WO2022033226A1 - Thermal cycling device - Google Patents

Thermal cycling device Download PDF

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Publication number
WO2022033226A1
WO2022033226A1 PCT/CN2021/103962 CN2021103962W WO2022033226A1 WO 2022033226 A1 WO2022033226 A1 WO 2022033226A1 CN 2021103962 W CN2021103962 W CN 2021103962W WO 2022033226 A1 WO2022033226 A1 WO 2022033226A1
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WO
WIPO (PCT)
Prior art keywords
sample block
heating
blind holes
blind
cooling
Prior art date
Application number
PCT/CN2021/103962
Other languages
French (fr)
Chinese (zh)
Inventor
李晓东
阳方义
Original Assignee
深圳市瑞沃德生命科技有限公司
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Application filed by 深圳市瑞沃德生命科技有限公司 filed Critical 深圳市瑞沃德生命科技有限公司
Publication of WO2022033226A1 publication Critical patent/WO2022033226A1/en

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L7/00—Heating or cooling apparatus; Heat insulating devices
    • B01L7/52—Heating or cooling apparatus; Heat insulating devices with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples

Definitions

  • the present application relates to the technical field of reaction vessels for performing chemical reactions or biological reactions, and in particular, to a thermal cycle device.
  • the device for performing the above-mentioned series of temperature cycles is the polymerase chain reaction (PCR, Polymerase Chain Reaction). chain reaction) nucleic acid amplification instrument, also known as PCR instrument, thermal cycler.
  • the thermal cycling device includes a sample block on which an array of blind holes is uniformly arranged, and a heating device and a cooling device are arranged under the opposite sides of the sample block. Put the PCR plate or PCR tube containing the biological sample into the blind hole of the sample block, and make the biological sample undergo several temperature cycles in the thermal cycler by presetting the heating temperature and heating time, cooling temperature and cooling time.
  • the two heating devices When heating the sample block, the two heating devices are independently heated to different preset temperatures, and the two sides of the corresponding sample block are heated, and the part between the two sides of the sample block can be heated between the two preset temperatures through heat conduction. Between the step temperatures, the heat is conducted to the biological sample through the blind wells of the sample block and the PCR plate. When the sample block is cooled, the cooling device moves under the opposite sides of the sample block to perform a heat dissipation process. The characteristics of the temperature on the sample block are similar to the heating process, and will not be repeated here.
  • the temperature of the two sides of the sample block corresponding to the heating device and the cooling device can be accurately controlled to the preset temperature, and the temperature of the part between the two sides of the sample block will affect the repeatability of the experiment due to the uncontrollable heat conduction. .
  • the embodiments of the present application provide a thermal cycling device, which aims to solve the problems of accuracy and experimental repeatability of temperature control of each part of the sample block in the prior art.
  • a thermal cycling device comprising:
  • a sample block (1) provided with an array of blind holes
  • N heating and cooling devices (2) where N is a positive integer greater than 2;
  • blind holes (11) are connected, and N heating and cooling devices (2) respectively heat and/or cool the bottoms of the blind holes (11) located in N different regions of the sample block (1).
  • the area includes one or more blind holes (11).
  • the upper parts of the blind holes in the sample block are connected, and the bottoms of the blind holes in different regions of the sample block are heated and/or cooled respectively by N heating and cooling devices, which reduces the difference between the blind holes in different regions of the sample block.
  • the heat transfer effect between the samples improves the accuracy of temperature control in different regions of the sample block and the repeatability of the experiment.
  • FIG. 1 is an exploded view of the thermal cycle device provided in Embodiment 1 of the present application.
  • FIG. 2 is a top view and a bottom view of the sample block when the bottoms of the blind holes provided in the embodiment of the present application are not connected;
  • FIG. 3 is a top view and a bottom view of the sample block when the bottoms of the blind holes provided in the embodiment of the present application are connected in rows;
  • FIG. 4 is a top view and a bottom view of the sample block when the bottoms of the blind holes provided in the embodiment of the present application are connected in two rows;
  • FIG. 5 is a top view and a bottom view of a sample block when the bottoms of the blind holes provided by another embodiment of the present application are connected in two rows;
  • FIG. 6 is an exploded view of the thermal cycle device provided in Embodiment 2 of the present application.
  • Fig. 7 is the top view of the sample block provided by the second embodiment of the present application.
  • FIG. 9 is a schematic diagram of the thermal cycle device provided in the third embodiment of the present application.
  • the upper parts of the blind holes in the sample block are connected, and the bottoms of the blind holes in different regions of the sample block are heated and/or cooled respectively by N heating and cooling devices, which reduces the difference between the blind holes in different regions of the sample block.
  • the heat transfer effect between the samples improves the accuracy of temperature control in different regions of the sample block and the repeatability of the experiment.
  • FIG. 1 is an exploded view of the thermal cycle device provided in the first embodiment of the present application. As shown in FIG. 1 , the thermal cycling device includes a sample block 1 and N heating and cooling devices 2 .
  • the sample block 1 is provided with blind holes 11 evenly arranged at equal intervals to form a blind hole array.
  • Blind hole 11 refers to the hole groove on the sample block 1 where PCR tubes can be placed, and its size and spacing are set to match with standard or non-standard PCR plates and PCR tubes, so that the PCR plate with biological samples can be placed in the whole.
  • the inner wall of the blind hole 11 is as close as possible to the outer wall of the tube of the PCR plate, which is conducive to heat conduction.
  • Biological samples are substances subject to thermal cycling reactions, including but not limited to oligonucleotides as primers, dNTP mixtures, Taq DNA polymerase, PCR buffers, and the like.
  • the upper parts of all blind holes 11 are connected.
  • the connection part should be as close to the blind hole opening as possible or flush with the blind hole opening, and away from the bottom of the blind hole.
  • the connecting portion and each blind hole 11 can be integrally formed using the same material to form a whole sample block 1 .
  • the sample block 1 includes a first substrate 12 protruding toward the outer periphery at the upper portion of the blind hole 11 at the outermost periphery of the blind hole array.
  • the first substrate 12 may be an extension of the connection portion toward the outer periphery, and is integrally formed with the same material as the connection portion and the blind holes 11 .
  • the thermal cycler also includes a compression member 3 .
  • the pressing member 3 presses the sample block 1 on the N heating and cooling devices 2 through the first substrate 12 , and the blind hole array is exposed from the window in the middle of the pressing member 3 .
  • the sample block 1 as a whole can be made of materials with good thermal conductivity.
  • it is aluminum alloy, aluminum, copper or silver or the like.
  • N heating and cooling devices 2 are located below the sample block 1 , where N is a positive integer greater than 2. As shown in FIG. 1, N is six, but not limited thereto.
  • the heating and cooling device 2 includes, but is not limited to, a TEC (Semiconductor Refrigerator, Thermo Electric Cooler), a heating wire, a heating rod, an air conduction device or a liquid conduction device, and the like.
  • the six TECs independently heat and/or cool the bottoms of the blind holes 11 located in six different regions of the sample block 1 to the target temperature, and each region includes one or more blind holes 11 . As shown in FIG. 1 , one TEC heats and/or cools the bottoms of two rows (12) of blind vias 11 .
  • the sample block 1 is divided into different regions in the shape of TEC.
  • the blind hole 11 corresponding to each TEC is its heating and/or cooling area.
  • the bottoms of the blind vias may be connected by the bottoms of the M rows of blind vias as shown in FIG. 3 , FIG. 4 , and FIG. 5 , M is a positive integer greater than or equal to 1 and less than or equal to N.
  • M is a positive integer greater than or equal to 1 and less than or equal to N.
  • 3 is a top view and a bottom view of the sample block 1 when the bottoms of the blind holes 11 are connected in rows
  • FIG. 4 is a top view and a bottom view of the sample block 1 when the bottoms of the blind holes 11 are connected in two rows
  • the connecting portion at the bottom of the blind hole 11 and the sample block 1 can be integrally formed using the same material to form an integral sample block 1 .
  • the sample block 1 is divided into different regions based on different connection modes of the bottoms of the blind holes 11 , and correspondingly, a plurality of TECs independently heat and/or cool the bottoms of the blind holes in different regions. In this way, different heating temperatures, different heating times and different heating rates can be set for different regions of the sample block 1, and the volume and change of the biological sample in the PCR tube can also be changed according to the division of different regions of the sample block 1. primers in their PCR tubes to explore optimal conditions for conducting experiments.
  • the material for making the sample block 1 is a metal with good thermal conductivity, in order to reduce the overall weight of the sample block 1, the outer walls of all blind holes 11 are not connected except for the connection part at the upper part of the blind hole 11 and the connection part at the bottom of the blind hole 11.
  • the sample block 1 accommodates a PCR plate or PCR tube containing biological samples, and the biological samples are mainly distributed at the positions corresponding to the lower part of the blind hole 11.
  • the upper part of the blind hole in the sample block is connected,
