JP4740010B2 - Liquid feeding device, liquid feeding method thereof, and measuring device using total reflection attenuation - Google Patents

Description

  The present invention relates to a liquid feeding apparatus for feeding a sample solution into a flow path using a pipette, a liquid feeding method thereof, and a measuring apparatus using total reflection attenuation such as surface plasmon resonance provided with the liquid feeding apparatus. Is.

  2. Description of the Related Art There are known measuring apparatuses that measure the reaction of a sample by using total reflection attenuation when measuring an interaction between biochemical substances such as proteins and DNA, screening drugs, and the like.

  One of the measuring devices that use such total reflection attenuation is a measuring device that uses a surface plasmon resonance phenomenon (hereinafter referred to as an SPR measuring device). The surface plasmon is generated by the collective vibration of free electrons in the metal, and is a density wave of free electrons traveling along the surface of the metal.

  For example, in an SPR measurement apparatus that employs a Kretschmann arrangement known from Patent Document 1 or the like, a surface of a metal film formed on a transparent dielectric (hereinafter referred to as a prism) is used as a sensor surface, and a sample is formed on the sensor surface. After reacting, the metal film is irradiated from the back side of the sensor surface through the prism so as to satisfy the total reflection condition, and the reflected light is measured.

  Of the light irradiated to the metal film so as to satisfy the total reflection condition, a small amount of light called an evanescent wave passes through the metal film without being reflected and oozes out to the sensor surface side. At this time, if the frequency of the evanescent wave coincides with the frequency of the surface plasmon, SPR is generated and the intensity of the reflected light is greatly attenuated. In addition, the incident angle (resonance angle) of light at which this attenuation occurs varies depending on the refractive index on the metal film. That is, the SPR measurement device measures the reaction state of the sample on the sensor surface by capturing the reflected light from the metal film and detecting the resonance angle.

  By the way, biological samples such as proteins and DNA are often handled as sample solutions dissolved in a solvent such as physiological saline, pure water, or various buffer solutions in order to prevent denaturation and inactivation due to drying. The SPR measurement device described in Patent Document 1 is for examining such interaction between biological samples, and a flow path for feeding a sample solution is provided on the sensor surface. The flow path and the prism are arranged on a measurement stage provided in the apparatus main body, and the above-described measurement can be performed by mounting a chip-type sensor unit having a metal film formed on a glass substrate on the measurement stage. Done.

  In Patent Document 1, the sample solution is directly fed into the flow path from a container for storing the sample solution via a pipe (tube) connected to a pump, a valve, or the like. There is a problem that so-called contamination is likely to occur, in which the sample is mixed into a sample solution to be injected later.

  In order to solve this problem, the present applicant uses a pipette consisting of a substantially conical cylindrical pipette tip with a small hole formed at the tip and a head portion that detachably holds the pipette tip, and attaches it to the container. An SPR measurement device that sends a liquid such as a stored sample solution to a flow path has been proposed (see, for example, Japanese Patent Application No. 2004-288534). In this SPR measurement device, contamination occurring when liquid is fed into the flow path can be prevented by exchanging the pipette tip for each liquid to be fed.

  Further, in this SPR measurement device, the flow path member in which the flow path is formed, the prism having the metal film formed on the upper surface, and the bottom surface of the flow path member and the upper surface of the prism are joined (the flow path and the metal A sensor unit including a holding member that holds the film in a state of facing the film is used. The flow path is a liquid feed pipe formed by penetrating the flow path member in a substantially U shape, and both ends thereof are exposed on the upper surface of the flow path member. When using a pipette to feed the liquid into the flow path, insert the pipette into each of both ends of the flow path and suck it with one pipette to discharge the liquid (or air) in the flow path while The pipette is used to discharge the liquid and replace the fluid in the flow path.

