JP6068227B2 - Nucleic acid analyzer - Google Patents

Description

  The present invention relates to a nucleic acid analyzer having a flow path and a dispensing mechanism.

  A nucleic acid analyzer is a device that detects the type of a base from a nucleic acid of a sample and determines its sequence. In conventional nucleic acid analyzers, the base sequence is determined by electrophoresis of nucleic acid whose fluorescence has been modified in a glass capillary tube and reading fluorescence obtained by irradiation with excitation light.

  In recent years, a magnetic beads or nucleic acid holding a sample nucleic acid on a flat substrate called a flow cell has been added, and fluorescence can be read by an image sensor such as a CCD camera, enabling multiple nucleic acids to be efficiently analyzed in parallel. A device called a DNA sequencer has appeared. In these nucleic acid analyzers, a fluorescently labeled complementary probe (nucleic acid fragment) is extended on a sample nucleic acid by DNA polymerase or DNA ligase. By detecting fluorescence for each extension reaction, it is possible to determine the base sequence in parallel with a large number of nucleic acids.

  In the capillary method, the flow path for aspirating reagents and samples and transporting them to the fluorescence detection section has a single flow path structure, whereas in the next-generation DNA sequencer, the necessary amount of reagent is aspirated and discharged. Some have a liquid delivery system in which the injection mechanism and the magnetic beads holding the sample and the flow path through which the reagent reacts have different structures (Patent Document 1). With this structure, the reaction channel is shortened to prevent contamination and reduce the amount of reagent used.

JP 2012-173059 A

  In next-generation sequencers, magnetic beads, samples, and reagent components adhere to the waste liquid flow path, resulting in increased resistance in the flow path, which may cause clogging in the flow path and adversely affect analysis results. . In this case, it is necessary to prepare reagents and samples for remeasurement. The next-generation DNA sequencer needs to use an expensive reagent, and if it is measured again, the analysis cost increases due to the use of an extra reagent. In addition, the measurement that has been completed in several hours in the capillary method takes several days to several weeks in order to process a large number of samples in the next-generation DNA sequencer. For this reason, re-measurement results in a large time loss.

  As a method for detecting clogging in the flow path, for example, there is a method of directly measuring the pressure and capturing the pressure change in the flow path. However, in general, the pressure sensor is expensive, and there is a problem that the inside of the flow path becomes complicated.

  The present invention provides a nucleic acid analyzer having a function of detecting clogging in a flow path using a simple mechanism and automatically washing the clogged flow path.

  In the present invention, when clogging occurs in the flow path, clogging in the flow path is detected by utilizing a phenomenon in which the liquid level of the inlet becomes higher after the liquid is injected into the flow path than when there is no clogging. The height of the liquid level is detected by using a normal liquid level detection function by the tip of the dispensing nozzle.

  The nucleic acid analyzer of the present invention detects a liquid level by a dispensing nozzle that sucks and discharges a liquid, a nozzle drive unit that moves the dispensing nozzle to a desired position, and the tip of the dispensing nozzle contacting the liquid level. A liquid level detector, a reaction unit having an inlet, a reaction channel connected to the inlet and a waste liquid channel connected to the reaction channel, and a control / arithmetic unit for controlling each part of the apparatus The liquid level detection unit detects the liquid level of the injection port after dispensing the liquid from the dispensing nozzle to the injection port, and the control / calculation unit detects the liquid level detected by the liquid level detection unit. The clogging of the flow path system is detected based on the surface height. The control / arithmetic unit performs a cleaning process of injecting a cleaning liquid into the inlet of the flow path system in which clogging is detected.

  According to one aspect, the reaction unit includes a flat substrate provided with a reaction channel and a cover plate that is detachably fixed on the flat substrate, the reaction channel includes an inlet opening and an outlet opening, and the cover plate includes The inlet has an inlet, a channel connecting portion, and an opening, the inlet is connected to an inlet opening provided on the flat substrate, the channel connecting portion connects the outlet opening and the waste liquid channel, and the opening is a flat surface. Excitation light irradiation and fluorescence detection are performed on the magnetic beads located on the reaction flow path of the substrate and held in the reaction flow path through the opening of the cover plate.

According to the present invention, it is possible to detect clogging in the flow path without adding a new sensor such as a pressure sensor. As a result, the flow path can be prevented from becoming complicated and the cost can be reduced. Moreover, the deterioration of the analytical reaction due to clogging can be prevented by performing the washing treatment.
Problems, configurations, and effects other than those described above will be clarified by the following description of embodiments.

