Patent Publication Number: US-2021164882-A1

Title: Sample liquid-sending device, flow cytometer, and sample liquid-sending method

Description:
TECHNICAL FIELD 
     The present technology relates to a flow cytometer, and a sample liquid-sending device and a sample liquid-sending method that are used in the flow cytometer. 
     BACKGROUND ART 
     A flow cytometer flows a sample suspended in liquid through a tube using a sheath liquid, acquires data of scattered light and fluorescence obtained by a laser irradiator provided midway in the flow, and analyzes the data. For example, Patent Literature 1 discloses a sample liquid-sending device in a flow cytometer, the sample liquid-sending device including a stirring unit for performing stirring in a sample tube, and a nozzle that suctions a sample in the sample tube. Stirring is performed in the sample tube using the stirring unit, and thus the nozzle inserted into the sample tube serves as a stirring rod that moves relative to the sample tube (for example, refer to paragraphs [0014] and [0049] of the specification, and  FIG. 1 ). Performing stirring in a sample tube leads to dispersing, in liquid, the precipitate of the sample accumulated at the bottom of the sample tube, and delivering the sample efficiently. 
     CITATION LIST 
     Patent Literature 
     Patent Literature 1: Japanese Patent Application Laid-open No. 2016-153805 
     DISCLOSURE OF INVENTION 
     Technical Problem 
     As described above, there is a demand for a technique capable of sufficiently suctioning the precipitate of the sample accumulated at the bottom of the sample tube. 
     In view of the circumstances described above, it is an object of the present technology to provide a sample liquid-sending device capable of sufficiently suctioning a precipitate of a sample, a flow cytometer including the sample liquid-sending device, and a sample liquid-sending device method therefor. 
     Solution to Problem 
     In order to achieve the object described above, a sample liquid-sending device according to an embodiment of the present technology includes a drive mechanism, a suction mechanism, and a controller. 
     The drive mechanism supports a sample container and is configured to be capable of moving the sample container, the sample container including a storing portion that stores a suspension containing a sample. 
     The suction mechanism includes a nozzle configured to be inserted into the storing portion, and suctions the suspension through the nozzle. 
     The controller is configured to be capable of controlling the drive mechanism such that a bottom of the storing portion and a suction port of the nozzle are separated from each other by a predetermined distance. 
     According to this configuration, the sample container can be moved relative to the nozzle. This makes it possible to set the distance between the bottom of the storing portion and the suction port of the nozzle such that the precipitate of the sample can be sufficiently suctioned. Thus, according to the present technology, it is possible to sufficiently suction the precipitate of the sample accumulated at the bottom of the storing portion. 
     The controller may control a distance between the bottom and the suction port to be 0.4 mm or more and 0.8 mm or less. 
     The suction mechanism may include the nozzle including a hollow portion and an opening, the hollow portion being a flow path through which the suspension flows, the opening being provided in the suction port and communicating with the hollow portion. This makes it possible to suction the suspension while the suction port of the nozzle and the bottom of the well are in contact with each other, and to suction the suspension sufficiently. 
     The suction mechanism may include the nozzle including a plurality of openings provided in the suction port and communicating with the hollow portion. This improves the efficiency in suctioning the suspension. 
     The suction mechanism may include the nozzle including a notched bottom surface facing the bottom. With this configuration, a gap is formed between the tip of the suction port and the bottom of the storing portion when the suction port is accommodated in the storing portion that does not have a flat bottom, so that a flow path for suctioning the suspension is reliably secured. Thus, it is possible to sufficiently suction the suspension accumulated at the bottom of the storing portion. 
     The sample liquid-sending device may further include a holding mechanism including a detection unit that detects a contact between the bottom and the suction port, and capable of holding the nozzle at a predetermined position. This makes it possible to freely determine a relative position of the storing portion with respect to the nozzle. 
     In order to achieve the object described above, a flow cytometer according to an embodiment of the present technology includes the sample liquid-sending device described above, a holding mechanism, and an analysis unit. 
     The holding mechanism includes a detection unit that detects a contact between the bottom and the suction port, and is configured to be capable of holding the nozzle at a predetermined position. 
     The analysis unit analyzes a characteristic of the sample. 
     In order to achieve the object described above, a sample liquid-sending method according to an embodiment of the present technology includes: inserting a nozzle provided to a suction mechanism into a storing portion of a sample container supported by a drive mechanism, a suspension containing a sample being stored in the storing portion; separating a bottom of the storing portion and a suction port of the nozzle from each other by a predetermined distance; and suctioning the suspension through the nozzle by the suction mechanism. 
     In order to achieve the object described above, a sample liquid-sending method according to an embodiment of the present technology includes: inserting a nozzle provided to a suction mechanism into a storing portion of a sample container supported by a drive mechanism, a suspension containing a sample being stored in the storing portion; detecting a contact between a bottom of the storing portion and a suction port of the nozzle; and suctioning the suspension through the nozzle by the suction mechanism in a state where the bottom and the suction port are in contact with each other. 
     Advantageous Effects of Invention 
     As described above, according to the present technology, it is possible to sufficiently suction the precipitate of the sample. Note that the above effects are not necessarily limited, and any of the effects shown in the specification or other effects that can be grasped from the present specification may be achieved together with the above effects or in place of the above effects. 