Each pipette is provided with a syringe pump composed of a cylinder and a piston. The pistons of the two pipettes inserted into the flow path are linked to each other so that when one performs a suction operation by a cam mechanism or the like, the other performs a discharge operation, so that the suction and discharge timings coincide with each other. Has been.
Japanese Patent No. 3294605

  However, in the method using a pipette, when pulling out the pipette from the flow path, a small amount of liquid may leak from the tip of the pipette and enter the flow path. If the liquid to be discharged from the pipette on the suction side enters the flow path, it causes contamination. Further, there is a problem that an impact when a water droplet is dropped into the flow path becomes noise of a detection signal, and a countermeasure for preventing this is desired.

  The present invention has been made in view of the above problems, and a liquid feeding device that prevents liquid from leaking from its tip when a pipette is pulled out from a flow path, a liquid feeding method thereof, and total reflection attenuation. An object of the present invention is to provide a measuring apparatus using the above.

In order to achieve the above object, the present invention provides a sensor unit in which a flow path having a plurality of inlets and outlets and a sensor surface for detecting a reaction of a sample are opposed to each other, are detachably set. In the liquid feeding device for feeding the dissolved sample solution to the flow path and bringing it into contact with the sensor surface, a pipette group consisting of a plurality of pipettes inserted into the respective inlets and outlets is provided corresponding to each of the pipettes. A plurality of pumps for pressurizing or depressurizing the inside of each pipette to suck or discharge the sample solution to each of the pipettes, and a plurality of pressure sensors for converting the pressure applied to each of the pipettes into an electric signal When the causes independently driven of each pump, said in response to the electrical signal from the pressure sensor, and drive control means for controlling the corresponding one of the respective pump, the flow path When the liquid is fed, determination means for determining whether or not the pressure in each pipette is abnormal based on the electrical signal from each pressure sensor, and the determination means is abnormal for at least one of the pipettes When an abnormality is detected, an abnormality detection process is performed, and following the abnormality detection process, a recovery process is performed to recover the pressure abnormality in each pipette, and the abnormality detection process is canceled after the recovery process is performed. An abnormality detection processing means is provided .

The pipette is formed in a head that holds the pipette, and includes a nozzle connected to the pump via a pipe and the head, and a pipette tip that is detachably attached to the nozzle. It is preferable that the return processing performed by the above is replacement of the pipette tip or cleaning of a piping path from the pump to the nozzle.

  Furthermore, it is preferable that the abnormality detection process performed by the abnormality detection processing unit is to instruct the drive control unit to stop the pumps and stop the liquid supply to the flow path by the pipette group.

  When a plurality of the flow paths are provided in the sensor unit, it is preferable to provide a plurality of pipette groups corresponding to the respective flow paths. At this time, it is preferable that the abnormality detection unit performs the abnormality detection process only on the pipette group including the pipette that the determination unit has determined abnormality among the plurality of pipette groups.

  Moreover, when the determination means determines an abnormality, a notification means for notifying that an abnormality has occurred in the pressure in each pipette may be provided.

  Furthermore, it is preferable that a cancellation instruction input unit is provided for inputting a cancellation instruction for the abnormality detection process to the abnormality detection processing unit, and the abnormality detection processing unit continues the abnormality detection process until the cancellation instruction is input.

  The drive control means preferably controls each pump so that the inside of each pipette and the inside of the flow path are in a reduced pressure state when the pipette is pulled out from each inlet / outlet.

Further, the liquid feeding method of the present invention is the liquid feeding method of any one of the above liquid feeding devices , wherein the pipette is inserted into each of the inlets and outlets, and the pipette is inserted into the flow path from at least one of the pipettes. The sample solution is discharged, and at least one of the remaining pipettes sucks air or liquid in the flow path to send the sample solution to the sensor surface, and then sucks each pipette. The inside of each pipette and the inside of the flow path is in a reduced pressure state, and each pipette is pulled out from each entrance / exit.

  It is preferable that the suction of air or liquid in the flow path is stronger than the discharge of the sample solution, and the flow of the sample solution is reduced in the flow path.

  In addition, in the case of a ligand immobilization process to be described later, after feeding the sample solution into the flow channel, the suction and discharge of each pipette are alternately repeated, and the sample solution in the flow channel is then repeated. Is preferably stirred.

