suspected to be present and that is to be
  • the system of the invention comprises a measurement device for characterising the fluid, wherein the measurement device is arranged to obtain information based on an optical technique selected from the group consisting of fluorescence, chemiluminescence, time resolved fluorescence, time resolved chemiluminescence, colorimetry or a combination thereof, or from the group consisting of magnetic measurements, resistivity measurements, capacity measurements, surface plasma resonance (SPR) measurements, or a combination thereof.
  • This embodiment has the advantage that the measurement device can easily be arranged to the microfluidic device.
  • a preferred embodiment radiates the reaction chamber and detects emitted radiation.
  • An optical measurement device is arranged to obtain information based on a technique selected from the group consisting of fluorescence, chemiluminescence, time resolved fluorescence, or a combination thereof
  • a preferred embodiment uses a fluorescence technique.
  • the system of the invention characterises the concentration of at least one component present in the fluid. Preferably it is used to characterise one component, which has the advantage that the system can be fully optimised to characterise this one component. For instance the moiety present in the reaction chamber, the wash fluid, the detection are optimised. It provides microfluidic devices comprising all necessary material in the device.
  • the system of the invention comprises at least one pump. This pump can he present on the microfluidic device or in the measurement device.
  • this pump is a piezo-pump.
  • the present invention makes use of a piezo pump in a structure, which has as further advantage that it enables the fluid to be directed from a part of the recess to another recess.
  • the present invention further uses the piezo pump in order to perform all kinds of pumping functions, for instances to move fluids in controlled amounts form a part of the recess tot the other, to perform pumping cycles, to optimise piezo frequencies with respect to the dimensions of the recesses, to permit time intervals in between pumping etc.
  • the at least one piezo-pump preferably operates at a frequency up to 40 kHz. The frequency may also be used to reverse the preferred flow direction of the fluid diode.
  • the system is disposable all together. In extreme situations, such as emergency or war, there may be a need to identify the status of a patient on short notice, whereas the desire to maintain the measurement device is not an issue. Such a disposable system has in such a situation the advantage of providing a dedicated and quick answer to the status of a patient.
  • the measurement device suitable for use in a system characterises a fluid in the microfluidic device of the present invention, which fluid is suspected to comprise at least one component to be characterised or analysed, which measurement device is associated to the microfluidic device
  • Figure 6 represents a schematic layout of the actual detection in the measurement device.
  • a light source (41) is used to radiate (42) a component present in the reaction chamber (16) .
  • the light source is a laser.
  • a lens (43) may be used.
  • a component is present in the reaction chamber (16) that emits radiation (45)
  • this radiation can optionally be passed through a filter (46).
  • the component is or comprises a fluorescent label.
  • the measurement device further comprises, at least one communication port for transferring data, at least one read-out unit for reading in characteristics of the microfluidic device, at least one light source illuminating the reaction chamber in the microfluidic device, at least one detection element for detecting the radiation emitted from the reaction chamber, an information unit displaying characteristics of the fluid.
  • the result of a measurement is available within a limited amount of time. Typically a measurement from start to finish takes 1-15 minutes.
  • the results can be transferred to a data-collecting system, such as a computer, using the communication port.
  • the read-out unit allows for the information relating to the microfluidic device and the type of measurement to be transferred to the measuring device and subsequently to the data-collecting device, without any burden.
  • the information safeguards the correct use of the measurement device and therefore also of the results obtained.
  • the unit that is associated with the microfluidic device furthermore provides for a simple to perform measurement.
  • the information unit provides for the opportunity to directly obtain a visual result that can be used in a subsequent action, such as treatment.
  • the measurement device will typically be used to characterise or analyse a component that is selected from the group consisting an antibody, a cell receptor, an antigen, a receptor ligand, an enzyme, a body, an immunochemical, an immunoglobulin, a virus, a virus binding component, a protein, a cellular factor, hormones, allergenics, a growth factor, an cell- inhibitor, DNA, RNA, antigen to be bound to an antibody or receptor or a combination thereof
  • the measurement device further comprises a communication port of an USB-type. This is a standard interface for electronic devices, which allows for easy installation and easy data transfer. And it is economical.
  • the measurement device further comprises a chip-reader as the read-out unit.
  • the read-out unit can also be used to write data on the chip.
  • This data comprises the result or results of the characterisation or analysis.
  • the measurement device further comprises a laser as the light source.
  • a laser has the advantage of emitting nearly monochromatic light, though an option may be to use polychromatic (laser) light and use filters. The latter is preferably used in the case that the measurement device has a multipurpose use and/or is used to detect various wavelengths of emitted light at the same time.
  • the measurement device comprises a photodiode, a CCD, a photo multipher tube (PMT) or a series of photodiodes as the detection element.
