CN114181823B - PCR instrument with multiple temperature control modules and asynchronous optional channels and detection method thereof - Google Patents
PCR instrument with multiple temperature control modules and asynchronous optional channels and detection method thereof Download PDFInfo
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- CN114181823B CN114181823B CN202210139234.9A CN202210139234A CN114181823B CN 114181823 B CN114181823 B CN 114181823B CN 202210139234 A CN202210139234 A CN 202210139234A CN 114181823 B CN114181823 B CN 114181823B
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- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
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- G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
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Abstract
The invention discloses a PCR instrument with multiple temperature control modules and asynchronous optional channels and a detection method thereof; belongs to the field of medical examination and inspection instruments and molecular diagnosis and detection instruments; the technical key points are as follows: it includes: the device comprises m temperature control modules, m reaction pool component modules and a fluorescence detection component; the fluorescence detection module is an exciting light-receiving light integrated module structure; the optical fiber fixing plate is provided with through holes, the number of the optical fibers and the number of the reaction tanks are the same, and the optical fibers and the fluorescence detection modules are respectively positioned on two sides of the optical fiber fixing plate; one end of the optical fiber is fixedly communicated with the through holes one by one, and the other end of the optical fiber is inserted into the reaction tank. The invention aims to provide a PCR instrument with multiple temperature control modules and asynchronous optional channels and a detection method thereof.A set of fluorescence detection system can acquire fluorescence signals of m PCR reaction tanks without mutual interference; the channels can be selected and matched, so that the requirements of users can be better met, the cost is reduced, and the general type of equipment is enhanced.
Description
Technical Field
The invention relates to the field of medical examination and inspection instruments and molecular diagnosis and detection instruments, in particular to a PCR instrument with multiple temperature control modules and asynchronously selectable channels and a detection method thereof.
Background
Fluorescence detection is a common detection method.
Document 1: the establishment of immunofluorescence detection method for human H group rotavirus [ J ] virus proceedings 2020, 36(6):7 "reports that fluorescence detection is used for detecting rotavirus.
Document 2: the establishment of a method for detecting a swine fever virus antibody nano fluorescence detection test strip by Wuhaoxing, Liubaihong, Liuxue, and the like and the performance evaluation [ J ] biotechnological report 2020, 36(5): 6' report that fluorescence detection is used for detecting the swine fever virus.
Document 3: "Bao Yao phenanthrene, Xue Rubia, Wuhai duckweed, Zhongjie, Song Qin Xin, Zhou Hua, the research progress of the instant detection method for detecting novel coronavirus nucleic acid [ J ]. proceedings of Chinese pharmaceutical sciences university, 2020, 51(6): 11", the use of fluorescence detection for detecting novel coronavirus was reported.
In long-term production practice, the following technical requirements are placed on PCR instruments.
1) The PCR instrument needs to heat the reagent in the test tube to a certain temperature during the detection, and the heating process is not interrupted. When the device is actually used and used for detection, after the detection test tubes of the next group of people come in, the device can start detection only after the temperature rise and decrease of the detection test tubes of the previous group of people are finished. This causes a low detection efficiency. This is a demanding technical need.
2) The number of channels configured in the PCR instrument is directly related to the detection capability of the PCR instrument. Generally, the larger the number of channels to be arranged, the larger the detection capability (range). However, the larger the number of channels to be arranged, the higher the cost. From the perspective of reducing the cost of customers, the detection channel has the requirement of optional matching; however, no experience has been available at present for reference on how the above-mentioned concept of "optional matching" is implemented.
How to meet the two technical requirements is a difficult problem for fluorescent quantitative PCR instrument manufacturers.
Disclosure of Invention
The invention aims to provide a PCR instrument with multiple temperature control modules and asynchronous optional channels and a detection method thereof, aiming at the defects of the prior art.
The technical scheme of the invention is as follows:
a PCR instrument with multiple temperature control modules and asynchronous optional channels comprises m temperature control modules, m reaction pool assembly modules and a fluorescence detection assembly; wherein m is a natural number greater than or equal to 2;
the temperature control module is used for controlling the temperature of the reaction cell assembly module;
each reaction tank component module comprises a plurality of reaction tanks, and reagents are contained in the reaction tanks;
wherein, fluorescence detection subassembly includes: the device comprises a transmission module, more than one fluorescence detection module, an optical fiber fixing plate and an optical fiber;
the fluorescence detection module is an exciting light-receiving light integrated module structure;
the optical fiber fixing plate is provided with through holes, the number of the optical fibers and the number of the reaction tanks are the same, and the optical fibers and the fluorescence detection modules are respectively positioned on two sides of the optical fiber fixing plate; one end of the optical fiber is fixedly communicated with the through holes one by one, and the other end of the optical fiber is inserted into the reaction tank;
during detection, the through hole is used as an inlet of exciting light and an outlet of the receiving port; the through holes on the optical fiber fixing plate are arranged in a straight line;
the transmission module includes: a power mechanism, a slide block and a guide rail; the sliding block is matched with the guide rail in shape; the power mechanism can push the sliding block to move back and forth along the guide rail;
a space for placing n fluorescence detection modules is preset on the sliding block, and the fluorescence detection modules are detachably arranged on the sliding block; when the slide block is fully provided with n fluorescence detection modules, the openings of the fluorescence detection modules are also arranged in a straight line; n is a natural number greater than or equal to 5;
the straight line of the through hole array is parallel to the straight line of the opening array of the fluorescence detection module and is highly matched with the straight line of the opening array of the fluorescence detection module; during detection, when the sliding block moves along the guide rail, the openings of the fluorescence detection module can be sequentially aligned with all the through holes;
the moving direction of the sliding block and the direction of the guide rail are both parallel to the straight line arranged by the through holes. .
Further, the PCR instrument further comprises: m thermal cover modules; the hot cover module is used for sealing the upper opening of the reaction cell component module.