    
    
     
       BRIEF DESCRIPTION OF DRAWINGS 
         FIG. 1  is a schematic diagram mainly showing a sample liquid-sending device according to a first embodiment of the present technology, and schematically showing a configuration example of a flow cytometer including the sample liquid-sending device. 
         FIG. 2  is a schematic diagram showing a configuration example of a holding mechanism of the sample liquid-sending device. 
         FIG. 3  is a schematic diagram showing a configuration example of the holding mechanism. 
         FIG. 4  is a schematic diagram showing a configuration example of the holding mechanism. 
         FIG. 5  is a schematic diagram showing a configuration example of the holding mechanism. 
         FIG. 6  is a schematic diagram showing a configuration example of the holding mechanism. 
         FIG. 7  is a schematic diagram showing a configuration example of the holding mechanism. 
         FIG. 8  is a schematic diagram showing a configuration example of the holding mechanism. 
         FIG. 9  is a flowchart showing an operation procedure of the sample liquid-sending device. 
         FIG. 10  is a graph showing a relationship between an event rate and a distance from a suction port of a nozzle and a bottom of a well. 
         FIG. 11  is an enlarged diagram of the suction port of the nozzle according to a second embodiment of the present technology, showing a variation of the formation pattern of an opening provided in the suction port. 
         FIG. 12  is a diagram showing a variation of the formation pattern of the opening. 
         FIG. 13  is a diagram showing a variation of the formation pattern of the opening. 
         FIG. 14  is a diagram showing a variation of the formation pattern of the opening. 
         FIG. 15  is an enlarged diagram of a bottom surface of the nozzle, showing a variation of the formation pattern of the bottom surface. 
         FIG. 16  is an enlarged perspective diagram of the vicinity of the suction port, showing a nozzle accommodated in a storing portion. 
         FIG. 17  is a diagram showing a variation of the formation pattern of the bottom surface. 
         FIG. 18  is a diagram showing a variation of the formation pattern of the opening. 
         FIG. 19  is a diagram showing a variation of the formation pattern of the opening. 
         FIG. 20  is a diagram showing a variation of the formation pattern of the opening. 
         FIG. 21  is a table showing comparison between a dead volume in the case of using a conventional nozzle and a dead volume in the case of using the nozzle of the second embodiment. 
         FIG. 22  is a graph showing the time change of the event rate when using the nozzle of the second embodiment. 
     
    
    
     MODE(S) FOR CARRYING OUT THE INVENTION 
     Hereinafter, embodiments of the present technology will be described with reference to the drawings. 
     1. First Embodiment 
     1.1) Configuration of Flow Cytometer 
       FIG. 1  is a schematic diagram schematically showing a configuration example of a flow cytometer  100  according to a first embodiment. The flow cytometer  100  includes an analysis unit  10  and a sample liquid-sending device  20 . 
     [Analysis Unit] 
     The analysis unit  10  has a function of analyzing the characteristics of a sample detected in the sample liquid-sending device  20 . That is, the flow cytometer  100  of this embodiment typically functions as an analyzer. 
     The analysis unit  10  is connected to a sample detection unit  23  by, for example, an optical fiber F. The analysis unit  10  has a function of analyzing optical characteristics of scattered light generated by laser irradiation, fluorescence, and the like. The analysis unit  41  is typically configured by a computer. 
     [Sample Liquid-Sending Device] 
     The sample liquid-sending device  20  includes a drive mechanism  21 , a suction mechanism  22 , the sample detection unit  23 , a holding mechanism  24 , and a controller  25 . 
     (Drive Mechanism) 
     The drive mechanism  21  includes a support portion  211  and a drive unit  212 . The support portion  211  supports a well plate P (sample container). The drive unit  212  is configured to be capable of moving the well plate P in a longitudinal direction of a nozzle  224  and a plane direction orthogonal to the longitudinal direction via the support portion  211 . That is, the drive unit  212  is configured to be capable of moving the well plate P in three axial directions orthogonal to each other via the support portion  211 . 
     As the drive unit  212 , for example, a cylinder mechanism is employed. In this case, the drive unit  212  typically has an air cylinder mechanism, but is not limited thereto. Any mechanism of a dry cylinder type, a gas cylinder type, an oil cylinder type, and the like may be used. 
     As shown in  FIG. 1 , the well plate P includes a plurality of wells W (storing portions). Each of the plurality of wells W stores a suspension containing a sample. The sample is, for example, a biological cell. The inner diameter of the well W is not particularly limited, but is approximately 8 to 9 mm, for example. 
     The well plate P is, for example, a 6, 12, 24, 48, 96, or 384 well plate, but a 96 well plate is typically employed. The well plate P is made of a synthetic resin such as plastic, for example. Note that in this embodiment, the well plate P is supported by the support portion  211 , but the present technology is not limited thereto. For example, one or more sample tubes may be supported. 
     (Suction Mechanism) 
     The suction mechanism  22  includes pumps  221  and  222 , a nozzle  224 , a sample flow tube  225 , a sheath flow tube  226 , a junction tube  227 , a sheath tank  228 , and a drain tank  229 . 
     A sheath liquid is stored in the sheath tank  228 . The sheath liquid is liquid that serves to squeeze and focus the flow of the sample in the flow cytometer  100 . As the sheath liquid, for example, water, physiological saline, or the like is employed. 
