MOTION MODULATION FLUIDIC ANALYZER SYSTEM

• US 20150276589A1
• Filed: 04/22/2015
• Published: 10/01/2015
• Est. Priority Date: 03/31/2014
• Status: Active Grant

• Current Assignee: RedShift BioAnalytics, Inc.
• Original Assignee: Redshift Systems Corporation
• Inventors: Wagner, Matthias, Kuehl, Donald, Marshall, Charles McAlister, Guasto, Jeffrey
• Granted Patent: US 9,377,400 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: G01N 15/0205 by optical means
• CPC Class Codes: G01N 15/1404 Handling flow, e.g. hydrodynamic focusing
• CPC Class Codes: G01N 15/1436 the optical arrangement forming an integrated apparatus with the sample container, e.g. a flow cell
• CPC Class Codes: G01N 15/1484 microstructural devices
• CPC Class Codes: G01N 2021/399 Diode laser
• CPC Class Codes: G01N 21/0332 with temperature control control of temperature G05D23/00; cryostats F17C3/08
• CPC Class Codes: G01N 21/05 Flow-through cuvettes G01N21/09 takes precedence; handling fluid samples G01N1/10
• CPC Class Codes: G01N 21/3577 for analysing liquids, e.g. polluted water
• CPC Class Codes: G01N 21/39 using tunable lasers
• CPC Class Codes: G01N 21/532 with measurement of scattering and transmission
• CPC Class Codes: G01N 21/85 Investigating moving fluids or granular solids
• CPC Class Codes: G01N 2201/0612 Laser diodes
• CPC Class Codes: G01N 2201/10 Scanning

Abstract

A fluid analyzer includes an optical source and an optical detector defining an optical beam path through an interrogation region of a fluid flow cell. Motion control devices determine position of the interrogation region. Flow-control devices conduct analyte and reference fluids and manipulate fluid flow in response to control signals to position a fluid boundary across the interrogation region. A controller (1) generates a time-varying motion modulation signal to move the interrogation region across the fluid boundary, (2) samples an output signal from the optical detector at one time in which the interrogation region contains more analyte fluid than reference fluid and at a time at which the interrogation region contains more reference fluid than analyte fluid, thereby generating corresponding output signal samples, and (3) determines from the output signal samples a measurement value indicative of an optically measured characteristic of the analyte fluid.

Claims

1. A fluid analyzer, comprising:

an optical source and an optical detector defining a beam path of an optical beam;

a fluid flow cell disposed on the beam path defining an interrogation region in a fluid channel in the fluid flow cell in which the optical beam interacts with a fluid;

one or more flow-control devices configured to conduct an analyte fluid and a reference fluid stream through the fluid channel, a fluid boundary region component separating the analyte and reference fluids when flowing together through the fluid channel;

a motion control device operative in response to a motion modulation signal to position the interrogation region within the fluid channel; and

a controller operative (1) to generate the motion modulation signal having a time-varying characteristic to cause the interrogation region to be moved across the fluid boundary accordingly, (2) to sample an output signal from the optical detector at one interval of the motion modulation signal during which the interrogation region contains more analyte fluid than reference fluid and at a second interval during which the interrogation region contains more reference fluid than analyte fluid, thereby generating corresponding output signal samples, and (3) to determine from the output signal samples a measurement value indicative of an optically measured characteristic of the analyte fluid.

2. The fluid analyzer of claim 1, wherein the flow-control devices are configured to vary a relative pressure between the analyte and reference fluids to vary a position of the fluid boundary in a direction orthogonal to the flow direction in the fluid channel.

3. The fluid analyzer of claim 1, wherein the propagation direction of the optical beam and the direction of fluid flow are substantially parallel.

4. The fluid analyzer of claim 1, wherein the fluid channel supports multiple optical transmission pathlengths for the optical beam, and the controller is operative to select a pathlength as a function of the signal level on the detector or the optical absorption of the analyte or reference fluid.

5. The fluid analyzer of claim 1, further including a transducer for detecting the fluid boundary region and generating a fluid boundary motion signal for determining the timing of the sampling of the output signals relative to the motion modulation signal.

6. The fluid analyzer of claim 1, wherein the fluid flow cell is temperature controlled, a fluid flow cell temperature determines temperatures of the analyte fluid and reference fluid in the interrogation region, and the measurement value is determined as a function of the respective temperatures of the analyte fluid and reference fluid.

7. The fluid analyzer of claim 1, wherein the analyte fluid or reference fluid contain an analyte with a known value of an optically measured characteristic, and (1) a second measurement value of an analyte or reference fluid optical characteristic and (2) the known value for of an optically measured characteristic are used in determining the optically measured characteristic of the analyte fluid.

8. The fluid analyzer of claim 1, wherein a series of the measurement values are combined to improve measurement sensitivity, and a likely presence of a particle in the fluid is detected, and samples of the output signal likely to have values perturbed by the particle are excluded from the series of measurement values.

9. The fluid analyzer of claim 1, wherein the fluid flow cell includes an optical window that transmits the optical beam, and the analyte fluid includes a contaminant that adheres to the optical window thereby reducing a power of the optical beam in the interrogation region from a power that would occur without adherence of the contaminant, and wherein a ratio of respective samples of the output signal for the fluid and the reference fluid is substantially independent of a change in the quantity of window adhering contaminant.

10. The fluid analyzer of claim 1, wherein the controller is operative to (1) sample a boundary output signal from the detector during an interval in which the interrogation region is in the fluid boundary region, and (2) to determine from the boundary output signal a measurement value indicative of an optically measured characteristic of an interaction of the analyte fluid and reference fluid.

