Methods and systems for control of microfluidic devices

• US 7,987,022 B2
• Filed: 10/13/2005
• Issued: 07/26/2011
• Est. Priority Date: 03/28/2001
• Status: Active Grant

• Current Assignee: HandyLab Incorporated (Becton, Dickinson & Co)
• Original Assignee: HandyLab Incorporated (Becton, Dickinson & Co)
• Inventors: Handique, Kalyan, Ganesan, Karthik, Brahmasandra, Sundaresh N.
• Primary Examiner(s): Warden; Jill
• Assistant Examiner(s): CHAN, CEDRIC A
• Application Number:
  US11/251,188
• Publication Number:
  US 20060036348A1
• Time in Patent Office: 2,112 Days
• Field of Search: 422/68.1, 422/99, 422/100, 422/102, 422/104, 422/129, 422/502, 422/504, 436/174, 436/176, 436/180, 436807-809, 702/19, 702/22, 702/57, 702/80, 702/100, 700/266, 204450-452, 204/600, 204/603
• US Class Current: 700/266
• 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 33/3033 using heat to mix or move the fluids
• CPC Class Codes: B01J 19/0093 Microreactors, e.g. miniaturised or microfabricated reactors laboratory containers with capillary fluid transport in microfabricated channels or chambers B01L3/5027
• CPC Class Codes: B01J 2219/00783 Laminate assemblies, i.e. the reactor comprising a stack of plates
• CPC Class Codes: B01J 2219/00828 Silicon wafers or plates
• CPC Class Codes: B01J 2219/00831 Glass
• CPC Class Codes: B01J 2219/00833 Plastic
• CPC Class Codes: B01J 2219/00835 Comprising catalytically active material
• CPC Class Codes: B01J 2219/00837 comprising coatings other than catalytically active coatings
• CPC Class Codes: B01J 2219/0086 Dimensions of the flow channels
• CPC Class Codes: B01J 2219/00862 Dimensions of the reaction cavity itself
• CPC Class Codes: B01J 2219/00873 Heat exchange
• CPC Class Codes: B01J 2219/00889 Mixing micromixers B01F33/30
• CPC Class Codes: B01J 2219/00891 Feeding or evacuation
• CPC Class Codes: B01J 2219/00936 UV-radiations
• CPC Class Codes: B01J 2219/00943 Visible light, e.g. sunlight
• CPC Class Codes: B01J 2219/00945 Infrared light
• CPC Class Codes: B01J 2219/00961 Temperature
• CPC Class Codes: B01J 2219/0097 Optical sensors
• CPC Class Codes: B01J 2219/00986 Microprocessor
• CPC Class Codes: B01L 2200/0605 : Metering of fluids
• CPC Class Codes: B01L 2200/0673 : Handling of plugs of fluid surrounded by immiscible fluid
• CPC Class Codes: B01L 2200/14 : Process control and prevention of errors
• CPC Class Codes: B01L 2300/0816 : Cards, e.g. flat sample carriers usually with flow in two horizontal directions
• CPC Class Codes: B01L 2400/0442 : thermal energy, e.g. vaporisation, bubble jet
• CPC Class Codes: B01L 2400/0493 : Specific techniques used
• CPC Class Codes: B01L 2400/0677 : phase change valves; Meltable, freezing, dissolvable plugs; Destructible barriers
• 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: B01L 3/502792 : for moving individual droplets on a plate, e.g. by locally altering surface tension
• CPC Class Codes: B01L 7/52 : with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples amplification or hybridisation processes per se C12Q1/68; controlling sequential reactions for synthesis B01J19/0046
• CPC Class Codes: G01N 1/4077 : by other techniques involving separation of suspended solids
• CPC Class Codes: G01N 35/1083 : with one horizontal degree of freedom
• CPC Class Codes: Y10T 436/12 : Condition responsive control
• CPC Class Codes: Y10T 436/25 : including sample preparation
• CPC Class Codes: Y10T 436/2575 : Volumetric liquid transfer

Abstract

The present invention provides control methods, control systems, and control software for microfluidic devices that operate by moving discrete micro-droplets through a sequence of determined configurations. Such microfluidic devices are preferably constructed in a hierarchical and modular fashion which is reflected in the preferred structure of the provided methods and systems. In particular, the methods are structured into low-level device component control functions, middle-level actuator control functions, and high-level micro-droplet control functions. Advantageously, a microfluidic device may thereby be instructed to perform an intended reaction or analysis by invoking micro-droplet control function that perform intuitive tasks like measuring, mixing, heating, and so forth. The systems are preferably programmable and capable of accommodating microfluidic devices controlled by low voltages and constructed in standardized configurations. Advantageously, a single control system can thereby control numerous different reactions in numerous different microfluidic devices simply by loading different easily understood micro-droplet programs.