     The pump  221  is connected to the sheath flow tube  226  and the sheath tank  228  in the upstream of the flow cytometer  100 . The pump  221  has a function of suctioning the sheath liquid from the sheath tank  228  and transferring the suctioned sheath liquid to the downstream side. 
     The pump  222  is connected to the junction tube  227  and the drain tank  229  on the downstream side of the flow cytometer  100 . The pump  222  has a function of suctioning a mixed solution of the sheath liquid and the suspension from the upstream side and discharging the suctioned mixed solution to the drain tank  229 . 
     In this embodiment, as shown in  FIG. 1 , the two pumps  221  and  222  are respectively provided on the upstream side and downstream side of the flow cytometer  100 . Driving pressures and driving timings of the pumps, timings for opening and closing valves V 1  and V 2 , or the like are controlled, so that the flow of the liquid flowing through the sheath flow tube  226 , the sample flow tube  225 , the sample detection unit  23 , and the junction tube  227  is precisely controlled. 
     The nozzle  224  has a suction port  224   a . The sample liquid-sending device  20  suctions the suspension stored in the well W of the well plate P through the nozzle  224  (suction port  224   a ). At that time, the suction port  224   a  is accommodated in the well W. 
     An inner diameter D 4  and an outer diameter D 5  of the nozzle  224  are not particularly limited. For example, the inner diameter D 4  (the diameter of a hollow portion  224   b ) is approximately 0.2 mm, and the outer diameter D 5  is approximately 1.6 mm (see  FIG. 11 ). The material of the nozzle  224  is not particularly limited, and, for example, stainless steel or the like can be employed. The detailed configuration of the nozzle  224  will be described in a second embodiment to be described later. 
     The sample flow tube  225  connects the nozzle  224  and the sample detection unit  23 . Part or all of the sample flow tube  225  is made of a flexible material such as a silicon rubber. 
     The sheath flow tube  226  connects the pump  221  and the sample detection unit  23 . The sheath flow tube  226  includes the valve V 1 . The junction tube  227  connects the sample detection unit  23  and the pump  222  (a buffer  223  provided on the more upstream side). The junction tube  227  includes the valve V 2 . The valves V 1  and V 2  are typically opening and closing valves such as on-off valves, and include solenoid valves or pneumatic valves, for example. 
     (Sample Detection Unit) 
     As shown in  FIG. 1 , the sample detection unit  23  is connected to the sheath flow tube  226 , the sample flow tube  225 , and the junction tube  227 . The sample detection unit  23  has a function of forming a sheath flow with the sheath liquid coming from the sheath tank  228  and detecting samples. 
     The sample detection unit  23  mainly includes a cuvette. In the sample liquid-sending device  20 , the sheath flow of the sheath liquid is formed in this cuvette, and thus samples from the sample flow tube  225  flow in line. Here, in this embodiment, samples (e.g., biological cells) flowing in line in this cuvette are irradiated with a laser beam from a laser generator (not shown) and thus detected. 
     Typically, the sample detection unit  23  of this embodiment mainly incudes a cuvette, but it is not limited thereto. The sample detection unit  23  may be, for example, a sorting chip. As such a sorting chip, for example, one having an orifice size of 70 μm, 100 μm, or 130 μm is employed. 
     (Holding Mechanism) 
       FIGS. 2 to 8  are schematic diagrams each showing a configuration example of the holding mechanism  24 . Hereinafter, some configuration examples of the holding mechanism  24  will be described. Note that the X-, Y-, and Z-axis directions shown in those figures represent three mutually orthogonal axes, which are common to all the figures in this specification. 
     Configuration Example 1 
       FIG. 2  is a top view of the holding mechanism  24 ,  FIG. 3  is a front view of the holding mechanism  24  in the bottom dead center state (initial state),  FIG. 4  is a side view of  FIG. 3 , and  FIG. 5  is a side view of the holding mechanism  24  in the top dead center state. The holding mechanism  24  includes a nozzle arm  241 , a nozzle holder  242 , and a collision sensor  243  (detection unit). 
     The nozzle holder  242  is configured to support the nozzle  224  and to be movable in the Z-axis direction relative to the nozzle arm  241 . Thus, the nozzle  224  moves in the Z-axis direction together with the nozzle holder  242 . 
     The nozzle holder  242  includes a first flat plate portion  242   a , a second flat plate portion  242   d , and a coupling portion  242   c . The first flat plate portion  242   a  is placed on the upper surface of the nozzle arm  241  in the vertical direction when the holding mechanism  24  is in the bottom dead center state (see  FIG. 4 ). That is, the state in which the first flat plate portion  242   a  and the nozzle arm  241  is in contact with each other is the bottom dead center state of the holding mechanism  24 . The first flat plate portion  242   a  protrudes from the second flat plate portion  242   d  toward the collision sensor  243  in the X-axis direction. 
     Further, the first flat plate portion  242   a  of this embodiment has a protrusion  242   b  protruding in the X-axis direction at the center in the Y-axis direction. As shown in  FIG. 2 , the protrusion  242   b  enters a portion of the collision sensor  243 . 
     The second flat plate portion  242   d  is placed on a holding portion  241   a  of the nozzle arm  241  when the holding mechanism  24  is in the top dead center state (see  FIG. 5 ). That is, the state in which the second flat plate portion  242   d  and the holding portion  241   a  is in contact with each other is the bottom dead center state of the holding mechanism  24 . The second flat plate portion  242   d  functions as a stopper for restricting the movement of the nozzle holder  242  in the Z-axis direction. 