Further, the PCR instrument further comprises: a main control board;
the connection relation of the hot cover module, the main control board and the temperature control module is as follows: the upper top of the temperature control module is provided with a groove for accommodating the module part of the reaction cell assembly, and one part of the lower part of the reaction cell assembly module is arranged in the groove at the upper top of the temperature control module;
the main control board is provided with m hollowed-out areas, the positions of the m hollowed-out areas correspond to the positions of the m reaction tank assembly modules, the heights of the m temperature control modules are consistent, and the main control board is arranged on the upper surfaces of the m temperature control modules;
the reaction tank assembly module protrudes out of the upper surface of the main control board;
a thermal cover module is arranged above the reaction tank assembly module;
the hot cover module and the temperature control module are electrically connected with the main control board: the temperature change of the hot cover module and the temperature control module is controlled by the main control board.
Further, the fluorescence detection assembly further comprises: a base plate;
the transmission module includes: a motor, a sliding block and a guide rail; the sliding block is matched with the guide rail in shape; the motor drives the sliding block to move back and forth along the guide rail;
the fluorescence detection modules are all fixed on the sliding block;
the guide rail is arranged in parallel with the optical fiber fixing plate;
the guide rail and the optical fiber fixing plate are fixed on the bottom plate;
the optical fiber fixing plate is provided with a strip-shaped groove, and the sliding block penetrates through the strip-shaped groove.
Further, the fluorescence detection assembly further comprises: spacing module, spacing module includes: the optical coupler comprises a first optical coupler, a second optical coupler, a first blocking piece and a second blocking piece; the first optical coupler and the second optical coupler are respectively arranged on two sides of the bottom plate; the first blocking piece and the second blocking piece are respectively and fixedly arranged at two ends of the sliding block; the first separation blade corresponds to the first optocoupler, and the second separation blade corresponds to the second optocoupler.
Further, a fluorescence detection module comprising: the device comprises a light source, a first collimating lens, a second collimating lens, an exciting light filter, a coupling lens, a dichroic mirror, a receiving light filter, a focusing lens, a sensor and an opening; the light source adopts an LED lamp;
the light source emits light, the light vertically propagates, passes through the first collimating lens, the second collimating lens and the excitation light filter which are horizontally arranged in parallel, then passes through the dichroic mirror which is obliquely arranged at 45 degrees, after being reflected, the light passes through the coupling lens which is vertically arranged along the horizontal direction, then passes through the opening along the horizontal direction, and leaves the fluorescence detection module;
the received light enters the fluorescence detection module from the opening, passes through the coupling lens along the horizontal direction, then horizontally transmits through the dichroic mirror, then sequentially passes through the receiving light filter and the focusing lens along the horizontal direction, and finally enters the sensor along the horizontal direction.
Furthermore, the opening of the fluorescence detection module and the through hole of the optical fiber fixing plate are positioned at the same horizontal height; n groups of positioning bolt holes are preset on the sliding block, 1 group of positioning bolt holes are also arranged on the fluorescence detection module, 1 group of positioning bolt holes on the sliding block correspond to 1 group of positioning bolt holes of the fluorescence detection module, and the fluorescence detection module is detachably connected with the sliding block in a bolt-nut assembly mode.
Further, the LED lamp of the fluorescence detection module is G, the diameter of the optical fiber is d, and the following formula needs to be satisfied:
G×(-0.0047K2+0.0645K+0.003) ≥0.05
K=(π×d2)/4
wherein, the unit of G is w when selecting the value; the unit is mm when the numerical value of d is selected; k is an intermediate parameter and the unit is mm when selecting the value2。
A detection method of a PCR instrument with multiple temperature control modules and asynchronous optional channels comprises the following steps:
s100, installing and fixing a fluorescence detection module to be used on a sliding block;
s200, placing a reagent tube to be detected into any ith reaction tank assembly module, placing the reaction tank assembly module and the ith reaction tank assembly module into the ith temperature control module, covering the ith heat cover module above the ith reaction tank assembly module, controlling the ith temperature control module and the ith heat cover module through a main control board, and adjusting the temperature of the ith reaction tank assembly module to a preset temperature;
s300, after the temperature of the ith reaction tank assembly module reaches a preset temperature, starting detection:
s301, in an initial state, blocking the first blocking piece by the first light coupler;
s302, the motor starts, drives the slider motion, and fluorescence detection module straight line slides, and fluorescence detection module begins work simultaneously, and when the second baffle moved the position of second opto-coupler, motor stall, fluorescence detection module stop work, the reagent pipe homoenergetic of arbitrary ith reaction cell subassembly module can detect the completion:
each fluorescence detection module passes through the through hole of the optical fiber fixing plate corresponding to the ith reaction cell assembly module:
the detection mode of any one fluorescence detection module is as follows: the light source emits exciting light, the exciting light vertically propagates, passes through a first collimating lens, a second collimating lens and an exciting light optical filter which are horizontally arranged in parallel, then passes through a dichroic mirror which is obliquely arranged at 45 degrees, the exciting light is reflected, then passes through a coupling lens which is vertically arranged along the horizontal direction, leaves a fluorescence detection module, then enters an optical fiber through a through hole of an optical fiber fixing plate, then enters a reaction tank, a fluorescence signal excited by a sample is transmitted through the optical fiber, then returns along the optical fiber, returns to the fluorescence detection module through the through hole of the optical fiber fixing plate, then passes through the coupling lens, horizontally transmits through the dichroic mirror, passes through a receiving light optical filter, filters ineffective fluorescence, passes through a focusing lens, and finally reaches a sensor;
s400, after the detection of S300 is finished, carrying out the next detection:
s401, when the type of the virus to be detected needs to be changed, taking the fluorescence detection module of the S100 down from the slide block, and replacing the fluorescence detection module with the needed fluorescence detection module; when the virus species to be detected is not changed, the fluorescence detection module of S100 is not moved;
s402, repeating the steps S200-S300.