Schematic which shows the structural example of a nucleic acid analyzer. Schematic which shows the flow path of a nozzle drive part and a reaction unit. The exploded view of the reaction unit. Schematic of liquid level detection. The figure which shows the example of the signal used with a liquid level detection function. An explanatory view of an example of clogging in a channel. The figure which shows a mode that the dispensing nozzle is inserted in the inlet of a reaction flow path. The figure which shows a mode that the dispensing nozzle is moved upwards from the injection inlet after dispensing. The figure which shows a mode that the liquid level detection of the injection hole vicinity is carried out. The schematic sectional drawing of the injection port which provided the guide around. The flowchart which shows the example of a procedure which detects clogging of a flow path with a dispensing nozzle. The flowchart which shows the example of a procedure of washing | cleaning. The flowchart which shows the example of a procedure of washing | cleaning.

  Embodiments of the present invention will be described below with reference to the drawings.

[Example 1]
First, the configuration of the entire apparatus will be described. FIG. 1 is a schematic diagram illustrating a configuration example of a nucleic acid analyzer. The nucleic acid analyzer includes a liquid feeding unit 101, a reaction unit 102, a detection unit 103, and a control / calculation unit 104. The control / arithmetic unit 104 controls each part of the apparatus according to the analysis program while referring to the information stored in the memory, and executes the analysis.

  The liquid feeding unit 101 includes a reagent rack 105 that holds a reagent, a dispensing nozzle 107, a syringe 108, a nozzle driving unit 109, and the like. In the reagent rack 105, a plurality of reagent containers containing reagents are held and stored at a temperature suitable for reagent storage. On the reagent rack 105, a slider 106 provided with a plurality of openings in the same arrangement as the reagent containers is arranged so as to cover the reagent rack. By sliding the slider 106 left and right by the control / calculation unit 104, the upper part of the reagent container in the reagent rack 105 is opened and closed. The dispensing nozzle 107 sucks / discharges an appropriate amount of reagent by the operation of the syringe 108. In addition, the dispensing nozzle 107 is moved up and down, left and right and back and forth by a nozzle driving unit 109.

  The reaction unit 102 includes a stage 115 and a flat substrate 114. The stage 115 fixes the flat substrate 114 and moves to a reagent loading position and a detection position by a stage driving unit 116 driven according to an instruction from the control / calculation unit 104. The flat substrate 114 is provided with a reaction channel 121 in which a magnetic bead having a nucleic acid sample attached is accommodated. By dispensing a reagent from the dispensing nozzle 107 into the reaction channel 121, the magnetic bead is obtained. The reaction between the nucleic acid sample adhering to the reagent and the reagent occurs.

  The detection unit 103 includes a light source 117 and an image sensor 118. By irradiating excitation light from a light source 117 such as a xenon lamp, an image sensor 118 such as a CCD camera emits fluorescence emitted from a sample attached to and held by magnetic beads in a reaction channel 121 on a flat substrate 114. Detect by.

  The reagent is dispensed into the reaction channel 121 of the flat substrate 114 as follows. First, under the control of the control / arithmetic unit 104, the dispensing nozzle 107 is moved to a desired reagent container in the reagent rack 105 while the slider 106 is driven and the upper part of the reagent container held in the reagent rack 105 is opened. Then, the syringe 108 is driven to suck a predetermined amount of reagent. On the other hand, the flat substrate 114 is moved to the reagent loading position by the stage driving unit 116 controlled to be driven by the control / calculation unit 104. Next, the control / calculation unit 104 inserts the dispensing nozzle 107 into the injection port 110 of the flat substrate 114 moved to the reagent charging position, and drives the syringe 108 to dispense the reagent into the reaction channel 121.

  After the reagent dispensing, the control / calculation unit 104 moves the dispensing nozzle 107 to the cleaning port 111 and cleans the dispensing nozzle 107 with the cleaning liquid. Cleaning inside the nozzle (internal washing) is performed by discharging the cleaning liquid from the inside of the nozzle by opening and closing the pump mechanism and the valve. Cleaning outside the dispensing nozzle (outside washing) is performed by opening and closing the pump mechanism and the valve. The cleaning liquid is discharged from the reagent dispensing nozzle 107 to the outside of 112. The cleaning liquid after cleaning is stored in the waste liquid tank 113.