     The coupling portion  242   c  connects the first flat plate portion  242   a  and the second flat plate portion  242   d . As shown in  FIG. 3 , the coupling portion  242   c  is disposed between the pair of holding portions  241   a . The coupling portion  242   c  is configured to be movable in the Z-axis direction while facing the holding portions  241   a  in the Y-axis direction. 
     The nozzle arm  241  holds the nozzle  224  through the nozzle holder  242 . The nozzle arm  241  is configured to be capable of holding the nozzle holder  242  (coupling portion  242   c ) at an any position in the Z-axis direction. Thus, the nozzle holder  242  is held (fixed) at a predetermined position by the nozzle arm  241 , and thus it is possible to freely determine a relative position of the well W with respect to the nozzle  224 . The nozzle arm  241  includes the pair of holding portions  241   a  facing both side surfaces of the coupling portion  242   c  in the Y-axis direction and protruding in the X-axis direction. 
     In the nozzle arm  241 , the pair of holding portions  241   a  and the end surface facing in the X-axis direction between the holding portions  241   a  constitute an opening  241   b . As shown in  FIGS. 2 and 3 , the opening  241   b  accommodates the coupling portion  242   c  at predetermined intervals. 
     A width D 2  of the holding portion  241   a  in the Z-axis direction is configured to be narrower than a width D 1  of the coupling portion  242   c  in the Z-axis direction. This creates a backlash when the nozzle holder  242  moves in the Z-axis direction. 
     The collision sensor  243  includes a housing  243   a , an LED light source  243   b , and a photodiode  243   c . As shown in  FIGS. 4 and 5 , the housing  243   a  is provided on the nozzle arm  241  and has an opening S 1  that is opened toward the nozzle  224 . The opening S 1  accommodates one end of the protrusion  242   b  of the first flat plate portion  242   a.    
     The LED light source  243   b  and the photodiode  243   c  are provided in the housing  243   a  so as to face each other in the Y-axis direction through the opening S 1 , and are provided at respective positions facing one end of the protrusion  242   b  in the Y-axis direction when the holding mechanism  24  is in the top dead center state (see  FIG. 5 ). 
     The collision sensor  243  is configured to be capable of detecting the contact (touch) between the suction port  224   a  of the nozzle  224  and the bottom of the well W and outputting a detection signal based on the detection result to the controller  25 , in response to that the emitted light of the LED light source  243   b  is blocked by the protrusion  242   b  and that the photodiode  243   c  does not receive the emitted light. 
     For the collision sensor  243  of this embodiment, a transmissive photosensor is typically employed, but the present technology is not limited thereto. For example, a reflective photosensor may be employed. 
     Configuration Example 2 
     Next, another configuration example of the holding mechanism  24  will be described.  FIG. 6  is a top view of the holding mechanism  24 ,  FIG. 7  is a side view of the holding mechanism  24  in the bottom dead center state (initial state), and  FIG. 8  is a side view of the holding mechanism  24  in the top dead center state. Note that similar reference symbols are assigned to the similar configurations as in the configuration example 1, and description thereof will be omitted. 
     As shown in  FIGS. 7 and 8 , the collision sensor  243  of this embodiment may be a switch-type collision sensor. In this case, the collision sensor  243  is provided to the holding portion  241   a  so as to face the second flat plate portion  242   d.    
     Thus, the collision sensor  243  is configured to detect, when pressed by the second flat plate portion  242   d  in the top dead center state of the holding mechanism  24 , a contact between the bottom of the well W and the suction port  224   a  of the nozzle  224  and to output a detection signal based on the detection result to the controller  25 . Note that the configurations of the holding mechanism  24  shown in  FIGS. 2 to 8  are merely an examples, and the present technology is not limited to the configurations shown in those figures. 
     (Controller) 
     The controller  25  is configured to control the drive of the pumps  221  and  222 , the drive mechanism  21  (drive unit  212 ), the valves V 1  and V 2 , and other mechanisms. In particular, the controller  25  is configured to be capable of controlling the drive unit  212  such that the bottom of the well W and the suction port  224   a  of the nozzle  224  are separated from each other by a predetermined distance. The controller  25  basically includes, in addition to the drivers of those components, hardware necessary for a computer such as a central processing unit (CPU), a random access memory (RAM), and a read only memory (ROM). 
     The controller  25  may include a programmable logic device (PLD) such as a field programmable gate array (FPGA) instead of the CPU. Further, the controller  25  includes the drivers (not shown) for driving the pumps  221  and  222 , the drive mechanism  21 , the valves V 1  and V 2 , and the like. 
     1.2) Operation of Sample Liquid-Sending Device 
       FIG. 9  is a flowchart showing an operation procedure of the sample liquid-sending device  20 . Hereinafter, a typical operation of the sample liquid-sending device  20  of this embodiment will be described with reference to  FIG. 9  as appropriate. 
     First, the sample liquid-sending device  20  is started (Step S 101 ) to detect the tip position of the nozzle  224  (Step S 102 ). As a result, it is possible to grasp how far the suction port  224   a  of the nozzle  224  and the support portion  211  are separated from each other. The method of detecting the tip position of the nozzle  224  is not particularly limited, and for example, a position detection sensor or the like may be employed. 