The beneficial effect of this application lies in:
first, the basic idea of the present application is: solves the problem that the reaction area of the traditional real-time fluorescence quantitative PCR instrument can not independently control the temperature to carry out different PCR reaction experiments. This application can reduce instrument cost through sharing one set of fluorescence collection system, through software program control, realizes that m reaction cell subassembly module 300 fluorescence gathers each other noninterference. In order to realize the basic concept, the problem of how to arrange m temperature control modules needs to be solved. The first invention of the present application is that: the mutual position design of main control board, temperature control module, hot lid module. The hot cover module and the temperature control module are used for adjusting the temperature of the reagent in the reaction cell component module. And as the control assembly, the main control board is arranged between the hot cover module and the temperature control module, so that the hot cover module and the temperature control module can be conveniently controlled. If the position of the main control board is arranged above the hot cover module, the main control board needs to be provided with a longer connecting wire to be connected with the temperature control module; or, the position of the main control board is arranged below the temperature control module, and the main control board needs to be provided with a longer connecting line to be connected with the hot cover module, which are inconvenient. However, the main control board is disposed between the thermal cover module and the temperature control module, which again causes a problem: the reaction cell assembly module is already arranged in the groove of the temperature control module and protrudes out of the upper surface of the temperature control module, and the main control board and the reaction cell assembly module have a spatial contradiction. To solve the contradiction, a hollow-out area is arranged on a main control board (PCB), so that the problem that the space contradiction between the reaction tank assembly module and the main control board cannot be solved. The purpose of arranging the thermal cover module on the reaction cell component module 300 is to make the temperature of the position where the top of the reagent tube contacts the thermal cover higher than the temperature of the bottom of the reagent tube contacting the reaction cell, so that the evaporation of the reagent can be effectively prevented; in addition, the light-shielding effect can be achieved.
Secondly, another basic idea of the present application is that: the concept of 'optional channel matching' is provided, so that the requirements of users can be met better, and the cost of the instrument can be reduced. The fluorescence acquisition system adopted by the application consists of the fluorescence detection modules with independent channels, and the number of the channels can be selected by a user according to the requirement of the user. For the detection of viruses, a combined detection of several specific channels is required. The detection thereof involves three conditions: 1) the number of channels; 2) the kind of channel; 3) the order of the channels. For the channel, it comprises: a light source, an excitation light filter, a receiving light filter and a sensor. Each channel of different types is matched among the components, namely a light source, an exciting light filter, a receiving light filter and a sensor; i.e. it cannot be used at will. Thus, the essential idea of "channel matching" is: and determining the type combination of the installed channels according to the viruses to be detected.
For the "channel optional matching", the necessary technical features are as follows: the fluorescent detection module, the transmission module, the optical fiber fixing plate and the optical fiber are designed in a matching way (the second invention point of the application); firstly, the channel is modularly designed, that is, the corresponding light source, excitation light filter, receiving light filter and sensor are integrated into one module (i.e. fluorescence detection module), and the core idea of the modularly designed fluorescence detection module of the present application is as follows: the light source of the fluorescence detection module emits light, the light vertically propagates through the first collimating lens, the second collimating lens and the excitation light filter which are horizontally arranged in parallel, then passes through the dichroic mirror which is obliquely arranged at 45 degrees, the light is reflected, then passes through the coupling lens which is vertically arranged along the horizontal direction, then passes through the opening along the horizontal direction, and leaves the fluorescence detection module; the received light enters the fluorescence detection module from the opening, passes through the coupling lens along the horizontal direction, then horizontally transmits through the dichroic mirror, then sequentially passes through the receiving light filter and the focusing lens along the horizontal direction, and finally enters the sensor along the horizontal direction; namely, the exciting light and the received light need to leave and enter the fluorescence detection module along the horizontal direction through one opening; secondly, after solving the problem of how to realize modular design of the channel, one of the problems is that: how to realize the multi-reagent hole detection under the condition of variable channel quantity. For the detection of multi-channel multi-reagent wells, various approaches have been proposed in the prior art. However, the number of channels of the PCR instrument (CN 112326611B) of the prior art cannot be changed after the instrument is shipped. For example: in the CN112326611B solution, if the number of channels is increased, not only the number of optical fibers for incident light and the number of light sources need to be increased, but also the additional optical fibers for incident light need to be inserted into the plastic light guide rod (the radius of the plastic light guide rod is fixed, and new optical fibers cannot be inserted). And to solve the problem of multiple reagent wells with "variable" number of channels. The present application proposes the following means: the fluorescence detection module adopts a linear scanning type detection mode to solve the problems;
2.1 design of separating optical fiber and fluorescence detection module: the optical fiber adopts the design of single optical fiber, namely for the reaction tank, the incident light optical fiber and the receiving light optical fiber are the same optical fiber; one end of the optical fiber is fixedly communicated with the through holes one by one, and the other end of the optical fiber is inserted into the reaction tank; the through holes are arranged in a straight line on the optical fiber fixing plate and are all arranged on the same horizontal plane; the opening of the fluorescence detection module and the through hole are positioned at the same height, when in detection, the through hole is used as an inlet of the exciting light and an outlet of the receiving port, the selected fluorescence detection module moves along a horizontal straight line, and the selected fluorescence detection module can be aligned with the through holes of the optical fiber fixing plate one by one to realize detection;
2.2 a space for placing n fluorescence detection modules is preset on the slide block (n can be generally more than 5), the fluorescence detection modules are detachably arranged on the slide block (the slide block and the fluorescence detection modules can be connected in a bolt-nut manner, and nuts are arranged on the slide block, so that the fluorescence detection modules can be positioned; the fluorescence detection modules are also horizontally and linearly arranged on the sliding block, namely when the fluorescence detection modules are fully distributed on the sliding block, the openings of the fluorescence detection modules are also linearly arranged and are also on the same horizontal plane. The direction of arranging on the fluorescence detection module slider and the direction of removal when detecting are the collinear, and the quantity of fluorescence detection module is placed to promotion slider that this kind of design can the furthest limit, the volume of reduction PCR appearance that can the furthest limit. From the above description, it can be seen that: the fluorescent detection module, the transmission module, the optical fiber fixing plate and the optical fiber are designed in a matching way, and the fluorescent detection module, the transmission module, the optical fiber fixing plate and the optical fiber are a technical whole. That is, if the fluorescence detection module does not adopt the design of the present application, the transmission module, the relationship fixing plate and the optical fiber cannot realize the design concept of the multi-reagent-well detection under the condition of variable channels. However, if the design of the transmission module, the relation fixing plate and the optical fiber is not provided, the fluorescence detection module only changes an inlet and outlet mode, and cannot realize the multi-reagent-hole detection under the condition of variable channels.
In addition, the present application enables "asynchronous" detection. When which reaction cell assembly module needs to be detected, the fluorescence detection module is only required to detect the reaction cell of the module to be reacted, specifically, the matched fluorescence detection module moves to detect through a plurality of through holes corresponding to the reaction cell of the module to be reacted.