  The stage 115 that fixes the planar substrate 114 into which the reagent is dispensed in the reaction channel 121 is adjusted to a high temperature or a low temperature that is appropriate for the reagent reaction by the control / calculation unit 104 according to a series of reaction steps. . The planar substrate 114 that holds the sample that has undergone the reagent reaction is moved to the detection position by the stage driving unit 116, and fluorescence detection is performed by the detection unit 103. When one reaction and detection are completed, the cleaning liquid is injected into the reaction channel 121 of the flat substrate 114, and the reagent that has not contributed to the reaction is washed away. A waste liquid flow path 202 is connected to the reaction flow path 121, and the reagent and cleaning liquid after the reaction are sent to the waste liquid tank 113.

  FIG. 2 is a schematic diagram illustrating the nozzle drive unit and the flow path of the reaction unit of the present embodiment. FIG. 3 is an exploded view of the reaction unit.

  The nozzle drive unit 109 has a dispensing nozzle 107 and has a liquid level detection function for detecting the liquid level at the nozzle tip. For the liquid level detection, a known method can be used in which the liquid level is detected based on a change in capacitance before and after the tip of the dispensing nozzle 107 contacts the liquid level.

  The flat substrate 114 includes a reaction channel 121 inside, and at least the wall portion on the detection unit side of the reaction channel 121 is made of a transparent material that transmits excitation light and fluorescence and does not generate fluorescence when irradiated with excitation light. ing. Magnetic beads with a nucleic acid sample attached are held in the reaction channel 121 of the flat substrate 114. On the flat substrate 114, a cover plate 201 having a connection portion 203 to the inlet 110 and the waste liquid channel 202 is detachably fixed. Each reaction flow path 121 provided on the flat substrate 114 has an upward opening on the inlet side and the outlet side, the opening 122 on the inlet side is at the inlet 110 of the cover plate 201, and the opening 123 on the outlet side is the cover plate. 201 are connected in a liquid-tight manner to connecting portions 203 to the waste liquid flow paths. The cover plate 201 is provided with an opening 204 so that the reaction channel 121 of the flat substrate 114 can be seen through. Excitation light irradiation and fluorescence detection are performed on the magnetic beads held in the reaction channel 121 through the opening 204. Is called. The flat substrate 114 is fixed on the stage 115. The stage 115 has a temperature adjustment function.

  In the figure, the number of reaction channels is four, but the number of reaction channels may be one or plural other than four. As the number of reaction channels increases, analysis can be performed more efficiently. After completion of the reaction, the reagent is sent from the opening 123 on the outlet side of the reaction channel 121 to the waste fluid channel 202 via the connection portion 203 to the waste fluid channel of the cover plate 201 and stored in the waste fluid tank 113. .

  Next, the liquid level detection function used in this apparatus will be described with reference to FIG. The nozzle driving unit 109 is connected to the liquid level detection signal processing unit 301. In the metal dispensing nozzle 107, the tip of the dispensing nozzle 107 touches the liquid level when the nozzle driving unit 109 moves downward. At this time, the capacitance measured at the tip of the dispensing nozzle 107 changes. Compared with the air, when the dispensing nozzle 107 touches the liquid level, the capacitance increases. The liquid level detection is executed by the liquid level detection signal processing unit 301 by converting the amount of change in capacitance into a liquid level detection signal having a voltage as shown in FIG. 5 and comparing it with a threshold voltage. That is, when the liquid level detection signal exceeds the threshold voltage, the liquid level detection signal is output from the liquid level detection signal processing unit 301 to the control / calculation unit 104. The horizontal axis of FIG. 5 is the height of the dispensing nozzle tip with respect to the reference height. The liquid level detection result is used by the control / calculation unit 104 to control the apparatus.

(Detection of clogging in the flow path)
An example of clogging in the flow path will be described with reference to FIG. A magnetic bead 501 to which a nucleic acid sample is attached is fixed in the reaction channel 121 of the flat substrate 114. By repeatedly feeding the reagent and the cleaning liquid by the analysis operation, a part of the magnetic beads 501 is peeled off from the reaction flow path 121 in the flat substrate 114 and flows to the waste liquid flow path 202. The magnetic beads 501 adhere to and accumulate on the inner wall of the waste liquid flow path 202, thereby increasing flow path resistance and causing clogging.

  Next, clogging detection according to this embodiment will be described. FIG. 7 shows the dispensing nozzle 107 accessing the inlet 110 of the reaction channel 121. The control / calculation unit 104 controls the nozzle driving unit 109 to insert the dispensing nozzle 107 into the injection port 110 of the cover plate 201, and then drives the syringe 108 to protect the reaction channel 121 with a protective reagent (buffer solution). Or dispense the washing solution. Dispensing is performed with a certain amount of pressure.