     Next, the well plate P is set in the support portion  211  (Step S 103 ), and the controller  25  moves the drive unit  212  toward the nozzle  224  in a stepwise manner. As a result, the well plate P approaches the nozzle  224  in a stepwise manner, and the bottom of the well W comes into contact with the suction port  224   a  of the nozzle  224 . At that time, it is favorable that the moving distance of the well plate P per step is approximately 0.1 mm. As a result, the suction port  224   a  and the bottom of the well W are prevented from abutting on each other with an excessive force. 
     Next, the controller  25  further raises the drive unit  212  from the state in which the suction port  224   a  and the bottom of the well W are in contact with each other, and the second flat plate portion  242   d  comes into contact with the nozzle arm  241 . As a result, the holding mechanism  24  shifts from the bottom dead center state to the top dead center state, and the top dead center state is maintained by the nozzle arm  241  holding the coupling portion  242   c.    
     At that time, depending on whether the emitted light of the LED light source  243   b  is blocked by the protrusion  242   b  (see  FIG. 5 ) or the collision sensor  243  is pressed by the second flat plate portion  242   d  (see  FIG. 8 ), the collision sensor  243  detects the contact between the bottom of the well W and the suction port  224   a  (Step S 104 ), and outputs a detection signal based on the detection result to the controller  25 . Note that the moving distance of the first flat plate portion  242   a  when the holding mechanism  24  shifts from the bottom dead center state to the top dead center state is approximately 0.4 mm. 
     Next, in response to obtaining the detection signal from the collision sensor  243 , the controller  25  moves the drive unit  212  in a direction separating from the nozzle  224  by a predetermined distance. As a result, the suction port  224   a  and the bottom of the well W are separated from each other by a predetermined distance. At that time, a distance D 3  between the suction port  224   a  and the bottom of the well W is not particularly limited, but it is typically controlled to be 0.5 mm by the controller  25  (Step S 105 ). 
     Subsequently, the controller  25  opens the valves V 1  and V 2  to change the suction pressures of the pumps  221  and  222  (Step S 106 ). As a result, the suction mechanism  22  suctions the suspension in the well W via the nozzle  224 , and further suctions the sheath liquid in the sheath tank  228 . Then, the suspension and the sheath liquid merge in the sample detection unit  23 , and the mixed liquid of them is transferred toward the drain tank  229 . At that time, the mixed liquid flowing in the sample detection unit  23  is irradiated with a laser beam, and thus the sample measurement is performed (Step S 107 ). The sample measurement time is not particularly limited, but it is typically one second. 
     Next, if the sample measurement is to be continued (YES in Step S 108 ) and when the timing of stirring the suspension in the well W comes (YES in Step S 110 ), the controller  25  stops the pumps  221  and  222  or closes the valves V 1  and V 2 . Thus, the pressure in the nozzle  224  is set to zero (Step S 111 ). 
     Next, the controller  25  moves the drive unit  212  in a direction separating from the nozzle  224  by a predetermined distance. As a result, the suction port  224   a  and the bottom of the well W are further separated from each other by a predetermined distance. Although the distance D 3  between the suction port  224   a  and the bottom of the well W is not particularly limited at that time, the distance D 3  is controlled to be approximately 80 mm by the controller  25  if the suspension in the well W is swung and stirred in Step S 113  to be described later, and is controlled to be approximately 1.4 mm by the controller  25  if the suspension is stirred by the nozzle  224 . 
     Subsequently, in a state where the suction port  224   a  and the bottom of the well W are separated from each other by a predetermined distance, the suspension in the well W is stirred under the control of the controller  25 . At that time, stirring by swinging such as moving the drive mechanism  21  that supports the well plate P may be executed. Alternatively, vibrations may be generated by a vibrator (not shown) attached to the holding mechanism  24  to cause the nozzle  224  to stir the suspension. 
     In this embodiment, a series of operations from Step S 104  to Step S 113  (S 104 →S 105 →S 106 →S 107 →S 108 →S 110 →S 111 →S 112 →S 113 ) is repeated for one well W until the sample measurement is finished. 
     Meanwhile, if the sample measurement is not to be continued (NO in Step S 108 ), the controller  25  closes the valves V 1  and V 2  or stops the pumps  221  and  222 , thus terminating the sample measurement (Step S 109 ). Further, if the timing of stirring the suspension in the well W does not come (NO in Step S 110 ), the sample measurement is continuously performed. 
     In this embodiment, the series of operations from Step S 104  to Step S 113  described above is executed for all the wells W provided in the well plate P. 
     1.3) Verification 
     In order to confirm the effect of the first embodiment, the inventor conducted the following verification. In this verification, the inventor used a cell analyzer (product name: SA3800) manufactured by Sony Corporation. 
     The inventor has confirmed an event rate (events per second; eps) while changing the distance D 3  between the bottom of the well W and the suction port  224   a  of the nozzles  224  within the range of 0.3 mm or more and 1.4 mm or less under a constant suction pressure.  FIG. 10  is a graph showing results of the verification. In this case, a suspension in which sample beads (flow check beads) of a dried inorganic material are precipitated as samples in deionized water (DIW) is stored in the well W. Further, the event rate is the number of samples detected by the sample detection unit  23  per second. In addition, in this verification, the flow rate at which the suspension is suctioned was set to 33 μL/min. 
