Temperature control method and device, sequencing system, electronic device, and storage medium

Abstract

The present disclosure provides a temperature control method and device, a sequencing system, an electronic device and a storage medium. The temperature control method comprises: in a first sequencing cycle, when it is determined that the temperature control is in a stable state based on an acquisition temperature of a first temperature sensor and a preset initial control temperature, obtaining an initial internal temperature acquired based on a second temperature sensor; after the first sequencing cycle ends, in a non-first sequencing cycle, obtaining a current internal temperature acquired based on the second temperature sensor, and calculating a current control temperature according to the current internal temperature, the initial control temperature and the initial internal temperature; and performing temperature control on a sequencing chip according to the current control temperature. The embodiments of the present application can improve the accuracy of temperature control on the sequencing chip.

Description

TECHNICAL FIELD

[0001] The present disclosure relates to the technical field of bioinformatics, and particularly relates to a temperature control method and device, a sequencing system, an electronic device and a storage medium. BACKGROUND

[0002] Nanopore sequencing is a fourth-generation sequencing technology, and the core of nanopore sequencing is a sequencing chip. The sequencing chip reads sequences in real time by detecting the current change caused by the DNA molecule passing through the nanopore. Nanopore sequencing has the advantages of long read length and fast speed.

[0003] However, the sequencing chip generates heat when working, resulting in temperature rise and fluctuation. This situation will affect the accuracy, speed and stability of sequencing, and therefore the temperature of the chip needs to be accurately controlled.

[0004] Currently, temperature control can be performed based on a PID method. However, the temperature input into the PID temperature control system in the related art can have low accuracy, thereby affecting the accuracy of temperature control based on the PID temperature control system. SUMMARY

[0005] The main purpose of the embodiments of the present application is to provide a temperature control method and device, a sequencing system, an electronic device and a storage medium, which aims to improve the accuracy of temperature control of the sequencing chip.

[0006] To achieve the above-mentioned purpose, a first aspect of the embodiments of the present application provides a temperature control method applied to a sequencing chip, the sequencing chip comprising a substrate, a first temperature sensor and a signal processing chip, the first temperature sensor and the signal processing chip being arranged on the substrate, and the first temperature sensor being arranged within a preset range in the circumference of the signal processing chip, and the signal processing chip internally being provided with a second temperature sensor, the method comprising:

[0007] In a first sequencing cycle, when it is determined that the temperature control is in a stable state based on the collected temperature of the first temperature sensor and a preset initial control temperature, an initial internal temperature collected based on the second temperature sensor is obtained;

[0008] After the first sequencing cycle, in a non-first sequencing cycle, a current internal temperature collected based on the second temperature sensor is obtained, and a current control temperature is calculated according to the current internal temperature, the initial control temperature and the initial internal temperature;

[0009] The sequencing chip is controlled according to the current control temperature.

[0010] In some embodiments, the current control temperature is calculated according to the current internal temperature, the initial control temperature and the initial internal temperature, comprising:

[0011] The internal temperature change value is calculated according to the current internal temperature and the initial internal temperature;

[0012] The current control temperature is determined according to deviation data of the initial control temperature and the internal temperature change value.

[0013] In some embodiments, determining the current control temperature according to deviation data of the initial control temperature and the internal temperature change value comprises:

[0014] The temperature calibration coefficient is determined according to the current sequencing speed of the sequencing chip after the first sequencing period ends;

[0015] The internal temperature change value is temperature calibrated according to the temperature calibration coefficient to obtain a calibrated temperature;

[0016] The current control temperature is determined according to deviation data of the initial control temperature and the calibrated temperature.

[0017] In some embodiments, determining the temperature calibration coefficient according to the current sequencing speed of the sequencing chip after the first sequencing period ends comprises:

[0018] After the first sequencing period ends, the current sequencing speed of the sequencing chip is obtained;

[0019] A preset standard sequencing speed and a standard sequencing temperature are obtained, and the temperature calibration coefficient is calculated according to the standard sequencing speed, the standard sequencing temperature and the current sequencing speed.

[0020] In some embodiments, the method for determining that the temperature control is in a stable state based on the collected temperature of the first temperature sensor and the preset initial control temperature comprises:

[0021] In the first sequencing period, the sequencing chip is temperature controlled according to the initial control temperature, and an initial external temperature collected by the first temperature sensor is obtained;

[0022] When deviation data of the initial external temperature and the initial control temperature is less than or equal to a preset threshold, it is determined that the temperature control is in a stable state;

[0023] When the deviation data of the initial external temperature and the initial control temperature is greater than the preset threshold, the sequencing chip is temperature controlled again according to the initial control temperature.

[0024] To achieve the above object, a second aspect of the embodiments of the present application proposes a sequencing system, the system comprising:

[0025] The sequencing chip as in the first aspect;

[0026] The temperature control system is used for temperature controlling the sequencing chip according to the method as in the first aspect.

[0027] In some embodiments, the temperature control system comprises:

[0028] A refrigeration device, the refrigeration device is connected with the sequencing chip;

[0029] A temperature control device, the temperature control device is used for controlling the refrigeration device to heat or refrigerate according to a current control temperature, so that the acquisition temperature of the second temperature sensor is equal to an initial control temperature.

[0030] To achieve the above object, the third aspect of the embodiment of the present application proposes a temperature control device, the device is applied to a sequencing chip, the sequencing chip comprises a substrate, a first temperature sensor and a signal processing chip, the first temperature sensor and the signal processing chip are arranged on the substrate, and the first temperature sensor is arranged in a preset range of the signal processing chip in a circumferential direction, the signal processing chip is internally provided with a second temperature sensor, and the device comprises:

[0031] A first temperature acquisition unit, configured to acquire an initial internal temperature acquired based on the second temperature sensor when it is determined that the temperature control is in a stable state based on the acquisition temperature of the first temperature sensor and a preset initial control temperature in a first sequencing period;

[0032] A second temperature acquisition unit, configured to acquire a current internal temperature acquired based on the second temperature sensor in a non-first sequencing period after the first sequencing period, and to calculate a current control temperature according to the current internal temperature, the initial control temperature and the initial internal temperature;

[0033] A temperature control unit, configured to control the temperature of the sequencing chip according to the current control temperature.