Claims

1. A data acquisition system for controlling the operation of a digital-type micro fluidic device (i) wherein the microfluidic device (i) comprises one or more passages for confining one or more micro-droplets, the passages having one or more stable positions for the micro-droplets, and (ii) comprises one or more internal components responsive to control signals, the internal components operatively associated with the passages for control and monitoring the microfluidic device, the system comprising:

(a) programmable digital control circuitry interfaced to the microfluidic device, wherein the digital control circuitry provides control signals to the microfluidic device, and

(b) memory accessible to the programmable digital control circuitry comprising stored instructions and data representing one or more micro-droplet processing requests, wherein a micro-droplet processing request specifies performing at least one action on at least one micro-droplet, each micro-droplet processing request comprising two or more actuator processing requests, each specifying performing at least one action associated with at least one passage of the micro fluidic device, wherein the micro-droplet processing requests comprise at least one of;

(i) creating one or more new micro-droplets at selected stable positions,

(ii) moving one or more micro-droplets from current stable positions to selected next stable positions,

(iii) combining two or more micro-droplets into one or more new micro-droplets at selected stable positions, and

(iv) mixing one or more micro-droplets; and

wherein the actuator processing requests comprise;

(1) providing a gas pressure in a selected passage by causing an internal component configured to heat a gas to generate a gas pressure;

(2) determining, utilizing at least one internal component, the presence or absence of a micro-droplet at a selected position; and

(3 after determining the presence or absence of the micro-droplet, determining reaction products of one or more components of the microdroplet, if the micro-droplet was determined to be present;

wherein execution of the instructions and data causes the programmable digital control circuitry to generate control signals in a pattern and sequence that is responsive to each micro-droplet processing request so that the internal components of the microfluidic device function together to perform the micro-droplet processing requests in the microfluidic device; and

the memory further comprising stored instructions to add a value indicative of microdroplet presence to the memory when the presence of a microdroplet is determined and to add a value indicative of microdroplet absence to the memory when the absence of a microdroplet is determined.

2. The system of claim 1 further comprising at least one receptacle for receiving the microfluidic device, wherein the receptacle provides for transfer of the control signals between the programmable digital control circuitry and the microfluidic device.

3. The system of claim 1 wherein the programmable digital control circuitry further comprises an interface to a host computer system, wherein the host computer system is accessible to a user for monitoring and controlling the operation of the system.

4. The system of claim 1 wherein the programmable digital control circuitry further comprises:

(a) a processor, and

(b) peripheral circuitry controllable by the processor for generating the control signals.

5. The system of claim 4 wherein the peripheral circuitry further comprises:

(a) driver circuitry for providing electrical control signals to the microfluidic device, and

(b) sensor circuitry for receiving electrical control signals from the microfluidic device.

6. The system of claim 4 wherein the peripheral circuitry further comprises:

(a) driver circuitry for providing optical control signals to the microfluidic device, and

(b) sensor circuitry for receiving optical control signals from the microfluidic device.

7. The system of claim 1 wherein the instructions and data stored in the memory further comprise:

(a) request data representing one or more micro-droplet processing requests, and

(b) request-processing instructions, wherein execution of the request-processing instruction causes the programmable digital control circuitry to generate control signals for performing the represented micro-droplet processing requests in the microfluidic device.

8. The system of claim 7 wherein the instructions and data stored in the memory further comprise:

(a) micro-droplet configuration data representing identification of the micro-droplets present in the MF device and their respective positions,

(b) device configuration data representing the state of internal components of the microfluidic device, and

(c) configuration-update instructions that cause update of the configuration data upon completion of a processing request.

9. The system of claim 8 wherein the request-processing instructions further comprise instructions to verify that a micro-droplet processing request is consistent with the micro-droplet configuration data representing identification of that micro-droplet.

10. The system of claim 7 wherein the instructions and data stored in the memory further comprise MF micro fluidic device structure data that represents the internal components of the micro fluidic device and their mutual arrangement.

11. A data acquisition system for performing a chemical reaction in a digital-type micro fluidic device, wherein the micro fluidic device (i) comprises one or more passages for confining one or more micro-droplets, the passages having one or more stable positions for the micro-droplets, (ii) comprises one or more internal components responsive to control signals, the internal components operatively associated with the passages for control and monitoring the micro fluidic device, and (iii) is configured to receive one or more fluid reagents, wherein the fluid reagents comprise reactants necessary for the reaction, the system comprising:

(a) programmable digital control circuitry interfaced to the micro fluidic device, wherein the digital control circuitry provides control signals to the micro fluidic device, and

(b) memory accessible to the programmable digital control circuitry comprising stored instructions and data representing one or more micro-droplet processing requests, wherein a micro-droplet processing request specifies performing at least one action on at least one micro-droplet, each micro-droplet processing request comprising two or more actuator processing requests, each specifying performing at least one action associated with at least one passage of the micro fluidic device, wherein one of the actuator processing requests comprises determining the presence or absence of the micro-droplet, wherein the micro-droplet processing requests comprise at least one of;

(i) creating at least one final micro-droplet from the fluid reagents by providing control signals to the micro fluidic device, wherein the micro-droplets is positioned at a stable position and comprises the reactants necessary for the reaction,

(ii) determining, utilizing at least one internal component, a presence or absence of the at least one final micro-droplet,

(iii) moving the at least one final micro-droplet by heating a gas to generate a gas pressure within the micro fluidic device, and

(iv) after the steps of determining, utilizing the at least one internal components, the presence or absence of the at least one final micro-droplet and moving the at least one final micro-droplet, causing the reaction to occur in the at least one final micro-droplet; and

the memory further comprising stored instructions to add a value indicative of microdroplet presence to the memory when the presence of a microdroplet is determined and to add a value indicative of microdroplet absence to the memory when the absence of a microdroplet is determined.