  Next, as shown in FIG. 8, the control / calculation unit 104 controls the nozzle driving unit 109 to move the dispensing nozzle 107 that has finished dispensing upward from the injection port 110. As shown in FIG. 6, when a nucleic acid sample, magnetic beads, reagent, etc. adhere to the waste liquid flow path 202 downstream from the reaction flow path 121 and clogging occurs and the flow path resistance increases, the pressure is increased during dispensing. Therefore, when the dispensing nozzle 107 rises and separates from the injection port 110, a reverse flow of the liquid occurs in the flow path, and a phenomenon that the liquid dispensed from the injection port 110 overflows occurs. That is, the height of the liquid level near the inlet 110 is higher when the clogging is occurring in the flow path than when the clogging is not occurring.

  Therefore, the control / calculation unit 104 lowers the dispensing nozzle 107 from above the injection port 110 and touches the liquid overflowing from the injection port 110 as shown in FIG. Can be detected. The control / calculation unit 104 can determine whether or not clogging has occurred in the flow path by comparing the detected liquid level height with a preset threshold value.

  As shown in the sectional view of FIG. 10, a guide 701 may be provided in the cover plate 201 so as to surround the inlet 110. The guide 701 is for preventing a liquid pool generated at the injection port 110 from flowing around, and makes it easy to detect the liquid pool by holding the liquid overflowing from the injection port 110.

(Example of clogging detection operation)
With reference to the flowchart of FIG. 11, an example of a rough flow of the operation until the clogging of the flow path is detected by the dispensing nozzle 107 is shown.

  First, before starting the analysis operation, the control / calculation unit 104 controls the nozzle driving unit 109 to move the nozzle to the cleaning port 111 (S11). Next, the control / calculation unit 104 cleans the dispensing nozzle 107 by controlling the syringe 108 and the valve (S12). Next, the control / calculation unit 104 controls the nozzle drive unit 109 to move the dispensing nozzle 107 to the position of the container containing the protective reagent (buffer solution) in the reagent rack 105 and lower it (S13). Thereafter, the syringe 108 is controlled to aspirate the protective reagent (buffer solution) (S14).

  Next, the control / calculation unit 104 moves the nozzle driving unit 109 to above the injection port 110 (S15). Then, the dispensing nozzle 107 is lowered and inserted into the injection port 110 to dispense the protective reagent (buffer solution) (S16). The dispensing amount and dispensing time here can be arbitrarily set. The dispensing amount is preferably an amount that can fill the flow path. Further, step 13 to step 16 may be repeated a plurality of times. When the dispensing operation ends, the control / calculation unit 104 raises the dispensing nozzle 107 and waits for a predetermined time above the inlet 110 (S17).

  Next, the control / calculation unit 104 lowers the dispensing nozzle 107 again and detects the height of the liquid level at the injection port 110 (S18). Here, the control / calculation unit 104 compares the detected value with the set threshold value (S19). When the height of the injection port 110 exceeds the threshold, it is determined that clogging has occurred in the flow path connected to the injection port, and the position information of the injection port 110 that has been blocked in the memory of the control / calculation unit 104 is obtained. Record (S20). Subsequently, the controller / arithmetic unit 104 moves the dispensing nozzle 107 to the inlet 110 of another channel, and similarly performs the detection operation (S21). This detection operation is performed in all the flow paths (S22). When the detection operation is completed for all the inlets 110, the control / calculation unit 104 determines whether there is a flow path exceeding the threshold (S23). If there is no flow path exceeding the threshold value, the flow proceeds to the normal analysis operation (S25). If there is a flow path that exceeds the threshold, the process proceeds to a cleaning process (S24).

(Cleaning process)
The cleaning process in step 24 will be described. If there is a flow path whose liquid level at the inlet exceeds the threshold, the following processing is performed.

  For the flow path where the liquid level at the inlet exceeds the threshold, the control / calculation unit 104 determines that clogging has occurred in the flow path, and supplies a protective reagent (buffer solution) or a predetermined amount to the corresponding inlet 110. Dispense the cleaning solution.

  The dispensing operation at this time is performed in a state where the pressure is higher than the normal dispensing setting, and the pressure is applied by switching the operation parameter of the syringe 108. In the dispensing operation from the dispensing nozzle 107, the dispensing amount, the washing time, and the number of dispensings can be set by the control / calculation unit 104. By setting the washing parameters in the memory in advance, the washing operation can be performed. When the transition is made, the control / calculation unit 104 reads the parameter from the memory and controls the operation of the syringe 108 accordingly.

