EP1444042B1 - Verfahren zur förderung einer flüssigkeit in einer kapillare und fluidisches mikrosystem - Google Patents

Verfahren zur förderung einer flüssigkeit in einer kapillare und fluidisches mikrosystem Download PDF

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Publication number
EP1444042B1
EP1444042B1 EP02799424A EP02799424A EP1444042B1 EP 1444042 B1 EP1444042 B1 EP 1444042B1 EP 02799424 A EP02799424 A EP 02799424A EP 02799424 A EP02799424 A EP 02799424A EP 1444042 B1 EP1444042 B1 EP 1444042B1
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EP
European Patent Office
Prior art keywords
ferrofluid
fluid
capillary channel
train
slug
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
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EP02799424A
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English (en)
French (fr)
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EP1444042A1 (de
Inventor
Florence Ricoul
Jean Berthier
Jérôme Appt 119 résidence le Botticelli BOUTET
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Commissariat a lEnergie Atomique et aux Energies Alternatives CEA
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Commissariat a lEnergie Atomique CEA
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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
    • B01L3/502769—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 multiphase flow arrangements
    • B01L3/502784—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 multiphase flow arrangements specially adapted for droplet or plug flow, e.g. digital microfluidics
    • 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
    • B01L2200/0673—Handling of plugs of fluid surrounded by immiscible fluid
    • 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
    • B01L2400/043—Moving fluids with specific forces or mechanical means specific forces magnetic forces
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01F—MAGNETS; INDUCTANCES; TRANSFORMERS; SELECTION OF MATERIALS FOR THEIR MAGNETIC PROPERTIES
    • H01F1/00—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties
    • H01F1/44—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties of magnetic liquids, e.g. ferrofluids
    • H01F1/447—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties of magnetic liquids, e.g. ferrofluids characterised by magnetoviscosity, e.g. magnetorheological, magnetothixotropic, magnetodilatant liquids
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01F—MAGNETS; INDUCTANCES; TRANSFORMERS; SELECTION OF MATERIALS FOR THEIR MAGNETIC PROPERTIES
    • H01F21/00—Variable inductances or transformers of the signal type
    • H01F21/02—Variable inductances or transformers of the signal type continuously variable, e.g. variometers
    • H01F21/06—Variable inductances or transformers of the signal type continuously variable, e.g. variometers by movement of core or part of core relative to the windings as a whole