  • the bottoms of the blind holes in different regions of the sample block are heated and/or cooled respectively by N heating and cooling devices, which reduces the heat transfer effect between the blind holes in different regions of the sample block and the temperature of the blind holes in each region of the sample block. Uniformity improves the accuracy of temperature control in different regions of the sample block and the repeatability of experiments, and is suitable for the optimization of multiplex PCR nucleic acid amplification processes.
  • the basic structure of the thermal cycler is the same as that of the first embodiment, and the same reference numerals are used for the same components as the first embodiment, including all the features described in the first embodiment, which are not described here. Repeat.
  • FIG. 6 is an exploded view of the thermal cycle device provided in the second embodiment of the present application.
  • FIG. 7 is a top view of the sample block provided in the second embodiment of the present application. 6 and 7 , the thermal cycling device includes a sample block 1 , N heating and cooling devices 2 , and a pressing member 3 .
  • the sample block 1 also includes an array of through-holes provided in the plane where the upper parts of the blind holes 11 are connected. Through holes 13 are provided between the connecting parts of the upper parts of the blind holes 11 and between the blind holes 11 .
  • one through hole 13 is provided in the middle area surrounded by every four blind holes 11 .
  • the thermal circulation device further includes a heat insulating material filled in the through hole 13 and a heat insulating member 4 filled in the outer wall of the blind hole 11 .
  • the thermal conductivity of these insulating materials and heat insulating members 4 should be lower than that of air.
  • the sample block 1 includes a second substrate 14 protruding toward the outer periphery at the bottom of the blind hole at the outermost periphery of the blind hole array.
  • the first substrate 14 and each blind hole 11 are integrally formed using the same material. window exposed.
  • the upper parts of the blind holes in the sample block are connected, holes are punched in the connecting parts of the blind holes, and heat insulating materials are filled in the gaps of the sample block.
  • the bottom of the sample block is heated and/or cooled, which reduces the heat transfer effect between blind holes in different regions of the sample block, and improves the accuracy of temperature control in different regions of the sample block and the repeatability of the experiment.
  • the basic structure of the thermal cycler is the same as that of the first or second embodiment, and the same reference numerals are used for the same components as those of the first or second embodiment, including all the features described therein. Repeat.
  • FIG. 8 is an exploded view of the thermal cycle device provided in the third embodiment of the present application.
  • FIG. 9 is a schematic diagram of the thermal cycle device provided in the third embodiment of the present application. 8 and 9, the thermal cycling device includes a sample block 1, N heating and cooling devices 2, a pressing member 3, a first thermally conductive element 5, a TEC spacer 6, a second thermally conductive element 7, a heat dissipation device 8, a thermal Cover 9 and bottom case 10.
  • Bottom case 10 is used to carry all the weight of the thermal cycler.
  • the heat dissipation device 8 is fixed in the bottom case 10, and the upper part thereof is a flat plane.
  • a whole block or N second heat-conducting elements 7 are placed on the upper plane of the heat-dissipating device 8 , and the lower surface of the second heat-conducting element 7 is in contact with the upper surface of the heat-dissipating device 8 .
  • N TECs whose upper and lower surfaces are coated with thermally conductive silicone grease are respectively placed on the N second thermally conductive elements 7 , and the lower surfaces of the TECs are in contact with the upper surfaces of the second thermally conductive elements 7 .
  • a hollowed-out TEC spacer 6 separates the N TECs.
  • the TEC spacer 6 is a high-temperature-resistant heat insulating material.
  • the hollowed-out portion is determined according to the number and size of the TECs, so that the TECs are thermally isolated from each other.
  • the N first heat-conducting elements 5 are respectively placed on the N TECs, respectively, and the lower surface of the first heat-conducting element 5 is in contact with the upper surface of the TEC.
  • the first heat-conducting element 5 and the second heat-conducting element 7 include, but are not limited to, materials with high heat conduction efficiency, such as thermal pads, aluminum foil, copper foil, or silver foil.
  • the sample block 1 is placed on the N first thermally conductive elements 5 , and the bottom of each blind hole 11 is in contact with the upper surface of the first thermally conductive element 5 .
  • the pressing member 3 is pressed on the position of the first substrate 12 of the sample block 1, and then the pressing member 3 is connected to the heat sink 8 by screws, and the sample block 1, the first thermally conductive element 5, the TEC, and the second thermally conductive element 7 are further connected. Press on the heat sink 8.
  • the thermal grease and the first thermal element 5 fill the gap between the bottom of each blind hole 11 and the upper surface of the TEC under pressure, and the thermal grease and the second thermal element 7 fill the lower surface of the TEC and the heat sink 8 under pressure.
  • the gap on the upper surface is filled.
  • the seamless design reduces thermal resistance and increases heat transfer efficiency.
  • the thermal cycler may have various implementations for controlling the temperature of the bottom of the blind holes in different regions of the sample block 1 .
  • the PCR tubes contained in all the blind holes 11 of the sample block 1 react at the same temperature, and the N TECs are heated or refrigerated according to the same temperature instruction, so as to achieve the same temperature in all the blind holes 11 .
  • the PCR tubes accommodated in the blind holes 11 in different regions of the sample block 1 are reacted at different temperatures, so as to realize the temperature of the blind holes 11 in different regions of the sample block 1 during the same thermal cycle process. gradient change.
  • some blind holes 11 are selected from different regions of the sample block 1 to accommodate PCR tubes and react at different temperatures. The larger the distance between the selected blind holes 11 , the better, and TEC can be used for temperature compensation (heating or cooling) between adjacent blind holes 11 to reduce the thermal influence between the selected adjacent blind holes 11 .
  • the thermal cycle device further includes a heating and cooling control system, a central control system, and a heat dissipation control system.
  • a heating and cooling control system a central control system
  • a heat dissipation control system a control system for controlling the thermal cycle device.
  • different regions of the sample block 1 are respectively connected with different high-sensitivity thermal sensors (not shown in the figure).
  • the central control system issues a sample block heating command, which is transmitted to the heating and cooling control system through the central and heating-cooling control loop.
  • the heating and cooling control system acts on N TECs through the TEC control loop.
  • the upper surface of the TEC starts to heat up, and the lower surface starts to cool accordingly.
  • the thermal sensor sends the detected temperature back to the heating and cooling control system through the TEC control loop.
  • the heating and cooling control system judges whether the target temperature is reached, and then controls the TEC to continue heating or stop heating through the TEC control loop.
  • the TEC continuously conducts heat to the sample block 1, thereby continuously providing heat to the PCR plate or the biological sample in the PCR tube. This process requires several cycles.
  • the central control system issues a sample block cooling command, which is transmitted to the heating and cooling control system through the central and heating-cooling control loop, and to the cooling control system through the central and heat-dissipating control loop.
  • the heating and cooling control system acts on N TECs through the TEC control loop, the upper surface of the TEC starts to cool, and the lower surface starts to transmit heat to the heat sink 8 accordingly.
  • the thermal sensor sends the detected temperature back to the heating and cooling control system through the TEC control loop.
  • the heating and cooling control system judges whether the target temperature is reached, and then controls the TEC to continue cooling or stop cooling through the TEC control loop.
  • the TEC continuously absorbs heat from the sample block 1, thereby continuously cooling the biological sample in the PCR plate or PCR tube.
  • the heat dissipation control system acts on the heat dissipation device 8 through the heat dissipation control loop, and transfers the heat to the outside of the thermal cycle device. This process requires several cycles.
  • the heating cover 9 is provided with a heating device (not shown in the figure) and a high-sensitivity thermal sensor (not shown in the figure).
  • the central control system issues a heating cover heating command, which is sent to the heating and cooling control system by the central and heating-cooling control loop.
  • the heating and cooling control system acts on the hot lid 9 through the hot lid heating control circuit, and the heating device in the hot lid 9 starts to generate heat.
  • the thermal sensor transmits the detected temperature back to the heating and cooling control system through the heating control loop of the heating cover, and the heating and cooling control system judges whether the target temperature is reached, and then controls the heating device in the heating cover 9 to continue heating through the heating control loop of the heating cover Or stop heating.
  • the heating device in the heating cover 9 continuously conducts heat to the PCR plate or the nozzle of the PCR tube. This process requires several cycles.
  • heating and cooling control system central control system and heat dissipation control system can also be integrated into one control system, which is not limited herein.
  • the upper parts of the blind holes in the sample block are connected, and the bottoms of the blind holes in different regions of the sample block are heated and/or cooled respectively by N heating and cooling devices, which reduces the difference between the blind holes in different regions of the sample block.
  • the heat transfer effect between the samples improves the accuracy of temperature control in different regions of the sample block and the repeatability of the experiment.