Fourth, a third invention of the present application is: this application can realize the detection in arbitrary R passageway, T reagent hole. Compared with CN 112326611B: CN112326611B can only satisfy: r is more than or equal to 4 and less than or equal to 8, T is more than or equal to 4 and less than or equal to 8, and R + T is less than or equal to 16, but the influence is avoided, namely the detection capability of the method is greatly improved.
In addition, the present application is not only based on the improvement of the detection capability, but also aims to realize the arbitrary change of the number of channels. The core technical means for realizing the method are as follows.
3.1 design of fluorescence detection module, which enables integration of the optical system for incident light (i.e. excitation light) and for receiving light.
3.2 based on the design of 3.1, fiber 506 can simultaneously serve the dual functions of incident fiber + receiving fiber.
3.3 based on the design of 3.1, 3.2, can pass through a plurality of optic fibre through R fluorescence detection module order, promptly when the slider moves to another side from one side along the guide rail, just can realize that every reagent hole can both pass through the detection of R passageway. The change of the R channel can be realized by changing the type and the number of the fluorescence detection modules arranged on the sliding block; thereby being convenient for being suitable for the detection of the virus. However, it should be noted that: in the present application, if the optical fiber fixing plate is moved and the fluorescence detection module is fixed, the method is not suitable: first, because the optic fibre that a plurality of reaction cells that will be fixed with a plurality of reaction cell assembly modules 300 on the optic fibre fixed plate of this application connect usefulness (T value is great promptly, can reach 100), this just makes the length of optic fibre fixed plate very long, if the optic fibre fixed plate carries out so long displacement, the optic fibre between optic fibre fixed plate and reaction cell can receive taut even the stretch-break.
Fourth, the fourth invention of the present application is the following two points.
4.1 in order to meet the number of the optional distribution channels, the LED lamp has the requirement of low power. In order to satisfy the number of reaction cells, there is also a demand for making the diameter of the optical fiber small. If the power of the LED lamp is small and the diameter of the optical fiber is small, the received light signal is too weak, and the power of the LED lamp and the diameter of the optical fiber are two mutually restricted indexes of the measurement result of the sensor. That is, if a low power LED lamp is used to satisfy a larger number of selectable distribution channels, a large diameter optical fiber is required. However, the optical fiber is inserted into the reaction cell, and the reagent capacity of the reaction cell imposes a limit on the upper limit of the diameter of the optical fiber. If the number of reaction cells is equal, a small diameter optical fiber is needed, and a high power LED lamp is needed. The core difficulty lies in that: how to coordinate the relationship between LED lamp power and fiber diameter (this problem was first discovered in this application).
4.2 for the problem proposed by 4.1, the present application has conducted an intensive study, and the following design criteria (the opening of the fluorescence detection module is 3 mm) are proposed:
G×(-0.0047K2+0.0645K+0.003) ≥0.05
K=(π×d2)/4
4mm≥d≥0.5mm
wherein G represents the power of the LED lamp and the unit is w; d represents the fiber diameter in mm; k represents the area of the cross section of the optical fiber (the cross-sectional shape of the optical fiber is circular).
Drawings
The invention will be further described in detail with reference to examples of embodiments shown in the drawings to which, however, the invention is not restricted.
FIG. 1 is a schematic diagram of the three-dimensional design of the multi-temperature control module asynchronous channel-selectable PCR instrument of example 1.
FIG. 2 is a schematic side view of the multi-temperature control module asynchronous channel-selectable PCR instrument of example 1.
FIG. 3 is a schematic diagram of the front vertical surface design of the multi-temperature control module asynchronous channel-selectable PCR instrument of example 1.
FIG. 4 is a schematic diagram of the three-dimensional design of the multi-temperature control module asynchronous channel-selectable PCR instrument of example 1 from another perspective.
FIG. 5 is a schematic three-dimensional design of the fluorescence detection assembly and the reaction cell assembly module of example 1.
FIG. 6 is a schematic three-dimensional design of the fluorescence detection assembly of example 1.
FIG. 7 is a schematic design diagram of the fluorescence detection module of example 1.
FIG. 8 is a schematic diagram of the three-dimensional design of the multi-temperature control module asynchronous channel-selectable PCR instrument of example 1 from another perspective.
FIG. 9 shows the result of numerical simulation calculation of the luminous flux of excitation light entering the optical fiber when the power of the LED lamp is 1w and the diameter of the optical fiber is 0.5 mm.
FIG. 10 shows the result of numerical simulation calculation of the luminous flux of excitation light entering the optical fiber when the power of the LED lamp is 1w and the diameter of the optical fiber is 1 mm.
FIG. 11 shows the result of numerical simulation calculation of the luminous flux of excitation light entering the optical fiber when the power of the LED lamp is 1w and the diameter of the optical fiber is 3 mm.
The reference numerals are explained below:
the device comprises a hot cover module 100, m temperature control modules 200, m reaction pool assembly modules 300, a main control board 400 and a fluorescence detection assembly 500;
the device comprises a transmission module 501, a fluorescence detection module 502, an optical fiber fixing plate 503, a limiting module 504, a bottom plate 505 and an optical fiber 506;
a motor 501-1, a synchronous belt 501-2, a sliding block 501-3 and a guide rail 501-4;
a through hole 503-1;
the device comprises a light source 502-1, a first collimating lens 502-2, a second collimating lens 502-3, a coupling lens 502-4, a dichroic mirror 502-5, a focusing lens 502-6, a sensor 502-7, an excitation light filter 502-8 and a receiving light filter 502-9;
a first optical coupler 504-1, a second optical coupler 504-2, a first baffle 504-3, and a second baffle 504-4.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be described in further detail with reference to the accompanying drawings in conjunction with the following detailed description. It should be understood that the description is intended to be exemplary only, and is not intended to limit the scope of the present invention. Moreover, in the following description, descriptions of well-known structures and techniques are omitted so as to not unnecessarily obscure the concepts of the present invention.
< example 1: a PCR instrument with multiple temperature control modules and asynchronous optional channels >
< Overall construction >
Referring to fig. 1-4, a PCR instrument with multiple temperature control modules and asynchronous optional channels comprises: the device comprises m hot cover modules 100, m temperature control modules 200, m reaction pool assembly modules 300, a main control board 400 and a fluorescence detection assembly 500; wherein m is a natural number of 2 or more.