     Referring to  FIG. 10 , when the distance D 3  between the bottom of the well W and the suction port  224   a  is in the range of 0.9 mm or more and 1.4 mm or less, the event rate is hardly confirmed. That is, the precipitate of the samples accumulated at the bottom of the well W is hardly suctioned. This may be because the distance D 3  between the bottom of the well W and the suction port  224   a  is excessively large. 
     On the other hand, when the distance D 3  between the bottom of the well W and the suction port  224   a  is in the range of 0.4 mm or more and 0.8 mm or less, the event rate was confirmed, and a large event rate was confirmed particularly in the range of 0.4 mm or more and 0.7 mm or less. 
     However, when the distance D 3  between the bottom of the well W and the suction port  224   a  was 0.3 mm, the event rate was not confirmed. That is, when the distance D 3  was set to 0.3 mm or less, it was confirmed that the precipitate of the samples was not suctioned. This may be because a pressure loss occurs due to an excessively small distance D 3  between the bottom of the well W and the suction port  224   a.    
     Referring to  FIG. 10 , since the event rate was confirmed again when the distance D 3  between the bottom of the well W and the suction port  224   a  was 0.5 mm, the fact that the event rate was not confirmed when the distance D 3  was 0.3 mm is not due to the depletion of the sample in the suspension. 
     Through the above verification, it was proved that when the distance D 3  between the bottom of the well W and the suction port  224   a  was set in the range of 0.4 mm or more and 0.8 mm or less, the precipitate of the sample was sufficiently suctioned, and the precipitate of the samples was hardly suctioned outside the above range. That is, the effect of setting the distance D 3  in the range of 0.4 mm or more and 0.8 mm or less was proved. 
     1.4) Effects 
     According to the first embodiment, the bottom of the well W and the suction port  224   a  are controlled to be separated from each other by a predetermined distance by the control of the controller  25 . Specifically, the distance D 3  is controlled to be 0.5 mm. Therefore, since an event is constantly detected if the distance D 3  is 0.4 mm or more and 0.8 mm or less as verified above, the precipitate of the sample precipitated at the bottom of the well W is sufficiently suctioned if the distance D 3  is 0.5 mm (see  FIG. 10 ). 
     2. Second Embodiment 
     Next, a sample liquid-sending device  20  according to a second embodiment of the present technology will be described. Hereinafter, similar reference symbols are assigned to the similar configurations as in the first embodiment, and description thereof will be omitted. 
     2.1) Nozzle Configuration 
     2.1.1) Application Example 1 
     A nozzle  224  in the second embodiment may have an opening  224   c .  FIG. 11  is an enlarged side view of the periphery of a suction port  224   a  of the nozzle  224 , and  FIG. 12  is an enlarged diagram of the suction port  224   a  (bottom surface S 2 ) as viewed from the Z-axis direction. 
     As shown in  FIG. 11 , the opening  224   c  is provided at the tip of the suction port  224   a  of the nozzle  224 , and communicates with a hollow portion  224   b  that is a flow path through which the suspension flows. As shown in  FIG. 12 , the opening  224   c  is a groove formed linearly along the Y-axis direction. Note that the opening  224   c  shown in  FIG. 11  has a rectangular opening shape, but the shape is not limited thereto. The shape of the opening  224   c  may be triangular, semicircular, or the like. 
     In the present technology, the formation pattern of the opening  224   c  formed in the suction port  224   a  is not limited to the pattern shown in  FIGS. 11 and 12 .  FIGS. 13 and 14  are enlarged diagrams of the suction port  224   a  (bottom surface S 2 ) as viewed from the Z-axis direction, and show variations of the formation pattern of the opening  224   c.    
     [Pattern  1 ] 
     As shown in  FIG. 13 , the opening  224   c  may be configured to include a first groove T 1  formed linearly along the Y-axis direction and a second groove T 2  formed along the Z-axis direction. That is, the groove may be formed in a cross shape at the tip of the suction port  224   a  of the nozzle  224 . 
     [Pattern  2 ] 
     As shown in  FIG. 14 , a plurality of openings  224   c  may be provided around the Z-axis at the tip of the suction port  224   a  of the nozzle  224 . In this case, each of the plurality of openings  224   c  communicates with a recess C (recessed toward the sample flow tube  225 ) provided along the Z-axis direction as shown in the figure, and communicates with the hollow portion  224   b  via the recess C. Note that the number of the openings  224   c  shown in  FIG. 14  is eight, but the number is not limited thereto and may be eight or more or eight or less. 
     2.1.2) Application Example 2 
       FIGS. 15 and 17  are enlarged diagrams of the bottom surface S 2  of the nozzle  224  as viewed from the Z-axis direction. Further,  FIG. 16  is an enlarged perspective diagram of the periphery of the suction port  224   a  and shows the nozzle  224  accommodated in the well W. Note that the bottom surface S 2  of the nozzle  224  is a surface facing the bottom of the well W when the suction mechanism  22  suctions the suspension stored in the well W. 
     [Pattern  1 ] 
     The nozzle  224  of the second embodiment may have a configuration in which notches  224   d  are provided in the bottom surface S 2 . In this case, as shown in  FIG. 15 , a plurality of notches  224   d  is provided around the Z axis. With this configuration, when the suction port  224   a  is accommodated in the well W that does not have the flat bottom, gaps H are generated between the tip of the suction port  224   a  and the bottom of the well W, and a flow path for suctioning the suspension is reliably secured. Therefore, it is possible to sufficiently suction the suspension accumulated at the bottom of the well W and to reduce the dead volume. 