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  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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Abstract

A thermal cycling device, comprising: a sample block (1) provided with a blind hole array; and N heating and cooling devices (2), N being a positive integer greater than 2. Upper portions of all blind holes (11) are connected; and the N heating and cooling devices (2) respectively heat and/or cool bottom portions of the blind holes (11) located in N different regions of the sample block (1), each region comprising one or more blind holes (11).

Description

一种热循环装置A thermal cycler
本申请是以申请号为202010792851.X、申请日为2020年8月10日的中国专利申请为基础，并主张其优先权，该申请的全部内容在此作为整体引入本申请中。This application is based on the Chinese patent application with the application number of 202010792851.X and the filing date of August 10, 2020, and claims its priority. The entire content of this application is hereby incorporated into this application as a whole.
技术领域technical field
本申请涉及执行化学反应或者生物反应的反应容器技术领域，尤其涉及一种热循环装置。The present application relates to the technical field of reaction vessels for performing chemical reactions or biological reactions, and in particular, to a thermal cycle device.
背景技术Background technique
在探索生物样品或者化学样品的最佳反应温度和最佳反应时间的过程中，经常需要对生物样品或者化学样品设置和执行一系列温度循环，从中选出最佳的温度和时间组合。In the process of exploring the optimal reaction temperature and optimal reaction time for biological samples or chemical samples, it is often necessary to set and execute a series of temperature cycles for biological samples or chemical samples, and select the optimal temperature and time combination.
现有技术中执行上述一系列温度循环的装置有聚合酶链反应（PCR，Polymerase chain reaction）核酸扩增仪，又可称为PCR仪、热循环装置。热循环装置包含其上均匀设置有盲孔阵列的样品块，在样品块相对的两侧的下方均设置有加热装置和冷却装置。将装有生物样品的PCR板或者PCR管放入样品块的盲孔中，通过预设加热温度和加热时间、冷却温度和冷却时间，使生物样品在热循环装置内经历若干个温度循环。对样品块进行加热时，两个加热装置独立升温到不同的预设温度，对与其对应的样品块两侧进行加热，样品块两侧之间的部分通过热传导可实现在两个预设温度之间的阶梯温度，热量通过样品块的盲孔和PCR板传导至生物样品。对样品块进行冷却时，冷却装置移动到样品块相对的两侧的下方执行散热过程。样品块上温度的特点与加热过程相似，在此不再赘述。In the prior art, the device for performing the above-mentioned series of temperature cycles is the polymerase chain reaction (PCR, Polymerase Chain Reaction). chain reaction) nucleic acid amplification instrument, also known as PCR instrument, thermal cycler. The thermal cycling device includes a sample block on which an array of blind holes is uniformly arranged, and a heating device and a cooling device are arranged under the opposite sides of the sample block. Put the PCR plate or PCR tube containing the biological sample into the blind hole of the sample block, and make the biological sample undergo several temperature cycles in the thermal cycler by presetting the heating temperature and heating time, cooling temperature and cooling time. When heating the sample block, the two heating devices are independently heated to different preset temperatures, and the two sides of the corresponding sample block are heated, and the part between the two sides of the sample block can be heated between the two preset temperatures through heat conduction. Between the step temperatures, the heat is conducted to the biological sample through the blind wells of the sample block and the PCR plate. When the sample block is cooled, the cooling device moves under the opposite sides of the sample block to perform a heat dissipation process. The characteristics of the temperature on the sample block are similar to the heating process, and will not be repeated here.
由此，与加热装置、冷却装置对应的样品块两侧的温度可精准地控制到预设温度，样品块两侧之间的部分的温度则由于热传导作用的不可控而影响实验的可重复性。Therefore, the temperature of the two sides of the sample block corresponding to the heating device and the cooling device can be accurately controlled to the preset temperature, and the temperature of the part between the two sides of the sample block will affect the repeatability of the experiment due to the uncontrollable heat conduction. .
申请内容Application content
本申请实施例提供一种热循环装置，旨在解决现有技术中对样品块各部分的温度控制的准确性和实验可重复性的问题。The embodiments of the present application provide a thermal cycling device, which aims to solve the problems of accuracy and experimental repeatability of temperature control of each part of the sample block in the prior art.
第一方面，提供了一种热循环装置，包括：In a first aspect, a thermal cycling device is provided, comprising:
设置有盲孔阵列的样品块（1）；以及a sample block (1) provided with an array of blind holes; and
N个加热和冷却装置（2），N为大于2的正整数；N heating and cooling devices (2), where N is a positive integer greater than 2;
其中，所有盲孔（11）的上部相连，N个加热和冷却装置（2）分别对位于样品块（1）N个不同区域的盲孔（11）的底部进行加热和/或冷却，每个区域包括一个或者多个盲孔（11）。Wherein, the upper parts of all blind holes (11) are connected, and N heating and cooling devices (2) respectively heat and/or cool the bottoms of the blind holes (11) located in N different regions of the sample block (1). The area includes one or more blind holes (11).
本申请实施例将样品块中的盲孔的上部相连，通过N个加热和冷却装置分别对样品块不同区域的盲孔的底部进行加热和/或冷却，降低了样品块不同区域的盲孔之间的热传递作用，提高了对样品块不同区域的温度控制的准确性和实验的可重复性。In the embodiment of the present application, the upper parts of the blind holes in the sample block are connected, and the bottoms of the blind holes in different regions of the sample block are heated and/or cooled respectively by N heating and cooling devices, which reduces the difference between the blind holes in different regions of the sample block. The heat transfer effect between the samples improves the accuracy of temperature control in different regions of the sample block and the repeatability of the experiment.
附图说明Description of drawings
本申请上述的和/或附加的方面和优点从下面结合附图对实施例的描述中将变得明显和容易理解，其中：The above and/or additional aspects and advantages of the present application will become apparent and readily understood from the following description of embodiments taken in conjunction with the accompanying drawings, wherein:
图1是本申请实施例一提供的热循环装置的***图；1 is an exploded view of the thermal cycle device provided in Embodiment 1 of the present application;
图2是本申请实施例提供的盲孔底部不相连时样品块的俯视图和仰视图；2 is a top view and a bottom view of the sample block when the bottoms of the blind holes provided in the embodiment of the present application are not connected;
图3是本申请实施例提供的盲孔底部按列相连时样品块的俯视图和仰视图；3 is a top view and a bottom view of the sample block when the bottoms of the blind holes provided in the embodiment of the present application are connected in rows;
图4是本申请实施例提供的盲孔底部按两列相连时样品块的俯视图和仰视图；4 is a top view and a bottom view of the sample block when the bottoms of the blind holes provided in the embodiment of the present application are connected in two rows;
图5是本申请另一实施例提供的盲孔底部按两列相连时样品块的俯视图和仰视图；5 is a top view and a bottom view of a sample block when the bottoms of the blind holes provided by another embodiment of the present application are connected in two rows;
图6本申请实施例二提供的热循环装置的***图；6 is an exploded view of the thermal cycle device provided in Embodiment 2 of the present application;
图7是本申请实施例二提供的样品块的俯视图；Fig. 7 is the top view of the sample block provided by the second embodiment of the present application;
图8是本申请实施例三提供的热循环装置的***图；8 is an exploded view of the thermal cycle device provided in Embodiment 3 of the present application;
图9是本申请实施例三提供的热循环装置的示意图。FIG. 9 is a schematic diagram of the thermal cycle device provided in the third embodiment of the present application.
具体实施方式detailed description
下面详细描述本申请的实施例，所述实施例的示例在附图中示出，其中自始至终相同或类似的标号表示相同或类似的模块或具有相同或类似功能的模块。下面通过参考附图描述的实施例是示例性的，仅用于解释本申请，而不能理解为对本申请的限制。相反，本申请的实施例包括落入所附加权利要求书的精神和内涵范围内的所有变化、修改和等同物。The following describes in detail the embodiments of the present application, examples of which are illustrated in the accompanying drawings, wherein the same or similar reference numerals refer to the same or similar modules or modules having the same or similar functions throughout. The embodiments described below with reference to the accompanying drawings are exemplary and are only used to explain the present application, but should not be construed as a limitation on the present application. On the contrary, the embodiments of the present application include all changes, modifications and equivalents falling within the spirit and scope of the appended claims.