Wherein, the thermal cover module 100 is used for sealing the upper opening of the reaction cell assembly module 300 to increase the gas pressure and boiling point of the reagent; at the same time, it may also heat the reaction cell assembly module 300.
The temperature control module 200 is used for controlling the temperature (heating and cooling) of the reaction cell assembly module 300; that is, the temperature control module 200 is heated from the lower side of the reaction cell assembly module 300, and the thermal cover module 100 is heated from the upper side of the reaction cell assembly module 300, so that the reagent in the reaction cell assembly module has a more uniform temperature field when being heated.
The m independent temperature control modules 200 are used for solving the problem that the detection can be started only after the temperature rise and the temperature decrease of the detection test tubes of the former group of people are waited after the detection test tubes of the latter group of people come in during the detection in the background technology; the equipment of this application, m group's personnel are when the test, do not influence each other in the progress.
Wherein the i-th reaction cell assembly module 300 includes niA reaction cell in which a reagent is contained.
The main control board 400 is a PCB board and functions to control the temperature of the thermal cover module and the temperature control module.
The fluorescence detection assembly is used for generating an optical signal, transmitting the optical signal to the reaction cell, receiving the optical signal and analyzing the optical signal.
< connection relationship between the hot lid module 100, the main control board 400, and the temperature control module 200 >
As shown in fig. 1 to 4 and fig. 8, the connection relationship among the hot lid module 100, the main control board 400 and the temperature control module 200 is as follows:
wherein, the upper top of the temperature control module 200 is provided with a groove for accommodating part of the reaction cell component module 300, and the lower part of the reaction cell component module 300 is arranged in the groove of the upper top of the temperature control module 200;
the main control board 400 is provided with m hollow areas, the positions of the m hollow areas correspond to the positions of the m reaction tank assembly modules 300, and the main control board 400 is arranged on the upper surfaces of the m temperature control modules 200;
wherein the reaction cell assembly module 300 protrudes from the upper surface of the main control board 400;
wherein, a hot cover module 100 is disposed above the reaction cell assembly module 300;
the hot cover module 100 and the temperature control module 200 are both connected to the main control board 400.
< design of fluorescence detection Assembly 500 >
The fluorescence detection component is the key to solve the 'optional matching channel', and the problem is difficult to solve in the following three points.
1) If the "light source" for fluorescence detection is changed, the corresponding "excitation light filter, receiving light filter, sensor" is also changed. In order to realize quick replacement, a modular design is required; and how to realize modular design is the first difficulty.
2) If the modular design is realized, how to communicate with the reaction tank is the second difficulty.
3) The problem associated with the second difficulty is that how to measure the reaction cell after the modular design is the third difficulty.
As shown in fig. 4-8, a fluorescence detection assembly 500, includes: the device comprises a transmission module 501, R fluorescence detection modules 502, an optical fiber fixing plate 503, a limiting module 504, a bottom plate 505 and an optical fiber 506;
as shown in FIG. 7, the internal design of a fluorescence detection module 502 is illustrated. The fluorescence detection module 502 comprises a light source 502-1, a first collimating lens 502-2, a second collimating lens 502-3 (the divergence angle of an LED is larger, and 1 collimating lens is more difficult to collimate in a smaller space volume, so that two collimating lenses are used for better collimating light emitted by the LED and collecting more effective light), a coupling lens 502-4, a dichroic mirror 502-5, a focusing lens 502-6, a sensor 502-7, an opening, an excitation light filter 502-8 and a receiving light filter 502-9; the light source 502-1 is an LED lamp. The working principle is as follows: the light source 502-1 emits light, the light vertically propagates through the first collimating lens 502-2, the second collimating lens 502-3 and the excitation light filter 502-8 which are horizontally arranged in parallel, then passes through the dichroic mirror 502-5 which is obliquely arranged at 45 degrees, and after being reflected, the light passes through the vertically arranged coupling lens 502-4 along the horizontal direction, then passes through the opening along the horizontal direction, and leaves the fluorescence detection module 502.
As shown in fig. 5-6, the fiber holding plate 503 is arranged with n1+ n2+……+ nmA via 503-1 (T = n)1+ n2+……+ nm) The number of the optical fibers 506 is the same as that of the through holes of the optical fiber fixing plate 503, the optical fibers are respectively fixed on one side of the through holes of the optical fiber fixing plate 503 (the optical fibers and the fluorescence detection modules are respectively arranged on two sides of the optical fiber fixing plate), and the optical fibers are fixedly communicated with the through holes arranged on the optical fiber fixing plate one by one.
As shown in fig. 4 and 8, the transmission module 501 includes: a motor 501-1, a synchronous belt 501-2, a sliding block 501-3 and a guide rail 501-4; the sliding block 501-3 is matched with the shape of the guide rail 501-4, namely the sliding block 501-3 can only move along the direction of the guide rail 501-4; the motor 501-1 is connected with the synchronous belt 501-2, the slider 501-3 is fixed on the synchronous belt 501-2 (it should be noted that the power supply mode in which the motor 501-1 drives the slider 501-3 along the guide rail 501-4 can also be other modes in the prior art), and the motor 501-1 can drive the slider 501-3 to move back and forth along the guide rail 501-4. The motion mechanism of the transmission module 501 is as follows: the motor 501-1 rotates to drive the sliding block 501-3 to move along the direction of the guide rail 501-4, and the fluorescence detection module is fixed on the sliding block, so that the fluorescence detection module performs linear moving scanning.
The limiting module 504 includes: a first optical coupler 504-1, a second optical coupler 504-2, a first baffle 504-3 and a second baffle 504-4; the first optical coupler 504-1 and the second optical coupler 504-2 are respectively arranged on two sides of the bottom plate 505; the first baffle 504-3 and the second baffle 504-4 are respectively and fixedly arranged at two ends of the sliding block 501-3; the first shutter piece 504-3 corresponds to the first optocoupler 504-1, and the second shutter piece 504-4 corresponds to the second optocoupler 504-2.