[0034] To achieve the above object, the fourth aspect of the embodiment of the present application proposes an electronic device, comprising a memory and a processor, the memory stores a computer program, and the processor implements the method of the first aspect when executing the computer program.

[0035] To achieve the above object, the fifth aspect of the embodiment of the present application proposes a computer readable storage medium, the storage medium stores a computer program, and the computer program is executed by a processor to implement the method of the first aspect.

[0036] The temperature control method and device, the sequencing system, the electronic device and the storage medium provided in the embodiments of the present application can determine that the temperature control is in a stable state based on the collected temperature of the first temperature sensor in the first sequencing cycle, and obtain the initial internal temperature of the signal processing chip in the stable state. Then, in the non-first sequencing cycle, the initial internal temperature and the initial internal temperature of the signal processing chip are introduced to calculate the current control temperature. As can be seen, the embodiments of the present application not only retain the high-precision characteristics of the first temperature sensor, but also take into account the real temperature inside the signal processing chip, thereby improving the accuracy of temperature control and making the sequencing speed of the sequencing chip more stable and the sequencing quality higher. BRIEF DESCRIPTION OF DRAWINGS

[0037] The accompanying drawings are included to provide a further understanding of the technical solutions of the present disclosure, and constitute a part of the specification, and are used together with the embodiments of the present disclosure to explain the technical solutions of the present disclosure, and do not constitute a limitation on the technical solutions of the present disclosure.

[0038] Figure 1 is a flowchart of a temperature control method provided by the embodiments of the present application;

[0039] Figure 2 is a schematic diagram of a sequencing chip provided by the embodiments of the present application;

[0040] Figure 3 is a flowchart of determining that the temperature control is in a stable state provided by the embodiments of the present application;

[0041] Figure 4 is Figure 1 is an embodiment flowchart of step S120 in the method;

[0042] Figure 5 is Figure 4 is an embodiment flowchart of step S420 in the method;

[0043] Figure 6 is a schematic diagram of a sequencing system provided by the embodiments of the present application;

[0044] Figure 7 is a flowchart of a specific embodiment of a temperature control method provided by the embodiments of the present application;

[0045] Figure 8 is a flowchart of another specific embodiment of a temperature control method provided by the embodiments of the present application;

[0046] Figure 9 is a schematic diagram of a temperature control device provided by the embodiments of the present application;

[0047] Figure 10 is a hardware structure schematic diagram of an electronic device provided by the embodiments of the present application. DETAILED DESCRIPTION

[0048] In order to make the purpose, technical solutions and advantages of the present disclosure clearer, the present disclosure will be further described in detail below in combination with the drawings and examples. It should be understood that the specific examples described herein are only used to explain the present disclosure and do not limit the present disclosure.

[0049] Firstly, the terms related to the embodiments of the present application are explained:

[0050] PID (Proportional-Integral-Derivative): It is a feedback control algorithm that calculates the error between the target value and the actual value in real time, and generates a control signal based on the current size of the error (proportion P), the historical accumulation (integral I) and the future trend of change (derivative D), so as to quickly, accurately and stably maintain the actual state of the system on the target set value.

[0051] Nanopore sequencing is the fourth generation sequencing technology, and the core of nanopore sequencing is the sequencing chip. The sequencing chip reads the sequence in real time by detecting the current change caused by the DNA molecule passing through the nanopore. Nanopore sequencing has the advantages of long read length and fast speed.

[0052] However, the sequencing chip generates heat when working, resulting in temperature rise and fluctuation. This situation will affect the accuracy, speed and stability of sequencing, so the temperature of the chip needs to be accurately controlled. The goal of temperature control is:

[0053] 1. Maintain enzyme activity: The sequencing process relies on the activity of helicase and motor protein. These enzymes are best active in a specific temperature range (usually between 25°C - 40°C, depending on the type and optimization of the enzyme). Temperature fluctuations can significantly affect enzyme activity and reaction rate, thereby affecting sequencing speed and accuracy.

[0054] 2. Stabilize nanopore current: Ionic current through the nanopore is the basis for detecting base signals. Temperature directly affects the viscosity of the solution, ion mobility and the electrical properties of the nanopore. Temperature changes will introduce background current noise, reduce signal-to-noise ratio, and affect the accuracy of base calling.

[0055] 3. Prevent local overheating: Electronic components on the sequencing chip (such as ASIC chips) generate heat when working. Local overheating can damage the chip or affect the microenvironment of the biochemical reaction above it.

[0056] 4. Ensure reaction consistency: Ensure the uniformity of the temperature of the entire chip surface (or each pore), so as to obtain consistent sequencing performance. The control accuracy and stability of the sequencing temperature directly affect the quality of the sequencing data output.

[0057] Currently, the feedback temperature of the temperature sensor arranged at the position close to the sequencing chip is taken as the input data of the PID temperature control system (i.e., as the actual value in the PID control algorithm), so as to realize temperature control. However, due to the temperature gradient between the actual temperature inside the sequencing chip and the temperature at the position close to the sequencing chip, the control temperature and the actual temperature inside the sequencing chip (such as the working area) are different, thereby affecting the temperature control precision.

[0058] Therefore, the embodiment of the present application provides a temperature control method and device, a sequencing system, an electronic device and a storage medium, so as to improve the accuracy of temperature control of the sequencing chip.

[0059] The temperature control method provided by the embodiment of the present application relates to the field of biological information technology. The temperature control method provided by the embodiment of the present application can be applied to a terminal, can be applied to a server end, and can also be software running in the terminal or the server end. In some embodiments, the terminal can be a smart phone, a tablet computer, a notebook computer, a desktop computer, etc.; the server end can be configured as a separate physical server, can be configured as a server cluster or a distributed system composed of multiple physical servers, can also be configured as a cloud server providing basic cloud computing services such as cloud service, cloud database, cloud computing, cloud function, cloud storage, network service, cloud communication, middleware service, domain name service, security service, CDN, and big data and artificial intelligence platform; and the software can be an application for implementing the temperature control method, but is not limited to the above forms.

