EP3417931A1 - Generator von mikrofluidischen gradienten - Google Patents

Generator von mikrofluidischen gradienten Download PDF

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Publication number
EP3417931A1
EP3417931A1 EP17177540.6A EP17177540A EP3417931A1 EP 3417931 A1 EP3417931 A1 EP 3417931A1 EP 17177540 A EP17177540 A EP 17177540A EP 3417931 A1 EP3417931 A1 EP 3417931A1
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EP
European Patent Office
Prior art keywords
gradient
lines
fluid
soluble
output lines
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP17177540.6A
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English (en)
French (fr)
Inventor
Pedro NOVO
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Leibniz Institut fuer Analytische Wissenschaften ISAS eV
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Leibniz Institut fuer Analytische Wissenschaften ISAS eV
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Priority to EP17177540.6A priority Critical patent/EP3417931A1/de
Publication of EP3417931A1 publication Critical patent/EP3417931A1/de
Withdrawn legal-status Critical Current

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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
    • B01L3/502746—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the means for controlling flow resistance, e.g. flow controllers, baffles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F25/00—Flow mixers; Mixers for falling materials, e.g. solid particles
    • B01F25/40—Static mixers
    • B01F25/42—Static mixers in which the mixing is affected by moving the components jointly in changing directions, e.g. in tubes provided with baffles or obstructions
    • B01F25/43—Mixing tubes, e.g. wherein the material is moved in a radial or partly reversed direction
    • B01F25/431—Straight mixing tubes with baffles or obstructions that do not cause substantial pressure drop; Baffles therefor
    • B01F25/4316—Straight mixing tubes with baffles or obstructions that do not cause substantial pressure drop; Baffles therefor the baffles being flat pieces of material, e.g. intermeshing, fixed to the wall or fixed on a central rod
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F25/00—Flow mixers; Mixers for falling materials, e.g. solid particles
    • B01F25/40—Static mixers
    • B01F25/42—Static mixers in which the mixing is affected by moving the components jointly in changing directions, e.g. in tubes provided with baffles or obstructions
    • B01F25/43—Mixing tubes, e.g. wherein the material is moved in a radial or partly reversed direction
    • B01F25/431—Straight mixing tubes with baffles or obstructions that do not cause substantial pressure drop; Baffles therefor
    • B01F25/4317—Profiled elements, e.g. profiled blades, bars, pillars, columns or chevrons
    • B01F25/43172—Profiles, pillars, chevrons, i.e. long elements having a polygonal cross-section
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F25/00—Flow mixers; Mixers for falling materials, e.g. solid particles
    • B01F25/40—Static mixers
    • B01F25/42—Static mixers in which the mixing is affected by moving the components jointly in changing directions, e.g. in tubes provided with baffles or obstructions
    • B01F25/43—Mixing tubes, e.g. wherein the material is moved in a radial or partly reversed direction
    • B01F25/431—Straight mixing tubes with baffles or obstructions that do not cause substantial pressure drop; Baffles therefor
    • B01F25/43197—Straight mixing tubes with baffles or obstructions that do not cause substantial pressure drop; Baffles therefor characterised by the mounting of the baffles or obstructions
    • B01F25/431971—Mounted on the wall
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F25/00—Flow mixers; Mixers for falling materials, e.g. solid particles
    • B01F25/40—Static mixers
    • B01F25/42—Static mixers in which the mixing is affected by moving the components jointly in changing directions, e.g. in tubes provided with baffles or obstructions
    • B01F25/43—Mixing tubes, e.g. wherein the material is moved in a radial or partly reversed direction
    • B01F25/433—Mixing tubes wherein the shape of the tube influences the mixing, e.g. mixing tubes with varying cross-section or provided with inwardly extending profiles
    • B01F25/4331—Mixers with bended, curved, coiled, wounded mixing tubes or comprising elements for bending the flow
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
    • B01F33/30—Micromixers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/80—Forming a predetermined ratio of the substances to be mixed
    • B01F35/81—Forming mixtures with changing ratios or gradients
    • 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
    • B01L2200/0694—Creating chemical gradients in a fluid
    • 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
    • B01L2300/0867—Multiple inlets and one sample wells, e.g. mixing, dilution
    • 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
    • B01L2300/087—Multiple sequential chambers
    • 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
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/08—Regulating or influencing the flow resistance
    • B01L2400/084—Passive control of flow resistance
    • B01L2400/086—Passive control of flow resistance using baffles or other fixed flow obstructions

