TWI620814B - Thermal control apparatus and method thereof - Google Patents

Abstract

The invention provides a thermal control device and a thermal control method thereof. The thermal control device comprises a controller and a heating and cooling module. The heating and cooling module includes a temperature sensor for measuring a first current temperature of a first position of the heating and cooling module, and a heating refrigerator for relying on the controller A control signal to adjust the first current temperature at the first location. The controller calculates a predicted temperature at a second position in the heating and cooling module based on the first current temperature at the first location and a temperature model. The controller further automatically adjusts the first target temperature of the first position according to the calculated predicted temperature of the second position and a desired temperature, and controls the heating refrigerator to automatically adjust the first position. The first current temperature reaches the first target temperature.

Description

Thermal control device and thermal control method thereof

The present invention relates to temperature control, and more particularly to a thermal control device utilizing a virtual temperature model and a temperature inference mechanism and a thermal control method thereof.

Polymerase Chain Reaction (PCR) is a molecular biology technique used to amplify specific deoxyribonucleic acid (DNA) fragments. This method can be performed in vitro without relying on E. coli or yeast. Organisms such as bacteria. Microbial replication is a time-consuming and labor-intensive process. First, the DNA is cut by a restriction enzyme, and then Ligase is added to the carrier, followed by Electroporation or Heat Shock. The method is sent to the competent cell of Escherichia coli, and the bacteria are cultured and cultured in a culture dish, and after complicated separation and purification processes, it usually takes about one week to copy the fragments in large quantities. In contrast, a polymerase chain reaction requiring only about one hour of reaction time can save a lot of time and complicated operations. Polymerase chain reaction technology is widely used in medical and biological laboratories, for example, to determine whether a specimen exhibits a genetic disease map, infectious disease diagnosis, gene replication, and paternity testing.

The polymerase chain reaction usually needs to be carried out in a specific biochemical device, such as a polymerase chain reaction device. Because the process of the polymerase chain reaction needs to repeat the cycle of heating and cooling the polymerase, the PCR device usually places a container (eg, a test tube) containing the polymerase in a thermal control device for temperature control, for example, Control of heating and cooling is performed by placing the container on a substrate of a thermoelectric cooler. When performing a polymerase chain reaction, the process of heating the polymerase to a first specific temperature (for example, 90 to 95 degrees C) and cooling to a second specific temperature (for example, 40 to 60 degrees C) is called a PCR. Loop, and the PCR cycle needs to be repeated multiple times.

However, the polymerase chain reaction process relies on precise temperature control to achieve DNA replication. Generally, when the polymerase chain reaction process is carried out, the temperature of the liquid in the container in the thermal control device cannot be directly measured, and the liquid temperature is not consistent with the substrate temperature of the thermoelectric cooler, so the conventional temperature control cannot be directly used. The method to achieve the goal of precise liquid temperature control, and the manual adjustment of the control parameters of each thermal control device, will take a considerable amount of time, causing troubles in production line manufacturing.

Therefore, there is a need for a thermal control device and method thereof that can utilize a virtual temperature model and an inference mechanism for accurate temperature control to solve the above problems.

The invention provides a thermal control device comprising a controller and a heating and cooling module. The heating and cooling module includes: a temperature sensor for measuring a first current temperature of a first position of the heating and cooling module; and a heating refrigerator for receiving the control One of the control signals to adjust The first current temperature of the first location. The controller calculates a predicted temperature at a second position in the heating and cooling module based on the first current temperature at the first location and a temperature model. The controller further automatically adjusts the first target temperature of the first position according to the calculated predicted temperature of the second position and a desired temperature, and controls the heating refrigerator to automatically adjust the first position. The first current temperature reaches the first target temperature.

The invention further provides a thermal control method for a thermal control device, wherein the thermal control device comprises a temperature sensor and a heating and cooling module, and the thermal control method comprises the following steps: using the temperature sensor Measureing a first current temperature of one of the first positions of the heating and cooling module; adjusting the first current temperature at the first position by the heating refrigerator; according to the first position at the first position a current temperature and a temperature model to calculate a predicted temperature at a second position in the heating and cooling module; automatically adjusting the first position based on the calculated predicted temperature of the second position and a desired temperature a first target temperature; controlling the heating refrigerator to automatically adjust the first current temperature of the first position to reach the first target temperature.