(Example of cleaning process)
With reference to the flowchart of FIG. 12, an example of the cleaning process when the detection operation is completed and there are a plurality of injection ports 110 exceeding the threshold will be described.

  First, the control / calculation unit 104 controls the nozzle driving unit 109 to move the dispensing nozzle 107 to the cleaning port 111 (S31). Next, the control / calculation unit 104 controls the syringe 108 and cleans the dispensing nozzle 107 (S32). Next, the control / calculation unit 104 changes the operation parameter of the syringe 108 (S33).

  Subsequently, the control / calculation unit 104 controls the nozzle driving unit 109 to move to the position of the inlet 110 of the flow path exceeding the threshold value, and lowers the dispensing nozzle 107 (S34). Next, the control / calculation unit 104 controls the syringe 108 and the valve, and injects the cleaning liquid from the dispensing nozzle 107 into the injection port (S35). At this time, an operation of causing the cleaning liquid to flow through the flow path a predetermined number of times may be performed (S36).

  When the injection of the cleaning liquid into one injection port is completed, the control / calculation unit 104 moves the dispensing nozzle 107 to the injection port 110 of the next channel and performs a cleaning operation (S37). When all the cleaning of the flow path of the inlet 110 whose liquid level has exceeded the threshold value is completed (S38), the liquid level detection operation is performed again on the cleaned inlet 110 (S39). If there is an inlet that exceeds the threshold, the flow from step 31 to step 40 is executed again. If there is no injection port exceeding the threshold value, the flow proceeds to the analysis operation (S41). In washing, a protective reagent (buffer solution) may be used instead of the washing solution.

  Here, the example in which the flow of FIGS. 11 and 12 is performed before the analysis operation has been described, but it may be performed during or after the analysis. The pressure in the flow path is preferably set to an upper limit that does not damage the sample in the reaction section.

[Example 2]
A second embodiment of the present invention will be described. In the present embodiment, when performing the cleaning operation described in the first embodiment, the temperature of the stage 115 to which the flat substrate 114 is fixed is controlled in order to flow hot water into the flow path, and the dispensing operation and the heating operation are performed simultaneously. To warm the cleaning solution. By increasing the temperature of the cleaning liquid, the cleaning efficiency of the flow path can be increased.

[Example 3]
A third embodiment of the present invention will be described. If a high pressure is applied excessively when the cleaning liquid is injected into the flow path, there may be a problem that a part of the sample or magnetic beads adhering to the inside of the reaction flow path flows.

  In this embodiment, a cleaning-dedicated planar substrate having a high-pressure channel that does not hold a sample therein is prepared, and the planar substrate 114 is replaced with a cleaning-dedicated planar substrate only during cleaning. That is, when cleaning the waste liquid flow path, the cleaning liquid is not flowed into the waste liquid flow path 202 through the reaction flow path of the flat substrate 114 holding the magnetic beads with the sample attached inside, but the height of the cleaning dedicated flat substrate is increased. The cleaning liquid is caused to flow at a relatively high pressure to the waste liquid flow path 202 that is clogged through the pressure resistant flow path. The cleaning-use flat substrate has the same structure as the flat substrate 114 for analysis, and the material is preferably made of glass, resin such as acrylic resin, or anodized aluminum, or metal such as iron or copper.

  As described with reference to FIG. 3, the cover plate 201 is detachably fixed to the plane substrate 114 for analysis. Therefore, the cover plate 201 is removed from the plane substrate 114 during cleaning, and is instead replaced with a plane substrate dedicated for cleaning. A cover plate 201 is attached and fixed on the stage 115 to perform a cleaning process. As a result, the sample can be protected, and the flow path downstream from the reaction flow path can be washed at high pressure in a short time.

