System and method for temperature control

• US 7,188,001 B2
• Filed: 01/27/2003
• Issued: 03/06/2007
• Est. Priority Date: 03/23/1998
• Status: Expired due to Term

• Current Assignee: Cepheid (Danaher Corporation)
• Original Assignee: Cepheid (Danaher Corporation)
• Inventors: Kovacs, Gregory T. A., Petersen, Kurt E., Northrup, M. Allen, McMillan, William A., Christel, Lee A., Othmer, Konstantin, Young, Steven J.
• Primary Examiner(s): Gordon; Brian R.
• Application Number:
  US10/353,186
• Publication Number:
  US 20040122559A1
• Time in Patent Office: 1,499 Days
• Field of Search: 422/50, 422/55, 422/62, 422/67, 422/68.1, 422/82.05, 422/105, 422108-109, 436/43, 436/50, 436/5, 436/147, 436/157, 436164-166, 436/55, 436/174, 700/266, 700/268, 700/274
• US Class Current: 700/266
• 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: G05B 13/021 in which a variable is automatically adjusted to optimise the performance
• CPC Class Codes: G05D 23/1913 delivering a series of pulses
• CPC Class Codes: Y10T 436/12 Condition responsive control

Abstract

A system for controlling the temperature of a reaction mixture comprises at least one heating device for heating the mixture and a power regulator for regulating the amount of power supplied to the heating device. A controller in communication with the power regulator includes program instructions for heating the reaction mixture by setting a variable target temperature that initially exceeds a desired setpoint temperature for the mixture. When the heating device reaches a threshold temperature, the variable target temperature is decreased to the desired setpoint temperature. In another embodiment, the controller includes an adaptive control program for dynamically adjusting the duration or intensity of power pulses provided to the heating device.

Claims

1. A system for controlling the temperature of a reaction mixture contained in a reaction vessel, the system comprising:

a) at least one heating device for heating the vessel;

b) at least one temperature sensor;

c) at least one power regulator for regulating an amount of power supplied to the heating device; and

d) at least one controller in communication with the power regulator and with the temperature sensor, wherein the controller includes program instructions for heating the reaction mixture by;

i) determining a level of power to be provided to the heating device, wherein the level of power is determined in dependence upon a variable target temperature that initially exceeds a desired setpoint temperature for the mixture;

ii) sending a control signal instructing the power regulator to provide power to the heating device at the level determined;

when the sensor measures a temperature greater than or equal to a threshold temperature,

iii) decreasing the variable target temperature;

iv) determining a new level of power to be provided to the heating device, wherein the new level of power is determined in dependence upon the decreased target temperature; and

v) sending a new control signal instructing the power regulator to provide power to the heating device at the new level.

2. The system of claim 1, wherein the target temperature is decreased to a temperature less than or equal to the desired setpoint temperature.

3. The system of claim 1, wherein the controller includes program instructions for repeating steps (iii) through (v) until the variable target temperature is less than or equal to the desired setpoint temperature.

4. The system of claim 3, wherein the controller includes program instructions for decreasing the variable target temperature by exponentially decaying the amount by which the variable target temperature exceeds the desired setpoint temperature.

5. The system of claim 4, wherein the amount by which the variable target temperature exceeds the desired setpoint temperature is exponentially decayed as a function of time according to the equation:

Δ

=(_max)*e<sup>(−

t/tau)</sup>

where Δ

is equal to the amount by which the variable target temperature exceeds the desired setpoint temperature, Δ

_max is equal to the difference between the initial value of the variable target temperature and the desired setpoint temperature, t is equal to the elapsed time from the start of decay, and tau is equal to a decay time constant.

6. The system of claim 3, wherein the controller includes program instructions for linearly decreasing the variable target temperature.

