Thermal cycler for automatic performance of the polymerase chain reaction with close temperature control

Abstract

A thermal cycler for automatic performance of the polymerase chain reaction is provided. The thermal cycler comprises a heater control that provides close temperature control of the reaction.

1 . An apparatus comprising:
 a heating and cooling system,   a heat exchanger in heat transfer communication with the heating and cooling system and adapted to hold at least one sample tube in heat transfer communication with the heat exchanger, wherein the at least one sample tube is adapted to contain a known volume of a sample;   a temperature sensor adapted to determine the temperature of the heat exchanger in a first sample interval, wherein the first sample interval is an interval of time designated as time n; and   a computing apparatus adapted to control the heating and cooling system and wherein the computing apparatus is adapted to determine the temperature of a sample as a function of the temperature of the heat exchanger over time by utilizing the relationship:
     T samp n   =T samp n-1 +( TB   n   −T samp n-1 )*tinterval/tau 
   where Tsamp n  is equal to the sample temperature in the first sample interval, Tsamp n-1  is a sample temperature in a second sample interval immediately preceding the first sample interval, the second sample interval designated as time n−1, TB n  is equal to the temperature of the heat exchanger in the first sample interval, tinterval is a time in seconds between consecutive sample intervals, and tau is a function of thermal characteristics of the apparatus.   
   
   
       2 . The apparatus of  claim 1 , wherein the heat exchanger comprises a conical cavity. 
   
   
       3 . The apparatus of  claim 1 , wherein the shape of the heat exchanger complements a shape of a respective sample tube. 
   
   
       4 . The apparatus of  claim 1 , wherein the heat exchanger comprises a block. 
   
   
       5 . The apparatus of  claim 1 , wherein the heat exchanger comprises a block with wells formed therein. 
   
   
       6 . The apparatus of  claim 1 , wherein the heat exchanger comprises a liquid bath. 
   
   
       7 . The apparatus of  claim 1 , wherein the heat exchanger comprises an oven. 
   
   
       8 . The apparatus of  claim 1 , wherein the thermal characteristics comprise a first thermal time constant corresponding to at least one sample tube and a volume of a sample, and a second thermal time constant corresponding to a temperature sensor thermally coupled to the heat exchanger, and tau equals approximately the first thermal time constant minus the second thermal time constant. 
   
   
       9 . The apparatus of  claim 1 , further comprising an input device for receiving user defined setpoints defining a hold time/temperature profile, wherein the computing apparatus includes a controller adapted to control the heating and cooling system as a function of the user defined setpoints and a sample temperature. 
   
   
       10 . The apparatus of  claim 1 , wherein the heat exchanger is adapted to receive at least one sample tube containing a volume of sample in the range of from approximately 20 microliters to approximately 100 microliters. 
   
   
       11 . The apparatus of  claim 1 , wherein the heat exchanger further comprises an enclosure, the enclosure defining an enclosed ambient atmosphere, and wherein the heat exchanger is in heat transfer communication with the enclosed ambient atmosphere. 
   
   
       12 . The apparatus of  claim 11 , wherein the heating and cooling system comprises a heater thermally coupled to the enclosed ambient atmosphere. 
   
   
       13 . The apparatus of  claim 1 , wherein the heat exchanger is in heat transfer communication with cooling channels. 
   
   
       14 . The apparatus of  claim 1 , wherein the means for determining the temperature of the heat exchanger in the first sample interval comprises means for determining the temperature of the heat exchanger in the first sample interval as a function of at least one temperature of the heat exchanger in a previous sample interval. 
   
   
       15 . The apparatus of  claim 1 , further comprising an input device for receiving a tube type and a reaction volume, and wherein the computing apparatus comprises means for determining the thermal time constant for a sample tube as a function of the tube type and a sample volume. 
   