Definitions

  • the present invention relates to a method of moving a fluid of interest in a capillary and a fluid microsystem.
  • microfluidics including fluidic microsystems. It makes it possible to carry out high-throughput biological or chemical processes.
  • the present invention can be combined with other functions to form a more complete and more accurate system of biological analysis.
  • variable surface states to regulate flows, but they impose constraints on the physicochemical properties of the fluids to be transported and a precise treatment of the surfaces. It is also possible to use bubble generation to regulate flow rates inside capillaries. Finally, mechanical systems for regulating the hydrostatic pressure also exist, implanted upstream of the microcircuits or downstream, for example by placing a wick made of an absorbent material.
  • the present invention also provides a fluidic microsystem for displacing a fluid of interest comprising on the one hand a capillary in which at least one ferrofluid train is placed and, on the other hand, outside said capillary, a magnetic system for producing a magnetic field for controlling the movement of the ferrofluid train in the capillary, said ferrofluid train comprising a ferrofluid plug and, placed at at least one of the two ends of the ferrofluid plug and secured thereto, a plug of liquid immiscible with the ferrofluid and the fluid of interest.
  • fluid of interest any liquid or gaseous fluid that is necessary to move in a capillary, for example in analytical microsystems.
  • the fluid of interest may be, for example, a chemical reagent, a biological liquid, an aqueous solution, etc.
  • Plug means a volume of fluid in the capillary and forming by capillarity a "cylinder" conforming to the shape of the inner wall of the capillary.
  • the fluid placed in the capillary forms a plug when it occupies, over a length that depends on the volume of this fluid, the entire section of the capillary.
  • a ferrofluid train also referred to as a "train” in the present description, comprises a ferrofluid plug and at least one cap of liquid immiscible with the ferrofluid and the fluid of interest integral therewith.
  • the ferrofluid train moves in its entirety with the stopper (s) of fluid immiscible with the ferrofluid and the fluid of interest.
  • ferrofluids or magnetic fluids are fluids containing essentially two constituents: (1) monodomain grains of ferromagnetic substance, about 5 to 10 nm of magnetite or maghemite, (2) a carrier fluid.
  • the ferrofluid When the carrier fluid is an organic compound, as is the case with most commercial ferrofluids, the ferrofluid is said to be "organic-based” and the magnetic particles are dispersed in the carrier fluid by surfactants.
  • the carrier fluid is water
  • the ferrofluid is said to be “ion-based” and the particles are dispersed either by electrostatic forces or by surfactant bilayers.
  • the choice of the ferrofluid corresponds to the choice of the inventors of a control, or control, by magnetic field to carry out the method of the present invention.
  • the ferrofluids that can be used according to the invention preferably have a low viscosity and a good physicochemical stability in time and as a function of temperature.
  • the ferrofluid is preferably an ionic ferrofluid, for example a ferrofluid such as those described in document GB-A-2244987.
  • these ferrofluids have a high particle density, a high magnetic susceptibility, and a high stability over time. They are obtained by attaching to the surface of precursor magnetic particles charged molecules that provide colloidal stability without the use of surfactants.
  • the fluid of interest is generally in the form of an aqueous solution.
  • the solution a priori the simplest to implement ferrofluid according to the invention, in microchannels or microtubes of "lab-on a chip" is to work with ferrofluids based on organic, because they are not miscible with 'water. But then there may be the problem of contaminant deposits and non-biocompatible, for example in the form of magnetic particles based on iron oxide, may interfere in the chemical reactions involved.
  • the inventors have demonstrated that the preferred combination of an ion ferrofluid plug, a cap of a fluid immiscible with the ferrofluid and the fluid of interest, and preferably a hydrophobic capillary wall, according to the invention.
  • the present invention unexpectedly makes it possible to provide a solution to the aforementioned problems. Indeed, laboratory tests have shown an absence of contaminating film on the inner wall of the capillary using the present invention.
  • the capillary is preferably a capillary whose inner wall is hydrophobic, that is to say whose inner wall has a contact angle greater than 90 °.
  • This can be achieved for example by a suitable chemical treatment such as silanization, or by using hydrophobic materials such as those mentioned above.
  • the material constituting the capillary can be chosen for example depending on the fluid of interest and the physicochemical conditions of the chemical reactions performed in the capillary.