11. The fluid analyzer of claim 10, wherein the optically measured characteristic of the interaction is a diffusion coefficient.

12. The fluid analyzer of claim 1, wherein the analyte fluid and the reference fluid are chosen to have substantially the same value for the optically measured characteristic and an operating condition of the fluid analyzer is adjusted in a feedback loop over more than one motion modulation signal period to set the measurement value at a desired level for subsequent operation of the fluid analyzer.

13. The fluid analyzer of claim 1, wherein the fluid boundary is substantially orthogonal to a flow direction of the fluids in the fluid channel.

14. The fluid analyzer of claim 1, wherein the fluid boundary is substantially parallel to a flow direction of the fluids in the fluid channel.

15. The fluid analyzer of claim 14, wherein the controller is further operative (1) to generate a motion signal to the fluidic control devices to cause the fluid boundary to be moved in the channel.

16. The fluid analyzer of claim 14, wherein the controller is further operative (1) to generate a fluidic motion signal to the fluidic control devices having a time-varying characteristic to cause the fluid boundary to be moved in the channel, the motion modulation signal and the fluidic motion signal being synchronous to each other.

17. The fluid analyzer of claim 16, wherein the fluidic motion signal and motion modulation signal are the same frequency and out of phase with respect to each other.

18. The fluid analyzer of claim 1, wherein the flow control device is operative to move the fluid boundary with respect to the channel, and the motion modulation signal includes a component that results in a translation of the interrogation region correlated to the motion of the fluid boundary.

19. The fluid analyzer of claim 1, wherein the fluid cell comprises two optically transmissive windows defining two surfaces of the fluid channel, each window having a first surface in contact with the analyte or reference fluid and a second surface, the angle of incidence of the optical beam on the first and second surfaces substantially at the Brewster angle to reduce optical reflections relative to a non-Brewster angle of incidence, and the optical beam substantially maintaining the Brewster angles at the first and second intervals.

20. The fluid analyzer of claim 1, wherein the optically measured characteristic is an optically measured characteristic of an interaction of the analyte fluid and the microfluidic cell.

21. The fluid analyzer of claim 1, wherein the optically measured characteristic is an optically measured characteristic of an interaction of the analyte fluid and the reference fluid.

22. The fluid analyzer of claim 1, wherein the optically measured characteristic is an optically measured characteristic of an interaction of the analyte fluid and the optical beam

23. The fluid analyzer of claim 1, wherein a known optical characteristic of the reference fluid is used to calculate a correction to the measurement value to account for displacement of a fluid within the analyte fluid by an analyte in the analyte fluid.

24. A fluid analyzer, comprising:

an optical source and an optical detector defining a beam path of an optical beam;

a fluid flow cell disposed on the beam path defining an interrogation region in a fluid channel in the fluid flow cell in which the optical beam interacts with a fluid;

one or more flow-control devices configured to conduct an analyte fluid and a reference fluid stream through the fluid channel, a fluid boundary region separating the analyte and reference fluids when flowing together through the fluid channel;

a controller operative (1) to generate a motion modulation signal having a time-varying characteristic to cause the interrogation region to be moved relative to the fluid boundary accordingly, (2) to sample an output signal from the optical detector at one interval of the motion modulation signal during which the interrogation region contains more boundary region fluid than analyte and reference fluid and at a second interval during which the interrogation region contains more analyte or reference fluid than boundary region fluid, thereby generating corresponding output signal samples, and (3) to determine from the output signal samples a measurement value indicative of an optically measured characteristic of the interaction of the analyte and reference fluids.

25. The fluid analyzer of claim 24, further comprising a motion control device configured to position the interrogation region at two or more positions in the fluid channel in the direction of fluid flow, the optically measured characteristic determined at each interrogation region position and used to determine a variation in time of the optically measured characteristic.

26. The fluid analyzer of claim 24, further comprising structures within the optical channel that modify mixing of the analyte fluid and reference fluid in the fluid boundary region.

27. A fluid analyzer, comprising:

an optical source and an optical detector defining a beam path of an optical beam;

a fluid flow cell disposed on the beam path defining an interrogation region in a fluid channel in the fluid flow cell in which the optical beam interacts with a fluid;

one or more flow-control devices configured to conduct an analyte fluid and a reference fluid stream through the fluid channel, a fluid boundary region separating the analyte and reference fluids when flowing together through the fluid channel;

a controller operative (1) to sample an output signal from a transducer to detect a particle within the fluid channel, (2) to generate a motion modulation signal having a time-varying characteristic to cause the particle to be moved relative to the interrogation region, (3) to sample the output signal from the optical detector at one interval of the motion modulation signal during which the interrogation region contains substantially the particle and at a second interval during which the interrogation region contains substantially the fluid surrounding the particle, thereby generating corresponding output signal samples, and (4) to determine from the output signal samples a measurement value indicative of an optically measured characteristic of the particle.

28. The fluid analyzer of claim 27, further comprising a motion control device configured to position the interrogation region location in the fluid channel.

29. The fluid analyzer of claim 27, wherein the optical signal incident on the detector has been spatially filtered for the purpose of detecting scattered optical signal.

30. The fluid analyzer of claim 27, wherein the optical signal incident on the detector has been spatially filtered for the purpose of removing scattered optical signal.

31. The fluid analyzer of claim 27, wherein the optically measured characteristic of the particle is an optically measured characteristic of an interaction of the particle and the surrounding fluid.

32. The fluid analyzer of claim 27, wherein the optically measured characteristic of the particle is an optically measured characteristic of an interaction of the particle and the optical beam.

33. The fluid analyzer of claim 27, wherein the optically measured characteristic of the particle is an optically measured characteristic of an interaction of the particle and the microfluidic cell.