[0060] The present application can be used in many general or special computer system environments or configurations. For example: personal computers, server computers, handheld devices or portable devices, tablet devices, multi-processor systems, microprocessor-based systems, set-top boxes, programmable consumer electronics, network PCs, minicomputers, mainframe computers, distributed computing environments including any of the above systems or devices, etc. The present application can be described in the general context of computer-executable instructions executed by a computer, such as program modules. Generally, program modules include routines, programs, objects, components, data structures, etc. that perform specific tasks or implement specific abstract data types. The present application can also be practiced in a distributed computing environment, in which tasks are performed by remote processing devices connected by a communication network. In a distributed computing environment, program modules can be located in local and remote computer storage media, including storage devices.

[0061] The temperature control method provided by the embodiment of the present application is described below.

[0062] Reference Figure 1 and Figure 2The temperature control method provided by the embodiments of the present application is applied to a sequencing chip, and the sequencing chip comprises a substrate, a first temperature sensor and a signal processing chip. The first temperature sensor and the signal processing chip are arranged on the substrate, and the first temperature sensor is arranged within a preset range in the circumference of the signal processing chip, and the signal processing chip is internally provided with a second temperature sensor. The temperature control method can comprise but is not limited to the following steps S110 to S130.

[0063] In step S110, in the first sequencing cycle, when it is determined that the temperature control is in a stable state based on the collected temperature of the first temperature sensor and the preset initial control temperature, the initial internal temperature collected based on the second temperature sensor is acquired.

[0064] In step S120, after the first sequencing cycle, in the non-first sequencing cycle, the current internal temperature collected based on the second temperature sensor is acquired, and the current control temperature is calculated according to the current internal temperature, the initial control temperature and the initial internal temperature.

[0065] In step S130, the temperature control of the sequencing chip is performed according to the current control temperature.

[0066] First, in order to facilitate understanding, the sequencing chip is first described. Specifically, as shown in Figure 2 The sequencing chip 200 can comprise a substrate 201, a first temperature sensor 202 and a signal processing chip 203. The substrate 201 can refer to a mechanical support and electrical connection platform of the sequencing chip 200, and the substrate 201 can usually be realized by a printed circuit board (such as a PCB). The first temperature sensor 202 is an independent high-precision temperature sensing unit, which can be directly installed on the substrate 201 and closely attached to the signal processing chip 203 (i.e. within a preset range in the circumference of the signal processing chip 203, and the size of the preset range is not limited, which can refer to the range of the area extending outward from the edge of the signal processing chip 203), so as to be able to sense the ambient temperature of the signal processing chip 203. "High precision" can refer to the fact that the first temperature sensor 202 can measure the absolute temperature value at the location with very small error. The first temperature sensor 202 can usually adopt a patch NTC thermistor, a digital temperature sensor chip, etc. The signal processing chip 203 can refer to a computing unit in the sequencing chip 200 for processing specific electrical signals generated by a nanopore, such as an ASIC chip. The signal processing chip 203 is installed on the substrate 201. The signal processing chip 203 can be internally integrated with a second temperature sensor. The second temperature sensor can have the characteristics of poor absolute temperature accuracy and good relative temperature accuracy, i.e. the second temperature sensor can capture the slight change of the internal temperature of the signal processing chip 203, but the temperature reading can have a large deviation from the actual temperature of the signal processing chip 203.

[0067] Since the first temperature sensor 202 collects the temperature of the environment in which the signal processing chip 203 is located, and the temperature may have a temperature gradient with the actual temperature inside the signal processing chip 203. Therefore, if the temperature collected by the first temperature sensor 202 is directly used for temperature control, the feedback temperature for temperature control cannot truly reflect the thermal state of the working area of the signal processing chip 203. Based on this, the present application provides a temperature control method, which uses the temperature collected by the second temperature sensor as the reference temperature for temperature control. In this way, the high-precision characteristics of the first temperature sensor 202 are retained, and the actual temperature inside the signal processing chip 203 is considered, thereby improving the accuracy of temperature control and making the sequencing speed of the sequencing chip 200 more stable and the sequencing quality higher.

[0068] As follows, the temperature control method provided by the embodiment of the present application is specifically described.

[0069] In step S110 of some embodiments, the first sequencing cycle can refer to the first complete running cycle after the start of the entire sequencing process. In the first sequencing cycle, the temperature control system is activated for the first time and attempts to establish a stable thermal environment. Specifically, the temperature collected by the first temperature sensor in real time can be used as a feedback signal, and a temperature control actuator (i.e., a device capable of heating or cooling, so as to cool or heat the signal processing chip) is driven to work through, for example, a PID control algorithm, so that the temperature collected by the first temperature sensor is accurately maintained at an initial control temperature (denoted as TSV0, i.e., the initial control temperature is used as the target temperature of the PID control algorithm, and the collection temperature of the first temperature sensor is used as the actual temperature of the PID control algorithm). The initial control temperature TSV0 can refer to a pre-set target value, which is usually determined by the optimal temperature condition required for biochemical reactions in sequencing. When it is determined based on the collection temperature of the first temperature sensor that the current temperature has reached a “stable” state (e.g., the temperature collected by the first temperature sensor has a small fluctuation relative to the initial control temperature TSV0 within a pre-set time period), the temperature value measured by the second temperature sensor integrated in the signal processing chip (i.e., the initial internal temperature, denoted as TAV0) is read and recorded.

[0070] In some embodiments, with reference to Figure 3 The method for determining that the temperature control is in a stable state based on the collection temperature of the first temperature sensor and the initial control temperature can include, but is not limited to, steps S310 to S330.

[0071] Step S310, in the first sequencing cycle, the sequencing chip is controlled according to the initial control temperature, and the initial external temperature collected by the first temperature sensor is obtained;

[0072] Step S320, when the deviation data of the initial external temperature and the initial control temperature is less than or equal to the preset threshold, it is determined that the temperature control is in a stable state;

[0073] Step S330, when the deviation data of the initial external temperature and the initial control temperature is greater than the preset threshold, the temperature control of the sequencing chip is performed again according to the initial control temperature.

