Manipulation of fluids, fluid components and reactions in microfluidic systems

• US 8,592,221 B2
• Filed: 04/18/2008
• Issued: 11/26/2013
• Est. Priority Date: 04/19/2007
• Status: Active Grant

• Current Assignee: Brandeis University, President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: Brandeis University, President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Fraden, Seth, Boukellal, Hakim, Jia, Yanwei, Selimovic, Seila, Rowat, Amy, Agresti, Jeremy, Weitz, David A.
• Primary Examiner(s): Hyun, Paul
• Application Number:
  US12/595,107
• Publication Number:
  US 20100252118A1
• Time in Patent Office: 2,048 Days
• Field of Search: 422502-504, 422/507, 422/509, 137/2, 137/14, 436/180
• US Class Current: 436/180
• CPC Class Codes: B01L 2200/0673 Handling of plugs of fluid surrounded by immiscible fluid
• CPC Class Codes: B01L 2300/0861 Configuration of multiple channels and/or chambers in a single devices
• CPC Class Codes: B01L 2300/087 Multiple sequential chambers
• CPC Class Codes: B01L 2300/0877 Flow chambers
• CPC Class Codes: B01L 2400/0487 fluid pressure, pneumatics
• CPC Class Codes: B01L 2400/0688 surface tension valves, capillary stop, capillary break
• CPC Class Codes: B01L 2400/0694 vents used to stop and induce flow, backpressure valves
• CPC Class Codes: B01L 2400/082 Active control of flow resistance, e.g. flow controllers
• 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: F17D 1/12 Conveying liquids or viscous products by pressure of another fluid
• CPC Class Codes: G01N 1/28 Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Qmounting specimens on microscopic slides G02B21/34; means for supporting the objects or the materials to be analysed in electron microscopes H01J37/20 ; laboratory gas handling apparatus B01L5/00
• CPC Class Codes: G01N 15/0272 with screening; with classification by filtering B01D takes precedence
• CPC Class Codes: G01N 15/1484 microstructural devices
• CPC Class Codes: G01N 2015/0092 Monitoring flocculation or agglomeration
• CPC Class Codes: Y10T 137/0324 With control of flow by a condition or characteristic of a fluid
• CPC Class Codes: Y10T 137/0391 Affecting flow by the addition of material or energy
• CPC Class Codes: Y10T 137/0396 Involving pressure control
• CPC Class Codes: Y10T 137/2082 Utilizing particular fluid
• CPC Class Codes: Y10T 137/218 Means to regulate or vary operation of device
• CPC Class Codes: Y10T 436/2575 : Volumetric liquid transfer

Abstract

Microfluidic structures and methods for manipulating fluids, fluid components, and reactions are provided. In one aspect, such structures and methods can allow production of droplets of a precise volume, which can be stored/maintained at precise regions of the device. In another aspect, microfluidic structures and methods described herein are designed for containing and positioning components in an arrangement such that the components can be manipulated and then tracked even after manipulation. For example, cells may be constrained in an arrangement in microfluidic structures described herein to facilitate tracking during their growth and/or after they multiply.

Claims

1. A method, comprising:

providing a microfluidic network comprising a first region and a microfluidic channel in fluid communication with the first region;

flowing a first fluid in a first direction in the microfluidic channel;

flowing a second fluid in the first direction in the microfluidic channel;

partitioning at least a portion of the first fluid in the first region by flowing the second fluid past the first region, so as to form a first droplet of the first fluid in the first region; and

maintaining the droplet in the first region while the second fluid is flowing in the first direction.

2. A method as in claim 1, wherein the first fluid and the second fluid are immiscible.

3. A method as in claim 1, wherein forming of the first droplet in the first region does not require the use of a surfactant in the first or second fluids.

4. A method as in claim 1, wherein maintaining the first droplet in the first region does not require the use of a surfactant in the first or second fluids.

5. A method as in claim 1, wherein a fluid immiscible with the first fluid is flowed in the microfluidic channel prior to flowing of the first fluid.