本申请实施例将样品块中的盲孔的上部相连，通过N个加热和冷却装置分别对样品块不同区域的盲孔的底部进行加热和/或冷却，降低了样品块不同区域的盲孔之间的热传递作用，提高了对样品块不同区域的温度控制的准确性和实验的可重复性。In the embodiment of the present application, the upper parts of the blind holes in the sample block are connected, and the bottoms of the blind holes in different regions of the sample block are heated and/or cooled respectively by N heating and cooling devices, which reduces the difference between the blind holes in different regions of the sample block. The heat transfer effect between the samples improves the accuracy of temperature control in different regions of the sample block and the repeatability of the experiment.
实施例一Example 1
图1是本申请实施例一提供的热循环装置的***图。如图1所示，该热循环装置包括样品块1、N个加热和冷却装置2。FIG. 1 is an exploded view of the thermal cycle device provided in the first embodiment of the present application. As shown in FIG. 1 , the thermal cycling device includes a sample block 1 and N heating and cooling devices 2 .
在本申请实施例中，样品块1上设置有均匀等间距排列的盲孔11，形成盲孔阵列。盲孔11指的是样品块1上可以放置PCR管的孔槽，其尺寸和间距设置为与标准的或者非标准的PCR板、PCR管匹配，使得装有生物样品的PCR板可整体放入盲孔阵列中，并且盲孔11的内壁与PCR板的管子的外壁尽量贴近，有利于热传导。生物样品为需经历热循环反应的物质，包括但不限于作为引物的寡核苷酸、dNTP混合物、Taq DNA 聚合酶和PCR缓冲液等。所有盲孔11的上部相连。连接部分尽量靠近盲孔开口或者与盲孔开口平齐，远离盲孔底部。连接部分和各盲孔11可使用相同的材料一体成型制作而成，形成一整块的样品块1。In the embodiment of the present application, the sample block 1 is provided with blind holes 11 evenly arranged at equal intervals to form a blind hole array. Blind hole 11 refers to the hole groove on the sample block 1 where PCR tubes can be placed, and its size and spacing are set to match with standard or non-standard PCR plates and PCR tubes, so that the PCR plate with biological samples can be placed in the whole. In the blind hole array, the inner wall of the blind hole 11 is as close as possible to the outer wall of the tube of the PCR plate, which is conducive to heat conduction. Biological samples are substances subject to thermal cycling reactions, including but not limited to oligonucleotides as primers, dNTP mixtures, Taq DNA polymerase, PCR buffers, and the like. The upper parts of all blind holes 11 are connected. The connection part should be as close to the blind hole opening as possible or flush with the blind hole opening, and away from the bottom of the blind hole. The connecting portion and each blind hole 11 can be integrally formed using the same material to form a whole sample block 1 .
作为本申请的一个实施例，样品块1包括在盲孔阵列的最***盲孔11的上部朝外周凸出的第一基板12。第一基板12可为上述连接部分朝外周的延伸，与上述连接部分、各盲孔11使用相同的材料一体成型制作而成。热循环装置还包括压固件3。压固件3通过第一基板12将样品块1压紧在N个加热和冷却装置2上，盲孔阵列从压固件3中间的窗口露出。As an embodiment of the present application, the sample block 1 includes a first substrate 12 protruding toward the outer periphery at the upper portion of the blind hole 11 at the outermost periphery of the blind hole array. The first substrate 12 may be an extension of the connection portion toward the outer periphery, and is integrally formed with the same material as the connection portion and the blind holes 11 . The thermal cycler also includes a compression member 3 . The pressing member 3 presses the sample block 1 on the N heating and cooling devices 2 through the first substrate 12 , and the blind hole array is exposed from the window in the middle of the pressing member 3 .
样品块1作为一个整体，材质可选用具有良好热传导性能的材料。优选地，为铝合金、铝、铜或者银等。The sample block 1 as a whole can be made of materials with good thermal conductivity. Preferably, it is aluminum alloy, aluminum, copper or silver or the like.
N个加热和冷却装置2位于样品块1的下方，N为大于2的正整数。如图1所示N为六，但不限于此。加热和冷却装置2包括但不限于TEC（半导体制冷器，Thermo Electric Cooler）、发热丝、发热棒、空气传导装置或者液体传导装置等。在本申请实施例中，六个TEC分别独立地对位于样品块1的六个不同区域的盲孔11的底部进行加热和/或冷却到目标温度，每个区域包括一个或者多个盲孔11。如图1所示，一个TEC对两列（12个）盲孔11的底部进行加热和/或冷却。N heating and cooling devices 2 are located below the sample block 1 , where N is a positive integer greater than 2. As shown in FIG. 1, N is six, but not limited thereto. The heating and cooling device 2 includes, but is not limited to, a TEC (Semiconductor Refrigerator, Thermo Electric Cooler), a heating wire, a heating rod, an air conduction device or a liquid conduction device, and the like. In the embodiment of the present application, the six TECs independently heat and/or cool the bottoms of the blind holes 11 located in six different regions of the sample block 1 to the target temperature, and each region includes one or more blind holes 11 . As shown in FIG. 1 , one TEC heats and/or cools the bottoms of two rows (12) of blind vias 11 .
图2为所有盲孔11的底部不相连时样品块1的俯视图和仰视图，在这种情况下，以TEC的形状对样品块1划分不同的区域。每个TEC对应的盲孔11即为其加热和/或冷却的区域。2 is a top view and a bottom view of the sample block 1 when the bottoms of all blind holes 11 are not connected. In this case, the sample block 1 is divided into different regions in the shape of TEC. The blind hole 11 corresponding to each TEC is its heating and/or cooling area.
考虑对不同区域的盲孔11温度均匀性的问题，作为本申请的实施例，各盲孔的底部连接方式可为如图3、图4、图5所示的M列盲孔的底部相连，M为大于等于1、小于等于N的正整数。图3为盲孔11的底部按列相连时样品块1的俯视图和仰视图；图4为盲孔11的底部按两列相连时样品块1的俯视图和仰视图；图5为盲孔11的底部按两列相连时样品块1的俯视图和仰视图，并且在该连接部分设置凹槽，凹槽不贯通该连接部分。盲孔11的底部的连接部分和样品块1可使用相同的材料一体成型制作而成，形成一整块的样品块1。基于盲孔11的底部的不同连接方式，样品块1被划分为了不同的区域，对应地，多个TEC分别独立地对不同区域的盲孔的底部进行加热和/或冷却。通过这种方式，可以对样品块1的不同区域设定不同的加热温度、不同的加热时间和不同的升温速率，还可以根据样品块1不同区域的划分改变其PCR管内生物样品的体积、改变其PCR管内的引物，来探索进行实验的最优条件。Considering the temperature uniformity of the blind vias 11 in different regions, as an embodiment of the present application, the bottoms of the blind vias may be connected by the bottoms of the M rows of blind vias as shown in FIG. 3 , FIG. 4 , and FIG. 5 , M is a positive integer greater than or equal to 1 and less than or equal to N. 3 is a top view and a bottom view of the sample block 1 when the bottoms of the blind holes 11 are connected in rows; FIG. 4 is a top view and a bottom view of the sample block 1 when the bottoms of the blind holes 11 are connected in two rows; The top view and bottom view of the sample block 1 when the bottoms are connected in two rows, and a groove is provided in the connecting part, and the groove does not penetrate through the connecting part. The connecting portion at the bottom of the blind hole 11 and the sample block 1 can be integrally formed using the same material to form an integral sample block 1 . The sample block 1 is divided into different regions based on different connection modes of the bottoms of the blind holes 11 , and correspondingly, a plurality of TECs independently heat and/or cool the bottoms of the blind holes in different regions. In this way, different heating temperatures, different heating times and different heating rates can be set for different regions of the sample block 1, and the volume and change of the biological sample in the PCR tube can also be changed according to the division of different regions of the sample block 1. primers in their PCR tubes to explore optimal conditions for conducting experiments.
由于制作样品块1的材料为热传导性能良好的金属，为了降低样品块1的整体重量，除盲孔11上部的连接部分和盲孔11底部的连接部分，所有盲孔11的外壁不相连。Since the material for making the sample block 1 is a metal with good thermal conductivity, in order to reduce the overall weight of the sample block 1, the outer walls of all blind holes 11 are not connected except for the connection part at the upper part of the blind hole 11 and the connection part at the bottom of the blind hole 11.
