Digital microfluidics cartridge and system for operating a flow cell

• US 9,863,913 B2
• Filed: 10/14/2013
• Issued: 01/09/2018
• Est. Priority Date: 10/15/2012
• Status: Active Grant

• Current Assignee: Advanced Liquid Logic, Inc. (Illumina Incorporated)
• Original Assignee: Advanced Liquid Logic, Inc. (Illumina Incorporated)
• Inventors: Pollack, Michael G.
• Primary Examiner(s): Ball, J. Christopher
• Application Number:
  US14/428,219
• Publication Number:
  US 20150212043A1
• Time in Patent Office: 1,548 Days
• CPC Class Codes: B01L 2300/0816 Cards, e.g. flat sample carriers usually with flow in two horizontal directions
• CPC Class Codes: B01L 2300/0867 Multiple inlets and one sample wells, e.g. mixing, dilution
• CPC Class Codes: B01L 2300/088 Channel loops
• CPC Class Codes: B01L 2300/0883 Serpentine channels
• CPC Class Codes: B01L 2300/1827 using resistive heater
• CPC Class Codes: B01L 2400/0427 Electrowetting
• CPC Class Codes: B01L 2400/043 magnetic forces
• CPC Class Codes: B01L 2400/0457 passive flow or gravitation
• 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 3/502792 for moving individual droplets on a plate, e.g. by locally altering surface tension
• CPC Class Codes: G01N 27/44743 Introducing samples
• CPC Class Codes: G01N 27/44791 Microapparatus sample containers with integrated microfluidic structures B01L3/5027

Abstract

A liquid handling system for supplying liquids to a flow cell (FC). The system may include a droplet actuator cartridge, wherein the droplet actuator and a flow cell are fluidly coupled to, or situated within, a droplet operations gap of the droplet actuator.

Claims

1. A digital microfluidic liquid handling system, comprising:

liquid reservoirs;

a droplet actuator, comprising;

a bottom substrate separated from a top substrate to form a droplet operations gap, wherein the droplet operations gap is filled with a filler fluid, and wherein the top substrate includes an opening;

reservoir electrodes disposed on the bottom substrate, wherein each reservoir electrode corresponds with a respective one of the liquid reservoirs;

outlet electrodes disposed on the bottom substrate and arranged proximal to the opening;

droplet operations electrodes defining a path between the reservoir electrodes and the outlet electrodes; and

a flow cell fluidly coupled to the droplet operations gap through the opening in the top substrate, said flow cell being external with respect to the droplet actuator;

wherein said liquid reservoirs being external reservoirs fluidly coupled to the droplet operations gap through a second opening in one of the bottom substrate or top substrate.

2. The system of claim 1 wherein each of the external reservoirs comprises a gravity-driven liquid dispenser.

3. The system of claim 1 wherein a portion of the droplet operations electrodes form a loop that is fluidly connected to each of the reservoir electrodes, and an other portion of the droplet operations electrodes form a snaking path that is fluidly connected to the outlet electrodes, and wherein the snaking path is to provide a cache for accumulating and storing droplets between their source and destination.

4. The system of claim 3 wherein a conductive layer is disposed on the top substrate.

5. The system of claim 4 wherein the conductive layer is disposed on a side of the top substrate that is facing the droplet operations gap.

6. The system of claim 4 wherein the conductive layer is configured as a ground reference plane with respect to the reservoir electrodes, the droplet operations electrodes, and the outlet electrodes.

7. The system of claim 1 wherein a height of the droplet operations gap varies.

8. The system of claim 7 wherein the height of the droplet operations gap at the reservoir electrodes is greater than the height of the droplet operations gap at the droplet operations electrodes.

9. The system of claim 1 wherein the opening is fluidly coupled to an inlet of the flow cell via a tube and further comprising a pump for providing negative pressure on an end of the tube at the flow cell and causing liquid to flow from the outlet electrodes through the opening and through the tube and then through the flow cell.

10. The system of claim 1 wherein one of the liquid reservoirs corresponds with one of the reservoir electrodes, and wherein the one of the reservoir electrodes feeds the outlet electrodes with a dedicated arrangement of the droplet operations electrodes, and wherein a remainder of the liquid reservoirs and their corresponding reservoir electrodes share a common pathway of the droplet operations electrodes that is separate from the dedicated arrangement of the droplet operations electrodes.

11. The system of claim 1 wherein the reservoir electrodes are arranged radially with respect to the outlet electrodes and wherein dedicated arrangements of the droplet operations electrodes connect each reservoir electrode with the outlet electrodes.

12. The system of claim 2 wherein the gravity-driven liquid dispenser comprises a vessel;

an outlet; and

an inlet at a defined height from the outlet.

13. The system of claim 12 wherein the inlet comprises a hydrophobic pore.

14. The system of claim 12 wherein the outlet is fluidly coupled to the droplet operations gap and aligned with the corresponding reservoir electrode.

15. The system of claim 1 wherein the flow cell is integrated into the droplet actuator and wherein the reservoir electrodes, the droplet operations electrodes, and the outlet electrodes have surfaces that comprise one or more hydrophilic spots.

16. A method of supplying liquids to a flow cell using a digital microfluidic liquid handling system, comprising:

dispensing one or more droplets from a liquid reservoir onto a reservoir electrode corresponding with the liquid reservoir;

transferring the one or more droplets from the reservoir electrode to outlet electrodes along a pathway defined by droplet operations electrodes;

transferring the one or more droplets from the outlet electrodes through an opening arranged proximal thereto and into a flow cell in a predetermined sequence;

monitoring an impedance at the outlet electrodes during flow of the one or more droplets;

detecting a change in the impedance in response to the transfer of the one or more droplets from the outlet electrodes; and

in response to the detecting, stopping a pump used to transfer the one or more droplets from the outlet electrodes until additional droplets are pooled at the outlet electrodes.

17. The method of claim 16 wherein the transferring of the one or more droplets along the pathway includes:

transferring the one or more droplets between a plurality of reservoir electrodes using droplet operations along a loop of the pathway; and

transferring the one or more droplets from the loop to the outlet electrodes using droplet operations along a snaking path of the pathway.

18. The method of claim 16 wherein the reservoir electrode is one of a plurality of reservoir electrodes arranged radially with respect to the outlet electrodes, and wherein each of the plurality of reservoir electrodes is connected to a dedicated arrangement of the droplet operations electrodes.

19. The method of claim 16 wherein the one or more droplets are transferred to the flow cell in a predetermined sequence for performing sequencing-by-synthesis reactions.

20. A digital microfluidic liquid handling system for supplying liquids to a flow cell, comprising:

a processor for executing code and a memory in communication with the processor, the system comprising code stored in the memory that causes the processor at least to;

dispense one or more droplets from a liquid reservoir onto a reservoir electrode corresponding with the liquid reservoir, the reservoir electrode being positioned in a droplet operations gap of a droplet actuator including a top substrate and a bottom substrate separated to form the droplet operations gap, wherein the top substrate includes an opening;

fill the droplet operations gap of the droplet actuator with a filler fluid;

transfer the one or more droplets from the reservoir electrode to outlet electrodes along a pathway defined by droplet operations electrodes;

transfer the one or more droplets from the outlet electrodes through the opening arranged proximal thereto and into a flow cell in a predetermined sequence;

monitor an impedance at the outlet electrodes during flow of the one or more droplets;

detect a change in the impedance in response to the transfer of the one or more droplets from the outlet electrodes; and

in response to the detection, stop a pump used to transfer the one or more droplets from the outlet electrodes until additional droplets are pooled at the outlet electrodes.