7. The system of claim 1, further comprising a cooling device for cooling the mixture, wherein the controller further includes program instructions for cooling the mixture by:

i) setting a second variable target temperature, wherein the second variable target temperature is initially lower than a desired second setpoint temperature for the mixture;

ii) activating the cooling device to cool the mixture until the sensor measures a temperature less than or equal to a second threshold temperature;

iii) increasing the second variable target temperature;

iv) determining another level of power to be provided to the heating device in dependence upon the increased second variable target temperature; and

v) sending a control signal instructing the power regulator to provide power to the heating device at the level determined.

8. The system of claim 7, wherein the second variable target temperature is increased to a temperature greater than or equal to the second setpoint temperature.

9. The system of claim 7, wherein the controller includes program instructions for repeating steps (iii) through (v) until the second variable target temperature is greater than or equal to the second setpoint temperature.

10. The system of claim 1, further comprising at least one optical detector in communication with the controller for generating optical data regarding the reaction mixture in the vessel, wherein the controller further includes program instructions for adjusting at least one thermal processing parameter in dependence upon the optical data.

11. The system of claim 1, further comprising at least one optical detector in communication with the controller for generating optical data regarding the reaction mixture in the vessel, wherein the controller further includes program instructions for processing the optical data and adjusting at least one process control selected from the group consisting of temperature control, completion of reaction, profile display, and signal generation regarding the need for addition of reagents.

12. The system of claim 1, wherein the temperature sensor is positioned to measure the temperature of the heating device, and wherein the variable target temperature is decreased when the temperature of the heating device is greater than or equal to the threshold temperature.

13. The system of claim 12, wherein the level of power in step (i) is determined in dependence upon the difference between the target temperature and the temperature of the heating device.

14. The system of claim 12, wherein the new level of power is determined in dependence upon the difference between the decreased target temperature and the temperature of the heating device.

15. The system of claim 1, wherein the heating device comprises a plate and a heating element coupled to the plate.

16. The system of claim 15, wherein the temperature sensor is positioned to measure the temperature of the plate, and wherein the power regulator regulates the amount of power supplied to the heating element.

17. A system for controlling the temperature of a reaction mixture contained in a reaction vessel, the system comprising:

a) at least one heating device for heating the vessel;

b) at least one cooling device for cooling the vessel;

c) at least one temperature sensor;

d) at least one power regulator for regulating an amount of power supplied to the heating device; and

e) at least one controller in communication with the cooling device, the power regulator, and the temperature sensor, wherein the controller includes program instructions for cooling the mixture by;

i) setting a variable target temperature, wherein the variable target temperature is initially lower than a desired setpoint temperature for the mixture;

ii) activating the cooling device to cool the mixture until the sensor measures a temperature less than or equal to a threshold temperature;

iii) increasing the variable target temperature;

iv) determining a level of power to be provided to the heating device in dependence upon the increased variable target temperature; and

v) sending a control signal instructing the power regulator to provide power to the heating device at the level determined.

18. The system of claim 17, wherein the variable target temperature is increased to a temperature greater than or equal to the setpoint temperature.

19. The system of claim 17, wherein the controller includes program instructions for repeating steps (iii) through (v) until the variable target temperature is greater than or equal to the setpoint temperature.

20. The system of claim 17, further comprising at least one optical detector in communication with the controller for generating optical data regarding the reaction mixture in the vessel, wherein the controller further includes program instructions for adjusting at least one thermal processing parameter in dependence upon the optical data.

21. The system of claim 17, further comprising at least one optical detector in communication with the controller for generating optical data regarding the reaction mixture in the vessel, wherein the controller further includes program instructions for processing the optical data and adjusting at least one process control selected from the group consisting of temperature control, completion of reaction, profile display, and signal generation regarding the need for addition of reagents.

22. The system of claim 17, wherein the temperature sensor is positioned to measure the temperature of the heating device.

23. The system of claim 22, wherein the level of power is determined in dependence upon the difference between the increased target temperature and the temperature of the heating device.

24. The system of claim 17, wherein the heating device comprises a plate and a heating element coupled to the plate.

25. The system of claim 24, wherein the temperature sensor is positioned to measure the temperature of the plate, and wherein the power regulator regulates the amount of power supplied to the heating element.