100‧‧‧ Thermal control device

110‧‧‧temperature control module

111‧‧‧ Controller

112‧‧‧ memory unit

112A‧‧‧ volatile memory

112B‧‧‧Non-volatile memory

113‧‧‧Control signal

114‧‧‧ Temperature inference mechanism

115‧‧‧temperature model

116‧‧‧ Temperature feedback signal

120‧‧‧heating cooling module

121‧‧‧ Container

122‧‧‧Experimental liquid

123‧‧‧Substrate

124‧‧‧heating refrigerator

125‧‧‧temperature sensor

200‧‧‧ curve

210, 220‧‧ points

A, B‧‧‧ position

S310-S370‧‧‧Steps

S410-S450‧‧‧Steps

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a functional block diagram showing a thermal control device in accordance with an embodiment of the present invention.

Figure 2 is a schematic diagram showing a temperature model in accordance with an embodiment of the present invention.

Figure 3 is a flow chart showing a method of inferring a target substrate temperature in accordance with an embodiment of the present invention.

Figure 4 is a flow chart showing a thermal control method in accordance with an embodiment of the present invention.

The above described objects, features and advantages of the present invention will become more apparent from the description of the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a functional block diagram showing a thermal control device in accordance with an embodiment of the present invention. As shown in FIG. 1 , the thermal control device 100 includes a temperature control module 110 and a heating and cooling module 120 .

The temperature control module 110 includes a controller 111 and a memory unit 112. In an embodiment, the controller 111 can be, for example, a general-purpose processor, a digital signal processor (DSP), or a microcontroller, but the present invention Not limited to this.

The memory unit 112 includes a volatile memory 112A and a non-volatile memory 112B. The volatile memory 112A may be, for example, a static random access memory (SRAM) or a dynamic random access memory (DRAM), but the present invention is not limited thereto. The non-volatile memory 112B can be, for example, a read only memory (ROM), an electronic erasable programmable read only memory (EEPROM), a hard disk, or a solid-state disk. However, the invention is not limited thereto.

In one embodiment, the non-volatile memory 112B stores a temperature inference mechanism 114 (which may be, for example, an application or code) and a temperature model 115, the details of which will be detailed later.

The heating and cooling module 120 includes one or more containers 121, a heating base 123, a thermoelectric cooling device (TEC device) 124, and a temperature sensor 125. The container 121 contains an experimental liquid 122, such as a polymerase, for example during a polymerase chain reaction. In other experiments, the experimental liquid can be a different type of liquid.

The container 121 is placed on the substrate 123. The substrate 123 may also be referred to as a heating substrate. For example, the substrate may be made of a material that is easy to conduct heat, such as a metal. However, the present invention is not limited thereto. The heating chiller 124 is based on a control signal 113 from one of the controllers 111 for heating or cooling. The heating refrigerator 124 can be, for example, a thermoelectric cooling IC or a heating and cooling device that can be realized by a conventional electric heater and a fan.

A temperature sensor 125 is disposed on the substrate 123 to instantly measure the current substrate temperature of the substrate 123 and report the current substrate temperature to the controller 111 through a temperature feedback signal 116.

For example, the heating chiller 124 can heat or cool the test liquid 122 in the container 121 through the substrate 123. Because the PCR process requires a plurality of heating and cooling cycles (for example, a PCR cycle) for the test liquid 122 (for example, a polymerase), and the objective is to allow the test liquid 122 to heat up to a temperature during the heating and cooling cycle. a temperature threshold (eg, a specific temperature range between 90 and 95 degrees C), and a temperature drop to a second temperature threshold (eg, a specific temperature range between 40 and 60 degrees C), wherein The first temperature threshold and the second temperature threshold are adjusted depending on the type and characteristics of the experimental liquid 122.

However, when using the polymerase chain reaction process, if The instrumental measurement of the liquid temperature of the test liquid 122 will not be convenient, so the polymerase chain reaction equipment generally cannot measure the liquid temperature. In addition, conventional polymerase chain reaction devices are unable to calculate the current liquid temperature in real time based on the measured substrate temperature.

Figure 2 is a schematic diagram showing a temperature model in accordance with an embodiment of the present invention. The invention can establish a temperature model between the liquid temperature and the substrate temperature before performing the polymerase chain reaction process, for example, the experimental statistical results in multiple environments and the mathematical convergence analysis can be performed to obtain the liquid temperature and the substrate. Temperature model between temperatures. The temperature model records a relationship model between substrate temperature and liquid temperature, wherein the relationship model can be expressed, for example, by the following equation: T _{l_predicted} ( n ) = α . T _{l_predicte d} ( n -1) + β . T _{c_measure d} ( n -1)+ k (1)

Where T _{l_predicted} (n) is the predicted current liquid temperature; T _{l_predicted} (n-1) is the liquid temperature predicted at the previous time point; T _{c_measured} (n-1) is the substrate measured at the previous time point Temperature; α and β are model parameters; k is the temperature model compensation coefficient, which is used to compensate the temperature model and mistakenly believes that its output has reached the target liquid temperature (Note: there is still an error between the actual liquid temperature and the target liquid temperature).