在实验的过程中，样品块1容纳装有生物样品的PCR板或者PCR管，生物样品主要分布在与盲孔11下部对应的位置，本申请实施例将样品块中的盲孔的上部相连，通过N个加热和冷却装置分别对样品块不同区域的盲孔的底部进行加热和/或冷却，降低了样品块不同区域的盲孔之间的热传递作用，样品块各区域内的盲孔温度均一，提高了对样品块不同区域的温度控制的准确性和实验的可重复性，适合于多重PCR核酸扩增过程的优化。During the experiment, the sample block 1 accommodates a PCR plate or PCR tube containing biological samples, and the biological samples are mainly distributed at the positions corresponding to the lower part of the blind hole 11. In the embodiment of the present application, the upper part of the blind hole in the sample block is connected, The bottoms of the blind holes in different regions of the sample block are heated and/or cooled respectively by N heating and cooling devices, which reduces the heat transfer effect between the blind holes in different regions of the sample block and the temperature of the blind holes in each region of the sample block. Uniformity improves the accuracy of temperature control in different regions of the sample block and the repeatability of experiments, and is suitable for the optimization of multiplex PCR nucleic acid amplification processes.
实施例二Embodiment 2
在本申请实施例中，热循环装置的基本结构与实施例一相同，与实施例一相同的各部件沿用与实施例一相同的标号，包括在实施例一中描述的全部特征，在此不再赘述。In the embodiments of the present application, the basic structure of the thermal cycler is the same as that of the first embodiment, and the same reference numerals are used for the same components as the first embodiment, including all the features described in the first embodiment, which are not described here. Repeat.
图6是本申请实施例二提供的热循环装置的***图。图7是本申请实施例二提供的样品块的俯视图。结合图6和图7，该热循环装置包括样品块1、N个加热和冷却装置2、压固件3。样品块1还包括在盲孔11的上部相连的面内设置的通孔阵列。在盲孔11上部的连接部分、各盲孔11之间设置通孔13。在本申请实施例中，如图7所示，在每四个盲孔11包围的中间区域设置了一个通孔13。进一步地，在该区域和/或每两个盲孔11之间设置多个通孔13。由此，将该区域的金属传热改变为空气传热，降低了盲孔11之间的热传导作用。为了进一步降低该热传导作用，热循环装置还包括填充在通孔13中的隔热材料和填充在盲孔11外壁的隔热件4。这些隔热材料和隔热件4的热传导性能应低于空气的热传导性能。FIG. 6 is an exploded view of the thermal cycle device provided in the second embodiment of the present application. FIG. 7 is a top view of the sample block provided in the second embodiment of the present application. 6 and 7 , the thermal cycling device includes a sample block 1 , N heating and cooling devices 2 , and a pressing member 3 . The sample block 1 also includes an array of through-holes provided in the plane where the upper parts of the blind holes 11 are connected. Through holes 13 are provided between the connecting parts of the upper parts of the blind holes 11 and between the blind holes 11 . In the embodiment of the present application, as shown in FIG. 7 , one through hole 13 is provided in the middle area surrounded by every four blind holes 11 . Further, a plurality of through holes 13 are arranged in this area and/or between every two blind holes 11 . As a result, the metal heat transfer in this area is changed to air heat transfer, and the heat transfer effect between the blind holes 11 is reduced. In order to further reduce the heat conduction effect, the thermal circulation device further includes a heat insulating material filled in the through hole 13 and a heat insulating member 4 filled in the outer wall of the blind hole 11 . The thermal conductivity of these insulating materials and heat insulating members 4 should be lower than that of air.
在本申请实施例中，样品块1包括在盲孔阵列的最***盲孔的底部朝外周凸出的第二基板14。第一基板14与各盲孔11使用相同的材料一体成型制作而成压固件3通过第二基板14将样品块1压紧在N个加热和冷却装置2上，盲孔阵列从压固件3中间的窗口露出。In the embodiment of the present application, the sample block 1 includes a second substrate 14 protruding toward the outer periphery at the bottom of the blind hole at the outermost periphery of the blind hole array. The first substrate 14 and each blind hole 11 are integrally formed using the same material. window exposed.
本申请实施例将样品块中的盲孔的上部相连，在盲孔的连接部分打孔，在样品块的空隙填充隔热材料，通过N个加热和冷却装置分别对样品块不同区域的盲孔的底部进行加热和/或冷却，降低了样品块不同区域的盲孔之间的热传递作用，提高了对样品块不同区域的温度控制的准确性和实验的可重复性。In the embodiment of the present application, the upper parts of the blind holes in the sample block are connected, holes are punched in the connecting parts of the blind holes, and heat insulating materials are filled in the gaps of the sample block. The bottom of the sample block is heated and/or cooled, which reduces the heat transfer effect between blind holes in different regions of the sample block, and improves the accuracy of temperature control in different regions of the sample block and the repeatability of the experiment.
实施例三Embodiment 3
在本申请实施例中，热循环装置的基本结构与实施例一或者实施例二相同，与实施例一或者实施例二相同的各部件沿用相同的标号，包括其中描述的全部特征，在此不再赘述。In the embodiment of the present application, the basic structure of the thermal cycler is the same as that of the first or second embodiment, and the same reference numerals are used for the same components as those of the first or second embodiment, including all the features described therein. Repeat.
图8是本申请实施例三提供的热循环装置的***图。图9是本申请实施例三提供的热循环装置的示意图。结合图8和图9，该热循环装置包括样品块1、N个加热和冷却装置2、压固件3、第一导热元件5、TEC隔离件6、第二导热元件7、散热装置8、热盖9和底壳10。FIG. 8 is an exploded view of the thermal cycle device provided in the third embodiment of the present application. FIG. 9 is a schematic diagram of the thermal cycle device provided in the third embodiment of the present application. 8 and 9, the thermal cycling device includes a sample block 1, N heating and cooling devices 2, a pressing member 3, a first thermally conductive element 5, a TEC spacer 6, a second thermally conductive element 7, a heat dissipation device 8, a thermal Cover 9 and bottom case 10.
底壳10用于承载热循环装置的所有重量。散热装置8固定在底壳10内，其上部为平整的平面。一整块或者N个第二导热元件7平放在散热装置8上部的平面上，第二导热元件7的下表面和散热装置8的上表面接触。上表面和下表面均涂抹了导热硅脂的N个TEC分别对应放置在N个第二导热元件7上，TEC的下表面和第二导热元件7的上表面接触。镂空的TEC隔离件6将上述N个TEC分隔开，TEC隔离件6为耐高温隔热材料，镂空部分根据TEC的数量和尺寸确定，使得TEC之间相互热隔离。N个第一导热元件5分别对应放置在N个TEC上，第一导热元件5的下表面和TEC的上表面接触。第一导热元件5和第二导热元件7包括但不限于热垫片、铝箔、铜箔或者银箔等热传导效率高的材料。样品块1放置在N个第一导热元件5上，各盲孔11的底部和第一导热元件5的上表面接触。压固件3压放在样品块1的第一基板12的位置，再通过螺钉将压固件3连接到散热装置8上，进一步将样品块1、第一导热元件5、TEC、第二导热元件7压紧在散热装置8上。其中，导热硅脂和第一导热元件5在压力下将各盲孔11的底部和TEC上表面的缝隙填满，导热硅脂和第二导热元件7在压力下将TEC下表面和散热装置8的上表面的缝隙填满。无缝隙的设计可减少热阻、增加热传导效率。Bottom case 10 is used to carry all the weight of the thermal cycler. The heat dissipation device 8 is fixed in the bottom case 10, and the upper part thereof is a flat plane. A whole block or N second heat-conducting elements 7 are placed on the upper plane of the heat-dissipating device 8 , and the lower surface of the second heat-conducting element 7 is in contact with the upper surface of the heat-dissipating device 8 . N TECs whose upper and lower surfaces are coated with thermally conductive silicone grease are respectively placed on the N second thermally conductive elements 7 , and the lower surfaces of the TECs are in contact with the upper surfaces of the second thermally conductive elements 7 . A hollowed-out TEC spacer 6 separates the N TECs. The TEC spacer 6 is a high-temperature-resistant heat insulating material. The hollowed-out portion is determined according to the number and size of the TECs, so that the TECs are thermally isolated from each other. The N first heat-conducting elements 5 are respectively placed on the N TECs, respectively, and the lower surface of the first heat-conducting element 5 is in contact with the upper surface of the TEC. The first heat-conducting element 5 and the second heat-conducting element 7 include, but are not limited to, materials with high heat conduction efficiency, such as thermal pads, aluminum foil, copper foil, or silver foil. The sample block 1 is placed on the N first thermally conductive elements 5 , and the bottom of each blind hole 11 is in contact with the upper surface of the first thermally conductive element 5 . The pressing member 3 is pressed on the position of the first substrate 12 of the sample block 1, and then the pressing member 3 is connected to the heat sink 8 by screws, and the sample block 1, the first thermally conductive element 5, the TEC, and the second thermally conductive element 7 are further connected. Press on the heat sink 8. The thermal grease and the first thermal element 5 fill the gap between the bottom of each blind hole 11 and the upper surface of the TEC under pressure, and the thermal grease and the second thermal element 7 fill the lower surface of the TEC and the heat sink 8 under pressure. The gap on the upper surface is filled. The seamless design reduces thermal resistance and increases heat transfer efficiency.
