Abstract:
Provided are a temperature control method and apparatus for driving a polymerize chain reaction (PCR) chip. In the temperature control apparatus, which is for a polymerize chain reaction chip, PCR chips receive electric power from the outside and generating heat to maintain a predetermined temperature and for outputting actual temperature information to the outside. electric power supply units supply electric power to the PCR chips according to input control signals, and a controller generates the control signals based on control information including pre-established control temperature and control time information and the actual temperature information supplied from the PCR chips in order to supply the control signals to the electric power supply units. In the present invention, it is possible to examine various kinds of DNA at the same time because the temperature control apparatus controls the temperatures of DNA samples at the same time.

Description:
BACKGROUND OF THE INVENTION 
   1. Field of the Invention 
   The present invention relates to a temperature control method and apparatus, and more particularly, to a temperature control method and apparatus for driving a polymerase chain reaction (PCR) chip. 
   2. Description of the Related Art 
   A conventional apparatus for amplifying deoxyribonucleic acid (DNA) is by using a PCR, which amplifies multiple DNA samples at the same temperature cycles. Such a process can amplify more than 14 samples of DNA wherein each sample is placed into a tube having a content of 0.5 ml or 0.2 ml. The conventional apparatus has an advantage of analyzing the DNA samples of a plurality of patients at the same time; however, it is difficult to examine various kinds of DNAs at the same time because temperature conditions for maximizing the amplification of DNAs are different depending on the kind of DNA. In addition, an amount of the DNA samples required for the experiment is at least 0.2 ml. Accordingly, the conventional method needs to extract a large amount of the DNA samples from the patients. In addition, since large amounts of carcinogenic materials are added to the conventional PCR apparatus, an environmental contamination occurs. 
   SUMMARY OF THE INVENTION 
   To solve the above-described and related problems, the present disclosure provides a temperature control method and apparatus for a polymerase chain reaction (PCR) chip. 
   To accomplish this, there is provided a temperature control apparatus for a PCR chip, the temperature control apparatus comprising: PCR chips for receiving electric power from the outside and generating heat to maintain a predetermined temperature and for outputting actual temperature information to the outside; electric power supply units for supplying electric power to the PCR chips according to input control signals; and a controller for generating the control signals based on control information including pre-established control temperature and control time information and the actual temperature information supplied from the PCR chips in order to supply the control signals to the electric power supply units. 
   Preferably, the temperature control apparatus further includes: a selector for receiving a first selection signal for selecting the PCR chip to be controlled and the control signal from the controller, in order to select the electric power supply unit for supplying the electric power to the PCR chip to be controlled and supply the control signal to the selected electric power supply unit; and a multiplexer for receiving a second selection signal for selecting one of the PCR chips from the controller and supplying the actual temperature information on a predetermined PCR chip to the controller according to the second selection signal. 
   Preferably, at least one PCR chip in the temperature control apparatus includes: a heater for receiving electric power from the electric power supply unit to generate heat; and a temperature sensor for measuring the temperature of the PCR chip and outputting the temperature to the outside. 
   Preferably, the temperature control apparatus further includes: an input/output (I/O) unit for receiving control information including the control temperature and time information from a user, in order to supply the control information to the controller and outputting the control result of the temperature of a predetermined PCR chip to the outside according to the control information. 
   The present disclosure further provides a temperature control method for a PCR chip, the method comprising: (a) receiving control information including the control temperature and time of a PCR chip; (b) generating a control signal for the PCR chip to maintain the control temperature for the predetermined time; and (c) controlling the temperature of the PCR chip according to the control signal. 
   Preferably, step (b) includes (b 1 ) generating a selection signal for selecting a PCR chip to be controlled by the control signal when a plurality of PCR chips are arranged, and in step (c), the temperature of the predetermined PCR chip is controlled according to the selection signal and the control signal. 
   Preferably, the temperature control method further includes: (d) measuring the temperature of the PCR chip; and (e) repeating (b) when the actual temperature and the control temperature of the PCR chip are different. 
   Preferably, step (e) includes: (e 1 ) generating information for selecting a predetermined PCR chip when a plurality of PCR chips are arranged; and (e 2 ) subsequently comparing the actual temperature of the selected PCR chip with the control temperature corresponding to the selected PCR chip to perform (b) when the actual temperature and control temperature are different. 
   The disclosure further provides a recording medium readable in a computer, wherein a program for operating a method among the above methods is recorded. 