In some embodiments, the temperature model compensation coefficient k can be calculated to temperature compensate for the predicted liquid temperature output by the temperature model. In some embodiments, the temperature model compensation coefficient k can be mathematically integrated into the parameters of other temperature models, so the temperature model compensation coefficient k can be omitted. The graph of the temperature model is shown in Fig. 2, in which the X-axis is the substrate temperature and the Y-axis is the liquid temperature. As shown in Figure 2, in a single PCR cycle, the temperature of the liquid changes as the substrate temperature increases or decreases. For example, starting from point 210 in curve 200 of the temperature model, as the substrate temperature increases, the liquid temperature first moves to the right along curve 210. When the warming up process is completed and the temperature begins to cool down, the liquid temperature will move from the point 220 at the right point to the left along the curve 200. It should be noted that the curve 200 is only a schematic diagram, and it does not mean that the reaction of the PCR is necessarily the temperature model represented by the curve 200.

In the conventional thermal control device, experience can be used to pre-establish a temperature lookup table, but in the actual temperature control process, it is not possible to immediately respond to slight temperature dynamic changes. In addition, conventional thermal controls do not reflect the effects of tolerances on machine assembly.

In one embodiment, the controller 111 can read the temperature inference mechanism application and the temperature model stored in the non-volatile memory 112B to the volatile memory 112A and perform a temperature inference mechanism (for example, can be fuzzy logic ( Fuzzy logic), or other type of inference algorithm), wherein the temperature inference mechanism can calculate a desired temperature of a substrate according to a temperature model and one or more liquid desired temperatures, and the controller 111 can be based on The calculated desired temperature of the substrate is subjected to temperature control (for example, temperature rise or temperature reduction) of the heating refrigerator 124 in the heating and cooling module 120, thereby allowing the liquid of the test liquid contained in the container 121 in the heating and cooling module 120 to be heated. The temperature actually reaches the desired liquid desired temperature.

For example, the temperature inference method performed by the controller 111 can utilize the predicted liquid temperature and a desired liquid temperature output by the temperature model as inputs and generate a target substrate temperature. The controller 111 can update the substrate target reference temperature table according to the target substrate temperature.

Figure 3 is a flow chart showing a method of inferring a target substrate temperature in accordance with an embodiment of the present invention. As shown in Figure 3, the temperature rise and temperature down processes in the PCR cycle can be treated separately. For example, during the temperature rise of the PCR cycle, the desired liquid temperature can be set to a first temperature threshold, for example, a specific temperature between 90 and 95 degrees C or a specific temperature interval, and the temperature of the liquid is predicted to rise to the first The temperature threshold is maintained and maintained for a predetermined period of time. During the cooling of the PCR cycle, the desired liquid temperature can be set to a second temperature threshold, such as a specific temperature between 40 and 60 degrees C or a specific temperature interval, and the temperature of the liquid is predicted to drop to the first temperature. After the threshold is maintained and maintained for a predetermined period of time.

For example, taking the upper half of FIG. 3 as an example, which represents the temperature rising process of the temperature control cycle, in step S310, a current substrate temperature is obtained and a temperature model is used to calculate a predicted liquid according to the target substrate temperature. Temperature, for example 96.4 degrees C.

At step S315, a temperature model compensation coefficient is utilized to adjust the predicted liquid temperature. The temperature model compensation coefficient is the temperature model compensation coefficient k described in the foregoing embodiment. In some embodiments, the temperature model compensation coefficient k can be mathematically integrated into the parameters of other temperature models, in which case the temperature model compensation coefficient k and step S315 can be omitted.

In step S320, a temperature inference mechanism is executed to generate a target substrate temperature based on the predicted liquid temperature and a desired liquid temperature. For example, the temperature inference mechanism may directly generate the target substrate temperature according to the predicted liquid temperature and the desired liquid temperature, or may generate a target substrate temperature correction value, which represents a difference between the target substrate temperature and the current substrate temperature. value. If the target substrate temperature correction value is a positive value, it means that the current substrate temperature needs to be increased. If the target substrate temperature is corrected to a negative value, it means that the current substrate temperature needs to be lowered to reach the target substrate temperature.

In step S325, the current substrate temperature is adjusted to the target substrate temperature.