26. A system for controlling the temperature of a reaction mixture contained in a reaction vessel, the system comprising:

a) at least one heating device for heating the vessel;

b) at least one temperature sensor for measuring a temperature of the heating device;

c) at least one power regulator for regulating the amount of power supplied to the heating device;

d) at least one memory storing;

i) a pulse intensity value indicating an intensity of a power pulse to be supplied to the heating device to heat the heating device to a desired setpoint temperature; and

ii) a pulse length value indicating a duration of the power pulse to be supplied to the heating device; and

e) at least one controller in communication with the memory, the power regulator, and the temperature sensor, wherein the controller includes program instructions for heating the reaction mixture by;

i) sending a control signal instructing the power regulator to provide the power pulse to the heating device at the intensity and for the duration indicated by the pulse intensity value and the pulse length value, respectively;

ii) receiving temperature signals from the temperature sensor indicating measured temperatures of the heating device;

iii) terminating the power pulse when the measured temperature of the heating device reaches a threshold value or when the duration of time indicated by the pulse length value has elapsed; and

iv) adjusting the pulse length value or the pulse intensity value stored in the memory in dependence upon the difference between the setpoint temperature and the measured temperature of the heating device after the power pulse is completed;

wherein the system further includes at least one optical detector in communication with the controller for generating optical data regarding the reaction mixture in the vessel, and wherein the controller further includes program instructions for processing the optical data and adjusting at least one process control selected from the group consisting of temperature control, completion of reaction, profile display, and signal generation regarding the need for addition of reagents.

27. The system of claim 26, further comprising a cooling device for cooling the heating device, wherein the memory further stores a cooling length value indicating a duration of time the cooling device is to be activated to cool the heating device to a second setpoint temperature, and the controller further includes program instructions for cooling the mixture by:

i) activating the cooling device to begin cooling the heating device;

ii) receiving temperature signals from the sensor indicating measured temperatures of the heating device;

iii) deactivating the cooling device when the measured temperature of the heating device decreases to a predetermined value or when the duration of time indicated by the cooling length value has elapsed; and

iv) adjusting the cooling length value stored in the memory in dependence upon the difference between the second setpoint temperature and the measured temperature of the heating device after the active cooling is completed.

28. The system of claim 26, wherein the heating device comprises a plate and a heating element coupled to the plate.

29. The system of claim 26, wherein the controller includes program instructions for processing the optical data and adjusting at least one optical detection parameter in dependence upon the optical data.

30. The system of claim 26, wherein the controller includes program instructions for adjusting at least one thermal processing parameter in dependence upon the optical data.

31. A system for controlling the temperature of a reaction mixture contained in a reaction vessel, the system comprising:

a) at least one heating device for heating the vessel;

b) at least one temperature sensor for measuring a temperature of the heating device;

c) at least one power regulator for regulating the amount of power supplied to the heating device;

d) at least one memory storing;

i) a pulse intensity value indicating an intensity of a power pulse to be supplied to the heating device to heat the heating device to a desired setpoint temperature; and

ii) a pulse length value indicating a duration of the power pulse to be supplied to the heating device; and

e) at least one controller in communication with the memory, the power regulator, and the temperature sensor, wherein the controller includes program instructions for heating the reaction mixture by;

i) sending a control signal instructing the power regulator to provide the power pulse to the heating device at the intensity and for the duration indicated by the pulse intensity value and the pulse length value, respectively;

ii) receiving temperature signals from the temperature sensor indicating measured temperatures of the heating device;

iii) terminating the power pulse when the measured temperature of the heating device reaches a threshold value or when the duration of time indicated by the pulse length value has elapsed; and

iv) adjusting the pulse length value or the pulse intensity value stored in the memory in dependence upon the difference between the setpoint temperature and the measured temperature of the heating device after the power pulse is completed;

wherein the system further includes at least one optical detector in communication with the controller for generating optical data regarding the reaction mixture in the vessel, and wherein the controller further includes program instructions for processing the optical data and adjusting at least one optical detection parameter in dependence upon the optical data.