In the measurement apparatus using total reflection attenuation according to the present invention, a flow path having a plurality of entrances and exits and a dielectric block having a thin film layer formed on one surface for detecting a reaction of a sample are provided to face each other. A total reflection attenuation including a light source for irradiating the sensor unit with light so as to satisfy the total reflection condition and a detection unit that receives the reflected light from the sensor unit and photoelectrically converts it into an electrical signal is used. In the measuring device, a pipette group consisting of a plurality of pipettes inserted into the respective inlets and outlets, and provided for each of the pipettes, the sample solution is applied to the pipettes by pressurizing or depressurizing the pipettes. a plurality of pump for sucking or discharging, said plurality of pressure sensors for converting the electric signal of pressure applied to each of the pipettes, the when the independently driven of each pump together The in response to the electrical signal from the pressure sensor, and drive control means for controlling the corresponding one of the respective pump, when performing liquid feed to the flow channel, based the on the electrical signal from the pressure sensor Determining means for determining whether or not the pressure in each pipette is abnormal, and when the determining means determines an abnormality for at least one of the pipettes, it performs an abnormality detection process and follows the abnormality detection process. And an abnormality detection processing means for performing a recovery process for recovering the pressure abnormality in each pipette and canceling the abnormality detection process after performing the recovery process .

  According to the present invention, since each pipette is pressurized or depressurized and provided with a plurality of pumps for sucking or discharging a liquid such as a sample solution to each pipette, and a drive control means for driving each pump independently. For example, when each pipette is pulled out from the flow path, the liquid can be prevented from leaking from the tip of each pipette by pulling out while sucking each pipette.

  As shown in FIG. 1, the measurement method using SPR is roughly divided into three steps: a fixing step, a measurement processing step (data reading step), and a data analysis step. The SPR measuring device includes a fixing machine 10 that performs a fixing process, a measuring machine 11 that performs a measuring process, and a data analyzer that analyzes data obtained by the measuring machine 11.

  The measurement is performed using the sensor unit 12 that is an SPR sensor. The sensor unit 12 has a metal film (thin film layer) 13 whose one surface becomes a sensor surface 13a on which SPR occurs, and a prism (dielectric block) 14 bonded to the light incident surface 13b on the back surface of the sensor surface 13a. And a flow path member 41 which is disposed to face the sensor surface 13a and in which a flow path 16 through which a ligand or an analyte is fed is formed.

  As the metal film 13, for example, gold or silver is used, and the film thickness is, for example, 50 nm. This film thickness is appropriately selected according to the material of the metal film, the emission wavelength of the irradiated light, and the like. The prism 14 is a transparent dielectric having the metal film 13 formed on the upper surface thereof, and condenses the light irradiated so as to satisfy the total reflection condition toward the light incident surface 13b. The flow path 16 is a liquid feeding pipe bent in a substantially U shape, and has an inlet (inlet / outlet) 16a for injecting liquid and an outlet (inlet / outlet) 16b for discharging the liquid. The tube diameter of the channel 16 is, for example, about 1 mm, and the interval between the inlet 16a and the outlet 16b is, for example, about 10 mm.

  The bottom of the channel 16 is open, and this open part is covered and sealed with the sensor surface 13a. A sensor cell 17 is constituted by the flow path 16 and the sensor surface 13a. As will be described later, the sensor unit 12 includes a plurality of such sensor cells 17 (see FIG. 3).

  The fixing step is a step of fixing the ligand to the sensor surface 13a. The fixing process is performed by setting the sensor unit 12 to the fixing machine 10. The fixing machine 10 is provided with a pipette pair (a pipette group) 19 including a pair of pipettes 19a and 19b. In the pipette pair 19, the pipettes 19a and 19b are inserted into the inlet 16a and the outlet 16b, respectively. Each of the pipettes 19a and 19b has a function of injecting liquid into the flow channel 16 and sucking out from the flow channel 16, and when one of them performs the injection operation, the other performs the suction operation. So that they work together. Using this pipette pair 19, a ligand solution 21 in which a ligand is dissolved in a solvent is injected from the injection port 16a.