  • the capillary, or microtubes or microchannels may for example have an internal diameter of less than 1 mm, for example of 0.5 mm and less, which corresponds to the usual dimensions of the fluidic microsystems.
  • the liquid immiscible with the ferrofluid and the fluid of interest may be, for example, oil, especially when the ferrofluid is an ionic ferrofluid and the fluid of interest is an aqueous solution.
  • the oil may be an organic oil, for example dodecane, or mineral, for example the M3516 oil marketed by Sigma-Aldrich.
  • a priori a thin film of oil can be created during the displacement of the ferrofluid train on the internal wall of the capillary because the oil wets the hydrophobic surface better than the water. But this is not penalizing if the oil is compatible with the fluid of interest.
  • a biocompatible oil for example a mineral oil.
  • a pre-wetting of the walls of the micro-channels can be achieved by first circulating a plug of oil of sufficient volume.
  • a step of pre-wetting the inner wall of the capillary with the oil before disposing in said capillary the ferrofluid train can be carried out.
  • oil plugs may also be arranged in the capillary, alone, without ferrofluid plug, for example to separate two identical or different fluid plugs of interest located between two ferrofluid trains, or before or after a single ferrofluid train.
  • at least one cap of liquid immiscible with the ferrofluid and the fluid of interest can be disposed in the capillary between two fluid plugs of interest.
  • the ferrofluid train may consist of a ferrofluid plug and a ferrofluid immiscible liquid plug and the fluid of interest.
  • This embodiment is for example useful for moving a fluid of interest placed on one side of the ferrofluid train, that is to say on the side of the immiscible liquid plug.
  • a cap of liquid immiscible with the ferrofluid and the fluid of interest can be placed at each of the two ends of the ferrofluid plug.
  • the ferrofluid train comprises a ferrofluid plug and two plugs of liquid immiscible with the ferrofluid and the fluid of interest. This embodiment is for example useful for moving a fluid of interest placed on either side of the ferrofluid train, or two different liquids of interest separated by the ferrofluid train.
  • a plurality of ferrofluid trains may be disposed in the capillary, with ferrofluids identical or different from one train to another, and ferrofluid immiscible liquid plugs and fluid of equal or different interest in the same train or train to another.
  • This embodiment is for example useful for moving several plugs of one or more fluid (s) of the same or different interest, each fluid plug of interest being separated from the next by a ferrofluid train according to the present invention or by a single cap of liquid immiscible with the ferrofluid and the fluid of interest.
  • the magnetic system necessary for moving the fluid of interest in the capillary, ie to control the flow of this fluid may be constituted for example by permanent magnets or by electrical circuits, ie electromagnets located for example in the immediate vicinity of the capillaries.
  • This magnetic system can be fixed or mobile.
  • the mobility of the magnetic field can be obtained for example by mechanically moving a permanent magnet or an electromagnet along the capillary, or sequentially "activating" adjacent coils of electromagnets.
  • the permanent magnet can be by example in the form of a magnetized bar, the electromagnet for example in the form of a coil or a solenoid.
  • ferrofluid plugs and magnets are adapted to the conditions of the desired application of the method of the present invention, ie for example at the fluid velocity or the radius of the capillary, so as to allow a good coupling.
  • the magnets may have a length of between 0.5 and 2 mm and the ferrofluid plugs about twice that length.
  • the number of magnetic systems can be a function of the number of ferrofluid trains used.
  • n fluid trains may require n magnetic systems.
  • control of the displacement of the fluid of interest in said capillary by action on said ferrofluid plug of a magnetic field generated by the magnetic system disposed outside said capillary can be achieved in different ways .
  • the flow or displacement of the fluid of interest in the microchannel can be obtained under the impulse of a pressure or a driving depression applied in the capillary.
  • the control according to the present invention can consist of blocking, or unblocking, the displacement of the fluid in the capillary by blocking, respectively unlocking, the movement of the ferrofluid train by means of the magnetic system.
  • This can be achieved for example by means of a ferrofluid train consisting of a ferrofluid plug with two plugs of oil on each side and a single permanent magnet or electromagnet. Removing the permanent magnet or stopping the electric current supplying the electromagnet enables the flow of the fluid of interest to be resumed.
  • n ferrofluid plugs provided with 2xn oil plugs and magnets or electromagnets, with m ⁇ n. Additional oil caps without a ferrofluid cap are used to isolate biological reagents from one stopper to another. In this configuration, the flow is stopped sequentially each time a ferrofluid plug goes under a magnet.