The matching relationship among the transmission module 501, the fluorescence detection module 502, the optical fiber fixing plate 503, the limiting module 504, the bottom plate 505 and the optical fiber 506 is as follows:
the guide rail 501-4 is arranged in parallel with the optical fiber fixing plate 503;
the optical fiber fixing plate 503 is fixed on the bottom plate 505;
the motor 501-1 and the synchronous belt 501-2 are distributed on one side of the optical fiber fixing plate 503, and the guide rail 501-4 and the fluorescence detection module 502 are distributed on the other side of the optical fiber fixing plate 503; the optical fiber fixing plate 503 is provided with a strip-shaped groove, and the sliding block 501-3 penetrates through the strip-shaped groove;
the number of the fluorescence detection modules 502 is set according to actual needs, and the fluorescence detection modules 502 are fixedly arranged on the sliding block 501-3.
The opening of the fluorescence detection module 502 and the through hole of the optical fiber fixing plate are at the same level.
< detection method of PCR instrument with multiple temperature control modules and asynchronous optional channels >
The detection mode of the application comprises the following steps:
s100, installing and fixing a fluorescence detection module to be used on a sliding block;
s200, placing a reagent tube to be detected into any ith reaction tank assembly module, placing the reaction tank assembly module and the ith reaction tank assembly module into the ith temperature control module, covering the ith heat cover module above the ith reaction tank assembly module, controlling the ith temperature control module and the ith heat cover module through a main control board, and adjusting the temperature of the ith reaction tank assembly module to a preset temperature;
s300, after the temperature of the ith reaction tank assembly module reaches a preset temperature, starting detection:
s301, in an initial state, blocking the first blocking piece by the first light coupler;
s302, the motor starts, drives the slider motion, and fluorescence detection module straight line slides, and fluorescence detection module begins work simultaneously, and when the second baffle moved the position of second opto-coupler, motor stall, fluorescence detection module stop work, the reagent pipe homoenergetic of arbitrary ith reaction cell subassembly module can detect the completion:
each fluorescence detection module passes through the through hole of the optical fiber fixing plate corresponding to the ith reaction cell assembly module:
the detection mode of any one fluorescence detection module is as follows: the light source emits exciting light, the exciting light vertically propagates, passes through a first collimating lens, a second collimating lens and an exciting light optical filter 502-8 which are horizontally arranged in parallel, then passes through a dichroic mirror which is obliquely arranged at 45 degrees, the exciting light is reflected, then passes through a coupling lens which is vertically arranged along the horizontal direction, leaves a fluorescence detection module, then enters an optical fiber through a through hole of an optical fiber fixing plate, then enters a reaction tank, a fluorescence signal excited by a sample is transmitted through the optical fiber, then returns along the optical fiber, returns to the fluorescence detection module through the through hole of the optical fiber fixing plate, then passes through the coupling lens, horizontally transmits through the dichroic mirror, passes through a receiving light optical filter 502-9, filters ineffective fluorescence, passes through a focusing lens and finally reaches a sensor;
s400, after the detection of S300 is finished, carrying out the next detection:
s401, when the type of the virus to be detected needs to be changed, taking the fluorescence detection module of the S100 down from the slide block, and replacing the fluorescence detection module with the needed fluorescence detection module; when the virus species to be detected is not changed, the fluorescence detection module of S100 is not moved;
s402, repeating the steps S200-S300.
< design of core difficulties >
The fluorescence detection module is designed in an integrated mode of exciting light and receiving light, and two problems still exist in design.
First, the volume of the fluorescence detection module imposes a constraint on the number of channels that can be configured. To meet the number of selectable dispensing channels, a small volume fluorescence detection module is required. The smaller the volume of the LED lamp is required, and the power of the LED lamp is inevitably affected. If the power is too low, the signal of the reflected light is too weak, which may affect the sensor judgment.
Second, the thickness of the optical fiber imposes a constraint on the number of reaction cells, i.e., on the number of m. Because the length of the optical fiber fixing plate is fixed, the larger the optical fiber, the larger the through hole (the diameter of the through hole is matched with the diameter of the optical fiber).
The two points are integrated: in order to meet the number of the selectable channels, the LED lamp needs to adopt low power. In order to satisfy the number of reaction cells, there is also a demand for making the diameter of the optical fiber small. If the power of the LED lamp is small and the diameter of the optical fiber is small, the received light signal is too weak, and the measurement result of the sensor is affected.
From the above analysis, the LED lamp power and the fiber diameter are two mutually restrictive indicators. That is, if a low power LED lamp is used to satisfy a larger number of selectable distribution channels, a large diameter optical fiber is required. However, the optical fiber is inserted into the reaction cell, and the reagent capacity of the reaction cell imposes a limit on the upper limit of the diameter of the optical fiber. If the number of reaction cells is equal, a small diameter optical fiber is needed, and a high power LED lamp is needed.
The core difficulty lies in that: how to coordinate the relationship of LED lamp power to fiber diameter.
For the above problems, intensive research is carried out, and the following design indexes are proposed:
G×(-0.0047K2+0.0645K+0.003) ≥0.05
K=(π×d2)/4
wherein G represents the power of the LED lamp and the unit is w; d represents the fiber diameter in mm; k represents the area of the cross section of the optical fiber (the cross-sectional shape of the optical fiber is circular).
The units of G, d, and K are only for explaining how to select numerical values, and are not substituted into dimensions in actual calculation.
The research and development process of the indexes is as follows:
first, how to ensure that the received light signal of the fluorescence detection module of the present application meets the basic requirements.
The theoretical basis is as follows:
(1) the optical fiber return received optical power A is larger than or equal to a sensor response threshold value F;
for the sensor response threshold F on the right side of the above equation, which is a known quantity, most sensor response thresholds are between w. The calculation of the received optical power a returned by the optical fiber on the left side of the above formula is difficult because the fluorescence detection module and the single optical fiber of the present application are used as the excitation-reception optical fiber at the same time, and both of these factors have an influence on the calculation of a. When the problem is considered, numerical simulation is directly adopted, although some data can be obtained, because the variables have too much influence, it is unclear which variables have large influence and which variables have small influence (namely, the data are too chaotic), and therefore, theoretical results with guiding significance cannot be extracted.
To this problem, the ingenious solution lies in: the formula of the optical fiber return received optical power A being larger than or equal to the sensor response threshold F is changed as follows:
the power V of the exciting light transmitted by the optical fiber is larger than or equal to the response threshold F x of the sensor (the power V of the exciting light transmitted by the optical fiber/the power A of the received light transmitted back by the optical fiber).
