Manipulation of fluids and reactions in microfluidic systems

• US 8,772,046 B2
• Filed: 02/06/2008
• Issued: 07/08/2014
• Est. Priority Date: 02/06/2007
• Status: Active Grant

• Current Assignee: Brandeis University
• Original Assignee: Brandeis University
• Inventors: Fraden, Seth, Cristobal-Azkarate, Galder
• Primary Examiner(s): Hyun, Paul
• Application Number:
  US12/525,749
• Publication Number:
  US 20100163109A1
• Time in Patent Office: 2,344 Days
• Field of Search: 422/502, 422/503, 137/2, 137/14, 436/180
• US Class Current: 436/180
• CPC Class Codes: B01L 2200/0621 Control of the sequence of chambers filled or emptied
• CPC Class Codes: B01L 2200/0642 Filling fluids into wells by specific techniques
• CPC Class Codes: B01L 2200/0668 Trapping microscopic beads
• CPC Class Codes: B01L 2200/0673 Handling of plugs of fluid surrounded by immiscible fluid
• CPC Class Codes: B01L 2300/0816 Cards, e.g. flat sample carriers usually with flow in two horizontal directions
• 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 2300/1822 using Peltier elements
• CPC Class Codes: B01L 2400/0406 capillary forces
• CPC Class Codes: B01L 2400/0655 pinch valves
• CPC Class Codes: B01L 3/06 Crystallising dishes
• 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 3/502715 characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
• CPC Class Codes: B01L 3/50273 characterised by the means or forces applied to move the fluids micropumps F04B19/006, of the membrane type F04B43/043
• CPC Class Codes: B01L 3/502746 characterised by the means for controlling flow resistance, e.g. flow controllers, baffles B01L3/502738 takes precedence
• 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 7/54 using spatial temperature gradients
• CPC Class Codes: C30B 29/58 Macromolecular compounds
• CPC Class Codes: C30B 7/00 Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions from molten solvents C30B9/00; by normal or gradient freezing C30B11/00; under a protective fluid C30B27/00
• CPC Class Codes: G01N 1/38 Diluting, dispersing or mixing samples
• CPC Class Codes: G01N 2001/386 : Other diluting or mixing processes
• CPC Class Codes: Y10T 137/0318 : Processes
• CPC Class Codes: Y10T 436/2575 : Volumetric liquid transfer

Abstract

Microfluidic structures and methods for manipulating fluids and reactions are provided. Such structures and methods may involve positioning fluid samples, e.g., in the form of droplets, in a carrier fluid (e.g., an oil, which may be immiscible with the fluid sample) in predetermined regions in a microfluidic network. In some embodiments, positioning of the droplets can take place in the order in which they are introduced into the microfluidic network (e.g., sequentially) without significant physical contact between the droplets. Because of the little or no contact between the droplets, there may be little or no coalescence between the droplets. Accordingly, in some such embodiments, surfactants are not required in either the fluid sample or the carrier fluid to prevent coalescence of the droplets. Structures and methods described herein also enable droplets to be removed sequentially from the predetermined regions.

Claims

1. A method, comprising:

providing a microfluidic network comprising a plurality of regions and a microfluidic channel in fluid communication with the plurality of regions;

flowing an oil in the microfluidic channel;

flowing a first plurality of aqueous droplets into the microfluidic channel through an inlet;

positioning each of the plurality of aqueous droplets in a plurality of separate regions;

maintaining the plurality of aqueous droplets in the separate regions while the oil is flowing in the microfluidic channel; and

removing the plurality of aqueous droplets positioned in the separate regions;

wherein the aqueous droplets are removed in the order that they flowed into the microfluidic channel.

2. A method as in claim 1, wherein the oil or the first fluid do not comprise a surfactant.

3. A method as in claim 1, wherein a first portion of the plurality of droplets comprises a first aqueous fluid and a second portion of the plurality of droplets comprises a second fluid.

4. A method as in claim 3, wherein the second fluid does not comprise a surfactant.

5. A method as in claim 3, wherein the first and second portions of aqueous droplets do not come into physical contact with each other during the positioning or maintaining steps.

6. A method as in claim 1, wherein positioning or maintaining a first aqueous droplet in a first region is independent of flow rate of the oil in the microfluidic channel.

7. A method as in claim 1, wherein a first region is closer in distance to the inlet than a second region.

8. A method as in claim 7, wherein a first aqueous droplet is positioned in the first region before a second droplet is positioned in the second region.

9. A method as in claim 8, further comprising removing the first aqueous droplet from the first region and then removing the second aqueous droplet from the second region.

10. A method as in claim 8, comprising flowing a fluid comprising a surfactant in the microfluidic channel.

11. A method as in claim 8, comprising coating the first or second aqueous droplet with a surfactant.

12. A method as in claim 8, comprising dewetting the first or second aqueous droplet from a surface of the microfluidic channel.

13. A method as in claim 8, wherein positioning of the first aqueous droplet in the first region affects a direction of flow of the second aqueous droplet in the microfluidic network.

14. A method as in claim 1, wherein the microfluidic channel comprises an upstream portion, a downstream portion, and first and second fluid paths, at least one fluid path branching from the upstream portion and reconnecting at the downstream portion.

15. A method as in claim 14, wherein the first and second fluid paths have different resistances to flow.

16. A method as in claim 15, wherein the first fluid path comprises a fluid constriction.

17. A method as in claim 16, wherein a first region is positioned within the first fluid path.

18. A method as in claim 16, wherein the first fluid path has less resistance to flow compared to the second fluid path prior to positioning of the first aqueous droplet in the first region, and the first fluid path has greater resistance to flow after positioning of the first aqueous droplet in the first region.

19. A method as in claim 1, wherein a first region comprises a cross-sectional area approximately the same as a cross-sectional area of the microfluidic channel in fluid communication with the first region.

20. The method of claim 1, wherein the microfluidic channel has a maximum cross sectional dimension of 500 microns or smaller.

21. The method of claim 20, wherein the microfluidic channel has a maximum cross sectional dimension of 100 microns or smaller.

22. The method of claim 1, wherein the first aqueous droplet has a volume of less than 1 nL.

23. The method of claim 1, wherein the oil is a fluorinated oil.

24. A method, comprising:

providing a microfluidic network comprising at least a first inlet to a microfluidic channel, a first and a second region for positioning a first and a second aqueous droplet, respectively, the first and second regions in fluid communication with the microfluidic channel, wherein the first region is closer in distance to the first inlet than the second region;

flowing an oil in the microfluidic channel;

flowing the first aqueous droplet in the microfluidic channel through the first inlet;

positioning the first aqueous droplet in the first region;

flowing the second droplet in the microfluidic channel through the first inlet and past the first region without the second aqueous droplet physically contacting the first aqueous droplet;

positioning the second aqueous droplet in the second region;

flowing the first aqueous droplet from the first region toward the first inlet; and

flowing the second droplet from the second region past the first region and toward the first inlet without the second aqueous droplet physically contacting the first aqueous droplet, wherein the first and second droplets leave the first inlet in the order in which they entered.

25. The method of claim 24, wherein positioning the first droplet in the first region does not require the use of a surfactant in the oil or the first droplet.