   
     BRIEF DESCRIPTION OF THE DRAWINGS 
     The above objective and advantages of the present invention will become more apparent by describing in detail preferred embodiments thereof with reference to the attached drawings in which: 
       FIG. 1  is a block diagram illustrating a temperature control apparatus for a PCR chip; 
       FIG. 2  is a block diagram illustrating a PCR chip; 
       FIG. 3  is a flowchart explaining a temperature control method for a PCR chip; 
       FIG. 4  is a diagram illustrating an exemplary configuration of the temperature control apparatus of the PCR chip of  FIG. 1 ; 
       FIG. 5  is a diagram illustrating an exemplary configuration of the PCR chip of  FIG. 2 ; 
       FIG. 6  illustrates a waveform of a voltage of a platinum sensor measured at an analog/digital converter input terminal by using an oscilloscope; 
       FIG. 7  illustrates a waveform of a voltage of a platinum sensor measured at the CPU of  FIG. 5 ; 
       FIG. 8  illustrates an overshoot of the platinum heater temperature of  FIG. 5 ; 
       FIG. 9  illustrates a normal state error of the platinum heater temperature of  FIG. 5 ; and 
       FIG. 10  illustrates an amplified deoxyribonucleic acid fluorescent image generated by a temperature control apparatus. 
   

   DETAILED DESCRIPTION OF THE INVENTION 
     FIG. 1  is an exemplary embodiment of a block diagram illustrating a temperature control apparatus for a polymerase chain reaction (PCR). An input/output (I/O) unit  101  receives selection information, control temperature and time information for a particular PCR chip (“a selected PCR chip”), which is to be controlled at a predetermined temperature and for a predetermined time, from a user (not shown), and supplies the information to a controller  102 . In addition, I/O unit  101  receives the control result information for the selected PCR chip, i.e., actual temperature information about the selected PCR chip, from controller  102 , and provides the control result information about the selected PCR chip, i.e., the actual temperature information about the selected PCR chip, to a user. 
   Controller  102  generates a control signal based on the selection information, the control temperature and time information from I/O unit  101 , and collects the actual temperature information about the selected PCR chip in order to supply the actual temperature information to I/O unit  101 . In addition, controller  102  generates a selection signal for selecting the selected PCR chip (whose temperature will be read out in order) among a plurality of PCR chips  105 ( 1 ),  105 ( 2 ), . . . ,  105 (N) and provides the selection signal to a multiplexer  106 . 
   A selector  103  selects one of electric power supply units  104 ( 1 ),  104 ( 2 ), . . . , and  104 (N) that provides an electric power to the corresponding selected PCR chip according to the control signal from controller  102 , respectively, and provides the control signal to the selected electric power supply units  104 ( 1 ),  104 ( 2 ), . . . , and  104 (N) respectively. 
   Electric power supply units  104 ( 1 ),  104 ( 2 ), . . . , and  104 (N) respectively supply electric power to the corresponding PCR chip  105 ( 1 )  105 ( 2 ), . . . , and  105 (N), which is connected to electric power supply unit  104 ( 1 ),  104 ( 2 ), . . . , and  104 (N), respectively, based on the control signal from selector  103 . 
   PCR chips  105 ( 1 ),  105 ( 2 ), . . . , and  105 (N) respectively receive electric power from electric power supply units  104 ( 1 ),  104 ( 2 ), . . . , and  104 (N) and generate heat by using the electric power, thereby controlling the chip temperature. PCR chips  105 ( 1 ),  105 ( 2 ), . . . , and  105 (N) respectively measure their own temperatures and respectively supply the temperature values to multiplexer  106 . 
   Multiplexer  106  receives actual temperature information for the PCR chips  105 ( 1 ),  105 ( 2 ), . . . , and  105 (N) from the PCR chips  105 ( 1 ),  105 ( 2 ), . . . , and  105 (N) and receives the selection signal for selecting the selected PCR chip from controller  102  in order to provide the actual temperature information for the selected PCR chip selected by the selection signal to an analog/digital (A/D) conversion unit  107 . 
   A/D convertor  107  receives the actual temperature information for the selected PCR chip selected by the selection information from multiplexer  106 , converts the actual temperature information into a digital signal, and supplies the digital signal to controller  102 . 