该热循环装置对样品块1不同区域的盲孔底部的温度控制可以有多种实施方式。作为本申请的一个实施例，样品块1所有盲孔11内容纳的PCR管按照相同的温度进行反应，N个TEC按照同一温度指令加热或者制冷，以达到所有盲孔11的温度一致。作为本申请的另一实施例，样品块1不同区域的盲孔11内容纳的PCR管按照不同的温度进行反应，实现在同一次热循环过程中，样品块1不同区域的盲孔11的温度呈梯度变化。作为本申请的又一实施例，从样品块1不同区域选取部分盲孔11容纳PCR管且按照不同的温度进行反应。选取的盲孔11的间距越大越好，相邻的盲孔11之间可以采用TEC进行温度补偿（加热或者冷却），达到减少选取的相邻盲孔11之间的热影响。The thermal cycler may have various implementations for controlling the temperature of the bottom of the blind holes in different regions of the sample block 1 . As an embodiment of the present application, the PCR tubes contained in all the blind holes 11 of the sample block 1 react at the same temperature, and the N TECs are heated or refrigerated according to the same temperature instruction, so as to achieve the same temperature in all the blind holes 11 . As another embodiment of the present application, the PCR tubes accommodated in the blind holes 11 in different regions of the sample block 1 are reacted at different temperatures, so as to realize the temperature of the blind holes 11 in different regions of the sample block 1 during the same thermal cycle process. gradient change. As another embodiment of the present application, some blind holes 11 are selected from different regions of the sample block 1 to accommodate PCR tubes and react at different temperatures. The larger the distance between the selected blind holes 11 , the better, and TEC can be used for temperature compensation (heating or cooling) between adjacent blind holes 11 to reduce the thermal influence between the selected adjacent blind holes 11 .
如图9所示，该热循环装置还包括加热及冷却控制***、中央控制***、散热控制***。在本申请实施例中，样品块1的不同区域分别连接不同的高灵敏度的热敏传感器（图中未示出）。As shown in FIG. 9 , the thermal cycle device further includes a heating and cooling control system, a central control system, and a heat dissipation control system. In the embodiment of the present application, different regions of the sample block 1 are respectively connected with different high-sensitivity thermal sensors (not shown in the figure).
进行加热时，中央控制***发出样品块加热指令，该指令通过中央与加热冷却控制回路传送到加热及冷却控制***。加热及冷却控制***经过处理后再通过TEC控制回路作用于N个TEC，TEC上表面开始发热，下表面相应地开始制冷。热敏传感器将检测到的温度通过TEC控制回路传回加热及冷却控制***，加热及冷却控制***判断是否达到目标温度，然后通过TEC控制回路控制TEC继续加热或者停止加热。若为继续加热，TEC不断地将热量传导至样品块1，从而不断地为PCR板或者PCR管内的生物样品提供热量。此过程需要循环若干次。During heating, the central control system issues a sample block heating command, which is transmitted to the heating and cooling control system through the central and heating-cooling control loop. After the heating and cooling control system is processed, it acts on N TECs through the TEC control loop. The upper surface of the TEC starts to heat up, and the lower surface starts to cool accordingly. The thermal sensor sends the detected temperature back to the heating and cooling control system through the TEC control loop. The heating and cooling control system judges whether the target temperature is reached, and then controls the TEC to continue heating or stop heating through the TEC control loop. For continuous heating, the TEC continuously conducts heat to the sample block 1, thereby continuously providing heat to the PCR plate or the biological sample in the PCR tube. This process requires several cycles.
进行冷却时，中央控制***发出样品块冷却指令，该指令通过中央与加热冷却控制回路传送到加热及冷却控制***、通过中央与散热控制回路传送到散热控制***。加热及冷却控制***经过处理后再通过TEC控制回路作用于N个TEC，TEC的上表面开始制冷，下表面相应地开始将热量传递给散热装置8。热敏传感器将检测到的温度通过TEC控制回路传回加热及冷却控制***，加热及冷却控制***判断是否达到目标温度，然后通过TEC控制回路控制TEC继续冷却或者停止冷却。若为继续制冷，TEC从样品块1不断地吸取热量，从而不断地为PCR板或者PCR管内的生物样品进行冷却。散热控制***经过处理后再通过散热控制回路作用于散热装置8，将热量传递至热循环装置的外部。此过程需要循环若干次。During cooling, the central control system issues a sample block cooling command, which is transmitted to the heating and cooling control system through the central and heating-cooling control loop, and to the cooling control system through the central and heat-dissipating control loop. After the heating and cooling control system is processed, it acts on N TECs through the TEC control loop, the upper surface of the TEC starts to cool, and the lower surface starts to transmit heat to the heat sink 8 accordingly. The thermal sensor sends the detected temperature back to the heating and cooling control system through the TEC control loop. The heating and cooling control system judges whether the target temperature is reached, and then controls the TEC to continue cooling or stop cooling through the TEC control loop. For continuous cooling, the TEC continuously absorbs heat from the sample block 1, thereby continuously cooling the biological sample in the PCR plate or PCR tube. After processing, the heat dissipation control system acts on the heat dissipation device 8 through the heat dissipation control loop, and transfers the heat to the outside of the thermal cycle device. This process requires several cycles.
热盖9内部设置有加热装置（图中未示出）和高灵敏度的热敏传感器（图中未示出）。进行加热时，中央控制***发出热盖加热指令，该指令中央与加热冷却控制回路传送到加热及冷却控制***。加热及冷却控制***经过处理后再通过热盖加热控制回路作用于热盖9，热盖9中的加热装置开始发热。热敏传感器将检测到的温度通过热盖加热控制回路传回加热及冷却控制***，加热及冷却控制***判断是否达到目标温度，然后通过热盖加热控制回路控制热盖9中的加热装置继续加热或者停止加热。若为继续加热，热盖9中的加热装置不断地将热量传导到PCR板或者PCR管的管口。此过程需要循环若干次。The heating cover 9 is provided with a heating device (not shown in the figure) and a high-sensitivity thermal sensor (not shown in the figure). When heating is performed, the central control system issues a heating cover heating command, which is sent to the heating and cooling control system by the central and heating-cooling control loop. After the heating and cooling control system is processed, it acts on the hot lid 9 through the hot lid heating control circuit, and the heating device in the hot lid 9 starts to generate heat. The thermal sensor transmits the detected temperature back to the heating and cooling control system through the heating control loop of the heating cover, and the heating and cooling control system judges whether the target temperature is reached, and then controls the heating device in the heating cover 9 to continue heating through the heating control loop of the heating cover Or stop heating. In order to continue heating, the heating device in the heating cover 9 continuously conducts heat to the PCR plate or the nozzle of the PCR tube. This process requires several cycles.
上述的加热及冷却控制***、中央控制***和散热控制***也可集成为一个控制***，在此不做限定。The above-mentioned heating and cooling control system, central control system and heat dissipation control system can also be integrated into one control system, which is not limited herein.
本申请实施例将样品块中的盲孔的上部相连，通过N个加热和冷却装置分别对样品块不同区域的盲孔的底部进行加热和/或冷却，降低了样品块不同区域的盲孔之间的热传递作用，提高了对样品块不同区域的温度控制的准确性和实验的可重复性。In the embodiment of the present application, the upper parts of the blind holes in the sample block are connected, and the bottoms of the blind holes in different regions of the sample block are heated and/or cooled respectively by N heating and cooling devices, which reduces the difference between the blind holes in different regions of the sample block. The heat transfer effect between the samples improves the accuracy of temperature control in different regions of the sample block and the repeatability of the experiment.
尽管上面已经示出和描述了本申请的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本申请的限制，本领域的普通技术人员在本申请的范围内可以对上述实施例进行变化、修改、替换和变型。Although the embodiments of the present application have been shown and described above, it should be understood that the above embodiments are exemplary and should not be construed as limitations to the present application. Embodiments are subject to variations, modifications, substitutions and variations.