  • the detection element is capable of detecting the light that is emitted by the at least one component to be characterised or analysed.
  • the advantage of photodiodes or CCD is that they are quite specific with respect to the wavelength chosen.
  • the measurement device further comprises software. The software is used for at least directing the at least one pump to transfer an external pressure to at least one of the chambers of the microfluidic device of the invention.
  • the software further provides for the information on the microfluidic device to be transferred to the measurement device and subsequently to perform the reaction sequence. It provides for the determination of the concentration of the at least one component suspected to be present in the fluid. It therefore provides for a simple operation procedure and minimises the risk for mistakes.
  • the measurement device may comprise a local memory and/or computing chip, in order to store and retrieve data as well as to perform calculations and to control the other components present. For the man skilled in the art it is a routine job to construct such a measurement device out of widely available parts.
  • the invention describes a method for characterising or analysing at least one component that is suspected to be present in a fluid comprising, a. introducing a fluid to be characterised or analysed in a microfluidic device according to the invention, b. moving the fluid to a reaction chamber, c. reacting the fluid with the moiety that binds, d. moving a washing fluid to the reaction chamber and washing the reaction chamber, e. illuminating the reaction chamber to a light source emitting radiation, f. detecting the radiation emitted.
  • the method comprises separating a mixture of components, which mixture of components may contain the components of interest.
  • the mixture of components or the separated components are contacted to a component-binding moiety specific to the component of interest.
  • the component-binding moiety binds to the component of interest and is detected, thereby detecting the component of interest, either by measuring the component-bonding moiety directly or by measuring the result of competition with other components, that have been replaced by the component of interest.
  • the embodiment of the present invention has the further advantage that the complete procedure can be performed on one microfluidic device and the measurement result can be obtained directly from the measurement device associated with it.
  • a component of interest is labelled with a detectable label, subsequently bound to the binding moiety and then detected.
  • the detection signal is then calculated to a concentration, using a calibration curve of the label.
  • the microfluidic device is in arrangement with a piezo-pump. The piezo-pump is instructed to perform complicated pumping cycles, involving pumping a fluid, leaving the fluid to react and repeating such steps.
  • complex pumping cycles of one fluid are alternated with complex pumping cycles of another fluid. For instance, first a label fluid is moved to the reaction chamber with such a pumping cycle and subsequently a wash fluid, which steps are repeated if required.
  • the reaction in the chamber can be optimised by controlling the amount of fluid moved to the reaction chamber. This is important as the reaction is mainly determined by fluid dynamics. By supplying an amount of fluid each time the fluid dynamics cause exhaustion, the reaction rate is significantly enhanced. Therefore the reaction rate is to a large extend determined by the kinetics of the pumping, rather than by the movement of components in the fluid due to concentration gradients. This improves the reaction time as well as the sensitivity.
  • a further advantage is that the amount of fluid used are minimised with such a procedure. This has the further advantage that even more complicated pumping operations and reaction sequences can be performed.
  • the moiety can be present in the form of (magnetic and/or non-magnetic antibody) coated particles.
  • the particles are optionally stacked in a detection region.
  • the component-binding moiety thereby binds to the component of interest, thus providing detection of the component of interest.
  • the method comprises providing a body structure having a plurality of recesses disposed therein, the plurality comprising a microfluidic separation recess and at least one side recess intersecting the separation recess, wherein the separation recess and the side recess are fluidly coupled.
  • a mixture of components is flowed through the separation recess, resulting in separated components.
  • a labelled component-binding moiety is subsequently flown through a side recess and into the separation recess, wherein it binds to the component of interest.
  • the component-binding moiety is then detected, thereby detecting the component of interest.
  • the steps d and e are repeated a number of times. This has the advantage that more label (step d) is bound to the moiety and thereby the emitted radiation in the detection steps is increased.
  • the method for characterising or analysing at least one component that is suspected to be present in a fluid comprises, a. introducing a fluid to be characterised or analysed in a microfluidic device according to the invention, b. moving the fluid towards a reaction chamber, c. combining the fluid with at least one label fluid forming a combined fluid before the reaction chamber, d. reacting the label with the component to be characterised or analysed, e. moving the combined fluid to the reaction chamber and reacting the label with the moiety that binds, f. washing the reaction chamber with a washing fluid, g. illuminating the reaction chamber to a light source emitting radiation, and detecting the radiation emitted.
  • This embodiment has the advantage that the label and component to be characterised or analysed mix and react in the fluid flow towards the reaction chamber a further inside the reaction chamber. Thereby the amount of label and/or component reacted is increased, due to improved kinetics in the flow. Further the incubation time is reduced, resulting in a shorter overall measurement time.
