Feedback control in microfluidic systems

• US 9,116,124 B2
• Filed: 10/02/2013
• Issued: 08/25/2015
• Est. Priority Date: 04/16/2010
• Status: Active Grant

• Current Assignee: Opko Diagnostics, LLC (Opko Health, Inc.)
• Original Assignee: Opko Diagnostics, LLC (Opko Health, Inc.)
• Inventors: Linder, Vincent, Steinmiller, David
• Primary Examiner(s): Xu, Robert
• Application Number:
  US14/044,247
• Publication Number:
  US 20140038166A1
• Time in Patent Office: 692 Days
• US Class Current: 1/1
• CPC Class Codes: B01L 2200/025 Align devices or objects to ensure defined positions relative to each other
• CPC Class Codes: B01L 2200/026 Fluid interfacing between devices or objects, e.g. connectors, inlet details
• CPC Class Codes: B01L 2200/027 for microfluidic devices
• CPC Class Codes: B01L 2200/028 Modular arrangements
• CPC Class Codes: B01L 2200/0673 Handling of plugs of fluid surrounded by immiscible fluid
• CPC Class Codes: B01L 2200/0684 Venting, avoiding backpressure, avoid gas bubbles
• CPC Class Codes: B01L 2200/143 Quality control, feedback systems
• CPC Class Codes: B01L 2200/146 Employing pressure sensors
• CPC Class Codes: B01L 2200/147 Employing temperature sensors
• CPC Class Codes: B01L 2300/021 Identification, e.g. bar codes
• CPC Class Codes: B01L 2300/023 Sending and receiving of information, e.g. using bluetooth
• CPC Class Codes: B01L 2300/027 Digital display, e.g. LCD, LED
• CPC Class Codes: B01L 2300/04 Closures and closing means
• CPC Class Codes: B01L 2300/0654 Lenses; Optical fibres
• 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 2300/12 Specific details about materials
• CPC Class Codes: B01L 2300/14 Means for pressure control
• CPC Class Codes: B01L 2300/16 Surface properties and coatings
• CPC Class Codes: B01L 2300/168 Specific optical properties, e.g. reflective coatings
• CPC Class Codes: B01L 2300/1827 : using resistive heater
• CPC Class Codes: B01L 2300/1894 : Cooling means; Cryo cooling
• CPC Class Codes: B01L 2400/0475 : specific mechanical means and fluid pressure
• CPC Class Codes: B01L 2400/049 : vacuum
• CPC Class Codes: B01L 2400/0666 : Solenoid valves
• CPC Class Codes: B01L 2400/082 : Active control of flow resistance, e.g. flow controllers
• CPC Class Codes: B01L 3/5027 : by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip B01L3/5023 takes precedence; micromixers B01F33/30; microreactors for synthesis B01J19/0093; microcapillary devices in general B81B1/00
• 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 3/502738 : characterised by integrated valves microvalves F16K99/0001
• CPC Class Codes: B01L 3/502746 : characterised by the means for controlling flow resistance, e.g. flow controllers, baffles B01L3/502738 takes precedence
• 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 21/05 : Flow-through cuvettes G01N21/09 takes precedence; handling fluid samples G01N1/10
• CPC Class Codes: G01N 21/59 : Transmissivity G01N21/25 takes precedence
• CPC Class Codes: G01N 21/64 : Fluorescence; Phosphorescence
• CPC Class Codes: G01N 21/76 : Chemiluminescence; Bioluminescence
• CPC Class Codes: G01N 2201/02 : Mechanical
• CPC Class Codes: G01N 2201/0612 : Laser diodes
• CPC Class Codes: G01N 2201/062 : LED's
• CPC Class Codes: G01N 2201/0621 : Supply
• CPC Class Codes: G01N 2201/0697 : Pulsed lasers
• CPC Class Codes: G01N 2333/96433 : Serine endopeptidases (3.4.21)
• CPC Class Codes: G01N 33/54313 : the carrier being characterised by its particulate form
• CPC Class Codes: G01N 33/54366 : Apparatus specially adapted for solid-phase testing
• CPC Class Codes: G01N 33/57434 : of prostate
• CPC Class Codes: Y10T 137/0324 : With control of flow by a condition or characteristic of a fluid
• CPC Class Codes: Y10T 436/12 : Condition responsive control

Abstract

Systems and methods for controlling fluids in microfluidic systems are generally described. In some embodiments, control of fluids involves the use of feedback from one or more processes or events taking place in the microfluidic system. For instance, a detector may detect one or more fluids at a measurement zone of a microfluidic system and one or more signals, or a pattern of signals, may be generated corresponding to the fluid(s). In some cases, the signal or pattern of signals may correspond to an intensity, a duration, a position in time relative to a second position in time or relative to another process, and/or an average time period between events. Using this data, a control system may determine whether to modulate subsequent fluid flow in the microfluidic system. In some embodiments, these and other methods can be used to conduct quality control to determine abnormalities in operation of the microfluidic system.