12. The system of claim 11, wherein the micro-droplet processing request for causing the reaction to occur in the at least one final micro-droplet further comprises waiting for a time sufficient for occurrence of the reaction.

13. The system of claim 11, wherein the micro-droplet processing request for causing the reaction to occur in the at least one final micro-droplet further comprises exciting the final micro-droplet by providing control signals to the micro fluidic device, wherein the excitation is sufficient to cause occurrence of the reaction.

14. The system of claim 13 wherein the micro-droplet processing request for exciting the final micro-droplet further comprises thermally heating or optically irradiating the microdroplet.

15. The system of claim 11 wherein the micro-droplet processing requests further comprise sensing the composition of the reacted micro-droplet by providing control signals to the micro fluidic device.

16. The system of claim 11 wherein the chemical reaction comprises performing analysis of a sample.

17. The system of claim 11 wherein the micro-droplet processing request for creating at least one final micro-droplet further comprises:

(a) providing a micro-droplet processing request, wherein a micro-droplet processing request specifies performing at least one action on at least one micro-droplet, the request comprising one of;

(i) creating one or more new micro-droplets at selected stable positions;

(ii) moving one or more micro-droplets from current stable positions to selected next stable positions;

(iii) combining two or more micro-droplets into one or more new micro-droplets at selected stable positions;

or

(iv) mixing one or more micro-droplets, and

(b) generating control signals for each micro-droplet processing request, which are provided to the micro fluidic device, wherein the control signals are generated in a pattern and sequence that is responsive to each micro-droplet processing request so that the internal components of the micro fluidic device that are responsive to the control signals function together to perform the requested micro-droplet processing in the micro fluidic device.

18. The system of claim 17 further comprising:

(a) before the step of providing a micro-droplet processing request, providing a micro-droplet processing program, wherein a micro-droplet processing program comprises one or more micro-droplet processing requests, and wherein the step of providing a micro-droplet processing request further comprises selecting an indicated request from the provided program, and

(b) repeating the steps of providing a request and generating signals with each micro-droplet processing request until the provided program indicates that no further requests are available for selection.

19. The system of claim 17 wherein each provided micro-droplet processing request further comprises one or more actuator processing requests, wherein an actuator processing request specifies performing at least one action physically associated with at least one passage of the micro fluidic device, wherein the generated pattern and sequence of control signals that is responsive to a micro-droplet processing request further comprises sub-patterns and subsequences that are responsive to each actuator processing request of the micro-droplet processing request, and wherein the sub-pattern and sub-sequence of control signals that is responsive to each actuator processing request cause the responsive internal components of the micro fluidic device to function together to perform the requested action.

20. The system of claim 19 wherein the actuator processing requests comprise:

(a) opening or closing a selected controlled passage using one or more internal components acting as a controllable valve,

(b) providing controllable gas pressure in a selected passage using one or more internal components acting as pressure generator,

(c) sensing the presence or absence of a micro-droplet at a selected position in a selected passage using one or more internal components acting as a micro-droplet presence sensor, or

(d) sensing the composition of a micro-droplet at a selected position in a selected passage using one or more internal components acting as a micro-droplet presence sensor.

21. A control system for a micro fluidic processor, the control system comprising:

a programmable microprocessor;

memory; and

peripheral interface circuitry in communication with the micro fluidic processor,

wherein;

the micro fluidic processor comprises one or more positions in one or more passages at which a microdroplet of fluid may stably reside;

the microprocessor is programmed to cause the peripheral interface circuitry to generate control signals controlling one or more internal components operatively associated with the passages for control and monitoring of the microdroplet in the passage corresponding to one or more micro-droplet control operations selected from the group consisting of;

(i) creating a new micro-droplet from a fluid sample;

(ii) moving a micro-droplet from a first stable position to a second stable position;

(iii) mixing one or more micro-droplets, at a stable position; and

(iv) performing a reaction in a micro-droplet at a stable position;

wherein the control signals comprise two or more actuator processing requests, wherein one of the actuator processing requests comprises determining the presence or absence of the micro-droplet;

wherein the memory comprises instructions to add a value indicative of microdroplet presence to the memory when the presence of a microdroplet is determined and to add a value indicative of microdroplet absence when the absence of a microdroplet is determined; and

the peripheral interface circuitry is adapted to communicate the control signals to the micro fluidic processor, and to receive one or more sense signals from the micro fluidic processor in response to completion of the one or more micro-droplet control operations.