[0074] In step S310 of some embodiments, in the first sequencing cycle, the collected temperature of the first temperature sensor (referred to as the initial external temperature) can be obtained, and the initial external temperature is compared with the target temperature (i.e. the initial control temperature TSV0) to generate an error signal. The error signal can be processed by a PID control algorithm, and then drive the temperature control actuator to heat or cool, so as to realize the temperature control of the sequencing chip. After driving the temperature actuator, the initial external temperature collected by the first temperature sensor can also be continuously obtained, and the initial external temperature at this time reflects the real-time thermal state of the external region of the signal processing chip after the temperature control is performed.

[0075] In step S320 of some embodiments, the initial external temperature is compared with the initial control temperature TSV0, and it is judged whether the absolute value of the deviation data of the two is less than or equal to the preset threshold. The preset threshold can refer to the pre-set allowable error range (such as an error of plus or minus 0.2°C), and the specific value of the preset threshold can be adaptively set according to actual needs, which is not limited. The deviation data can refer to the difference between the two temperatures (such as the initial external temperature and the initial control temperature TSV0), or the result obtained by other processing (such as weighting) on the difference.

[0076] When the judgment result indicates that the absolute value of the deviation data of the initial external temperature and the initial control temperature TSV0 is less than or equal to the preset threshold, it indicates that the initial external temperature ≈ the initial control temperature TSV0. At this time, if the initial external temperature ≈ the initial control temperature TSV0 still holds within the subsequent preset time (the value is not limited), it can be considered that the temperature control is in a stable state, and the initial external temperature corresponding to the stable state is recorded as TPV0. The "stable state" indicates that the first temperature sensor with high precision is used as an observation point, and the temperature fluctuation of the first temperature sensor has been controlled in an acceptable extremely small range, and the temperature control system enters a dynamic balance.

[0077] In step S330 of some embodiments, when the judgment result indicates that the absolute value of the deviation data of the initial external temperature and the initial control temperature TSV0 is greater than the preset threshold, it indicates that the current control has not made the temperature enter the stable interval. Therefore, the temperature actuator needs to be driven again according to the initial control temperature TSV0 for temperature control, and the operation is repeated multiple times until the initial external temperature ≈ the initial control temperature TSV0 and lasts for a preset time.

[0078] The embodiment of the application takes a high-precision external first temperature sensor as feedback, takes the initial control temperature TSV0 determined based on a biochemical reaction as a target, introduces a preset threshold stability state determination mechanism, and constructs an initialization process based on the data in a loop feedback. In this way, a stable initial state can be established in the first sequencing cycle, thereby providing an important prerequisite for accurately capturing the correlation between the internal temperature of the signal processing chip and the external control target in subsequent cycles.

[0079] In step S120 of some embodiments, in other sequencing cycles (i.e., non-first sequencing cycles) after the first sequencing cycle, for each non-first sequencing cycle (such as the Xth sequencing cycle), the current internal temperature (denoted as TAV X ) collected by the second temperature sensor can be acquired in real time or periodically. X The current internal temperature TAV X reflects the internal real-time temperature of the signal processing chip during the working process after the first sequencing cycle due to the heat generated by the dynamic power consumption of the circuit itself. Then, the current control temperature TSV X can be calculated based on the current internal temperature TAV X , the initial control temperature TSV0 and the initial internal temperature TAV0. It can be understood that the sequencing cycle can be determined according to a preset sequencing time length, a preset number of cycles (a cycle can refer to a complete and repeatable biochemical reaction step), etc., and no specific limitation is made thereto.

[0080] Referring to Figure 4 , in some embodiments, the step of calculating the current control temperature according to the current internal temperature, the initial control temperature and the initial internal temperature in step S120 can include but is not limited to steps S410 to S420.

[0081] In step S410, an internal temperature change value is calculated according to the current internal temperature and the initial internal temperature.

[0082] In step S420, the current control temperature is determined according to the deviation data of the initial control temperature and the internal temperature change value.

[0083] In step S410 of some embodiments, the internal temperature change value =TAV X -TAV0 is calculated according to the current internal temperature TAV X and the initial internal temperature TAV0. The internal temperature change value quantifies the thermal state change of the core working area of the signal processing chip after the initial stable state. When the internal temperature change value When the internal temperature change value is positive, it indicates that heat is accumulated in the signal processing chip due to its own circuit power consumption, etc., resulting in a current temperature higher than the initial reference (i.e., the initial internal temperature TAV0 collected in the stable state). When the internal temperature change value is negative, it indicates that the internal temperature of the signal processing chip is lower than the initial reference, which may be due to changes in the environment or heat dissipation conditions. However, whether the internal temperature change value is positive or negative, a larger internal temperature change value will affect the biochemical reaction.

[0084] In step S420 of some embodiments, the current control temperature TSV may be calculated according to the initial control temperature TSV0 and the internal temperature change value X = TSV0- It can be seen that this method of determining the current control temperature TSV X is a reverse compensation method, for example, when it is detected that the internal temperature of the signal processing chip has increased (i.e., the internal temperature change value is positive), the target temperature is set to the current control temperature TSV X , and the corresponding value is reduced (i.e., TSV X < TSV0). In this way, the temperature control actuator can be driven to cool, so that the temperature of the internal working area of the signal processing chip can be pulled back to the initial control temperature TSV0, so that the sequencing chip can still be maintained within the optimal biochemical reaction temperature range.

[0085] The embodiments of the present application realize reverse and equal dynamic compensation based on the initial control temperature TSV0, so that the working area of the signal processing chip can be dynamically temperature controlled, so that the temperature of the working area of the signal processing chip is consistent with the initial control temperature TSV0, which ensures the accuracy and reliability of the sequencing results.

[0086] Referring to Figure 5 , in some embodiments, step S420 can include but is not limited to steps S510 to S530.

[0087] Step S510, determining a temperature calibration coefficient according to the current sequencing speed of the sequencing chip after the first sequencing cycle ends;

[0088] Step S520, temperature calibrating the internal temperature change value according to the temperature calibration coefficient to obtain a calibrated temperature;

[0089] Step S530, determining a current control temperature according to the deviation data of the initial control temperature and the calibrated temperature.