32. The system of claim 31, further comprising a cooling device for cooling the heating device, wherein the memory further stores a cooling length value indicating a duration of time the cooling device is to be activated to cool the heating device to a second setpoint temperature, and the controller further includes program instructions for cooling the mixture by:

i) activating the cooling device to begin cooling the heating device;

ii) receiving temperature signals from the sensor indicating measured temperatures of the heating device;

iii) deactivating the cooling device when the measured temperature of the heating device decreases to a predetermined value or when the duration of time indicated by the cooling length value has elapsed; and

iv) adjusting the cooling length value stored in the memory in dependence upon the difference between the second setpoint temperature and the measured temperature of the heating device after the active cooling is completed.

33. The system of claim 31, wherein the heating device comprises a plate and a heating element coupled to the plate.

34. The system of claim 31, wherein the controller further includes program instructions for adjusting at least one thermal processing parameter in dependence upon the optical data.

35. A system for thermally controlling a plurality of reaction mixtures contained in a plurality of reaction vessels, the system comprising:

a) a plurality of heat-exchanging modules for receiving the vessels, wherein each of the modules comprises;

i) at least one heating device for heating one of the vessels; and

ii) a temperature sensor for measuring the temperature of the heating device;

b) at least one power reaulator for regulating the amount of power supplied to the heating device of each heat-exchanging module;

c) at least one memory storing for each of the heat-exchanging modules;

i) a pulse intensity value indicating an intensity of a power pulse to be supplied to the heating device to heat the heating device to a desired setpoint temperature; and

ii) a pulse length value indicating a duration of the power pulse to be supplied to the heating device; and

d) at least one controller in communication with the memory, the power regulator, and with the temperature sensor of each heat-exchanging module, wherein the controller includes program instructions for independently controlling each heat-exchanging module to heat a reaction mixture by;

i) sending a control signal instructing the power regulator to provide the power pulse to the heating device at the intensity and for the duration indicated by the pulse intensity value and the pulse length value,

ii) receiving temperatures signals from the temperature sensor indicating measured temperatures of the heating device;

iii) terminating the power pulse when the measured temperature of the heating device reaches a threshold value or when the duration of time indicated by the pulse length value has elapsed; and

iv) adjusting the pulse length value or the pulse intensity value stored in the memory in dependence upon the difference between the setpoint temperature and the measured temperature of the heating device after the power pulse is completed;

wherein each heat-exchanging module further includes a cooling device for cooling the heating device, the memory further stores a cooling length value indicating a duration of time the cooling device is to be activated to cool the heating device to a second setpoint temperature, and the controller further includes program instructions for independently controlling each heat-exchanging module by;

i) activating the cooling device to begin cooling the heating device;

ii) receiving temperature signals from the sensor indicating measured temperatures of the heating device;

iii) deactivating the cooling device when the measured temperature of the heating device decreases to a predetermined value or when the duration of time indicated by the cooling length value has elapsed; and

iv) adjusting the cooling length value stored in the memory in dependence upon the difference between the second setpoint temperature and the measured temperature of the heating device after the active cooling is completed.

36. A system for thermally controlling a plurality of reaction mixtures contained in a plurality of reaction vessels, the system comprising:

a) a plurality of heat-exchanging modules for receiving the vessels, wherein each of the modules comprises;

i) at least one heating device for heating one of the vessels; and

ii) a temperature sensor for measuring the temperature of the heating device;

b) at least one power regulator for regulating the amount of power supplied to the heating device of each heat-exchanging module;

c) at least one memory storing for each of the heat-exchanging modules;

i) a pulse intensity value indicating an intensity of a power pulse to be supplied to the heating device to heat the heating device to a desired setpoint temperature; and

ii) a pulse length value indicating a duration of the power pulse to be supplied to the heating device; and