   
       16 . An apparatus comprising:
 a heating and cooling system;   a heat exchanger thermally coupled with the heating and cooling system and adapted to hold at least one sample tube, the at least one sample tube being thermally coupled with the heat exchanger and being adapted to contain a known volume of a sample;   a temperature sensor adapted to determine the temperature of the heat exchanger in a first period of time; and   a computing apparatus adapted to control the heating and cooling system and determine the temperature of a sample in the first period of time and in a second earlier period of time that precedes the first period of time by a third period of time, with the temperature of the sample in the first period of time determined as a function of the difference between the temperature of the heat exchanger in the first period of time and the temperature of the sample in the second earlier period of time.   
   
   
       17 . The apparatus of  claim 16 , wherein the function comprises a factor by which the difference between the temperature of the heat exchanger in the first period of time and the temperature of the sample in the second earlier period of time is multiplied. 
   
   
       18 . The apparatus of  claim 17 , wherein the factor comprises the third period of time. 
   
   
       19 . The apparatus of  claim 17 , wherein the factor comprises thermal characteristics of the apparatus. 
   
   
       20 . The apparatus of  claim 16 , wherein the heat exchanger comprises a liquid bath. 
   
   
       21 . The apparatus of  claim 16 , wherein the heat exchanger comprises an oven. 
   
   
       22 . A method for thermal cycling, comprising:
 providing at least one sample tube in a thermal cycler, the at least one sample tube containing a volume of sample;   entering sample tube type information into a control computer;   identifying control information by looking up control information corresponding to the sample tube type information entered; and   controlling the thermal cycler with the control computer, based on the sample tube type information entered, to thermally cycle the sample.   
   
   
       23 . The method of  claim 22 , wherein the controlling the thermal cycler with the control computer comprises sensing a temperature using at least one sensor and thermally cycling the sample based on the sensed temperature. 
   
   
       24 . The method of  claim 22 , further comprising calculating a sample temperature of the sample. 
   
   
       25 . The method of  claim 24 , further comprising displaying the calculated sample temperature on a display. 
   
   
       26 . The method of  claim 22 , wherein the thermal cycler comprises a sample block, and the controlling the thermal cycler with the control computer comprises sensing a temperature of the sample block using at least one sensor and thermally cycling the sample based on the sensed temperature. 
   
   
       27 . The method of  claim 22 , further comprising entering sample volume information into the control computer, wherein the controlling is also based on the sample volume information. 
   
   
       28 . The method of  claim 27 , wherein the identifying control information comprises looking up control information corresponding to the sample tube type information and the sample volume information. 
   
   
       29 . The method of  claim 28 , wherein the controlling the thermal cycler with the control computer is also based on the sample volume information entered. 
   
   
       30 . The method of  claim 22 , wherein the control information comprises a thermal time constant. 
   
   
       31 . The method of  claim 30 , wherein the controlling the thermal cycler with the control computer is based on the thermal time constant. 
   
   
       32 . The method of  claim 30 , wherein the thermal time constant corresponds to a thermal resistance between the sample tube and the sample, multiplied by a heat capacity of the sample. 
   
   
       33 . The method of  claim 22 , wherein the sample tube type information comprises sample tube wall thickness information. 
   
   
       34 . The method of  claim 22 , wherein the sample tube type information comprises sample tube material information. 
   
   
       35 . A method for thermal cycling, comprising:
 providing at least one sample tube in a thermal cycler, the at least one sample tube containing a volume of sample;   entering sample volume information into a control computer;   identifying control information by looking up control information corresponding to the sample volume information entered; and   controlling the thermal cycler with the control computer, based on the sample volume information entered, to thermally cycle the sample.   
   
   
       36 . A method for thermal cycling, comprising:
 providing at least one sample tube in a thermal cycler, the at least one sample tube containing a volume of sample;   entering a thermal time constant into a control computer;   identifying control information by looking up control information corresponding to the thermal time constant entered; and   controlling the thermal cycler with the control computer, based on the thermal time constant entered, to thermally cycle the sample.