FIG. 13 shows an example of a flow for performing the cleaning process by exchanging the flat substrate with a cleaning-specific flat substrate at the time of cleaning.
First, the clogging detection operation shown in steps 11 to 22 in FIG. 11 is performed (S51). When there is an injection port whose liquid level exceeds the threshold value by this detection operation (S52), the control / calculation unit 104 announces an error message for urging replacement to the cleaning-specific flat substrate on the apparatus display unit. (S53), prompting the user to replace the planar substrate currently attached to the reaction unit with a planar substrate dedicated for cleaning. When the completion of replacement is detected by an input from the user (S54), the control / calculation unit 104 starts the cleaning process shown in steps 31 to 38 in FIG. 12 (S55). After the cleaning process is completed (S56), the control / arithmetic unit 104 makes an announcement to prompt the user to replace the cleaning-only flat substrate with the flat substrate 114 (S57). When the exchange completion is detected by user input (S58), the control / calculation unit 104 shifts to a normal analysis operation (S59). If there is no value exceeding the threshold value due to the detection operation in step 52, the control / calculation unit 104 shifts to a normal analysis operation.

  As described above, according to the present embodiment, when clogging occurs in the flow path, clogging can be detected by using the liquid level detection function using the dispensing nozzle without installing a new sensor. . Further, the inside of the flow path can be automatically cleaned. The deterioration of the analytical reaction due to clogging can be prevented.

  In addition, this invention is not limited to an above-described Example, Various modifications are included. For example, the above-described embodiments have been described in detail for easy understanding of the present invention, and are not necessarily limited to those having all the configurations described. Further, a part of the configuration of one embodiment can be replaced with the configuration of another embodiment, and the configuration of another embodiment can be added to the configuration of one embodiment. Further, it is possible to add, delete, and replace other configurations for a part of the configuration of each embodiment.

DESCRIPTION OF SYMBOLS 101 Liquid supply unit 102 Reaction unit 103 Detection unit 104 Control / calculation part 105 Reagent rack 106 Slider 107 Dispensing nozzle 108 Syringe 109 Nozzle drive part 110 Inlet 111 Washing port 112 Outer washing outlet 113 Waste liquid tank 114 Flat substrate 115 Stage 116 Stage Drive unit 117 Light source 118 Image sensor 121 Reaction channel 201 Cover plate 202 Waste liquid channel 203 Connection unit 301 Liquid level detection signal processing unit 501 Magnetic beads 701 Guide

Claims (8)

A dispensing nozzle that sucks and discharges liquid;
A nozzle drive unit for moving the dispensing nozzle to a desired position;
A liquid level detection unit that detects the liquid level by the tip of the dispensing nozzle contacting the liquid level;
A reaction unit having a flow path system including an inlet, a reaction flow path connected to the inlet, and a waste liquid flow path connected to the reaction flow path;
A control / calculation unit for controlling each part of the device,
The liquid level detection unit detects the liquid level height of the injection port after pressurizing and dispensing liquid from the dispensing nozzle to the injection port,
The nucleic acid analyzer according to claim 1, wherein the control / calculation unit detects clogging of the flow path system based on a comparison between a liquid level detected by the liquid level detection unit and a preset threshold value . The nucleic acid analyzer according to claim 1, wherein
The nucleic acid analyzer according to claim 1, wherein the controller / arithmetic unit performs a cleaning process of injecting a cleaning liquid into an inlet of a flow path system in which clogging is detected. The nucleic acid analyzer according to claim 1, wherein
The reaction unit includes a plurality of reaction channels. The nucleic acid analyzer according to claim 1, wherein
The reaction unit includes a flat substrate provided with the reaction flow path and a cover plate that is detachably fixed on the flat substrate,
The reaction channel comprises an inlet opening and an outlet opening;
The cover plate includes the inlet, a flow path connection portion, and an opening, and the injection port is connected to the inlet opening provided in the planar substrate, and the flow path connection portion includes the outlet opening and the waste liquid. A nucleic acid analyzer, wherein the nucleic acid analyzer is connected to a flow path, and the opening is located on the reaction flow path of the planar substrate. The nucleic acid analyzer according to claim 1, wherein
The nucleic acid analyzer, wherein the cover plate is provided with a guide that surrounds the periphery of the injection port and holds the liquid overflowing from the injection port. The nucleic acid analyzer according to claim 1, wherein
The nucleic acid analyzer, wherein the reaction unit includes a stage having a temperature adjustment function below the flat substrate. The nucleic acid analyzer according to claim 1, wherein
The nucleic acid analyzer characterized in that the reaction channel holds magnetic beads to which a nucleic acid sample is attached. The nucleic acid analyzer according to claim 4, wherein
A flat substrate exclusively for cleaning provided with a high-pressure-resistant channel in the same channel structure as the planar substrate,
When the clogging of the flow path system is detected, the flat substrate is replaced with the flat substrate exclusively for cleaning, and the flow path system is cleaned by injecting a cleaning liquid from the injection port.

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