d) at least one controller in communication with the memory, the power regulator, and with the temperature sensor of each heat-exchanging module, wherein the controller includes program instructions for independently controlling each heat-exchanging module to heat a reaction mixture by;

i) sending a control signal instructing the power regulator to provide the power pulse to the heating device at the intensity and for the duration indicated by the pulse intensity value and the pulse length value, respectively, stored for the module;

ii) receiving temperature signals from the temperature sensor indicating measured temperatures of the heating device;

iii) terminating the power pulse when the measured temperature of the heating device reaches a threshold value or when the duration of time indicated by the pulse length value has elapsed; and

iv) adjusting the pulse length value or the pulse intensity value stored in the memory in dependence upon the difference between the setpoint temperature and the measured temperature of the heating device after the power pulse is completed;

wherein each heat-exchanging module further includes at least one optical detector in communication with the controller for generating optical data regarding the reaction mixture in the vessel, and wherein the controller further includes program instructions for adjusting at least one thermal processing parameter in dependence upon the optical data.

37. A system for thermally controlling a plurality of reaction mixtures contained in a plurality of reaction vessels, the system comprising:

a) a plurality of heat-exchanging modules for receiving the vessels, wherein each of the modules comprises;

i) at least one heating device for heating one of the vessels; and

ii) a temperature sensor for measuring the temperature of the heating device;

b) at least one power regulator for regulating the amount of power supplied to the heating device of each heat-exchanging module;

c) at least one memory storing for each of the heat-exchanging modules;

i) a pulse intensity value indicating an intensity of a power pulse to be supplied to the heating device to heat the heating device to a desired setpoint temperature; and

ii) a pulse length value indicating a duration of the power pulse to be supplied to the heating device; and

d) at least one controller in communication with the memory, the power regulator, and with the temperature sensor of each heat-exchanging module, wherein the controller includes program instructions for independently controlling each heat-exchanging module to heat a reaction mixture by;

i) sending a control signal instructing the power regulator to provide the power pulse to the heating device at the intensity and for the duration indicated by the pulse intensity value and the pulse length value, respectively, stored for the module;

ii) receiving temperature signals from the temperature sensor indicating measured temperatures of the heating device;

iii) terminating the power pulse when the measured temperature of the heating device reaches a threshold value or when the duration of time indicated by the pulse length value has elapsed; and

iv) adjusting the pulse length value or the pulse intensity value stored in the memory in dependence upon the difference between the setpoint temperature and the measured temperature of the heating device after the power pulse is completed;

wherein each heat-exchanging module further includes at least one optical detector in communication with the controller for generating optical data regarding the reaction mixture in the vessel, and wherein the controller further includes program instructions for processing the optical data and adjusting at least one process control selected from the group consisting of temperature control, completion of reaction, profile display, and signal generation regarding the need for addition of reagents.

38. A method for heating and optically interrogating a reaction mixture, the method comprising the steps of:

a) storing in at least one memory;

i) a pulse length value indicating a duration of a power pulse to be supplied to a heating device to heat the reaction mixture to a desired setpoint temperature; and

ii) a pulse intensity value indicating an intensity of the power pulse to be supplied to the heating device; and

b) sending a control signal instructing a power regulator to provide the power pulse to the heating device at the intensity and for the duration indicated by the pulse intensity value and the pulse length value, respectively;

c) receiving temperature signals from a sensor indicating measured temperatures of the heating device;

d) terminating the power pulse when the measured temperature of the heating device reaches a threshold value or when the duration of time indicated by the pulse length value has elapsed;

e) adjusting the pulse length value or the pulse intensity value stored in the memory in dependence upon the difference between the setpoint temperature and the measured temperature of the heating device after the power pulse is completed;

f) generating optical data regarding the reaction mixture; and

g) processing the optical data and adjusting at least one optical detection parameter.