  • n depends on the application and technology considered, for example the length of the micro-channels, the multiplexing, the lateral injection etc. The larger the m, the smaller the magnetic force per magnet needs to be large, which can be interesting when a miniaturization of the magnets is sought.
  • the microsystem may comprise one or n ferrofluid plugs respectively provided with one or 2xn oil buffer plugs and a sliding magnetic field obtained either by mechanically moving a permanent magnet along the capillary, or by "activating" sequentially adjacent coils of electromagnets.
  • the displacement of the magnetic field serves as motive force to move the ferrofluid train, and therefore the fluid of interest in the capillary.
  • the present invention also has the advantage of implementing an external control or control of the displacement of the fluid of interest in the capillary, of limiting or avoiding deposits of the ferrofluid in the form of a liquid film on the walls of the capillary. and avoid contamination problems related to devices of the prior art. It also provides a precise and easy to implement method for controlling flows of fluids in microcannals.
  • the present invention can be advantageously implemented for example in an automated in vitro diagnostic system, or a system for detecting biological contaminants in fields such as food processing and / or industrial microbiological control.
  • a possible industrial use of the ionic ferrofluid plugs isolated by oil plugs according to the present invention is therefore the external control of liquid plugs inside microchannels of microsystems type "lab-on-a-chip" for which a reaction Biological PCR such as for example is carried out in series in each aqueous cap and in parallel on several microchannels.
  • the ferrofluid train (3) comprises a ferrofluid plug (5) with two plugs (7) of fluid immiscible with the ferrofluid and the fluid of interest.
  • the ferrofluid plug is an ionic ferrofluid plug containing 20% by mass magnetic maghemite particles coated with nitrate group and dispersed in water.
  • the average particle diameter is 7.5 nm.
  • the liquid immiscible with the ferrofluid and the fluid of interest (7) consists of M3516 oil marketed by Sigma-Aldrich
  • the capillary (1) is made of glass and has a diameter of 500 ⁇ m.
  • the ferrofluid train has a length of 2mm.
  • FIG. 2 shows the same capillary with a magnetic system (11) which is a permanent magnet in the form of magnetized bars.
  • FIG. 3 shows the same capillary with a magnetic system (11) which is an electromagnet in the form of a solenoid.
  • This configuration of the microsystem of the present invention makes it possible to block and unblock a flow having a speed V indicated by the arrow in the capillary or microchannel.
  • the flow is created by an external driving pressure ⁇ p. Removal of magnets permanent or the stop of the electric current allows the resumption of the flow.
  • FIG. 4a A first application is shown in Figure 4a.
  • a single ferrofluid train (3) is used with several plugs (7) of mineral oil.
  • an alternation of fluid of interest (L) and oil plugs (7) precedes a ferrofluid train (3).
  • FIG. 4b A second application is shown in Figure 4b.
  • several ferrofluids train (3) are used alternately with several fluid plugs (L) of interest.
  • a pressure ⁇ p causes the flow of fluid plugs L in the capillary.
  • the magnetic system (11) allows as in Example 1 to block or unblock this flow.
  • This example shows that additional plugs of oil without a ferrofluid plug make it possible, for example, to isolate biological reagents from one plug to the other.
  • Example 2 the same ferrofluid train used in Example 1 is used in an application shown diagrammatically in FIG. 4c.
  • This application differs from that shown in FIG. 4a, in that the magnetic system is mobile according to the arrows indicated in this figure.
  • the displacement of the magnetic field serves as motive force for the movement of the ferrofluid train in the capillary, that is to say also of the fluid of interest (L).
  • the application of a driving pressure is not necessary here.
  • FIGS. 5a and 5b numerical simulations using the Matlab (registered trademark) software show, for example, the cessation of the flow in a capillary comprising a succession of ferrofluid trains as in FIG. 4b and of water.
  • the magnetic field is created either by two permanent magnets (fig.5a) in opposition or by a solenoid (fig.5b). In these two cases, magnets and solenoid, the magnetic field is 350 Gauss on the axis at the center of the capillary.
  • the diameter of the solenoid is 1 mm and it has 10 turns and its length is that of a ferrofluid plug: 2 mm. For the 2 permanent magnets facing each other, the dimensions are 3 cm x 1 cm x 1 mm.
  • FIGS. 6a and 6b are photographs showing the embodiment of the process of the present invention in a 300 ⁇ m diameter capillary made of teflon (registered trademark) and using mineral oil plugs (reference Sigma-Aldrich M3516), colorless, of on both sides of an ion ferrofluid plug such as that described in Example 1, to avoid contamination with the aqueous phase plugs (fluid of interest) stained with methylene blue.