     FIG. 2  is a block diagram illustrating an exemplary PCR chip that may be utilized in the temperature control apparatus of  FIG. 1 . Each of the PCR chips  105 ( 1 ), . . . , and  105 (N) comprises a heater  201  and a temperature sensor  202 . Heater  201  receives electric power from the corresponding electric power supply units  104 ( 1 ),  104 ( 2 ), . . . , and  104 (N) to generate heat. 
   Temperature sensor  202  measures the actual temperature of heater  201  and outputs the temperature to multiplexer  106 . 
     FIG. 3  is a flowchart depicting an exemplary temperature control method for a PCR chip. The I/O unit inputs control information, including temperature information and time information for a selected PCR chip, into the controller (step  301 ). The controller generates a control signal for controlling the temperature of the PCR chip according to the control information (step  302 ). Thereafter, the selected PCR chip is selected among the PCR chips by the control signal to control the temperature of the selected PCR chip (step  303 ). Next, the actual temperature of the selected PCR chip is measured (step  304 ) and the measured temperature is compared with the control temperature of the control information (step  305 ). When the temperatures are the same, the method proceeds to step  304 . When the temperatures are different, the method proceeds to step  302 . 
     FIG. 4  shows an exemplary configuration of the temperature control apparatus depicted in  FIG. 1 . In this exemplary embodiment, 128 PCR chips are used. When a constant current is applied to the platinum sensors of the different PCR chips, different voltages are generated at both ends of the platinum sensors according to the temperatures of the PCR chips. The different voltages are processed and transferred to a CPU. The CPU converts the analog voltage information into digital information and compares the measured temperature of the PCR chip with a target temperature. If the measured temperature is higher than the target temperature, a heater of the chip is turned off. If the measured temperature is lower than the target temperature, the heater of the chip is turned on. 
   For instance, a CPU  401  corresponds to controller  102  of  FIG. 1 . CPU  401  generates a control signal for controlling a temperature of a PCR chip (a selected PCR chip) to be controlled based on a predetermined control temperature and time information about the selected PCR chip. The control signal includes heater on/off signals that are supplied to photo MOSFETs  404001 , . . . , and  404128  (which each correspond to one of the electric power supply units  104 ( 1 ), . . . , and  104 (N) of  FIG. 1 ), and 4-bit address signals for selecting the selected PCR chip. The heater on/off signals are supplied to 8-bit latches  40301 , . . . , and  40316 , and the 4-bit address signals are supplied to the 8-bit latches  40301 , . . . , and  40316  through a decoder  402 . Accordingly, decoder  402  and 8-bit latches  40301 , . . . , and  40316  correspond to selector  103  of  FIG. 1 . 
   Latches  40301 , . . . , and  40316  select the selected PCR chip among the plurality of PCR chips  405001 , . . . , and  405128  by using the 4-bit address signals, and supply the heater on/off signals to the photo MOSFET  404001 , . . . , and  404128  that supply an electric power to the PCR chips  405001 , . . . , and  405128 , respectively. The Photo MOSFET  404001 , . . . , and  404128  respectively supply an electric power to the PCR chips  405001 , . . . , and  405128  according to the heater on/off signals, and the PCR chips  405001 , . . . , and  405128  respectively generate a heat by using the supplied electric power. In addition, actual temperature information about the PCR chips is generated and supplied to analog multiplexers  40601 , . . . , and  40608 , respectively. 
   Analog multiplexers  40601 , . . . , and  40608  receive the selection signal for selecting the selected PCR chip, whose temperature will be read out, from CPU  401 , and receive the actual temperature information about the selected PCR chip to provide the actual temperature information of the selected PCR chip to CPU  401 . 
     FIG. 5  is an exemplary configuration of a PCR chip of  FIG. 2 . Here, a PCR chip comprises a platinum heater  5021  and a platinum sensor  5022 . In order to generate a fine constant current for measurement, for example, a regulator ADP3301 having an output voltage error of 0.8% and a high performance op-amp MC33184 are used to generate a constant current of 4 mA, and the constant current is supplied to platinum sensor  5022 . Here, a four-point probe method is used to measure the voltages generated in the platinum sensor. In this case, the voltages at both ends of the platinum sensor are measured by using an instrumentation amplifier. In addition, DC offset and amplification rates of the voltages are controlled at an end circuit, and the voltages are supplied to analog multiplexers through an over voltage limiter including two diodes. A CPU recognizes the temperature of the PCR chip based on the supplied information and generates a control command by comparing the temperature of the PCR chip with the target temperature. In addition, the CPU switches an external electric power supplied to a heater by using a high-speed photo MOSFET, instead of a relay, to control the temperature of the PCR chip. 