For example, when the desired liquid temperature is higher than the predicted liquid temperature, that is, the current substrate temperature needs to be increased to raise the temperature of the experimental liquid 122, the target substrate temperature correction value may be a positive value, for example, the current substrate temperature may be added. The target substrate temperature correction value is taken as the target substrate temperature. When the liquid temperature is lower than the predicted liquid temperature, it means that the current substrate temperature needs to be lowered to cool the experimental liquid 122, so the target substrate temperature correction value may be a negative value, for example, the current substrate temperature may be added to the target substrate temperature correction. The value is used as the target substrate temperature, or the target substrate temperature is directly calculated and adjusted.

At step S330, it is determined whether the current temperature control loop is an end point condition. If so, the control of adjusting the temperature is ended (step S370). If not, the process returns to step S310, and the temperature control loop is repeated. It should be noted that the above end condition may be a predetermined value. For example, the PCR process needs to repeat a plurality of PCR cycles, which is the number of PCR cycles to be repeated. For example, if the 16th predicted liquid temperature has met the target liquid temperature condition, the control of the adjusted temperature is ended when the 16th temperature control cycle is completed.

The flow of steps S310 to S330 illustrates the temperature target substrate temperature inference process in the temperature control cycle, and the steps S340 to S360 of the lower half of FIG. 3 illustrate the temperature reduction target substrate in the temperature control cycle. Temperature inference process. The process of steps S340~S360 is similar to step S310. ~S330.

In step S340, a current substrate temperature is obtained and a temperature model is used to calculate a predicted liquid temperature, for example, 60.4 degrees C.

At step S345, a temperature model compensation coefficient is utilized to adjust the predicted liquid temperature. The temperature model compensation coefficient is the temperature model compensation coefficient k described in the foregoing embodiment. In some embodiments, the temperature model compensation coefficient k can be mathematically integrated into the parameters of other temperature models, in which case the temperature model compensation coefficient k and step S345 can be omitted.

In step S350, a temperature inference mechanism is executed to generate a target substrate temperature based on the predicted liquid temperature and a desired liquid temperature. For example, the temperature inference mechanism may directly generate the target substrate temperature according to the predicted liquid temperature and a first desired liquid temperature, or may generate a target substrate temperature correction value, which is between the target substrate temperature and the current substrate temperature. The difference. If the target substrate temperature correction value is a positive value, it means that the current substrate temperature needs to be raised to reach the target substrate temperature. If the target substrate temperature correction value is a negative value, it means that the current substrate temperature needs to be cooled to reach the target substrate. temperature. It should be noted that the second desired liquid temperature in step S350 is different from the first desired liquid temperature in step S320.

In step S355, the current substrate temperature is adjusted to the target substrate temperature.

For example, when the desired liquid temperature is higher than the predicted liquid temperature, that is, the current substrate temperature needs to be increased to raise the temperature of the experimental liquid 122, the target substrate temperature correction value may be a positive value, for example, the current substrate temperature may be used. The target substrate temperature correction value is added as the target substrate temperature. When the liquid temperature is lower than the predicted liquid temperature, it means that the current substrate temperature needs to be lowered to cool the experimental liquid 122, so the target substrate temperature correction value may be a negative value, for example, the current substrate temperature may be added to the target substrate temperature correction. The value is taken as the target substrate temperature.

In step S360, it is determined whether the current temperature control loop is an end point condition. If so, the control of adjusting the temperature is ended (step S370). If not, the process returns to step S340, and the temperature control loop is repeated. It should be noted that the above end condition may be a predetermined value. For example, the PCR process needs to repeat a plurality of PCR cycles, which is the number of PCR cycles to be repeated. For example, if the 16th predicted liquid temperature has met the target liquid temperature, the control of the adjusted temperature is ended when the 16th temperature control cycle is completed.

In some embodiments, steps S340-S360 in the flow of FIG. 3 may be omitted, that is, the temperature of the experimental liquid can be controlled by the upper half of the temperature control loop.

It should be noted that the target temperature inference method in the present invention is not limited to the PCR process only. The target temperature inference method in the present invention can utilize the virtual temperature model and the temperature inference mechanism to repeat the temperature control loop to accurately control the waiting process. The temperature of the object (for example, a specific experimental liquid) is measured and applied to a situation in which the temperature of the object to be tested cannot be directly measured by the temperature sensor.

Figure 4 is a flow chart showing a thermal control method in accordance with an embodiment of the present invention. It should be understood that the target temperature inference method in FIG. 3 of the present invention is not limited to the PCR process, but can be widely applied to two of the thermal control devices. Temperature control at different locations. Please also refer to Figures 1 and 4.