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  • Chemical & Material Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Analytical Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Clinical Laboratory Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Physical Or Chemical Processes And Apparatus (AREA)
  • Automatic Analysis And Handling Materials Therefor (AREA)
  • Manufacturing Of Micro-Capsules (AREA)
  • Feeding, Discharge, Calcimining, Fusing, And Gas-Generation Devices (AREA)

Claims (16)

  1. Verfahren zur Förderung bzw. Verschiebung einer interessierenden Flüssigkeit in einer Kapillare, die folgenden Schritte umfassend:
    - man bildet in der genannten Kapillare einen Ferrofluid-Zug, wobei der Ferrofluid-Zug einen Ferrofluid-Pfropfen und an wenigstens einem der beiden Enden des Ferrofluid-Pfropfens und mit diesem vereinigt einen Pfropfen aus einer mit dem Ferrofluid und dem interessierenden Fluid nicht mischbaren Flüssigkeit umfasst,
    - man sieht in der Kapillare das genannte interessierende Fluid in unmittelbarer Nähe des Pfropfens aus der mit dem Ferrofluid und dem interessierenden Fluid nicht mischbaren Flüssigkeit vor,
    - man steuert die Verschiebung der interessierenden Flüssigkeit in der genannten Kapillare durch die Wirkung eines Magnetfelds auf den Ferrofluid-Pfropfen, das erzeugt wird durch ein außerhalb der Kapillare angeordnetes magnetisches System.
  2. Verfahren nach Anspruch 1 bei dem das Ferrofluid ein ionisches Ferrofluid ist.
  3. Verfahren nach Anspruch 1 oder 2, bei dem die Kapillare eine Kapillare ist, deren Innenwand hydrophob ist.
  4. Verfahren nach Anspruch 1, bei dem die Kapillare einen Durchmesser unter 1 mm hat.
  5. Verfahren nach Anspruch 1, das außerdem einen Schritt zur Vorausbenetzung der Innenwand der Kapillare mit Öl umfasst, ehe der genannte Ferrofluid-Zug in der Kapillare gebildet wird.
  6. Verfahren nach Anspruch 1, bei dem ein Pfropfen aus einer mit dem Ferrofluid und dem interessierenden Fluid nicht mischbaren Flüssigkeit an jedem der beiden Enden des Ferrofluidpfropfens vorgesehen ist.
  7. Verfahren nach Anspruch 1, bei dem in der Kapillare eine Vielzahl von Ferrofluid-Zügen gebildet wird.
  8. Verfahren nach Anspruch 1, bei dem zwischen zwei Pfropfen aus dem interessierenden Fluid wenigstens ein Pfropfen aus einer mit dem Ferrofluid und dem interessierenden Fluid nicht mischbaren Flüssigkeit vorgesehen ist.
  9. Fluidische Mikrosysteme zur Verschiebung eines interessierenden Fluids, einerseits eine Kapillare (1), in der wenigstens ein Ferrofluid-Zug (3) vorgesehen ist, und andererseits, außerhalb der genannten Kapillare, ein magnetisches System (11) umfassend, das ermöglicht, ein Magnetfeld zu erzeugen, um die Verschiebung des Ferrofluid-Zugs in der Kapillare zu steuern, wobei der genannte Ferrofluid-Zug (3) einen Ferrofluid-Pfropfen (5) und einen Pfropfen (7) aus einer nicht mit dem Ferrofluid und dem interessierenden Fluid mischbaren Flüssigkeit umfasst, der sich an wenigstens einem der beiden Enden des Ferrofluid-Pfropfens befindet und mit diesem vereinigt ist.
  10. Fluidisches Mikrosystem nach Anspruch 9, bei dem das Ferrofluid ein ionisches Ferrofluid ist.
  11. Fluldisches Mikrosystem nach Anspruch 9 oder 10, bei dem die Kapillare eine Kapillare ist, deren Innenwand hydrophob ist.
  12. Fluidisches Mikrosystem nach Anspruch 9, bei dem die Kapillare einen Durchmesser unter 1 mm hat.
  13. Fluidisches Mikrosystem nach Anspruch 9, bei dem ein Pfropfen aus einer mit dem Ferrofluid und dem interessierenden Fluid nicht mischbaren Flüssigkeit an jedem der beiden Enden des Ferrofluidpfropfens vorgesehen ist.
  14. Fluidisches Mikrosystem nach Anspruch 9, das eine Vielzahl Ferrofluid-Züge umfasst.
  15. Fluidisches Mikrosystem nach Anspruch 9, bei dem in der Kapillare wenigstens ein Pfropfen aus einer mit dem Ferrofluid und dem interessierenden Fluid nicht mischbaren Flüssigkeit zwischen zwei Pfropfen aus dem interessierenden Fluid vorgesehen ist.
  16. Verwendung eines fluidischen Mikrosystems nach Anspruch 9 in einem automatisierten In-Vitro-Diagnosesystem oder einem System zur Detektion biologischer Kontaminationsstoffe.
EP02799424A 2001-09-21 2002-09-19 Verfahren zur förderung einer flüssigkeit in einer kapillare und fluidisches mikrosystem Expired - Lifetime EP1444042B1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR0112192 2001-09-21
FR0112192A FR2829948B1 (fr) 2001-09-21 2001-09-21 Procede de deplacement d'un fluide d'interet dans un capillaire et microsysteme fluidique
PCT/FR2002/003207 WO2003026798A1 (fr) 2001-09-21 2002-09-19 Procede de deplacement d'un fluide d'interet dans un capillaire et microsysteme fluidique

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EP1444042A1 EP1444042A1 (de) 2004-08-11
EP1444042B1 true EP1444042B1 (de) 2006-07-12

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US (1) US20040241693A1 (de)
EP (1) EP1444042B1 (de)
JP (1) JP4106328B2 (de)
AT (1) ATE332748T1 (de)
DE (1) DE60213120T2 (de)
FR (1) FR2829948B1 (de)
WO (1) WO2003026798A1 (de)

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JP4106328B2 (ja) 2008-06-25
EP1444042A1 (de) 2004-08-11
FR2829948B1 (fr) 2004-07-09
DE60213120D1 (de) 2006-08-24
JP2005503572A (ja) 2005-02-03
WO2003026798A1 (fr) 2003-04-03
DE60213120T2 (de) 2007-01-11
FR2829948A1 (fr) 2003-03-28
US20040241693A1 (en) 2004-12-02

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