Claims

1. A method, comprising:

passing a sample across a first measurement zone of a microfluidic system;

passing at least a first wash fluid and a second wash fluid across the first measurement zone;

measuring light transmittance or light absorbance through at least the sample, first wash fluid, and second wash fluid at the first measurement zone;

forming signals corresponding to the passing of at least the sample, first wash fluid, and second wash fluid across the first measurement zone,

wherein an intensity of each signal is indicative of the fluid passing across the first measurement zone, and wherein a duration of each signal is indicative of a volume and/or flow rate of the fluid passing across the first measurement zone; and

determining whether to modulate fluid flow in the microfluidic system and/or alerting a user of an abnormality in an analysis being conducted in the microfluidic system based at least in part on information derived from the intensity and/or duration of one or more signals.

2. A method as in claim 1, comprising continuously or periodically detecting the passing of any fluids across the first measurement zone.

3. A method as in claim 1, comprising determining whether to modulate fluid flow in the microfluidic system.

4. A method as in claim 3, wherein determining whether to modulate fluid flow in the microfluidic system comprises determining whether to stop an analysis being conducted in the microfluidic system.

5. A method as in claim 3, further comprising transmitting an electrical signal from the control system to a component of the microfluidic system that can modulate fluid flow as a result of the transmitting step.

6. A method as in claim 5, wherein the component of the microfluidic system is a pump or a vacuum.

7. A method as in claim 5, wherein the component of the microfluidic system is a valve.

8. A method as in claim 1, comprising alerting a user of an abnormality in an analysis being conducted in the microfluidic system.

9. A method as in claim 8, comprising providing the user with information about the analysis based on detection of an abnormality during the analysis.

10. A method as in claim 9, wherein providing the user with information comprises alerting the user via a user interface.

11. A method as in claim 9, wherein the information provided to the user comprises information that results of the analysis should not be relied upon, that the analysis needs to be performed again, that the analysis may take longer to perform, or that the user should take some action.

12. A method as in claim 9, wherein the information provided to the user comprises information that the analysis is cancelled and/or the results should be disregarded.

13. A method as in claim 9, comprising seeking further input from the user after providing the user with the information.

14. A method as in claim 1, wherein the sample comprises whole blood.

15. A method as in claim 1, wherein the sample is serum or plasma.

16. A method as in claim 1, comprising measuring light transmittance or light absorbance as a function of time.

17. A method as in claim 1, comprising applying a substantially constant vacuum at an outlet in fluid communication with the first measurement zone during flow of at least the first and second wash fluids across the first measurement zone.

18. A method as in claim 1, comprising continuously or periodically detecting the passing of fluids across a second measurement zone of the microfluidic system, wherein the first and second measurement zones are positioned in series with respect to one another.

19. A method as in claim 18, wherein detecting the passing of fluids across the second measurement zone comprises measuring light transmittance or light absorbance.

20. A method as in claim 1, further comprising passing at least a third wash fluid and a fourth wash fluid across the first measurement zone.

21. A method as in claim 1, wherein the first wash fluid and the second wash fluid are liquids, the method further comprising passing a gaseous plug across the first measurement zone after the passing of the second wash fluid.

22. A method as in claim 21, comprising determining whether to modulate fluid flow in the microfluidic system and/or alerting a user of an abnormality in an analysis being conducted in the microfluidic system based at least in part on information derived from the intensity and/or duration of a signal obtained from the passing of the gaseous plug across the first measurement zone.

23. A method as in claim 1, comprising determining whether to modulate fluid flow in the microfluidic system and/or alerting a user of an abnormality in an analysis being conducted in the microfluidic system based at least in part on information derived from the intensity and/or duration of signals obtained from the passing of the first wash fluid and the second wash fluid across the first measurement zone.

24. A method as in claim 23, wherein the first wash fluid is a liquid and the second wash fluid is a gas.

25. A method as in claim 23, wherein the first and second wash fluids are liquids.

26. A method as in claim 1, comprising determining whether to modulate fluid flow in the microfluidic system and/or alerting a user of an abnormality in an analysis being conducted in the microfluidic system based at least in part on the number of wash fluids that pass across the first measurement zone.

27. A method as in claim 1, comprising forming signals corresponding to the passing of each fluid passing across the first measurement zone.

28. A method as in claim 1, wherein the intensity of each signal is indicative of the concentration of a component in a fluid and/or the amount of a component in a fluid passing across the first measurement zone.

29. A method as in claim 1, wherein the intensity of each signal is indicative of the type of fluid passing across the first measurement zone.

30. A method as in claim 1, wherein intensity is determined by an opacity of a fluid or a component of the fluid.

31. A method as in claim 1, comparing an intensity of a signal with a threshold intensity programmed into a control system.

32. A method as in claim 1, comprising depositing a sample component from the sample at the first measurement zone.

33. A method as in claim 32, comprising determining opacity of the sample component or a material associated with the sample component at the first measurement zone as a function of time.

34. A method as in claim 1, comprising determining whether to modulate fluid flow in the microfluidic system and/or alerting a user of an abnormality in an analysis being conducted in the microfluidic system based at least in part on information derived from the intensity and/or duration of a signal obtained from the passing of the sample across the first measurement zone.