Electronic control of fluidic species

• US 8,765,485 B2
• Filed: 02/23/2006
• Issued: 07/01/2014
• Est. Priority Date: 08/27/2003
• Status: Active Grant

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Link, Darren Roy, Weitz, David A., Cristobal-Azkarate, Galder, Cheng, Zhengdong, Ahn, Keunho
• Primary Examiner(s): Gordon, Brian R
• Application Number:
  US11/360,845
• Publication Number:
  US 20070003442A1
• Time in Patent Office: 3,050 Days
• Field of Search: 422 99-102, 422/104, 422/110, 422/111, 422/256, 422/500, 422502-504, 422/536, 422551-553, 436/174, 436/176, 436/180, 436807-809, 702/19, 702/22, 702/57, 702/80, 702/100, 204600-601
• US Class Current: 436/180
• CPC Class Codes: B01F 25/23 Mixing by intersecting jets
• CPC Class Codes: B01F 25/433 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
• CPC Class Codes: B01F 25/4338 Mixers with a succession of converging-diverging cross-sections, i.e. undulating cross-section
• CPC Class Codes: B01F 25/45 Mixers in which the materials to be mixed are pressed together through orifices or interstitial spaces, e.g. between beads B01F25/44 takes precedence
• CPC Class Codes: B01F 25/45211 the elements being cylinders or cones which obstruct the whole diameter of the tube, the flow changing from axial in radial and again in axial
• CPC Class Codes: B01F 33/302 the materials to be mixed flowing in the form of droplets
• CPC Class Codes: B01F 33/3021 the components to be mixed being combined in a single independent droplet, e.g. these droplets being divided by a non-miscible fluid or consisting of independent droplets
• CPC Class Codes: B01F 33/3031 using electro-hydrodynamic [EHD] or electro-kinetic [EKI] phenomena to mix or move the fluids
• CPC Class Codes: B01F 33/305 using mixing means not otherwise provided for B01F25/00, B01F27/00, B01F29/00, B01F31/00, B01F33/301 - B01F33/3045, B01F33/40 and B01F33/45 take precedence
• CPC Class Codes: B01J 19/0093 Microreactors, e.g. miniaturised or microfabricated reactors laboratory containers with capillary fluid transport in microfabricated channels or chambers B01L3/5027
• CPC Class Codes: B01J 2219/00783 Laminate assemblies, i.e. the reactor comprising a stack of plates
• CPC Class Codes: B01J 2219/00862 Dimensions of the reaction cavity itself
• CPC Class Codes: B01L 2200/0636 Focussing flows, e.g. to laminate flows
• CPC Class Codes: B01L 2200/0652 Sorting or classification of particles or molecules
• CPC Class Codes: B01L 2200/0673 Handling of plugs of fluid surrounded by immiscible fluid
• CPC Class Codes: B01L 2300/0864 comprising only one inlet and multiple receiving wells, e.g. for separation, splitting
• CPC Class Codes: B01L 2300/0867 Multiple inlets and one sample wells, e.g. mixing, dilution
• CPC Class Codes: B01L 2300/161 Control and use of surface tension forces, e.g. hydrophobic, hydrophilic
• CPC Class Codes: B01L 2400/0415 electrical forces, e.g. electrokinetic
• CPC Class Codes: B01L 2400/0439 ultrasonic vibrations, vibrating piezo elements
• CPC Class Codes: B01L 2400/0487 : fluid pressure, pneumatics
• CPC Class Codes: B01L 3/0241 : Drop counters; Drop formers making arrays for combinatorial libraries B01J19/0046; automation of dispensing for analysis G01N35/10
• CPC Class Codes: B01L 3/5027 : 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 B01L3/5023 takes precedence; micromixers B01F33/30; microreactors for synthesis B01J19/0093; microcapillary devices in general B81B1/00
• CPC Class Codes: B01L 3/502761 : specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads, for physically stretching molecules investigating characteristics of particles G01N15/00
• CPC Class Codes: B01L 3/502776 : specially adapted for focusing or laminating flows
• CPC Class Codes: B01L 3/502784 : specially adapted for droplet or plug flow, e.g. digital microfluidics automatic analysis using a stream of discrete samples in a tube system G01N35/08
• CPC Class Codes: B01L 3/502792 : for moving individual droplets on a plate, e.g. by locally altering surface tension
• CPC Class Codes: B01L 3/5088 : confining liquids at a location by surface tension, e.g. virtual wells on plates, wires B01L3/50857 takes precedence
• CPC Class Codes: C12Q 2563/159 : Microreactors, e.g. emulsion PCR or sequencing, droplet PCR, microcapsules, i.e. non-liquid containers with a range of different permeability's for different reaction components
• CPC Class Codes: C12Q 2565/629 : being a microfluidic device
• CPC Class Codes: G01N 15/10 : Investigating individual particles
• CPC Class Codes: G01N 15/14 : Optical investigation techniques, e.g. flow cytometry
• CPC Class Codes: G01N 15/1459 : the analysis being performed on a sample stream
• CPC Class Codes: G01N 15/1484 : microstructural devices
• CPC Class Codes: G01N 15/149 : specially adapted for sorting particles, e.g. by their size or optical properties
• CPC Class Codes: G01N 2015/1006 : for cytology
• CPC Class Codes: G01N 2015/1028 : Sorting particles
• CPC Class Codes: Y10S 436/807 : Apparatus included in process claim, e.g. physical support structures
• CPC Class Codes: Y10T 436/118339 : with formation of a segmented stream
• CPC Class Codes: Y10T 436/2525 : Stabilizing or preserving
• CPC Class Codes: Y10T 436/2575 : Volumetric liquid transfer