Claims (10)

  1. 一种热循环装置，其特征在于，包括：A thermal cycle device, characterized in that, comprising:
    设置有盲孔阵列的样品块（1）；以及a sample block (1) provided with an array of blind holes; and
    N个加热和冷却装置（2），N为大于2的正整数；N heating and cooling devices (2), where N is a positive integer greater than 2;
    其中，所有盲孔（11）的上部相连，所述N个加热和冷却装置（2）分别对位于所述样品块（1）N个不同区域的盲孔（11）的底部进行加热和/或冷却，每个区域包括一个或者多个盲孔（11）。Wherein, the upper parts of all blind holes (11) are connected, and the N heating and cooling devices (2) respectively heat and/or heat and/or the bottoms of the blind holes (11) located in N different regions of the sample block (1). For cooling, each zone includes one or more blind holes (11).
  2. 根据权利要求1所述的热循环装置，其特征在于，所有盲孔（11）的底部不相连。The thermal cycle device according to claim 1, characterized in that the bottoms of all blind holes (11) are not connected.
  3. 根据权利要求1所述的热循环装置，其特征在于，M列盲孔（11）的底部相连，M为大于等于1、小于等于N的正整数。The thermal cycling device according to claim 1, characterized in that the bottoms of M rows of blind holes (11) are connected, and M is a positive integer greater than or equal to 1 and less than or equal to N.
  4. 根据权利要求1-3任一项所述的热循环装置，其特征在于，所述样品块（1）还包括在盲孔（11）的上部相连的面内设置的通孔阵列。The thermal cycling device according to any one of claims 1-3, characterized in that, the sample block (1) further comprises an array of through-holes provided in the plane connected to the upper part of the blind holes (11).
  5. 根据权利要求4所述的热循环装置，其特征在于，还包括填充在通孔（13）中的隔热材料。The thermal cycle device according to claim 4, characterized in that, further comprising a heat insulating material filled in the through holes (13).
  6. 根据权利要求4所述的热循环装置，其特征在于，还包括填充在所述盲孔（11）外壁的隔热件（4）。The thermal cycle device according to claim 4, further comprising a heat insulating member (4) filled on the outer wall of the blind hole (11).
  7. 根据权利要求1所述的热循环装置，其特征在于，还包括压固件（3），所述压固件（3）将所述样品块（1）压紧在所述N个加热和冷却装置（2）上。The thermal cycle device according to claim 1, characterized in that it further comprises a pressing member (3), the pressing member (3) pressing the sample block (1) on the N heating and cooling devices ( 2) on.
  8. 根据权利要求7所述的热循环装置，其特征在于，所述样品块（1）还包括在所述盲孔阵列的最***盲孔（11）的上部朝外周凸出的第一基板（12）；所述压固件（3）通过所述第一基板（12）将所述样品块（1）压紧在所述N个加热和冷却装置（2）上。The thermal cycling device according to claim 7, characterized in that, the sample block (1) further comprises a first substrate (12) protruding toward the outer periphery at the upper part of the blind hole (11) at the outermost periphery of the blind hole array ); the pressing member (3) presses the sample block (1) on the N heating and cooling devices (2) through the first substrate (12).
  9. 根据权利要求7所述的热循环装置，其特征在于，所述样品块（1）还包括在所述盲孔阵列的最***盲孔（11）的底部朝外周凸出的第二基板（14）；所述压固件（3）通过所述第二基板（14）将所述样品块（1）压紧在所述N个加热和冷却装置（2）上。The thermal cycling device according to claim 7, characterized in that, the sample block (1) further comprises a second substrate (14) protruding toward the outer periphery at the bottom of the blind hole (11) at the outermost periphery of the blind hole array ); the pressing member (3) presses the sample block (1) on the N heating and cooling devices (2) through the second substrate (14).
  10. 根据权利要求1所述的热循环装置，其特征在于，所述加热和冷却装置（2）为半导体制冷器(Thermo Electric Cooler，TEC)。The thermal cycle device according to claim 1, characterized in that, the heating and cooling device (2) is a semiconductor refrigerator (Thermo Electric Cooler, TEC).
PCT/CN2021/103962 2020-08-10 2021-07-01 Thermal cycling device WO2022033226A1 (en)