[0090] In step S510 of some embodiments, the current sequencing speed SRV0 can refer to an effective data processing speed of successfully completing base recognition and outputting sequence information per unit time, such as the length of a DNA strand passing through a nanopore and performing base recognition, or the number of bases processed per unit time, etc. The current sequencing speed SRV0 reflects the comprehensive efficiency of biochemical reactions after the end of the first sequencing cycle (temperature control has reached a steady state). Thus, the temperature calibration coefficient TB can be determined according to the current sequencing speed SRV0, i.e., the temperature calibration coefficient TB can refer to a personalized offset correction value determined according to the current sequencing speed SRV0.

[0091] In some embodiments, step S510 can include but is not limited to the following steps:

[0092] After the end of the first sequencing cycle, the current sequencing speed of the sequencing chip is obtained;

[0093] The preset standard sequencing speed and standard sequencing temperature are obtained, and the temperature calibration coefficient is calculated according to the standard sequencing speed, the standard sequencing temperature, and the current sequencing speed.

[0094] In the embodiments of the present application, after the end of the first sequencing cycle, the current sequencing speed SRV0 of the sequencing chip is obtained, and the standard sequencing speed S and the standard sequencing temperature T are obtained. The standard sequencing speed S can refer to the best or target sequencing speed that the sequencing chip can reach in an ideal working state, and the standard sequencing temperature T can refer to the theoretical optimal working temperature corresponding to the standard sequencing speed S. Thus, the temperature calibration coefficient TB = (SRV0-S) / T can be calculated according to the current sequencing speed SRV0, the standard sequencing speed S, and the standard sequencing temperature T, i.e., the deviation between the actual performance (SRV0) and the ideal performance (S) is converted into a temperature compensation amount according to a standardized temperature coefficient (1 / T).

[0095] In step S520 of some embodiments, after the temperature calibration coefficient TB is determined, the internal temperature change value is calibrated according to the temperature calibration coefficient TB to obtain a calibrated temperature. For example, the calibrated temperature = +TB. By introducing the temperature calibration coefficient TB for temperature calibration, the temperature control target is changed from the original target (i.e., mechanically stabilizing the internal temperature at the initial TSV0) to intelligently setting the temperature to a more optimal personalized temperature that enables the sequencing speed to approach the standard sequencing speed S.

[0096] In step S530 of some embodiments, after the calibrated temperature is determined, the current control temperature TSV X can be calculated according to the calibrated temperature and the initial control temperature TSV0. For example, the current control temperature TSV X= TSV0 - (TB Therefore, the target temperature TSV X is adjusted by the dual adjustment of the internal physical temperature change (TB ) of the signal processing chip and the biochemical performance deviation (TB) of the signal processing chip.

[0097] The method for calculating the current control temperature TSV X by introducing the temperature calibration coefficient TB, realizes the dynamic fine tuning of the optimal working temperature of each independent sequencing chip, thereby ensuring that the sequencing speed of different sequencing chips and different sequencing cycles of the same sequencing chip is highly consistent and close to the theoretical optimal value.

[0098] In step S130 of some embodiments, the current control temperature TSV X is taken as the new target temperature in the current non-first sequencing cycle. In this way, the temperature control actuator can be driven based on the current control temperature TSV X so that the temperature collected by the first temperature sensor reaches and stabilizes at TSV X as soon as possible. It can be understood that, since the current control temperature TSV X is a compensatory adjustment for the internal temperature change, the process of driving the external temperature to TSV X is essentially equivalent to applying a reverse heat flow to the signal processing chip to offset the internal temperature fluctuation of the signal processing chip, thereby indirectly but accurately maintaining or pulling back the internal temperature of the signal processing chip to a level close to the initial stable state TAV0. In addition, steps S120 and S130 can be executed in a loop until all non-first sequencing cycles are completed.

[0099] The embodiment of the present application sets a first temperature sensor outside the signal processing chip and a second temperature sensor integrated in the chip, and proposes a dynamic target temperature compensation mechanism. After the corresponding relationship between the internal and external temperatures is established in the first sequencing cycle (i.e. in the stable state, the initial internal temperature TAV0 is recorded, that is, the corresponding relationship between the external target temperature TSV0 and the internal temperature TAV0 in the stable state is determined), in the subsequent non-first sequencing cycle, the internal temperature change of the signal processing chip is collected in real time, and the target temperature of the external temperature control actuator is adjusted in the reverse direction dynamically according to the internal temperature change, so as to effectively compensate the temperature gradient between the internal working area of the chip and the external sequencing point (i.e. the temperature range collected by the first temperature sensor) caused by the heat generated by the signal processing chip itself during work. In this way, the defects caused by the single external temperature sensor in the related art, which cannot perceive and respond to the real temperature change of the chip internal, are overcome, and finally the temperature of the sequencing chip working area is more accurately and stably controlled.

[0100] As shown in Figure 6 The embodiment of the present application also provides a sequencing system, which comprises the sequencing chip 200 and the temperature control system 100 as described in the foregoing embodiment. The temperature control system 100 is used for temperature control of the sequencing chip 200 according to the temperature control method as described in any of the foregoing embodiments.

[0101] It can be seen that the contents in the above-mentioned temperature control method embodiment are all applicable to the embodiment of the present sequencing system. The embodiment of the present sequencing system specifically realizes the same functions as the above-mentioned temperature control method embodiment, and achieves the same beneficial effects as the above-mentioned temperature control method embodiment.

[0102] In some embodiments, the temperature control system comprises a refrigeration component and a temperature control device. The refrigeration component can be connected with the sequencing chip 200. The temperature control device is used to control the refrigeration component to heat or cool according to the current control temperature, so that the collection temperature of the second temperature sensor is equal to the initial control temperature. Specifically, the refrigeration component is the aforementioned temperature control executor described in the embodiments, such as a semiconductor refrigerator TEC. When a direct current passes through the TEC, one end of the TEC absorbs heat (refrigeration), the other end releases heat (heating), and by changing the direction of the current, the heat flow direction can be conveniently switched, thereby realizing the bidirectional temperature control function of both refrigeration and heating. In this way, when one end of the refrigeration component is connected with the sequencing chip (specifically, the signal processing chip), the temperature control of the sequencing chip can be realized. Wherein, the "connection" can refer to a mechanical and physical combination mode capable of establishing an efficient heat conduction path, for example, the active temperature control surface of the refrigeration component can be attached to the signal processing chip through a thermal interface material such as thermal grease, thermal adhesive or thermal pad. In this way, it can be ensured that the cold or heat generated by the refrigeration component can be efficiently transferred to the signal processing chip. In addition, the waste heat surface generated by the refrigeration component can be timely discharged to the external environment through the combination of a heat sink and a fan.

