Manipulation of microfluidic droplets

• US 8,528,589 B2
• Filed: 03/23/2010
• Issued: 09/10/2013
• Est. Priority Date: 03/23/2009
• Status: Active Grant

• Current Assignee: Bio-Rad Laboratories Incorporated
• Original Assignee: Raindance Technologies Incorporated (Bio-Rad Laboratories Incorporated)
• Inventors: Miller, Benjamin, Hutchison, Brian, Wilson, Andrew, Larson, Jonathan, Zhong, Qun, Yurkovetsky, Yevgeny, Link, Darren, Weary, Mark
• Primary Examiner(s): Rivell, John
• Assistant Examiner(s): JELLETT, MATTHEW WILLIAM
• Application Number:
  US12/729,462
• Publication Number:
  US 20110000560A1
• Time in Patent Office: 1,267 Days
• Field of Search: 137/807, 137/826, 556/54, 436/53
• US Class Current: 137/487.5
• 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 35/2111 Flow rate
• CPC Class Codes: B01F 35/2202 Controlling the mixing process by feed-back, i.e. a measured parameter of the mixture is measured, compared with the set-value and the feed values are corrected
• CPC Class Codes: B01F 35/2211 Amount of delivered fluid during a period
• CPC Class Codes: B01L 2200/061 Counting droplets
• CPC Class Codes: B01L 2200/0673 Handling of plugs of fluid surrounded by immiscible fluid
• CPC Class Codes: B01L 2200/143 Quality control, feedback systems
• CPC Class Codes: B01L 2300/0877 Flow chambers
• CPC Class Codes: B01L 2400/0442 thermal energy, e.g. vaporisation, bubble jet
• CPC Class Codes: B01L 2400/0478 pistons
• 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 3/502715 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 3/502784 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: F16K 2099/0084 Chemistry or biology, e.g. "lab-on-a-chip" technology
• CPC Class Codes: F16K 99/0001 Microvalves microdevices B81B1/00; manufacture or treatment of devices or systems in or on a substrate B81C1/00; microfluidic structures B01L3/5027; micropumps F04B19/006
• CPC Class Codes: F17D 3/01 for controlling, signalling, or supervising the conveyance of a product
• CPC Class Codes: G01N 1/38 Diluting, dispersing or mixing samples
• CPC Class Codes: G01N 2021/0353 Conveyor of successive sample drops
• CPC Class Codes: G01N 2021/1725 Modulation of properties by light, e.g. photoreflectance
• CPC Class Codes: G01N 27/44791 : Microapparatus sample containers with integrated microfluidic structures B01L3/5027
• CPC Class Codes: Y10T 137/2185 : To vary frequency of pulses or oscillations
• CPC Class Codes: Y10T 137/2572 : One inflow supplements another
• CPC Class Codes: Y10T 137/7761 : Electrically actuated valve
• CPC Class Codes: Y10T 137/8158 : With indicator, register, recorder, alarm or inspection means
• CPC Class Codes: Y10T 137/8593 : Systems
• CPC Class Codes: Y10T 436/118339 : with formation of a segmented stream

Abstract

The invention provides methods for assessing one or more predetermined characteristics or properties of a microfluidic droplet within a microfluidic channel, and regulating one or more fluid flow rates within that channel to selectively alter the predetermined microdroplet characteristic or property using a feedback control.

Claims

1. A method for manipulating microfluidic droplet pairing ratios comprising:

providing a microfluidic system comprising at least one microfluidic channel;

providing a first plurality of fluidic droplets within said microfluidic channel at a first frequency;

providing a second plurality of fluidic droplets within said microfluidic channel at a second frequency, wherein at least one fluidic droplet from said first plurality and at least one fluidic droplet from said second plurality are paired;

assessing said first frequency and said second frequency using an image sensor; and

transmitting said assessment of said first and said second frequencies to a feedback controller;

wherein said feedback controller adjusts a flow rate of one or more fluids to provide a desired frequency ratio of said first to said second plurality of droplets, thereby manipulating the pairing ratios of said first and second pluralities of fluidic droplets within said microfluidic channel.

2. The method of claim 1, wherein the first plurality of fluidic droplets and the second plurality of fluidic droplets were provided at the same frequency and wherein said feedback controller adjusts a flow rate of one or more fluids to maintain said first and said second frequency at the same frequency.

3. The method of claim 1, wherein the first and second pluralities of fluidic droplets differ in size, color, refractive index, or extinction coefficient.

4. The method of claim 1, wherein the first and second pluralities of fluidic droplets contain a different biological, biochemical, or chemical entity.

5. The method of claim 1, wherein the desired frequency ratio of the first plurality of droplets to the second plurality of droplets is selected from the group consisting of 1:

1, 1;

2, 1;

3, 1;

4, 1;

5, 1;

6, 1;

7, 1;

8, 1;

9, and 1;

10.

6. The method of claim 5, wherein the desired frequency ratio of the first plurality of droplets to the second plurality of droplets is 1:

1.

7. The method of claim 1, wherein the image sensor is a linear array sensor.

8. The method of claim 1, wherein said first plurality of fluidic droplets have a maximum cross-sectional dimension of less than about 100 microns.

9. The method of claim 1, wherein said second plurality of fluidic droplets have a maximum cross-sectional dimension of less than about 100 microns.