   For instance, an electric power supply unit  501  comprises an external electric power source  5011  and a photo MOSFET  5012  that receives an on-signal or an off-signal from an outside to turn on or turn off external electric power source  5011 . The electric power of electric power supply unit  501  is supplied to platinum heater  5021  of a heater  502 . 
   Heater  502  comprises platinum heater  5021  and platinum sensor  5022 . Platinum heater  5021  converts the electric power supplied from external electric power source  5011  into heat. Platinum sensor  5022  receives a constant voltage and a constant current from a temperature sensor  503  to generate a voltage corresponding to the temperature of platinum heater  5021  and outputs the temperature. 
   Temperature sensor  503  comprises a constant voltage circuit  5031 , e.g., a regulator ADP3301, a constant current circuit  5032 , e.g., an op-amp MC33184, and an amplifier  5033  for amplifying a difference between an input voltage and an output voltage. Temperature sensor  503  supplies the constant voltage and constant current to platinum sensor  5022 , and measures the temperature of platinum heater  5021  by comparing the output voltage of platinum sensor  5022  corresponding to the temperature of platinum heater  5021  with an input voltage, i.e., the constant voltage. The actual temperature information about platinum heater  5021 , which is measured in circuit  503 , is output to an analog multiplexer. 
     FIGS. 6–10  depict data obtained from using the temperature control apparatus disclosed herein. PCR samples were prepared, wherein a plasmid deoxyribonucleic acid (DNA) was used as an amplifying sample, and a driving solution is formed by adding a buffering solution including primer, dNDP, salt, and DNA polymerase enzyme. After flowing the driving solution into an inlet of a PCR chip to fill a reaction chamber, the inlet and outlet of the reaction chamber were sealed with fine block and epoxy. The temperature control apparatus set temperature sections of 55° C., 72° C., and 95° C. and a maintenance time of 30 seconds for each temperature section. 
     FIG. 6  illustrates a waveform of a voltage of a platinum sensor measured at an A/D converter input terminal by using an oscilloscope according to an embodiment of the present disclosure. In  FIG. 6 , a temperature of a select PCR chip is controlled by using a PCR chip according to the present disclosure.  FIG. 7  illustrates a waveform of a voltage of a platinum sensor measured at the CPU of  FIG. 5 . As shown in  FIGS. 6 and 7 , the temperature control apparatus according to the present disclosure recognizes the output values of the platinum sensor. 
     FIG. 8  illustrates an overshoot of a platinum heater temperature according to an embodiment of the present disclosure, and  FIG. 9  illustrates a normal state error of a platinum heater temperature according to an embodiment of the present disclosure. As shown in  FIGS. 8 and 9 , a temperature control apparatus according to the present disclosure can control a micro PCR chip while having a normal state error of plus or minus about 0.4° C., an overshoot of less than about 0.6° C., and an increasing speed of about 6.8° C./sec. The above temperature control apparatus has a performance as good as the performance of a conventional product that amplifies a PCR by using tubes of 0.2 ml. 
     FIG. 10  illustrates an amplified DNA fluorescent image generated by using the temperature control apparatus disclosed herein. Here, clear amplified DNA bands are represented in the image of  FIG. 10 . 
   A temperature control apparatus and method according to the embodiments of the present disclosure may be embedded as computer programs in a computer so that the apparatus and method may be realized in a digital computer that operates the program by using a recording medium used in the computer. 
   The recording medium used in the computer may comprise a magnetic recording media, for example, ROM, floppy disks, and hard disks; an optical recording media, for example, CD-ROM and DVD; and a carrier wave, for example, transfer through the Internet. 
   According to an exemplary embodiment of the present disclosure, a plurality of DNA samples is simultaneously examined under different temperature conditions so that examination and analysis times can be reduced. In addition, only a small amount of samples are required for the examination; thus the burden on patients can be reduced while also reducing environmental contamination. 
   In addition, a temperature control apparatus according to the present disclosure controls the temperature of a fine PCR chip so that the temperature is rapidly increased and decreased. In addition, the temperature of a reaction chamber can be precisely measured in a short time by using a platinum sensor attached under the chamber of the PCR chip, so that the temperature of the PCR chip can be precisely controlled. 
   While this invention has been particularly shown and described with reference to preferred embodiments thereof, the preferred embodiments described above are merely illustrative and are not intended to limit the scope of the invention. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims and equivalents thereof.