6. A method as in claim 1, wherein the first fluid or the second fluid does not comprise a surfactant.

7. A method as in claim 1, wherein forming or maintaining the first droplet in the first region is independent of flow rate of the first fluid in the microfluidic channel.

8. A method as in claim 1, wherein the first droplet can be maintained in the first region in the absence of fluid flowing in the microfluidic channel.

9. A method as in claim 1, wherein the microfluidic channel comprises an upstream portion, a downstream portion, and first and second fluid paths extending from the upstream portion and reconnecting at the downstream portion.

10. A method as in claim 9, wherein the first and second fluid paths have different resistances to flow.

11. A method as in claim 10, wherein the first region is positioned within the first fluid path.

12. A method as in claim 11, wherein the first fluid path has less resistance to flow compared to the second fluid path prior to formation of the first droplet in the first region, and the first fluid path has greater resistance to flow after formation of the first droplet in the first region.

13. A method as in claim 1, wherein the microfluidic network comprises a plurality of regions including the first region, and the method comprises forming a plurality of droplets including the first droplet at the plurality of regions of the microfluidic network, wherein each droplet is formed from a different portion of the first fluid, and each droplet is formed in a separate region in the order in which each portion of the first fluid is introduced into the microfluidic network.

14. A method as in claim 13, further comprising removing the plurality of droplets positioned at regions of the microfluidic network, wherein each droplet is removed in the order the droplet was formed in the microfluidic network.

15. A method as in claim 14, further comprising removing the plurality of droplets positioned at regions of the microfluidic network, wherein each droplet is removed in the reverse order the droplet was formed in the microfluidic network.

16. A method as in claim 1, wherein the first droplet is in fluid communication with the microfluidic channel immediately after the partitioning step.

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

18. The method of claim 17, wherein the microfluidic channel has a maximum cross sectional dimension of 100 microns or smaller.

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

20. The method of claim 1, wherein the first fluid is an aqueous fluid.

21. The method of claim 1, wherein the second fluid is an oil.

22. The method of claim 21, wherein the oil is fluorinated.

23. A method, comprising:

providing a microfluidic network comprising a first region and a microfluidic channel in fluid communication with the first region;

flowing a first fluid in a first direction in the microfluidic channel;

flowing a second fluid in the first direction in the microfluidic channel;

partitioning at least a portion of the first fluid in the first region, at least in part through action of the second fluid, so as to form a first droplet of the first fluid in the first region; and

flowing a third fluid in the microfluidic channel after flowing of the second fluid;

partitioning at least a portion of the third fluid in a second region so as to form a second droplet of the third fluid in the second region; and

maintaining the droplet in the first region while the second fluid is flowing in the first direction.

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 forming a first and a second droplet, respectively, the first and second regions in fluid communication with the microfluidic channel;

flowing a first fluid in the microfluidic channel;

partitioning a first portion of the first fluid in the first region by flowing a second fluid past the first region, so as to form the first droplet in the first region; and

partitioning a second portion of the first fluid at the second region, at least in part through action of the second fluid, so as to form the second droplet at the second region.

25. The method of claim 24, wherein partitioning the second portion of the first fluid in the second region is caused by flowing the second fluid past the second region.

26. A method, comprising:

providing a microfluidic network comprising a first region and a microfluidic channel in fluid communication with the first region, the microfluidic channel comprising an upstream portion, a downstream portion, and first and second fluid paths extending from the upstream portion and reconnecting at the downstream portion, and the first region positioned within the first fluid path;

flowing a first fluid in a first direction in the microfluidic channel;

flowing a second fluid in the first direction in the microfluidic channel;

partitioning at least a portion of the first fluid in the first region, at least in part through action of the second fluid, so as to form a first droplet of the first fluid in the first region; and

maintaining the droplet in the first region while the second fluid is flowing in the first direction,

wherein the first fluid path has less resistance to flow compared to the second fluid path prior to formation of the first droplet in the first region, and the first fluid path has greater resistance to flow after formation of the first droplet in the first region.