Definitions

  • the present invention relates to the field of microfluidic devices and provides improved means and methods for the continuous generation of a concentration gradient of a soluble out of at least two fluids of different concentration.
  • concentration of solubles for example, electrolytes, drug compounds, hormones, neurotransmitters, or cytokines
  • concentration of solubles for example, electrolytes, drug compounds, hormones, neurotransmitters, or cytokines
  • living cells may even react to slight variations in concentration levels of a stimulant.
  • concentration levels of solubles are required to assess, for instance, such fine-tuned reactions of cells, of receptor populations, or of cell populations and systems to a specific compound or stimulant.
  • concentration gradients are of great importance, for example, for rapid and high throughput screening:
  • a concentration gradient of a soluble, for example, a stimulant the effective concentration range of that stimulant can be assessed on many cultured cells in parallel, whereby each individual cell is exposed to a particular concentration along that concentration gradient.
  • Gradients may be also employed to other applications, such as chemical synthesis, nanoparticle synthesis, electrophoresis, among others.
  • microfluidic devices may be provided. Such devices may generate a continuous flow of a concentration gradient, for example, by means of a gradient generation network or so-called "gradient tree".
  • gradient generation network for example, by means of a gradient generation network or so-called "gradient tree".
  • the gradient generated by known microfluidic devices with gradient tree architecture is greatly dependent of the actual flow rate of the fluids. That is, the distribution of the discrete concentrations at the plurality of outputs of the gradient tree is greatly influenced by the actual flow rate through the microfluidic device.
  • Alternative microfluidic devices which do not rely on gradient trees, such as know T- and H-mixers for instance, have been developed, but have other substantial drawbacks.
  • a microfluidic device which basic principle is based on a gradient tree comprised of two or more mixing stages or on at least one mixing stage having a at least two input lines and a plurality of output lines, which, according to the invention, comprises a microfluidic micromixer unit in each of the output lines.
  • a microfluidic device which is particularly characterized in comprising at least one mixing stage with at least two, i.e. a plurality of n fluid input lines that feed into, i.e. are in fluid connection with, a common gradient rail.
  • These input lines are arranged along said common rail and are spaced apart from each other, in particular are at least positioned at each opposite end of the common rail.
  • From that common gradient rail at least on more ( n + 1 ) fluid output lines are branching off i.e. are in fluid connection with that common gradient rail.
  • These output lines are arranged along the rail and are spaced apart from each other and positioned in between the input lines.
  • each of these output lines is comprised of a micromixer unit which is capable of thorough mixing of the fluids entering this output line from the common rail, more particular by chaotic advection, and independent of the flow rate.
  • micromixer units provide homogenous mixtures of fluids of different concentrations and hence the stable and flow rate independent generation of discrete gradients on multiple output lines of the device in a very short period and, be it at ultra-low flow rates of less than 1 ⁇ l/min or at high flow rates, for example as high as 200 ⁇ l/min.
  • the microfluidic device of the present invention not only allows for precise, stable and thus reliable generation of a discrete gradient, but also allows for high flow rates in the order of 100 to 1000 ⁇ l/min as well as for flexible and intra-experiment changes in the flow rate of one or more of the fluids if needed and thus allows for highly efficient, albeit precise and thus cost-effective high-throughput experiments on concentration-dependent effects of one or more stimulant to biological cells or cell systems, or other applicable studies as indicated above.
  • a "micromixer” or “micromixer unit” is understood as a structure, commonly a passive micromixer which confers non-turbulent, but chaotic flow of the fluids entering the unit, thus reducing the diffusion length between the fluids.
  • a particular technical effect conferred by such a micromixer is advection.
  • the operating parameters, such as the Reynolds number Re in the flow are preferably below 2300, more preferably ranging from 0.2 to 2000, more preferably ranging from 2 to 200, for example at mixing times of 50 ⁇ s.
  • Micromixers are known as such and in particular embodiments may also include mixing by lamination and/or injection.
  • the micromixer unit comprises a fluid channel with mixing obstacles to confer chaotic flow and thus mixing.
  • These obstacles are preferably selected from: slanted ribs, slanted grooves, staggered-herringbone ribs, staggered-herringbone grooves and combinations thereof, and two level channel modifications that confer fluid fractionation and recombination.
  • the micromixer unit comprises a twisted fluid channel to confer chaotic flow.
  • the micromixer may also comprise parts or consist of an active micromixer, for example, for mixing by means of active disturbance, including acoustic disturbance, pressure disturbance, thermal disturbance, mechanical disturbance, or hydrodynamic disturbance.