  • the characterising or analysing method further comprises the use of a fluorescent of chemiluminescent label.
  • the separated components are typically labelled components that are optionally detected simultaneously with the component-binding moiety.
  • This embodiment optionally includes deconvoluting the detection signal to identify the separated components and the component of interest.
  • This embodiment includes two detectably different label moieties having detectably different spectral characteristics, such as different excitation or emission maximum.
  • the different labels include, but are not limited to fluorescent labels, chemiluminescent labels and colorimetric labels.
  • the separated components are optionally labelled with a first fluorescent dye and the component-binding moiety is labelled a second fluorescent dye. These two dyes are typically detectably different.
  • the component of interest and the component-binding moiety are optionally labelled with detectably different colorimetric labels.
  • the component of interest is labelled with one type of label, e.g., chemiluminescent, and the component-binding moiety is labelled with a second type of label, e.g., fluorescent.
  • the characterising or analysing method the component to be characterised or analysed is selected from the group consisting an antibody, a cell receptor, an antigen, a receptor ligand, an enzyme, a body, an immunochemical, an immunoglobulin, a virus, a virus binding component, a protein, a cellular factor, hormones, allergenics, a growth factor, an cell-inhibitor, DNA, RNA, antigen to be bound to an antibody or receptor or a combination thereof.
  • the fluid is preferably a body fluid, such as a blood, serum, urine, saliva, or extracts, such as plant-extracts.
  • the characterising or analysing method further comprises the use of a laser as the light-source.
  • This example describes the measurement of myoglobin concentration in a blood sample.
  • a polymethylmethacrylate (PMMLA) -microfluidic device containing Piezo-pumps is cleaned with ethanol (70%) followed by demineralised water.
  • the microfluidic device is completely dried by applying compressed air.
  • a piece of transparent foil with the same size as the microfluidic device (seals the recesses in the PMMA structure from the environment.
  • the foil is from
  • the polyester support of the nitrocellulose strip was mounted on a double-sided adhesive tape. After that the nitrocellulose side is covered with a transparent plastic foil to avoid any damage. From these strips dots of 35 mm are prepared by using a revolver punch gripper from Conrad. It should be taken into consideration that the coated antibody is in the centre of the 35 mm dot of nitrocellulose.
  • the protection foil and the double side adhesive tape are removed, and the polyester support side is put in the centre of to a 15x10 mm piece of Permacel foil. This foil is put in the window where the reaction area is located.
  • the nitrocellulose should face the PMMA structure, and it is located as close as possible to the outlet of the microrecess.
  • the PMMA reaction area has a diameter of 36 mm.
  • the reaction area is sealed with the Permacel foil containing the piece of nitrocellulose.
  • the label and wash reservoirs are filled with their respective buffers. Both reservoirs are consisting of the chamber under the piezo-pump, the fluid diodes and the microrecesses, which are needed for a proper functioning.
  • the label solution is a HEPES based buffer (pH8) containing a biotinylated monoclonal antibody (anti Myoglobin) with the fluorescence labelled streptavidin (Molecular Probes).
  • the fluorescence signal is generated by a so-called Fluorescence Resonance Energy Transfer system. When the complex is excited at 635 nm it emits light at 778 nm.
  • a syringe is filled with sample (Myoglobin Std from SCIPAC (Scipac Ltd. Kent UK)) diluted with HEPES buffer pH 8, at a concentration of 0 ng/ml, 100 ng/ml or 1000 ng/ml respectively and connected to the sample inlet from the microfluidic device.
  • sample Myoglobin Std from SCIPAC (Scipac Ltd. Kent UK)
  • HEPES buffer pH 8 HEPES buffer pH 8
  • Piezo pumps are connected to the amplifier and the wash and label syringes were removed from the microfluidic device. At this stage, the microfluidic device was ready-to-use.
  • the wash-buffer After 5 seconds of pumping the wash-buffer the reaction area is soaked during 15 seconds.
  • the label fluid is refreshed eight times by 0,5 seconds pumping with 15 seconds diffusion in between.
  • the washing interval ends with 15 seconds of diffusion.
  • the openings for the wash, label and waste fluids are sealed with Permacel foil.
  • the sample syringe is removed and the sample inlet is also sealed with Permacel foil.
  • the piezo-pumps are disconnected and the piece of nitrocellulose including the labelled component is removed from the reaction chamber.
  • the piece of nitrocellulose is placed in a strip-holder (centre position, always in the same place) of the fluorescence reader from LRE Technology Partner GmbH and kept in the dark. After drying the nitrocellulose for 30 minutes it was read out with the LRE-Reader.
  • the reader excites the fluorescent label with a laser diode that emits at 642 nm, and a photodiode collecting the emitted light from the dye above 725 nm.