39. A method for heating and optically interrogating a reaction mixture, the method comprising the steps of:

a) storing in at least one memory;

i) a pulse length value indicating a duration of a power pulse to be supplied to a heating device to heat the reaction mixture to a setpoint temperature; and

ii) a pulse intensity value indicating an intensity of the power pulse to be supplied to the heating device; and

b) sending a control signal instructing a power regulator to provide the power pulse to the heating device at the intensity and for the duration indicated by the pulse intensity value and the pulse length value, respectively;

c) receiving temperature signals from a sensor indicating measured temperatures of the heating device;

d) terminating the power pulse when the measured temperature of the heating device reaches a threshold value or when the duration of time indicated by the pulse length value has elapsed;

e) adjusting the pulse length value or the pulse intensity value stored in the memory in dependence upon the difference between the setpoint temperature and the measured temperature of the heating device after the power pulse is completed;

f) generating optical data regarding the reaction mixture; and

g) processing the optical data and adjusting at least one process control selected from the group consisting of temperature control, completion of reaction, profile display, and signal generation regarding the need for addition of reagents.

40. A method for thermally controlling a plurality of reaction mixtures contained in a plurality of reaction vessels, the method comprising the steps of:

a) placing the reaction vessels into a corresponding plurality of heat-exchanging modules, wherein each of the modules comprises;

i) at least one heating device for heating one of the vessels; and

ii) a temperature sensor for measuring the temperature of the heating device;

b) for each of the heat-exchanging modules, storing in at least one memory;

i) a pulse length value indicating a duration of a power pulse to be supplied to the heating device of the module to heat the heating device to a desired setpoint temperature; and

ii) a pulse intensity value indicating an intensity of the power pulse to be supplied to the heating device;

c) independently controlling each heat-exchanging module to heat the reaction mixture contained therein by;

i) sending a control signal instructing a power regulator to provide the power pulse to the heating device at the intensity and for the duration indicated by the pulse intensity value and the pulse length value, respectively, stored for the module;

ii) receiving temperature signals from the sensor indicating measured temperatures of the heating device;

iii) terminating the power pulse when the measured temperature of the heating device reaches a threshold value or when the duration of time indicated by the pulse length value has elapsed;

iv) adjusting the pulse length value or the pulse intensity value stored in the memory in dependence upon the difference between the setpoint temperature and the measured temperature of the heating device after the power pulse is completed;

d) for each of the heat-exchanging modules, generating optical data regarding the reaction mixture in the module; and

e) processing the optical data and adjusting at least one optical detection parameter.

41. A method for thermally controlling a plurality of reaction mixtures contained in a plurality of reaction vessels, the method comprising the steps of:

a) placing the reaction vessels into a corresponding plurality of heat-exchanging modules, wherein each of the modules comprises;

i) at least one heating device for heating one of the vessels; and

ii) a temperature sensor for measuring the temperature of the heating device;

b) for each of the heat-exchanging modules, storing in at least one memory;

i) a pulse length value indicating a duration of a power pulse to be supplied to the heating device of the module to heat the heating device to a desired setpoint temperature; and

ii) a pulse intensity value indicating an intensity of the power pulse to be supplied to the heating device;

c) independently controlling each heat-exchanging module to heat the reaction mixture contained therein by;

i) sending a control signal instructing a power regulator to provide the power pulse to the heating device at the intensity and for the duration indicated by the pulse intensity value and the pulse length value, respectively, stored for the module;

ii) receiving temperature signals from the sensor indicating measured temperatures of the heating device;

iii) terminating the power pulse when the measured temperature of the heating device reaches a threshold value or when the duration of time indicated by the pulse length value has elapsed;

iv) adjusting the pulse length value or the pulse intensity value stored in the memory in dependence upon the difference between the setpoint temperature and the measured temperature of the heating device after the power pulse is completed;

d) for each of the heat-exchanging modules, generating optical data regarding the reaction mixture in the module; and

e) processing the optical data and adjusting at least one process control selected from the group consisting of temperature control, completion of reaction, profile display, and signal generation regarding the need for addition of reagents.