[0103] The control algorithm (such as the PID control algorithm) can be integrated inside the temperature control device. The temperature control device can determine the temperature difference between the current control temperature TSV X and the current external temperature collected by the first temperature sensor, and generate a control signal based on the temperature difference using the PID control algorithm. Then, the temperature control device can accurately adjust the current size and direction of the refrigeration component based on the control signal, so that the refrigeration component performs a refrigeration or heating operation of corresponding intensity. In this way, the working zone temperature perceived by the second temperature sensor can be indirectly maintained at a temperature level corresponding to the initial stable state (i.e., the initial control temperature TSV0).

[0104] In a specific embodiment, the temperature control method provided by the embodiments of the present application can include two embodiments of embodiment 1 and embodiment 2. First, embodiment 1 is described.

[0105] As shown in Figure 7 , the temperature control method can include the following steps:

[0106] Step 701, start sequencing, start the temperature control system (i.e., the temperature control system).

[0107] Step 702, in the first sequencing period (i.e., the first sequencing period), set the initial control temperature TSV0according to the optimal temperature of the biochemical reaction (i.e., take the initial control temperature TSV0as the target temperature of the PID control algorithm).

[0108] Step 703, judge whether the temperature control reaches a steady state. When the initial external temperature collected by the first temperature sensor is equal to the initial control temperature TSV0 and lasts for a preset time length, it is confirmed that the steady state is reached. Otherwise, it is considered that the steady state is not reached, and the temperature control system continues to perform temperature control based on the initial control temperature TSV0 until the steady state is reached.

[0109] Step 704, record the current external temperature (i.e. the initial external temperature) fed back by the first temperature sensor in the steady state as TPV0, and record the current internal temperature TAV0 collected by the second temperature sensor in the steady state.

[0110] Step 705, judge whether the first sequencing cycle is ended. If not, continue to wait; if yes, execute step 706.

[0111] Step 706, in the Xth sequencing cycle (i.e. the non-first sequencing cycle), acquire the current internal temperature TAVX collected by the second temperature sensor. X .

[0112] Step 707, take the current control temperature TSVX X =TSV0- (wherein, =TAV X -TAV0)as the new target temperature of the PID control algorithm, i.e. based on the current control temperature TSVX X perform temperature control in the Xth sequencing cycle.

[0113] Step 708, judge whether the Xth sequencing cycle is ended. If yes, execute step 709; if not, continue to wait.

[0114] Step 709, judge whether the overall sequencing is ended (i.e. whether all sequencing cycles are executed). If yes, execute step 710; if not, return to step 706 to perform temperature control operation on the next sequencing cycle (e.g. the X+1th sequencing cycle).

[0115] Step 710, turn off the temperature control.

[0116] Secondly, the embodiment 2 is described.

[0117] As shown in FIG. 2, it is a flowchart of the temperature control method of the embodiment 2. The steps 701-705 are the same as those of the embodiment 1, and thus the descriptions of the steps 701-705 are the same as those of the embodiment 1. Figure 8 Figure 7 As shown in FIG. 2, it is a flowchart of the temperature control method of the embodiment 2. The steps 701-705 are the same as those of the embodiment 1, and thus the descriptions of the steps 701-705 are the same as those of the embodiment 1. Figure 8 Figure 8 As shown in FIG. 2, it is a flowchart of the temperature control method of the embodiment 2. The steps 701-705 are the same as those of the embodiment 1, and thus the descriptions of the steps 701-705 are the same as those of the embodiment 1. As shown in FIG. 2, it is a flowchart of the temperature control method of the embodiment 2. The steps 701-705 are the same as those of the embodiment 1, and thus the descriptions of the steps 701-705 are the same as those of the embodiment 1.​

[0118] Step 806: After the first sequencing cycle is completed, record the current sequencing speed SRV0 of the sequencing chip, and calculate the temperature calibration coefficient TB = (SRV0 - S) / T based on the current sequencing speed SRV0, the standard sequencing speed S, and the standard sequencing temperature T.

[0119] Step 808, set the current control temperature TSV. X =TSV0-( +TB)(wherein, =TAV X -TAV0) is used as the new target temperature for the PID control algorithm, i.e., based on the current control temperature TSV. X Temperature control is performed during the Xth sequencing cycle.

[0120] For example, assuming TSV0 is 30.00℃, under stable conditions in the first sequencing cycle, the temperature collected by the first temperature sensor is TPV0, which is 29.98℃, and the temperature collected by the second temperature sensor is TAV0, which is 31.50℃. If the current sequencing speed SRV0 obtained after the first sequencing cycle is 360bp / s, T is set to a temperature constant of 30.00℃, and the standard sequencing speed S is set to 350bp / s, then the temperature calibration coefficient TB = (SRV0 - S) / T ≈ 0.33℃ can be calculated.

[0121] In the Xth sequencing cycle (i.e., the second, third, etc., non-first sequencing cycles), assuming that the temperature TAV2 collected by the second temperature sensor is 32.00℃ in the second sequencing cycle, the current control temperature for the second sequencing cycle can be calculated as TSV2 = TSV0 - (TAV2 - TAV0 + TB) ≈ 29.17℃. Therefore, 29.17℃ can be used as the new target temperature for the temperature control system.

[0122] Using the method described above, the temperature collected by the second temperature sensor (i.e., TAV) can be obtained. X This serves as the input data for the temperature control system to calculate the target temperature, thus ensuring that the temperature of the signal processing chip's working area is consistent with the required sequencing temperature TSV0.

[0123] Understandably, in some embodiments, a high-efficiency heat dissipation system can be added to both the first temperature sensor and the signal processing chip to reduce the temperature difference between the temperature collected by the first temperature sensor and the internal temperature of the signal processing chip. Furthermore, the first temperature sensor can be positioned above the signal processing chip, allowing its readings to more accurately reflect the temperature of the signal processing chip's operating area.