  • the slight difference in wavelength is caused by the difference between the theoretical value and the value actually used and/or obtained.
  • the fluorescence scanner obtains one value (in arbitrary fluorescence units) every 0.054 mm. In figure 7 the results of the measurement are shown.
  • the first three peaks are three assays done on the same body, which were incubated with 0, 100, and 1000 ng/ml of Myoglobin, successively.
  • the second part of the figure shows a group of three peaks under identical conditions but on another body.
  • the detector determines the peak width.
  • the detector scans the nitrocellulose, each time generating a signal. Going from left to right the maximum peak level increases with Myoglobin concentration. As the spots used were placed as a liquid on the nitrocellulose the peaks can be somewhat a-symmetrical.
  • the second series is somewhat different with respect to peak (height and width) as compared to the first series, which is due to statistical variation and reproducibility.
  • Example 2 The microfluidic device according to the present invention is produced by methods known to the person skilled in the art.
  • An embodiment according to the invention consists out of a PMMA body (see figure 4).
  • Figure 4 shows the layout, though the dimensions shown herein are different in reality.
  • the size of this body is 60 by 47 by 1 mm 3 .
  • the recesses in the front side and back side of the body are manufactured by injection- moulding the PMMA body.
  • the fluid diodes are made by injection moulding.
  • the width of the fluid connections is about 1 mm, the depth is approximately 450 ⁇ .
  • the diameter of the reaction chamber is about 4 mm.
  • the body consists out of one provision for an inlet.
  • first in connection with the meandering fluid path with the wash fluid the second in connection with the meandering fluid path for collecting the waste fluid
  • second in connection with the meandering fluid path for collecting the waste fluid the third in connection with the meandering fluid path with the label fluid.
  • It further contains fluid connections between the provision for the inlet and the reaction chamber, between the meandering fluid path for collecting the waste fluid and the reaction chamber, between the meandering fluid path with the wash fluid and the reaction chamber and between the meandering fluid path with the label fluid and the reaction chamber.
  • the cover layers are connected to the body by hot-welding PMMA.
  • a strip of nitrocellulose was place on the covering PMMA layer, in a location that it coincides with the reaction chamber.
  • the reaction chamber contains as a moiety monoclonal mouse IgG anti human Myoglobin. This moiety was deposited on the cover layer prior to the hot-welding step. A drop of fluid containing the moiety was dripped on the nitrocellulose strip, of which the location also coincides with the reaction chamber.
  • the pumps used are readily available piezo-pumps.
  • the wash fluid used is demineralised water.
  • the label fluid solution is a
  • a preferred embodiment of the characterising or analysing device is constructed out of components that are readily available.
  • the housing of the measurement device is constructed by injection moulding.
  • the material used in the housing is typically a polymer.
  • the communication ports used are standard USB-interfaces, consisting out of
  • USB-plugs and USB-sockets USB-plugs and USB-sockets.
  • the read-in unit is a standard chip-read-out unit, used for instance for banking-cards, which is widely available.
  • the receiving device is a standard receiving unit, used for instance for the intake of banking-cards in an ATM, which is widely available.
  • the measurement device contains a laser.
  • a preferred laser is a standard 635 nm laser, which is widely available. The type of laser and frequency used will clearly depend on the component that is suspected to be present and or the label used.
  • the detection unit is a standard 778 nm detection unit, which is widely available.
  • Typical voltage amplitudes applied to the piezo-pump are 150V and 300V.
  • the achieved pressure is from 200 to 4000 Pa, but may vary upon the piezo-pump used, the type of fluid diode and pumping altitude.
  • the information unit is a standard LCD-display, which is widely available.

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  • Health & Medical Sciences (AREA)
  • Dispersion Chemistry (AREA)
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  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Clinical Laboratory Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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Abstract

La présente invention concerne un système de caractérisation d'un fluide, qui comprend un dispositif microfluidique et un dispositif de mesure. Elle concerne également le dispositif microfluidique, le dispositif de mesure, et le procédé de caractérisation ou d'analyse d'une concentration d'un constituant.
PCT/NL2005/000061 2004-01-27 2005-01-27 Systeme de caracterisation d'un fluide, dispositif microfluidique de caracterisation ou d'analyse de concentrations de constituants, procede de caracterisation ou d'analyse de telles concentrations, dispositif de mesure WO2005070533A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP04075257.8 2004-01-27
EP04075257A EP1561507A1 (fr) 2004-01-27 2004-01-27 Système pour caractériser un fluide, dispositif microfluidique pour caractériser ou analyser les composants de concentrations, une méthode de caractériser ou d'analyser de telles concentrations et un dispositif de mesure

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