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Publication number Priority date Publication date Assignee Title
CN112827524A (en) * 2020-08-10 2021-05-25 深圳市瑞沃德生命科技有限公司 Thermal cycling device
CN117129511B (en) * 2023-09-18 2024-04-12 安徽工程大学 Terahertz online monitoring device and method for thermal fatigue behavior of thermal barrier coating

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030072685A1 (en) * 2001-10-11 2003-04-17 Goldman Jeffrey A. Heat conducting sample block
CN101583708A (en) * 2006-09-06 2009-11-18 应用生物***有限责任公司 Device for carrying out chemical or biological reactions
CN202214365U (en) * 2011-08-30 2012-05-09 张家林 Thermal cycler capable of realizing two-dimensional gradient
CN103347994A (en) * 2010-12-03 2013-10-09 拜欧法诊断有限公司 Thermal cycler apparatus and related methods
CN107949082A (en) * 2017-11-30 2018-04-20 南通成时医疗科技有限公司 A kind of new structure PCR amplification instrument heating module, thermometric and calibration method
US20180311672A1 (en) * 2003-05-30 2018-11-01 Applied Biosystems, Llc Thermal Cycling Apparatus and Method for Providing Thermal Uniformity
CN112827524A (en) * 2020-08-10 2021-05-25 深圳市瑞沃德生命科技有限公司 Thermal cycling device

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2401437T3 (en) * 2005-04-04 2013-04-19 Roche Diagnostics Gmbh Thermocycling of a block comprising multiple samples
US8232091B2 (en) * 2006-05-17 2012-07-31 California Institute Of Technology Thermal cycling system
CN102164674B (en) * 2008-09-23 2014-07-16 皇家飞利浦电子股份有限公司 Thermocycling device
US20100124766A1 (en) * 2008-11-14 2010-05-20 Life Technologies Corporation Apparatus and Method for Segmented Thermal Cycler
GB201604062D0 (en) * 2016-03-09 2016-04-20 Cell Therapy Catapult Ltd A device for heating or cooling a sample
CN107012086B (en) * 2017-04-07 2020-02-18 成都瀚辰光翼科技有限责任公司 Real-time fluorescence PCR thermal cycle device and PCR appearance
CN111269823B (en) * 2020-03-10 2020-11-03 杭州博日科技股份有限公司 Thermal cycling device and PCR instrument

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030072685A1 (en) * 2001-10-11 2003-04-17 Goldman Jeffrey A. Heat conducting sample block
US20180311672A1 (en) * 2003-05-30 2018-11-01 Applied Biosystems, Llc Thermal Cycling Apparatus and Method for Providing Thermal Uniformity
CN101583708A (en) * 2006-09-06 2009-11-18 应用生物***有限责任公司 Device for carrying out chemical or biological reactions
CN103347994A (en) * 2010-12-03 2013-10-09 拜欧法诊断有限公司 Thermal cycler apparatus and related methods
CN202214365U (en) * 2011-08-30 2012-05-09 张家林 Thermal cycler capable of realizing two-dimensional gradient
CN107949082A (en) * 2017-11-30 2018-04-20 南通成时医疗科技有限公司 A kind of new structure PCR amplification instrument heating module, thermometric and calibration method
CN112827524A (en) * 2020-08-10 2021-05-25 深圳市瑞沃德生命科技有限公司 Thermal cycling device

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