[0124] Reference Figure 9The embodiment of the application further provides a temperature control device, which is applied to a sequencing chip, the sequencing chip comprises a substrate, a first temperature sensor and a signal processing chip, the first temperature sensor and the signal processing chip are arranged on the substrate, the first temperature sensor is arranged within a preset range in the circumference of the signal processing chip, the signal processing chip is internally provided with a second temperature sensor, and the device comprises:

[0125] The first temperature acquisition unit 910 is configured to acquire an initial internal temperature collected by the second temperature sensor when it is determined that the temperature control is in a stable state based on the collected temperature of the first temperature sensor and the preset initial control temperature in the first sequencing cycle.

[0126] The second temperature acquisition unit 920 is configured to acquire a current internal temperature collected by the second temperature sensor in the non-first sequencing cycle after the first sequencing cycle, and to calculate a current control temperature according to the current internal temperature, the initial control temperature and the initial internal temperature.

[0127] The temperature control unit 930 is configured to control the temperature of the sequencing chip according to the current control temperature.

[0128] It can be seen that the content in the above-mentioned embodiment of the temperature control method is applicable to the embodiment of the temperature control device, the embodiment of the temperature control device specifically realizes the same functions as the above-mentioned embodiment of the temperature control method, and achieves the same beneficial effects as the above-mentioned embodiment of the temperature control method.

[0129] Reference Figure 10 , Figure 10 The hardware structure of an electronic device of another embodiment is illustrated, and the electronic device comprises:

[0130] The processor 1001 can be implemented in a general-purpose CPU (Central Processing Unit), a microprocessor, an ASIC (Application Specific Integrated Circuit), or one or more integrated circuits, and is configured to execute related programs to implement the technical solutions provided by the embodiments of the application.

[0131] The memory 1002 can be implemented in the form of a read-only memory (ROM), a static storage device, a dynamic storage device, or a random access memory (RAM), etc. The memory 1002 can store an operating system and other application programs. When the technical solutions provided by the embodiments of the present specification are implemented by software or firmware, the related program codes are stored in the memory 1002 and are called and executed by the processor 1001 to perform the temperature control method of the embodiments of the present application.

[0132] The input / output interface 1003 is configured to realize information input and output.

[0133] The communication interface 1004 is configured to realize the communication interaction between the device and other devices. The communication can be realized by a wired manner (for example, a USB, a network cable, etc.) or a wireless manner (for example, a mobile network, WIFI, Bluetooth, etc.).

[0134] The bus 1005 is configured to transmit information between various components (for example, the processor 1001, the memory 1002, the input / output interface 1003, and the communication interface 1004) of the device.

[0135] The processor 1001, the memory 1002, the input / output interface 1003, and the communication interface 1004 are connected to each other through the bus 1005 to realize the communication connection between the device.

[0136] The embodiments of the present application also provide a computer program product, which includes a computer program. The processor of the computer device reads the computer program and executes it, so that the computer device executes the temperature control method.

[0137] The embodiments of the present application also provide a computer readable storage medium, which stores a computer program. The computer program is executed by the processor to realize the temperature control method.

[0138] The memory is a non-transitory computer readable storage medium, which can be used to store non-transitory software programs and non-transitory computer executable programs. In addition, the memory can include a high-speed random access memory and can also include a non-transitory memory, such as at least one magnetic disk storage device, a flash memory device, or other non-transitory solid-state memory device. In some embodiments, the memory can optionally include a memory remotely arranged relative to the processor, and these remote memories can be connected to the processor through a network. Examples of the above network include but are not limited to the Internet, an intranet, a local area network, a mobile communication network, and a combination thereof.

[0139] The embodiments described in the specification are for more clearly illustrating the technical solutions of the embodiments of the present application, and do not constitute a limitation on the technical solutions provided by the embodiments of the present application. Those skilled in the art can know that, with the evolution of technology and the appearance of new application scenarios, the technical solutions provided by the embodiments of the present application are also applicable to similar technical problems.

[0140] Those skilled in the art can understand that the technical solutions shown in the figures do not constitute a limitation on the embodiments of the present application, and can include more or fewer steps than shown in the figures, or combine certain steps, or different steps.

[0141] The device embodiments described above are only schematic, and the units described as separate components can or can not be physically separate, i.e., can be located in one place, or can be distributed on multiple network units. Part or all of the modules can be selected according to actual needs to achieve the purpose of the embodiments of the present application.

[0142] Those skilled in the art can understand that all or some of the steps in the above disclosed method, the functional modules / units in the system and the device can be implemented as software, firmware, hardware and their appropriate combinations.

[0143] The terms "first", "second", "third", "fourth" and the like (if any) in the specification and above-described drawings of the present application are used to distinguish similar objects, and do not necessarily have to be used to describe a specific order or sequence. It should be understood that the data used in this way can be interchanged under appropriate circumstances, so that the embodiments of the present application described herein can be implemented in an order other than those illustrated or described herein. In addition, the terms "include" and "have" and any variations thereof are intended to cover non-exclusive inclusion, for example, a process, method, system, product or device that includes a series of steps or units does not have to be limited to those steps or units clearly listed, but can include other steps or units that are not clearly listed or inherent to these processes, methods, products or devices.

[0144] It should be understood that, in the application, "at least one" refers to one or more, and "multiple" refers to two or more. "And / or" is used to describe the association relationship of the associated objects, which means that there can be three relationships, for example, "A and / or B" can represent three cases of only A, only B, and A and B existing at the same time, wherein A and B can be singular or plural. The character " / " generally represents an "or" relationship between the associated objects before and after it. "At least one of the following" or similar expressions means any combination of these items, including any combination of single or multiple items. For example, at least one of a, b or c can represent a, b, c, "a and b", "a and c", "b and c", or "a and b and c", wherein a, b, and c can be single or multiple.

[0145] In several embodiments provided in the application, it should be understood that the disclosed devices and methods can be implemented in other ways. For example, the device embodiments described above are only schematic, for example, the division of the above units is only a logical function division, and actual implementation can have another division manner, for example, a plurality of units or components can be combined or integrated into another system, or some features can be ignored or not executed. In addition, the coupling or direct coupling or communication connection between the displayed or discussed mutual ones can be indirect coupling or communication connection through some interfaces, devices or units, and can be electrical, mechanical or other forms.