  • active disturbance including acoustic disturbance, pressure disturbance, thermal disturbance, mechanical disturbance, or hydrodynamic disturbance.
  • the device comprises a gradient tree that is comprised of three or more consecutive mixing stages, wherein each output line of the previous mixing stage is feeding into each individual input line of the following mixing stage.
  • each mixing stage has n input lines and at least n + 1 fluid output lines.
  • each mixing stage has n input lines and at least 2 n - 1 fluid output lines.
  • the consecutive mixing stage may thus comprise three input lines and may comprise five output lines.
  • the consecutive mixing stage may thus comprise five input lines and nine output lines.
  • the consecutive mixing stage may thus comprise nine input lines and 17 output lines, and so forth.
  • Such a device is capable of producing a gradient of a soluble out of line discrete concentration levels at the output lines of the third mixing stage, provided that the soluble is fed into one of the two input lines of the initial mixing stage at a given concentration.
  • the common rail to which the input lines feet and from which the output lines are branching of is preferably arranged substantially perpendicular to the flow direction of the input lines and output lines.
  • input lines feed to the common rail at an angle of about 90°.
  • output lines branch off from the common rail at an angle of about 90°. Upstream the entering point of the input lines and downstream the branching point of the output lines, respectively, input lines and output lines may follow other directions.
  • the net flow within input lines and output lines is co-linear, and is perpendicular to the extension of the common rail joining these input and output lines.
  • the present invention also encompasses microfluidic gradient networks which generate gradients with other distributions than linear, for example, exponential distribution, logarithmic distribution, Gaussian distribution, or combinations thereof.
  • Such distributions can be accomplished by variation of flow rate and pressure of the input lines, but also by the geometrics and design of the input lines, the common rail of each mixing stage, the output lines, and the actual positioning of input lines and/or output lines along the common rails, but in particular by the individual design of the micromixer in the output lines. That is, by specific design of each micromixer within the output lines of the mixing stages a specific concentration gradient can be obtained.
  • the present invention also foresees means for specific control of the hydrodynamic properties of individual mixing stages within the gradient generating network of the microfluidic device of the present invention. This allows for dynamic control of the gradient distribution or gradient profile at the individual output lines of the network.
  • the invention also provides a method for the generation of a discrete concentration gradient of one soluble, comprising the steps of: feeding a first fluid at a first concentration C 1 of a soluble into a common gradient rail at a first input line, and concomitant feeding of a second fluid at a second concentration C 2 of said soluble, or a fluid free from that soluble into this common gradient rail at at least one further input line along the common gradient rail spaced apart from said first input line; branching off the flow of the fluids in said common gradient rail into a plurality of output lines spaced apart from each other and in between the two input lines; to obtain a plurality of discrete concentrations of that soluble at specific ratios at the output lines.
  • the method is specifically characterized in that the fluids branching off from the common gradient rail are individually mixed in each of the output lines by means of micromixer units, preferably by chaotic advection.
  • a method for the generation of a discrete concentration gradient of one or more solubles comprising the steps of: feeding a first fluid at a first concentration C 1 of a first soluble into a common gradient rail at a first input line; concomitant feeding of at least one second or further fluid having at least one further concentration C 2 or C n of said first or of a further soluble into said common gradient rail having at least one further input line spaced apart from said first input line; branching off the flow of said fluids from said common gradient rail into a plurality of output lines spaced apart from each other and in between the input lines; and obtaining a plurality of discrete concentrations of said first and/or further soluble as a specific ratio of C 1 : C 2 ... : C n at the output lines; characterized in that the fluids branching off from the common gradient rail are individually mixed by chaotic advection by means of micromixer units in each of the output lines.
  • the invention also provides the use of a micromixer unit characterized herein for flow rate-independent generation of a discrete gradient of at least one soluble from at least two fluids in a microfluidic device having different concentrations of said soluble[s].
  • the invention also provides the use of the microfluidic device characterized herein for flow rate-independent generation of a discrete gradient of at least one soluble from at least two fluids having different concentrations of said soluble[s].