Abstract

Various aspects of the present invention relates to the control and manipulation of fluidic species, for example, in microfluidic systems. In one aspect, the invention relates to systems and methods for making droplets of fluid surrounded by a liquid, using, for example, electric fields, mechanical alterations, the addition of an intervening fluid, etc. The invention also relates to systems and methods for fusing droplets according to another aspect of the invention, for example, through charge and/or dipole interactions. In some cases, the fusion of the droplets may initiate or determine a reaction. In still another aspect, the invention relates to systems and methods for sorting droplets, e.g., by causing droplets to move to certain regions within a fluidic system. Examples include using electrical interactions (e.g., charges, dipoles, etc.) or mechanical systems (e.g., fluid displacement) to sort the droplets.

Claims

1. A method of coalescing droplets in a controlled manner in a microfluidic device, said method comprising the steps of:

providing a microfluidic device having at least one microchannel comprising a first region and a coalescence region, the coalescence region comprising an electric field;

providing a first droplet and a second droplet to the microchannel, wherein the first and second droplets comprise a surfactant that stabilizes the droplets and inhibits coalescence between the first and second droplets outside of the coalescence region; and

flowing the first and second droplets into the coalescence region, wherein the electric field is adapted to coalesce the first and second droplets into one combined droplet.

2. The method of claim 1, wherein the first or second droplet, prior to flowing through the electric field, has a neutral charge.

3. The method of claim 1, wherein the electric field induces a dipole moment in the first or second droplet.

4. The method of claim 1, wherein the first and second droplets each comprise a chemical, biological or biochemical entity in addition to the surfactant.

5. The method of claim 4, wherein the first and second droplets comprise the same chemical, biological or biochemical entity in addition to the surfactant.

6. The method of claim 4, wherein the first and second droplets comprise a different chemical biological or biochemical entity in addition to the surfactant.

7. The method of claim 1, wherein the first or second droplet comprises a cell.

8. The method of claim 1, wherein the first or second droplet comprises a first fluid completely surrounded by a second fluid.

9. The method of claim 8, wherein the second fluid is a liquid and the first fluid and second fluid are immiscible.

10. The method of claim 1, wherein the electric field is an alternating current field, a direct current field or a pulsed field.

11. The method of claim 1, wherein the electric field is produced by a voltage applied across a pair of electrodes positioned on or embedded within the microchannel, and the coalescence region comprises a portion of the microchannel between the electrodes.

12. The method of claim 1, wherein the electric field has an intensity of a least 0.01 V/micrometer.

13. The method of claim 1, further comprising initiating a reaction in the combined droplet between a species of the first droplet and a species of the second droplet.

14. The method of claim 1, further comprising flowing the first and second droplets through the first region of the microchannel, that does not have an electric field, before flowing the first and second droplets through the coalescence region.

15. The method of claim 14, wherein the first and second droplets are in contact with each other while flowing through the first region of the microchannel that does not have an electric field.

16. The method of claim 1, wherein the first and second droplets do not coalesce while flowing through the portions of the microchannel that donot include the coalescence region.

17. The method of claim 1, wherein the first or second droplet has a diameter of less than about 500 micrometers.

18. The method of claim 17, wherein the first or second droplet has a diameter of less than about 100 μ

m.

19. The method of claim 8, wherein the second fluid insulates the first fluid from the electric field.