Thermal cycler for PCR

• US 7,537,377 B2
• Filed: 02/15/2005
• Issued: 05/26/2009
• Est. Priority Date: 03/28/1997
• Status: Expired due to Term

• Current Assignee: Applied Biosystems LLC (Thermo Fisher Scientific Incorporated)
• Original Assignee: Applied Biosystems LLC (Thermo Fisher Scientific Incorporated)
• Inventors: Fawcett, Adrian, Atwood, John G., Hetherington, Paul M., Wittmer, Charles M., Widomski, John R., Olsen, Douglas E., Ferrara, Keith S., Noreiks, Richard W.
• Primary Examiner(s): Assouad; Patrick J
• Assistant Examiner(s): ADAMS, BRET W
• Application Number:
  US11/057,960
• Publication Number:
  US 20050145273A1
• Time in Patent Office: 1,561 Days
• Field of Search: 374/1, 374 11- 13, 374/44, 374101-102, 374/137, 374/171, 374/173, 374179-185, 374/204, 374/E7.004, 374/E7.014, 73/10.1, 136/201, 136203-204, 435/91.2, 422/99
• US Class Current: 374/1
• CPC Class Codes: B01L 2300/0829 Multi-well plates; Microtitration plates
• CPC Class Codes: B01L 2300/1822 using Peltier elements
• CPC Class Codes: B01L 2300/1827 using resistive heater
• CPC Class Codes: B01L 3/50853 with covers or lids
• 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: C12Q 1/686 Polymerase chain reaction [PCR]
• CPC Class Codes: F25B 21/04 reversible
• CPC Class Codes: F25B 2321/021 Control thereof
• CPC Class Codes: G01R 27/205 Measuring contact resistance of connections, e.g. of earth connections
• CPC Class Codes: G05D 23/1919 characterised by the type of controller
• CPC Class Codes: H10N 10/13 characterised by the heat-exchanging means at the junction
• CPC Class Codes: Y10T 137/1516 Thermo-electric

Abstract

A method for performing highly accurate PCR employing an assembly, a heated cover and an internal computer. The assembly is made up of a sample block, a number of Peltier thermal electric devices and heat sink, clamped together. The sample block temperature is changed exclusively by the thermoelectric devices controlled by the computer. The control software includes calibration diagnostics which permit variation in the performance of thermoelectric coolers from instrument to instrument to be compensated for such that all instruments perform identically. The block heat sink assembly can be changed to another of the same or different design. The assembly carries the necessary information required to characterize its own performance in an on-board memory device, allowing the assembly to be interchangeable among instruments while retaining its precision operating characteristics. The instrument monitors the thermoelectric devices and warns of changes in resistance that may result in failure.

Claims

1. A method for calibrating a removable assembly for cycling samples through a series of temperature excursions, the removable assembly being attached to an instrument and comprising

a sample block for receiving vials,

a plurality of thermoelectric devices,

a heat sink,

a clamping mechanism positioned so as to clamp said thermoelectric devices between said sample block and said heatsink, and

a memory device capable of storing data related to said removable assembly,

said method comprising:

applying power to said thermoelectric devices, causing said removable assembly to cycle through a desired series of temperature excursions;

measuring the actual temperature excursions;

comparing said actual temperature excursions with said desired temperature excursions;

calibrating the removable assembly by adjusting said power applied to said thermoelectric devices so that said actual temperature excursions match said desired temperature excursions and recording said adjusted power in said memory device for further utilization in obtaining said desired series of temperature excursions, to form a calibrated removable assembly;

removing the calibrated removable assembly from the instrument; and

attaching the removable assembly to a different instrument.

2. The method of claim 1, wherein at least one of the plurality of thermoelectric devices comprises a Peltier thermoelectric device.

3. The method of claim 1, wherein the removable assembly further comprises a heat leak connected to the sample block and the method further comprises leaking heat from the removable assembly through the heat leak.

4. The method of claim 1, wherein the adjusting said power applied to the thermoelectric devices comprises dynamically driving a temperature of the sample block to overshoot a desired temperature of the sample block.

5. The method of claim 4, further comprising driving the temperature of the sample block back to the desired temperature of the sample block.

6. The method of claim 1, wherein a portion of at least one of the plurality of thermoelectric devices is sealed from the environment.

7. The method of claim 1, further comprises cooling the block by heat pumping.

8. The method of claim 1, further comprising cooling the heat sink with a fan.

9. The method of claim 1, wherein the sample block contains at least one sample vial and the method further comprises applying pressure to the at least one sample vial with a heated cover.

10. The method of claim 1, wherein a temperature sensor is attached to the heat sink and the method further comprises using the temperature sensor to determine a temperature of the plurality of thermoelectric devices.

11. The method of claim 1, wherein a temperature sensor is attached to the sample block and the method further comprises using the temperature sensor to determine the temperature of the plurality of thermoelectric devices.

12. The method of claim 1, further comprising measuring the temperatures of the plurality of thermoelectric devices and using a feedback control system to compensate for temperature differences among the plurality of thermoelectric devices.

13. The method of claim 1, further comprising providing current in each of two directions to the plurality of thermoelectric devices using a bipolar amplifier in electrical communication with the plurality of thermoelectric devices.

14. The method of claim 1, wherein the removable assembly further comprises a perimeter heater positioned around the sample block and the method further comprises heating edges of the sample block with the perimeter heater.

15. The method of claim 14, wherein heating the edges comprises heating air in the immediate vicinity around a perimeter of the sample block.