     Note that the shape of the notch  224   d  shown in  FIG. 15  is V-shaped, but the shape is not limited thereto. The shape is not limited to a rectangular shape, a U-shaped shape, and the like. Further, the number of notches  224   d  shown in the figure is four, but the number is not limited thereto and may be four or more or four or less. 
     Here, the “dead volume” described above is the amount of a suspension that cannot be suctioned when the suspension is suctioned through the sample nozzle and also has the same meaning in the following description. 
     [Pattern  2 ] 
     In the nozzle  224  of the second embodiment, as shown in  FIG. 17 , the bottom surface S 2  may have a shape of a combination of straight lines S 3  and curved lines Cl. With this configuration, the operation and effect similar to those of the pattern  1  of the application example 2 can be obtained. In  FIG. 17 , each of the number of straight lines S 3  and the number of curved lines Cl is four, but it is needless to say that the number is not limited to this. 
     2.1.3) Application Example 3 
     The nozzle  224  of the second embodiment may have a configuration in which an opening  224   c  is provided in the suction port  224   a . The opening  224   c  is a through-hole that penetrates the side wall near the tip of the suction port  224   a .  FIG. 18  is an enlarged side view of the periphery of the suction port  224   a  of the nozzle  224 , and  FIGS. 19 and 20  are enlarged diagrams of the suction port  224   a  (bottom surface S 2 ) of the nozzle  224  as viewed from the Z-axis direction. 
     [Pattern  1 ] 
     As shown in  FIG. 19 , the opening  224   c  (through-hole) may be configured to be formed linearly along the Y-axis direction and to communicate with the hollow portion  224   b . Note that the opening shape of the opening  224   c  is a rectangular shape, but it is not limited thereto and may be any shape such as a triangular shape, a circular shape, or an elliptical shape. 
     [Pattern  2 ] 
     As shown in  FIG. 20 , the opening  224   c  (through-hole) may have a configuration including a first through-hole H 1  formed linearly along the Y-axis direction and communicating with the hollow portion  224   b  and a second through-hole H 2  formed along the X-axis direction and communicating with the hollow portion  224   b . Note that in the pattern  2 , the opening  224   c  includes two through-holes, but it is not limited thereto and may include two or more through-holes. 
     2.2) Operation of Sample Liquid-Sending Device 
     The sample liquid-sending device  20  of the second embodiment suctions the suspension through the nozzle  224  by the suction mechanism  22  in a state where the bottom of the well W and the suction port  224   a  of the nozzle  224  are in contact with each other. That is, in the operation of the sample liquid-sending device  20  of the second embodiment, Step S 105  described in the first embodiment is omitted. 
     2.3) Verifications 
     In order to prove the effect in the second embodiment, the inventor performed the following verifications 1 and 2. A cell analyzer (product name: SA3800) manufactured by Sony Corporation was used in the verifications. Further, in the verifications, the nozzle  224  having the opening  224   c  in the suction port  224   a  was used. In addition, in this verifications, the flow rate at which the suspension is suctioned was set to 33 μL/min. 
     2.3.1) Verification 1 
     In the verification 1, the nozzle  224  (suction port  224   a ) was brought into contact with the bottom of the well W, and it was confirmed how much dead volume existed when the suspension was suctioned through the nozzle  224 . In the verification 1, a conventional nozzle having no opening  224   c  was used as a comparative example, and the cases where the well W has a flat bottom and has a V bottom were verified.  FIG. 21  is a table summarizing the verification results. 
     Referring to  FIG. 21 , in a conventional method of suctioning a suspension through the nozzle having no opening  224   c  with a certain distance (e.g., 1 mm or more and 1.2 mm or less) between the tip of the nozzle and the bottom of the well, the dead volume was 35 to 40 μL in the case of the well having a flat bottom, and was 20 μL in the case of the well having a V bottom. 
     On the other hand, in this method of suctioning a suspension through the nozzle  224  having the opening  224   c  in the suction port  224   a  with the suction port  224   a  and the bottom of the well W being in contact with each other, the dead volume was 4 to 7 μm in the case of the well W having a flat bottom, and was 1 μm or less in the case of the well W having a V bottom. 
     Through the above verification, it was confirmed that the dead volume can be clearly reduced compared to the conventional method by bringing the suction port  224   a  having the opening  224   c  into contact with the bottom of the well W and suctioning the suspension through the nozzle  224 . That is, the effect of forming the opening  224   c  in the suction port  224   a  was proved. 
     2.3.2) Verification 2 
     In the verification 2, it was checked whether or not the event rate (events per second; eps) is changed before and after the suction port  224   a  is brought into contact with the bottom of the well W.  FIG. 22  is a graph showing results of the verification. In the verification 2, the suction port  224   a  was brought into contact with the bottom of the well W approximately 100 seconds after the start of the suction of the suspension. In this case, a suspension containing sample beads (flow check beads) of a dried inorganic material as samples in deionized water (DIW) is stored in the well W. Further, the event rate is the number of samples detected by the sample detection unit  23  per second. 