Firstly, for the optical fiber to transmit the exciting light power V, the influence factors are relatively few, and the theory with guiding significance can be extracted.
Secondly, transmitting exciting light power V by the optical fiber/transmitting receiving light power A by the optical fiber, and defining the power A as a transmission coefficient; for the return coefficient, based on numerical tests, the diameter of the optical fiber is within 0.3-5 mm within 1m of the length of the optical fiber, and the value is substantially between 100-500 (for example, the optical fiber transmits the excitation light power V =0.1w, and the optical fiber transmits the excitation light power V = 0.1/500-0.1/100 w). The sensor response threshold F is generally 0.0001w (ensuring the test precision), so the right side calculation result of the equation is between 0.01 and 0.05 w; slightly conservative, the right side of the equation is taken to be 0.05. In the above conversion mode, "optical fiber return receiving optical power a" which is difficult to be solved quantitatively is converted into two parameters which are easy to be solved: return coefficient, fiber optic transmission excitation light power V.
(2) The power V of the exciting light transmitted by the optical fiber is more than or equal to the minimum value of the PCR reaction solution; the minimum value of the PCR reaction solution is generally about 0.03 w. Namely V is more than or equal to 0.03 w.
Combining the above analysis, it is necessary to satisfy: v is more than or equal to 0.05.
Second, how to judge the luminous flux of the excitation light entering the optical fiber, i.e., how to calculate V.
Fig. 9-11 illustrate the calculation results of the light flux entering the optical fiber of the excitation light-receiving light integrated fluorescence detection module of the present application at different optical fiber diameters. As shown in FIG. 9, when the power of the LED lamp is 1w and the diameter of the optical fiber is 0.5mm, the numerical simulation calculation result of the luminous flux of the exciting light entering the optical fiber is as follows: total luminous flux 0.014747W. As shown in fig. 10, when the power of the LED lamp is 1w and the diameter of the optical fiber is 1mm, the numerical simulation calculation result of the luminous flux of the excitation light entering the optical fiber is: total luminous flux 0.10246W. As shown in fig. 11, the numerical simulation calculation result of the luminous flux of the excitation light entering the optical fiber when the power of the LED lamp is 1w and the diameter of the optical fiber is 3mm is: total luminous flux 0.22382W.
Based on multiple numerical simulation calculations (the foregoing is limited to space, and only three sets of numerical simulation calculations are shown), fitting toWhen the power of the LED lamp is G (w), the diameter of the optical fiber is d (mm), the sectional area of the optical fiber is K (mm 2), and the luminous flux of exciting light entering the optical fiber is as follows: v = gxx (-0.0047K2+0.0645K +0.003) (w). It should be noted here that, directly starting from V, d, it is difficult to find the relationship between the two (the correlation coefficient is low); and is converted into V, pi d2And 4, the reliability of the deduced formula is higher (the correlation coefficient is higher).
It should be noted that: the above formula is adapted to the conditions of the fluorescence detection module (the fluorescence detection module designed by the parameters is high in general type, and therefore, the fitting of the fluorescence detection module to the conditions has high universality).
The parameters of the focusing lens and the coupling lens are consistent and are as follows: the diameter is 8mm, the thickness is 5mm, the biconvex curvature is 8mm, and the material K9 is obtained; first collimating lens: the diameter is 8mm, the thickness is 3mm, the planoconvex curvature is 8mm, and the material K9 is obtained; a second collimating lens: 8mm in diameter, 3mm in thickness, 6mm in plano-convex curvature, material K9 (material K9 is K9 glass).
The above-mentioned embodiments are only for convenience of description, and are not intended to limit the present invention in any way, and those skilled in the art will understand that the technical features of the present invention can be modified or changed by other equivalent embodiments without departing from the scope of the present invention.
Claims (8)
1. A PCR instrument with multiple temperature control modules and asynchronous optional channels is characterized by comprising m temperature control modules, m reaction pool assembly modules and a fluorescence detection assembly; wherein m is a natural number greater than or equal to 2;
the temperature control module is used for controlling the temperature of the reaction cell assembly module;
each reaction tank component module comprises a plurality of reaction tanks, and reagents are contained in the reaction tanks;
wherein, fluorescence detection subassembly includes: the device comprises a transmission module, more than one fluorescence detection module, an optical fiber fixing plate and an optical fiber; the fluorescence detection module is an exciting light-receiving light integrated module structure; a fluorescence detection module comprising: the device comprises a light source, a first collimating lens, a second collimating lens, an exciting light filter, a coupling lens, a dichroic mirror, a receiving light filter, a focusing lens, a sensor and an opening; the light source adopts an LED lamp; the light source emits light, the light vertically propagates, passes through the first collimating lens, the second collimating lens and the excitation light filter which are horizontally arranged in parallel, then passes through the dichroic mirror which is obliquely arranged at 45 degrees, after being reflected, the light passes through the coupling lens which is vertically arranged along the horizontal direction, then passes through the opening along the horizontal direction, and leaves the fluorescence detection module; the received light enters the fluorescence detection module from the opening, passes through the coupling lens along the horizontal direction, then horizontally transmits through the dichroic mirror, then sequentially passes through the receiving light filter and the focusing lens along the horizontal direction, and finally enters the sensor along the horizontal direction;
the optical fiber fixing plate is provided with through holes, the number of the optical fibers and the number of the reaction tanks are the same, and the optical fibers and the fluorescence detection modules are respectively positioned on two sides of the optical fiber fixing plate; one end of the optical fiber is fixedly communicated with the through holes one by one, and the other end of the optical fiber is inserted into the reaction tank; during detection, the through hole is used as an inlet of exciting light and an outlet of the receiving port; the through holes on the optical fiber fixing plate are arranged in a straight line;
the transmission module includes: a power mechanism, a slide block and a guide rail; the sliding block is matched with the guide rail in shape; the power mechanism can push the sliding block to move back and forth along the guide rail;
a space for placing n fluorescence detection modules is preset on the sliding block, and the fluorescence detection modules are detachably arranged on the sliding block; when the slide block is fully provided with n fluorescence detection modules, the openings of the fluorescence detection modules are also arranged in a straight line; n is a natural number greater than or equal to 5;
the straight line of the through hole array is parallel to the straight line of the opening array of the fluorescence detection module and is highly matched with the straight line of the opening array of the fluorescence detection module; during detection, when the sliding block moves along the guide rail, the openings of the fluorescence detection module can be sequentially aligned with all the through holes;
the moving direction of the sliding block and the direction of the guide rail are both parallel to the straight line arranged by the through holes.
