Manipulation of Microfluidic Droplets

• US 20110000560A1
• Filed: 03/23/2010
• Published: 01/06/2011
• 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: Larson, Jonathan, Weary, Mark, Yurkovetsky, Yevgeny, Wilson, Andrew, Miller, Benjamin, Link, Darren, Hutchison, Brian, Zhong, Qun
• Granted Patent: US 8,528,589 B2
• Time in Patent Office: Days
• US Class Current: 137/561.R
• 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 feedback control system for microfluidic droplet manipulation comprising:

providing a microfluidic system comprising at least one microfluidic channel containing at least one fluidic droplet;

detecting at least one predetermined characteristics of said fluidic droplet at one or more positions within said microfluidic channel;

assessing said predetermined characteristic using an image sensor; and

transmitting said assessment from said image sensor to a feedback controller, wherein said feedback controller adjusts a flow rate of one or more fluids, thereby manipulating said fluidic droplet within said microfluidic channel.

2. The system of claim 1, wherein said detecting at least one predetermined characteristics of said fluidic droplet at one or more positions within said microfluidic channel further comprises acquiring a plurality of images of said fluidic droplet at a plurality of time points within said microfluidic channel, wherein said plurality of images comprises an image set.

3. The system of claim 2, further comprising:

assessing said predetermined characteristic of said fluidic droplet in said microfluidic channel, within each image set, using an image sensor;

comparing said assessment of said predetermined characteristic of said fluidic droplet in each image set; and

determining an average assessment of said predetermined characteristic of said fluidic droplet;

wherein said feedback controller adjusts a flow rate of one or more fluids, thereby increasing the accuracy of the assessment.

4. The system of claim 1, wherein the predetermined characteristic is droplet volume, droplet generation rate, droplet arrival frequency, droplet release rate, or total droplet count.

5. The system of claim 1, wherein the one or more fluids is a carrier fluid or a drive fluid.

6. The system of claim 5, wherein said carrier fluid or a drive fluid is a fluorocarbon oil.

7. The system of claim 1, wherein said fluidic droplet has a maximum cross-sectional dimension of less than about 100 microns.

8. The system of claim 1, wherein said fluidic droplet contains a different biological, biochemical, or chemical entity within an aqueous fluid.

9. A feedback control system for manipulating microfluidic droplet pairing ratios comprising:

providing a microfluidic system comprising at least one microfluidic channel;

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

producing 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 frequency from the image sensor 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.

10. The system of claim 9, wherein the first plurality of fluidic droplets and the second plurality of fluidic droplets were introduced 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.

11. The system of claim 9, wherein the first and second pluralities of fluidic droplets differ in size, color, refractive index, or extinction coefficient.

12. The system of claim 9, wherein the first and second pluralities of fluidic droplets contain a different biological, biochemical, or chemical entity.

13. The system of claim 9, 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.

14. The system of claim 13, wherein the desired frequency ratio of the first plurality of droplets to the second plurality of droplets is 1:

1.

15. A feedback control system for controlling microfluidic droplet count comprising:

providing a microfluidic system comprising at least one microfluidic channel;

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

assessing said first frequency using an image sensor;

determining the time required to produce a predetermined amount of fluidic droplets based upon said frequency assessment; and

transmitting said assessment to a feedback controller, wherein said feedback controller stops said introduction of said droplets after said determined time, thereby controlling the microfluidic droplet count.

16. A feedback control system for independently controlling microfluidic droplet volume and frequency comprising:

(a) providing a microfluidic system comprising at least one microfluidic channel;

(b) producing a plurality of fluidic droplets within a carrier fluid within said microfluidic channel using a drive fluid;

(b) assessing the frequency, volume, and flow rate of said plurality of droplets using an image sensor;

(c) transmitting said assessed frequencies, volumes, and flow rates of the plurality of droplets from said image sensor to a feedback controller;

(d) adjusting a flow rate of the carrier fluid using said feedback controller to attain a predetermined droplet frequency set point; and

(e) adjusting a flow rate of the drive fluid using said feedback controller to attain a predetermined droplet volume set point;

wherein said feedback control system independently determines and controls microfluidic droplet frequency and volume.

17. The system of claim 16, wherein said plurality of droplets are formed within the carrier fluid within said microfluidic channel.

18. The system of claim 16, wherein said plurality of droplets are pre-formed and are introduced to said microfluidic channel.

19. The system of claim 16, wherein said droplets within said plurality have a maximum cross-sectional dimension of less than about 100 microns.

20. The system of claim 16, wherein said droplets within said plurality contain a different biological, biochemical, or chemical entity within an aqueous fluid.