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  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dispersion Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Analytical Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Clinical Laboratory Science (AREA)
  • Physical Or Chemical Processes And Apparatus (AREA)
EP17177540.6A 2017-06-22 2017-06-22 Generator von mikrofluidischen gradienten Withdrawn EP3417931A1 (de)

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EP17177540.6A EP3417931A1 (de) 2017-06-22 2017-06-22 Generator von mikrofluidischen gradienten

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EP17177540.6A EP3417931A1 (de) 2017-06-22 2017-06-22 Generator von mikrofluidischen gradienten

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118002224A (zh) * 2024-04-10 2024-05-10 南昌航空大学 一种采用多微流控浓度梯度芯片的药物自动筛选平台

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040106192A1 (en) * 2002-10-04 2004-06-03 Noo Li Jeon Microfluidic multi-compartment device for neuroscience research
US20050217750A1 (en) * 2000-09-18 2005-10-06 President And Fellows Of Harvard College Method and apparatus for gradient generation
US20100190265A1 (en) * 2005-12-02 2010-07-29 Technical University Of Denmark Fluidics device for assay
US20160214103A1 (en) * 2011-10-25 2016-07-28 The University Of British Columbia Limit size lipid nanoparticles and related methods

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050217750A1 (en) * 2000-09-18 2005-10-06 President And Fellows Of Harvard College Method and apparatus for gradient generation
US20040106192A1 (en) * 2002-10-04 2004-06-03 Noo Li Jeon Microfluidic multi-compartment device for neuroscience research
US20100190265A1 (en) * 2005-12-02 2010-07-29 Technical University Of Denmark Fluidics device for assay
US20160214103A1 (en) * 2011-10-25 2016-07-28 The University Of British Columbia Limit size lipid nanoparticles and related methods

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LIU R H ET AL: "Passive mixing in a three-dimensional serpentine microchannel", JOURNAL OF MICROELECTROMECHANICAL SYSTEMS, IEEE SERVICE CENTER, US, vol. 9, no. 2, 1 June 2000 (2000-06-01), pages 190 - 197, XP011450833, ISSN: 1057-7157, DOI: 10.1109/84.846699 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118002224A (zh) * 2024-04-10 2024-05-10 南昌航空大学 一种采用多微流控浓度梯度芯片的药物自动筛选平台
CN118002224B (zh) * 2024-04-10 2024-06-07 南昌航空大学 一种采用多微流控浓度梯度芯片的药物自动筛选平台

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