2. The asynchronous channel-selectable PCR instrument of claim 1 further comprising: m thermal cover modules; the hot cover module is used for sealing the upper opening of the reaction cell component module.
3. The asynchronous channel-selectable PCR instrument of claim 2, further comprising: a main control board;
the connection relation of the hot cover module, the main control board and the temperature control module is as follows: the upper top of the temperature control module is provided with a groove for accommodating the module part of the reaction cell assembly, and one part of the lower part of the reaction cell assembly module is arranged in the groove at the upper top of the temperature control module;
the main control board is provided with m hollowed-out areas, the positions of the m hollowed-out areas correspond to the positions of the m reaction tank assembly modules, the heights of the m temperature control modules are consistent, and the main control board is arranged on the upper surfaces of the m temperature control modules;
the reaction tank assembly module protrudes out of the upper surface of the main control board;
a thermal cover module is arranged above the reaction tank assembly module;
the hot cover module and the temperature control module are electrically connected with the main control board: the temperature change of the hot cover module and the temperature control module is controlled by the main control board.
4. The apparatus of claim 1, wherein the fluorescence detection assembly further comprises: a base plate;
the power mechanism is a motor;
the guide rail is arranged in parallel with the optical fiber fixing plate;
the guide rail and the optical fiber fixing plate are fixed on the bottom plate;
the optical fiber fixing plate is provided with a strip-shaped groove, and the sliding block penetrates through the strip-shaped groove.
5. The apparatus of claim 4, wherein the fluorescence detection assembly further comprises: spacing module, spacing module includes: the optical coupler comprises a first optical coupler, a second optical coupler, a first blocking piece and a second blocking piece; the first optical coupler and the second optical coupler are respectively arranged on two sides of the bottom plate; the first blocking piece and the second blocking piece are respectively and fixedly arranged at two ends of the sliding block; the first separation blade corresponds to the first optocoupler, and the second separation blade corresponds to the second optocoupler.
6. The PCR instrument of claim 5, wherein the channel is selected from a group consisting of a multi-temperature control module, a multi-channel PCR instrument,
the through holes on the optical fiber fixing plate are all kept on the same horizontal plane, and the opening of the fluorescence detection module and the through holes of the optical fiber fixing plate are at the same horizontal height.
7. The PCR instrument of claim 5, wherein the LED lamp of the fluorescence detection module is G, the diameter of the optical fiber is d, and the following formula is satisfied:
G×(-0.0047K2+0.0645K+0.003) ≥0.05
K=(π×d2)/4
wherein, the unit of G is w when selecting the value; the unit is mm when the numerical value of d is selected; k is an intermediate parameter and the unit is mm when selecting the value2。
8. The PCR instrument of claim 1, wherein n sets of positioning bolt holes are preset on the slide block, 1 set of positioning bolt holes are also arranged on the fluorescence detection module, 1 set of positioning bolt holes on the slide block correspond to 1 set of positioning bolt holes on the fluorescence detection module, and the fluorescence detection module and the slide block are detachably connected by means of a bolt-nut assembly.
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| CN110628604A (en) * | 2019-09-11 | 2019-12-31 | 莫纳（苏州）生物科技有限公司 | PCR module movable fluorescent quantitative PCR instrument, PCR instrument set and method |
| TWI814449B (en) * | 2022-06-16 | 2023-09-01 | 財桂生物股份有限公司 | PCR comprehensive diagnostic instrument |
| CN117305050A (en) * | 2022-06-23 | 2023-12-29 | 中元汇吉生物技术股份有限公司 | Full-automatic PCR fluorescent quantitative analyzer |
| CN114940944B (en) * | 2022-07-21 | 2022-09-27 | 鲲鹏基因（北京）科技有限责任公司 | Optical detection device for PCR instrument |
| CN115074241B (en) * | 2022-07-21 | 2022-11-01 | 鲲鹏基因（北京）科技有限责任公司 | Amplification device for PCR instrument, control method thereof and PCR instrument |
| CN115011466A (en) * | 2022-08-03 | 2022-09-06 | 深圳市博德致远生物技术有限公司 | Fluorescence channel detection system for real-time fluorescence quantitative PCR |
| CN115125129B (en) * | 2022-09-01 | 2022-11-08 | 苏州雅睿生物技术股份有限公司 | Constant-temperature chromatography nucleic acid detection device and detection method |
| CN117402721B (en) * | 2023-11-03 | 2024-04-19 | 苏州思迈德生物科技有限公司 | Detection device and detection method for multicolor fluorescence detection |
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| CN205506684U (en) * | 2016-03-17 | 2016-08-24 | 苏州天隆生物科技有限公司 | A many fluorescence passageway detecting system for real -time fluorescence quantitative PCR |
| CN208104392U (en) * | 2018-03-23 | 2018-11-16 | 北京海维尔科技发展有限公司 | A kind of real-time fluorescence quantitative PCR instrument temperature control module lifting device |
| CN111830002A (en) * | 2020-08-10 | 2020-10-27 | 杭州天微基因科技有限公司 | Multi-channel detection system for real-time nucleic acid fluorescence detection |
| CN112326611B (en) * | 2020-10-29 | 2021-05-14 | 苏州雅睿生物技术有限公司 | N reagent hole M channel fluorescence detection method and design method |
| CN112304915B (en) * | 2020-10-29 | 2021-05-04 | 苏州雅睿生物技术有限公司 | Real-time fluorescence detection optical system and real-time fluorescence quantitative PCR instrument |
| CN112226359B (en) * | 2020-12-17 | 2021-03-02 | 苏州雅睿生物技术有限公司 | Portable small real-time fluorescence quantitative PCR instrument and detection method thereof |
| CN113308354B (en) * | 2021-05-28 | 2022-02-15 | 深圳市尚维高科有限公司 | Light path system of multicolor fluorescence quantitative PCR instrument and processing method |
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