In step S410, a first current temperature of one of the first positions of the heating and cooling module 120 is measured by the temperature sensor 125. For example, the first position may be, for example, the position of point B in FIG. 1 .

In step S420, the first current temperature at the first position is adjusted by the heating refrigerator 124.

In step S430, a predicted temperature of one of the second positions in the heating and cooling module is calculated based on the first current temperature at the first position and a temperature model. For example, the second position may be, for example, the point A of FIG. 1 , and the temperature model is a temperature relationship model between the first position and the second position.

In step S440, a first target temperature of the first position is automatically adjusted according to the calculated predicted temperature of the second position and a desired temperature of the second position.

In step S450, the heating refrigerator is controlled to automatically adjust the first current temperature of the first position to reach the first target temperature.

For example, as shown in Figure 1, the position of the object to be tested at position A (for example, a second position), and the temperature sensor is not directly used to measure the current position of the object to be tested at the point A. temperature. The point B (for example, a first position) is equipped with a temperature sensor that directly measures the current temperature of the substrate 123. The controller 111 can obtain the current temperature of the position B, and utilize the temperature model between the first position and the second position and the target temperature inference mechanism to repeat the temperature control cycle through the target temperature inference method of the present invention. Controlling the current state of the object to be tested (eg, a specific experimental liquid) that cannot be directly measured at point A temperature.

In summary, the present invention provides a thermal control device and a thermal control method thereof, which can utilize a virtual temperature model and a temperature inference mechanism to repeatedly perform a temperature control cycle to accurately control an object to be tested (eg, a specific experimental liquid, such as The temperature of the polymerase) can be applied to a situation where the temperature of the object to be tested cannot be directly measured by the temperature sensor.

The present invention has been disclosed in the above preferred embodiments, and is not intended to limit the scope of the present invention. Any one of ordinary skill in the art can make a few changes without departing from the spirit and scope of the invention. The scope of protection of the present invention is therefore defined by the scope of the appended claims.

Claims (10)

A thermal control device includes: a controller; and a heating and cooling module, comprising: a temperature sensor for measuring a first current temperature of a first position of the heating and cooling module; And a heating chiller for adjusting the first current temperature at the first position based on a control signal from the controller, wherein the controller is based on the first current temperature at the first position and a temperature model between the first position and a second position in the heating and cooling module to calculate a predicted temperature at the second position, wherein the controller is further configured according to the calculated second position The predicted temperature and a desired temperature of the second position to automatically adjust a first target temperature of the first position, and controlling the heating refrigerator to automatically adjust the first current temperature of the first position to reach the first target temperature. The thermal control device of claim 1, wherein the heating and cooling module further comprises a container and a substrate, wherein the container is for holding an experimental liquid in the second position, and the heating is cooled The device controls the temperature of the experimental liquid in the container through the substrate. The thermal control device of claim 2, wherein the experimental liquid is a polymerase. The thermal control device of claim 1, wherein the controller performs a temperature inference mechanism, wherein the temperature inference mechanism is based on the first current temperature at the first location and the temperature model to calculate The heating causes The predicted temperature of the second location in the cold module. The thermal control device of claim 4, wherein the temperature inference mechanism is a fuzzy logic algorithm. A thermal control method for a thermal control device, wherein the thermal control device comprises a heating and cooling module, and the heating and cooling module comprises a temperature sensor and a heating refrigerator, the method comprises: utilizing The temperature sensor measures a first current temperature of one of the first positions of the heating and cooling module; and the first current temperature of the first position is adjusted by the heating refrigerator; a temperature model between the first current temperature of the position and the first position and a second position in the heating and cooling module to calculate a predicted temperature at the second position; The predicted temperature of the second position and a desired temperature of the second position to automatically adjust a first target temperature of the first position; controlling the heating refrigerator to automatically adjust the first current temperature of the first position to reach the first A target temperature. The thermal control method of claim 6, wherein the heating and cooling module further comprises a container and a substrate, wherein the container is for holding an experimental liquid in the second position, and the heating is cooled The device controls the temperature of the experimental liquid in the container through the substrate. The thermal control method of claim 7, wherein the experimental liquid is a polymerase. For example, the thermal control method described in claim 6 of the patent scope further includes: A temperature inference mechanism is implemented, wherein the temperature inference mechanism is based on the first current temperature at the first location and the temperature model to calculate the predicted temperature at the second location in the heating and cooling module. The thermal control method of claim 9, wherein the temperature inference mechanism is a fuzzy logic algorithm.