Manipulation of fluids and reactions in microfluidic systems

• US 9,017,623 B2
• Filed: 06/03/2014
• Issued: 04/28/2015
• Est. Priority Date: 02/06/2007
• Status: Active Grant

• Current Assignee: Brandeis University
• Original Assignee: Raindance Technologies Incorporated (Bio-Rad Laboratories Incorporated)
• Inventors: Fraden, Seth, Cristobal-Azkarate, Galder
• Primary Examiner(s): Hyun, Paul
• Application Number:
  US14/294,737
• Publication Number:
  US 20140295572A1
• Time in Patent Office: 329 Days
• Field of Search: 422502-505
• US Class Current: 422/502
• 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 microfluidic chip, comprising:

a network adapted for a directional fluid flow along a fluid path that comprises 5 or more sections in a serial arrangement, each section comprising;

a first channel that receives the directional fluid flow;

a junction fluidicly coupled to the first channel;

a second channel fluidicly coupled to the junction and to the first channel of a subsequent section; and

a microwell fluidicly coupled to the junction and comprising a constricted fluid path that exits the microwell;

wherein the directional fluid flow follows a path of lower hydrodynamic resistance through the microwell when the constricted fluid path is open, and through the second fluid channel when the constricted fluid path is substantially plugged.

2. The microfluidic chip of claim 1, wherein:

greater than 50% of the directional fluid flow follows a path of lower hydrodynamic resistance through the microwell when the constricted fluid path is open.

3. The microfluidic chip of claim 1, wherein:

greater than 60% of the directional fluid flow follows a path of lower hydrodynamic resistance through the microwell when the constricted fluid path is open.

4. The microfluidic chip of claim 1, wherein:

greater than 70% of the directional fluid flow follows a path of lower hydrodynamic resistance through the microwell when the constricted fluid path is open.

5. The microfluidic chip of claim 1, wherein:

greater than 80% of the directional fluid flow follows a path of lower hydrodynamic resistance through the microwell when the constricted fluid path is open.

6. The microfluidic chip of claim 1, wherein:

greater than 90% of the directional fluid flow follows a path of lower hydrodynamic resistance through the microwell when the constricted fluid path is open.

7. The microfluidic chip of claim 1, wherein:

the network comprises 10 or more sections.

8. The microfluidic chip of claim 1, wherein:

the network comprises 30 or more sections.

9. The microfluidic chip of claim 1, wherein:

the network comprises 70 or more sections.

10. The microfluidic chip of claim 1, wherein:

the network comprises 100 or more sections.

11. The microfluidic chip of claim 1, wherein:

the network comprises 200 or more sections.

12. The microfluidic chip of claim 1, wherein:

the network comprises 500 or more sections.

13. The microfluidic chip of claim 1, wherein:

the network comprises 1000 or more sections.

14. The microfluidic chip of claim 1, wherein:

the junction further comprises a third channel fluidicly coupled to the junction.

15. The microfluidic chip of claim 1, wherein:

the constricted fluid path is substantially plugged by an element positioned in the microwell.

16. The microfluidic chip of claim 15, wherein:

the element comprises an aqueous droplet.

17. The microfluidic chip of claim 15, wherein:

the directional fluid flow comprises a plurality of the elements in a serial arrangement, wherein the elements follow the path of lower hydrodynamic resistance until positioned in the microwell of a section.

18. The microfluidic chip of claim 1, wherein:

the constricted fluid path is substantially plugged by a plurality of elements positioned in the microwell.

19. The microfluidic chip of claim 1, wherein:

the network comprises an inlet coupled to a channel fluidicly coupled to the junction of a first section.

20. The microfluidic chip of claim 1, wherein:

the directional fluid flow comprises a flow of a carrier fluid.

21. A microfluidic chip comprising:

a network adapted for a directional fluid flow along a fluid path that comprises a plurality of sections in a serial arrangement, each section comprising;

a first channel that receives the directional fluid flow;

a junction fluidicly coupled to the first channel;

a second channel fluidicly coupled to the junction and to the first channel of a subsequent section; and

a microwell fluidicly coupled to the junction and comprising a constricted fluid path that exits the microwell;

wherein the directional fluid flow follows a path of lower hydrodynamic resistance through the microwell when the constricted fluid path is open, and through the second fluid channel when the constricted fluid path is substantially plugged, and wherein the junction further comprises a valve adapted to restrict the directional fluid flow through the microwell.

22. The microfluidic chip of claim 21, wherein:

the valve comprises an open position and a closed position, wherein the directional fluid flow follows a path of lower hydrodynamic resistance through the microwell when the valve is in the open position, and through the second fluid channel when the valve is in the closed position.

23. The microfluidic chip of claim 22, wherein greater than 50% of the directional fluid flow follows the path of lower hydrodynamic resistance through the microwell when the valve is in the open position.

24. The microfluidic chip of claim 21, wherein the junction further comprises a third channel fluidicly coupled to the junction.

25. The microfluidic chip of claim 21, wherein the network further comprises an inlet coupled to a channel fluidicly coupled to the junction of a first section.