     Referring to  FIG. 22 , it was confirmed that the event rate did not change even when the suction port  224   a  and the bottom of the well W were brought into contact with each other. That is, this verification proved that the event rate is not affected even if the suspension is suctioned through the nozzle  224  having the opening  224   c  in the suction port  224   a  while the suction port  224   a  and the bottom of the well W are in contact with each other. 
     2.4) Effects 
     According to the second embodiment of the present technology, the opening  224   c  is provided in the suction port  224   a  of the nozzle  224 . As a result, the suspension can be suctioned in a state where the suction port  224   a  and the bottom of the well W are in contact with each other, so that the dead volume can be reduced (see  FIG. 21 ). In particular, when a plurality of openings  224   c  is provided in the suction port  224   a  (see  FIGS. 13, 14, and 20 ), the efficiency in suctioning the suspension is improved. 
     3. Modified Examples 
     Although the embodiments of the present technology have been described above, the present technology is not limited to the embodiments described above and can be variously modified. 
     For example, in the above embodiments, the controller  25  controls the distance D 3  between the suction port  224   a  of the nozzle  224  and the bottom of the well W, but the present technology is not limited thereto. The distance D 3  may be controlled by a manual operation by a person, for example. 
     Further, in the above embodiments, the drive mechanism (support portion  211 ) for supporting the well plate P is moved so as to control the distance D 3  between the suction port  224   a  and the bottom of the well W, but the present technology is not limited thereto. For example, the distance D 3  may be controlled by moving the nozzle arm  241  for supporting the nozzle holder  242 . 
     Furthermore, in the above embodiments, Step S 104  is typically executed for all the wells W, but the present technology is not limited thereto. For example, Step S 104  may be executed for every 3 or 4 wells or may be omitted as necessary. 
     In addition, in this specification, the “suction port” of the nozzle  224  conceptually includes at least the tip of the nozzle  224  facing the bottom of the well W when the suspension is suctioned, and the side wall near the tip. 
     Further, in the above embodiments, the example in which the sample liquid-sending device  20  is applied to a flow cytometer has been described, but the present technology is not limited thereto. The sample liquid-sending device  20  may be applied as, for example, a sorter, and may be used for any purpose. 
     Note that the present technology may take the following configurations. 
     (1) A sample liquid-sending device, including: 
     a drive mechanism that supports a sample container and is configured to be capable of moving the sample container, the sample container including a storing portion that stores a suspension containing a sample; 
     a suction mechanism that includes a nozzle configured to be inserted into the storing portion, and suctions the suspension through the nozzle; and 
     a controller configured to be capable of controlling the drive mechanism such that a bottom of the storing portion and a suction port of the nozzle are separated from each other by a predetermined distance. 
     (2) The sample liquid-sending device according to (1), in which the controller controls a distance between the bottom and the suction port to be 0.4 mm or more and 0.8 mm or less.
 
(3) The sample liquid-sending device according to (1) or (2), in which
 
     the suction mechanism includes the nozzle including a hollow portion and an opening, the hollow portion being a flow path through which the suspension flows, the opening being provided in the suction port and communicating with the hollow portion. 
     (4) The sample liquid-sending device according to (3), in which 
     the suction mechanism includes the nozzle including a plurality of openings provided in the suction port and communicating with the hollow portion. 
     (5) The sample liquid-sending device according to any one of (1) to (4), in which 
     the suction mechanism includes the nozzle including a notched bottom surface facing the bottom. 
     (6) The sample liquid-sending device according to any one of (1) to (5), further including 
     a holding mechanism including a detection unit that detects a contact between the bottom and the suction port, and configured to be capable of holding the nozzle at a predetermined position. 
     (7) A flow cytometer, including: 
     a drive mechanism that supports a sample container and is configured to be capable of moving the sample container, the sample container including a storing portion that stores a suspension containing a sample; 
     a suction mechanism that includes a nozzle configured to be inserted into the storing portion, and suctions the suspension through the nozzle; 
     a controller configured to be capable of controlling the drive mechanism such that a bottom of the storing portion and a suction port of the nozzle are separated from each other by a predetermined distance; 
     a holding mechanism including a detection unit that detects a contact between the bottom and the suction port, and configured to be capable of holding the nozzle at a predetermined position; and 
     an analysis unit that analyzes a characteristic of the sample. 
     (8) A sample liquid-sending method, including: 
     inserting a nozzle provided to a suction mechanism into a storing portion of a sample container supported by a drive mechanism, a suspension containing a sample being stored in the storing portion; 
     detecting a contact between a bottom of the storing portion and a suction port of the nozzle; 
     separating the storing portion and the suction port from each other by a predetermined distance; and 
     suctioning the suspension through the nozzle by the suction mechanism. 
     (9) A sample liquid-sending method, including: 
     inserting a nozzle provided to a suction mechanism into a storing portion of a sample container supported by a drive mechanism, a suspension containing a sample being stored in the storing portion; 
     detecting a contact between a bottom of the storing portion and a suction port of the nozzle; and 
     suctioning the suspension through the nozzle by the suction mechanism in a state where the bottom and the suction port are in contact with each other. 
     REFERENCE SIGNS LIST 
     
         
           20  sample liquid-sending device 
           21  drive mechanism 
           22  suction mechanism 
           24  holding mechanism 
           25  controller 
           100  flow cytometer 
           224  nozzle 
           224   a  suction port 
           224   b  hollow portion 
           224   c  opening 
           224   d  notch 
           243  detection unit