Flow-based thermocycling system with thermoelectric cooler

• US 8,633,015 B2
• Filed: 09/24/2010
• Issued: 01/21/2014
• Est. Priority Date: 09/23/2008
• Status: Active Grant

• Current Assignee: Lawrence Livermore National Security LLC (Government of the United States of America)
• Original Assignee: Bio-Rad Laboratories Incorporated
• Inventors: Ness, Kevin D., Masquelier, Donald A., Colston, Billy W. Jr., Hindson, Benjamin J.
• Primary Examiner(s): HOBBS, MICHAEL L
• Application Number:
  US12/890,550
• Publication Number:
  US 20110212516A1
• Time in Patent Office: 1,215 Days
• Field of Search: 435/303.1
• US Class Current: 435/287.2
• CPC Class Codes: B01F 23/41 Emulsifying
• CPC Class Codes: 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
• CPC Class Codes: B01L 2200/0673 Handling of plugs of fluid surrounded by immiscible fluid
• CPC Class Codes: B01L 2200/0689 Sealing
• CPC Class Codes: B01L 2300/0816 Cards, e.g. flat sample carriers usually with flow in two horizontal directions
• CPC Class Codes: B01L 2300/0819 Microarrays; Biochips
• CPC Class Codes: B01L 2300/087 Multiple sequential chambers
• CPC Class Codes: B01L 2300/1822 using Peltier elements
• CPC Class Codes: B01L 2400/0478 pistons
• CPC Class Codes: B01L 2400/0487 fluid pressure, pneumatics
• CPC Class Codes: B01L 2400/0622 distribution valves, valves having multiple inlets and/or outlets, e.g. metering valves, multi-way valves
• 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 3/502784 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 7/525 with physical movement of samples between temperature zones

Abstract

Thermocycling system, including methods and apparatus, for performing a flow-based reaction on a sample in fluid. The system may include a plurality of segments defining at least two temperature regions, and also may include a plurality of heating elements configured to maintain each temperature region at a different desired temperature. At least one of the heating elements may be a thermoelectric cooler operatively disposed to transfer heat to and/or from a temperature region The system further may include a fluid channel extending along a helical path that passes through the temperature regions multiple times such that fluid flowing in the channel is heated and cooled cyclically.

Claims

1. A thermocycling system for performing a flow-based reaction on a sample in fluid, comprising:

a thermally conductive core configured as a heat source and a heat sink;

a plurality of segments surrounding and discrete from the core and defining at least two temperature regions;

a plurality of heating elements configured to maintain each temperature region at a different desired temperature, at least one of the heating elements being a thermoelectric cooler disposed between the core and one of the segments and configured to transfer heat between the core and the one segment; and

a fluid channel extending along a helical path that passes through each temperature region multiple times such that fluid flowing in the channel is heated and cooled cyclically.

2. The thermocycling system of claim 1, wherein the segments collectively define a central opening, and wherein the core is disposed in the central opening.

3. The thermocycling system of claim 1, wherein the fluid channel includes fluidic tubing wrapped around the segments.

4. The thermocycling system of claim 3, wherein the fluidic tubing is disposed in grooves formed by the segments along the helical path.

5. The thermocycling system of claim 4, wherein the grooves include sloping edge contours.

6. The thermocycling system of claim 4, further comprising a cover disposed on the segments over the fluidic tubing, the cover defining an aperture that permits the fluidic tubing to extend into the grooves from outside the cover at any of a plurality of discrete groove positions along the aperture.

7. The thermocycling system of claim 6, wherein the segments are inner segments, and wherein the cover is formed by a plurality of outer segments.

8. The thermocycling system of claim 3, wherein the fluidic tubing includes a plurality of discrete tubes each extending along a same portion of the helical path.

9. The thermocycling system of claim 1, wherein the segments are inner segments, further comprising a plurality of outer segments attached to the inner segments with the fluid channel disposed between the inner segments and the outer segments.

10. The thermocycling system of claim 1, wherein the segments include external grooves, and wherein the fluid channel is defined by the grooves and by a fluid tight sheet wrapped around the segments.

11. The thermocycling system of claim 1, wherein at least one independently controllable and distinct thermoelectric cooler is disposed between each segment and the core.

12. The thermocycling system of claim 1, wherein the core includes a plurality of sections, each independently in thermal contact with a different one of the segments.

13. The thermocycling system of claim 1, wherein a resistive heater is operatively connected to at least one segment.

14. The thermocycling system of claim 13, wherein a distinct resistive heater is operatively connected to each segment.

15. The thermocycling system of claim 1, wherein a resistive heater is operatively connected to the core.

16. The thermocycling system of claim 1, wherein the helical path extends about a central axis, and wherein at least one temperature region varies in size along the central axis.

17. The thermocycling system of claim 1, wherein the fluid channel has a different path length for successive passes through at least one temperature region, thereby changing how much time a fluid portion spends in the at least one temperature region during the successive passes, if the fluid portion travels along the helical path at a uniform speed.

18. The thermocycling system of claim 1, wherein each of the segments is attached to the core.

19. The thermocycling system of claim 1, further comprising a droplet generator operatively connected to the fluid channel for introduction of droplets into the fluid channel.

20. The thermocycling system of claim 1, wherein the fluid channel changes in diameter one or more times as the fluid channel extends through the temperature regions multiple times.

21. The thermocycling system of claim 20, wherein the fluid channel includes an inlet and an outlet and has a larger diameter closer to the inlet and a smaller diameter closer to the outlet.