[0146] The units described above as separate components can or can not be physically separated, and the components shown as units can or can not be physical units, that is, they can be located in one place, or can be distributed on multiple network units. Part or all of the units can be selected according to actual needs to achieve the purpose of the embodiment scheme.

[0147] In addition, each functional unit in each embodiment of the application can be integrated into a processing unit, or each unit can exist physically, or two or more units can be integrated into one unit. The integrated unit can be realized in the form of hardware or in the form of a software functional unit.

[0148] The integrated unit, if implemented in the form of a software function unit and sold or used as an independent product, can be stored in a computer readable storage medium. Based on such understanding, the technical solutions of the present application, essentially or in other words, the part that contributes to the prior art or the whole or part of the technical solutions can be embodied in the form of a software product. The computer software product is stored in a storage medium, and includes multiple instructions for causing a computer device (which can be a personal computer, a server, or a network device, etc.) to execute all or part of the steps of the methods of the various embodiments of the present application. The aforementioned storage medium includes: a U disk, a mobile hard disk, a read-only memory (ROM), a random access memory (RAM), a magnetic disk or an optical disk, and various program storage media.

[0149] The preferred embodiments of the embodiments of the present application are described above with reference to the accompanying drawings, and are not limited to the scope of the embodiments of the present application. Any modifications, equivalent replacements and improvements made by those skilled in the art without departing from the scope and essence of the embodiments of the present application shall be within the scope of the embodiments of the present application.

Claims

1. A temperature control method, characterized in that, The method is applied to a sequencing chip, which includes a substrate, a first temperature sensor, and a signal processing chip. The first temperature sensor and the signal processing chip are disposed on the substrate, and the first temperature sensor is located within a predetermined range circumferentially of the signal processing chip. A second temperature sensor is disposed inside the signal processing chip. The method includes: In the first sequencing cycle, when the temperature is determined to be in a stable state based on the acquisition temperature of the first temperature sensor and the preset initial control temperature, the initial internal temperature acquired based on the second temperature sensor is obtained, wherein the initial control temperature is the target temperature determined based on the optimal temperature conditions for the biochemical reaction required for sequencing. After the first sequencing cycle ends and during non-first sequencing cycles, the current internal temperature is acquired based on the data collected by the second temperature sensor, and the current control temperature is calculated based on the current internal temperature, the initial control temperature, and the initial internal temperature. The sequencing chip is temperature-controlled based on the current control temperature, wherein the current control temperature is used as the new target temperature for the current non-first sequencing cycle.

2. The method according to claim 1, characterized in that, The step of calculating the current control temperature based on the current internal temperature, the initial control temperature, and the initial internal temperature includes: The internal temperature change value is calculated based on the current internal temperature and the initial internal temperature. The current control temperature is determined based on the deviation data between the initial control temperature and the internal temperature change value.

3. The method according to claim 2, characterized in that, Determining the current control temperature based on the deviation data between the initial control temperature and the internal temperature change value includes: The temperature calibration coefficient is determined based on the current sequencing speed of the sequencing chip after the first sequencing cycle. The internal temperature change value is calibrated according to the temperature calibration coefficient to obtain the calibration temperature. The current control temperature is determined based on the deviation data between the initial control temperature and the calibration temperature.

4. The method according to claim 3, characterized in that, The process of determining the temperature calibration coefficient based on the current sequencing speed of the sequencing chip after the first sequencing cycle includes: After the first sequencing cycle is completed, the current sequencing speed of the sequencing chip is obtained; Obtain the preset standard sequencing speed and standard sequencing temperature, and calculate the temperature calibration coefficient based on the standard sequencing speed, the standard sequencing temperature and the current sequencing speed.

5. The method according to claim 1, characterized in that, A method for determining a stable temperature control state based on the temperature collected by the first temperature sensor and a preset initial control temperature includes: During the first sequencing cycle, the sequencing chip is temperature-controlled according to the initial control temperature, and the initial external temperature collected by the first temperature sensor is obtained. When the deviation between the initial external temperature and the initial control temperature is less than or equal to a preset threshold, the temperature is determined to be in a stable state. When the deviation between the initial external temperature and the initial control temperature exceeds the preset threshold, the sequencing chip is subjected to temperature control again based on the initial control temperature.

6. A sequencing system, characterized in that, The system includes: The sequencing chip as described in claim 1; A temperature control system for controlling the temperature of the sequencing chip according to any one of claims 1 to 5.

7. The system according to claim 6, characterized in that, The temperature control system includes: A cooling component, wherein the cooling component is connected to the sequencing chip; A temperature control device is used to control the heating or cooling of the refrigeration component according to the current control temperature, so that the temperature collected by the second temperature sensor is equal to the initial control temperature.

8. A temperature control device, characterized in that, The device is applied to a sequencing chip, which includes a substrate, a first temperature sensor, and a signal processing chip. The first temperature sensor and the signal processing chip are disposed on the substrate, and the first temperature sensor is located within a predetermined range circumferentially of the signal processing chip. A second temperature sensor is disposed inside the signal processing chip. The device includes: The first temperature acquisition unit is used to acquire the initial internal temperature based on the second temperature sensor when the temperature is determined to be stable based on the acquisition temperature of the first temperature sensor and the preset initial control temperature during the first sequencing cycle. The initial control temperature is the target temperature determined based on the optimal temperature conditions for the biochemical reaction required for sequencing. The second temperature acquisition unit is used to acquire the current internal temperature based on the second temperature sensor after the first sequencing cycle ends and during non-first sequencing cycles, and to calculate the current control temperature based on the current internal temperature, the initial control temperature and the initial internal temperature. A temperature control unit is used to control the temperature of the sequencing chip according to the current control temperature, wherein the current control temperature is used as the new target temperature for the current non-first sequencing cycle.

9. An electronic device comprising a memory and a processor, wherein the memory stores a computer program, characterized in that, When the processor executes the computer program, it implements the temperature control method according to any one of claims 1 to 5.

10. A computer-readable storage medium storing a computer program, characterized in that, When the computer program is executed by the processor, it implements the temperature control method according to any one of claims 1 to 5.

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