# US 11,898,193 B2 · Manipulating droplet size

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- Number: US 11,898,193 B2
- Document ID: US11898193B2
- Status: Granted
- Kind: B2
- Application number: 16/565,773
- Filed: 2019-09-10
- Published: 2020-01-02
- Granted: 2024-02-13
- Earliest claimed: 2011-07-20
- Assignees: Bio-Rad Laboratories, Inc.
- Applicants: Bio-Rad Laboratories, Inc.
- Inventors: Benjamin J. Miller; Qun Zhong; Darren Roy Link
- Web page: https://patentgrep.com/patent/US11898193B2

## CPC

- C12Q 1/6806: Preparing nucleic acids for analysis, e.g. for polymerase chain reaction [PCR] assay (C12Q1/6804 takes precedence)
- B01F 23/41: Emulsifying
- B01F 33/3011: using a sheathing stream of a fluid surrounding a central stream of a different fluid, e.g. for reducing the cross-section of the central stream or to produce droplets from the central stream
- B01F 35/2213: {Pressure}
- B01L 3/502761: {specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads or physically stretching molecules}
- B01L 3/502784: {specially adapted for droplet or plug flow, e.g. digital microfluidics}
- B05B 1/02: designed to produce a jet, spray, or other discharge of particular shape or nature, e.g. in single drops, {or having an outlet of particular shape}(B05B1/26, B05B1/28, B05B1/34 take precedence)
- B05B 1/08: of pulsating nature, e.g. delivering liquid in successive separate quantities
- B05B 1/26: with means for mechanically breaking-up or deflecting the jet after discharge, e.g. with fixed deflectors; Breaking-up the discharged liquid or other fluent material by impinging jets
- B05B 7/0012: {Apparatus for achieving spraying before discharge from the apparatus}
- B01L 7/525: {with physical movement of samples between temperature zones}
- B01L 2200/025: Align devices or objects to ensure defined positions relative to each other
- B01L 2200/0647: Handling flowable solids, e.g. microscopic beads, cells, particles
- B01L 2200/141: Preventing contamination, tampering
- B01L 2200/143: Quality control, feedback systems
- B01L 2200/148: Specific details about calibrations
- B01L 2300/0867: Multiple inlets and one sample wells, e.g. mixing, dilution
- B01L 2300/14: Means for pressure control
- B01L 2400/0487: fluid pressure, pneumatics
- Y10T 436/2575: Volumetric liquid transfer
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- B01F: MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING (mixing paints B44D3/06)
- B01L: CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B05B: SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES (spray-mixers with nozzles B01F25/72; processes for applying liquids or other fluent materials to surfaces by spraying B05D)
- Y10T: TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION

## Abstract

The invention generally relates to methods and systems for manipulating droplet size. In certain aspects, the invention provides methods for manipulating droplet size that include forming droplets of aqueous fluid surrounded by an immiscible carrier fluid, and manipulating droplet size during the forming step by adjusting pressure exerted on the aqueous fluid or the carrier fluid.

## Claims

### Claim 1

A system for forming droplets, the system comprising:
a microfluidic substrate comprising a sample channel and a carrier fluid channel that connects to the sample channel at a junction;
a manifold in fluid communication with the microfluidic substrate, the manifold configured to deliver an aqueous fluid to the sample channel and an immiscible carrier fluid to the carrier channel to thereby form droplets of aqueous fluid surrounded by carrier fluid at the junction;
an imager configured to capture images of the droplets; and
a pump in fluid communication with the microfluidic substrate, the pump configured to regulate, based on the images of the droplets, pressure of the aqueous fluid at the junction to produce droplets of substantially uniform size.

### Claim 2 (depends on 1)

The system of claim 1, further comprising a plurality of microfluidic channels and a fluid interface comprising a plurality of interconnects, each aligned with and forming a seal with an inlet of one of the plurality of microfluidic channels.

### Claim 3 (depends on 2)

The system of claim 2, wherein the manifold is in fluid communication with the microfluidic substrate via the fluid interface.

### Claim 4 (depends on 1)

The system of claim 1, further comprising a control loop operable to measure volume of the droplets using real-time analysis of the images.

### Claim 5 (depends on 4)

The system of claim 4, wherein the system determines an estimated projected area for the droplets by the real-time analysis of the images.

### Claim 6 (depends on 1)

The system of claim 1, further comprising an outlet channel downstream of the junction.

### Claim 7 (depends on 1)

The system of claim 1, wherein the pump is coupled to an electronic pressure regulator.

### Claim 8 (depends on 1)

The system of claim 1, wherein the pump is a compressor comprising a reservoir of nitrogen, argon, or air.

### Claim 9 (depends on 1)

The system of claim 1, wherein the pump is an air cylinder with a linear actuator.

### Claim 10 (depends on 1)

The system of claim 1, wherein the pressure of the carrier fluid is regulated by automatic gain control.

### Claim 11 (depends on 1)

The system of claim 1, wherein the imager generates a projected droplet image and the system finds an outside projected area and an inside projected area from the projected droplet image to analyze droplet volume in real time.

### Claim 12 (depends on 1)

The system of claim 1, wherein the microfluidic substrate comprises a plurality of fluidic circuits, each comprising a sample channel.

### Claim 13 (depends on 1)

The system of claim 1, wherein each fluidic circuit is controlled by a separate pump.

### Claim 14 (depends on 13)

The system of claim 13, wherein the fluid interface is molded onto the microfluidic substrate.