  A linker film 22 that binds to the ligand is formed at substantially the center of the sensor surface 13a. The linker film 22 is formed in advance at the manufacturing stage of the sensor unit 12. Since the linker film 22 serves as a fixing group for fixing the ligand, it is appropriately selected according to the type of ligand to be fixed.

  Before performing the ligand immobilization process for injecting the ligand solution 21, first, the immobilization buffer solution is sent to the linker film 22, and the linker film 22 is moistened to facilitate the binding of the ligand film 22. Processing is performed. For example, in the amine coupling method, carboxymethyl dextran is used as the linker film 22, and the amino group in the ligand is directly covalently bonded to the dextran. As the activation liquid in this case, a mixed liquid of N ′-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) is used. After this activation process, the flow path 16 is washed with the fixing buffer solution.

  As the buffer solution for fixing and the solvent (diluent) of the ligand solution 21, for example, various buffer solutions (buffer solutions), physiological salt solutions represented by physiological saline, and pure water are used. The The type of each of these liquids, the pH value, the type of mixture and its concentration, etc. are appropriately determined according to the type of ligand. For example, when a biological substance is used as a ligand, physiological saline whose pH is adjusted to near neutral is often used. However, in the above-described amine coupling method, the linker film 22 is negatively (negatively) charged by carboxymethyl dextran. Therefore, the protein is positively (positively) charged so as to be easily bonded to the linker film 22. In some cases, a phosphate buffer solution (PBS: phosphatic-buffered, saline) having a strong buffering action containing a high concentration of phosphate may be used.

  After such activation processing and cleaning, the ligand solution 21 is injected into the sensor cell 17 and the ligand immobilization processing is performed. When the ligand solution 21 is injected into the flow path 16, the ligand 21 a diffusing in the solution gradually approaches the linker film 22 and binds. In this way, the ligand 21a is fixed to the sensor surface 13a. Immobilization usually takes about one hour, and during this time, the sensor unit 12 is stored in a state where environmental conditions including temperature are set to predetermined conditions. The ligand solution 21 in the channel 16 may be allowed to stand while the immobilization proceeds, but the ligand solution 21 in the channel 16 is preferably stirred and flowed. By doing so, the binding between the ligand and the linker film 22 is promoted, and the amount of the ligand immobilized can be increased.

  When the immobilization of the ligand 21a on the sensor surface 13a is completed, the ligand solution 21 is discharged from the flow path 16. The ligand solution 21 is sucked and discharged by the pipette 19b. After the immobilization, the sensor surface 13a is subjected to a cleaning process by injecting a cleaning liquid into the channel 16. After this washing, if necessary, a blocking liquid is injected into the flow path 16 to perform a blocking process for inactivating the reactive group to which no ligand is bound in the linker film 22. As the blocking liquid, for example, ethanolamine-hydrochloride is used. After this blocking process, the channel 16 is washed again. Thereafter, the drying preventing liquid is injected into the flow path 16. Thus, the sensor unit 12 is stored until measurement in a state in which the sensor surface 13a is immersed in the anti-drying liquid.

  The measurement process is performed with the sensor unit 12 set on the measuring machine 11. The measuring machine 11 is also provided with a pipette pair 26 similar to the pipette pair 19 of the fixing machine 10. By the pipette pair 26, various liquids are injected into the flow path 16 from the injection port 16a. In the measurement process, first, a measurement buffer solution is injected into the flow path 16. Thereafter, an analyte solution 27 in which the analyte is dissolved in a solvent is injected, and then the measurement buffer solution is injected again. Note that the flow path 16 may be once cleaned before the measurement buffer solution is first injected. Data reading is started immediately after the measurement buffer is first injected in order to detect a reference signal level, and is performed after the analyte solution 27 is injected and until the measurement buffer is injected again. . As a result, it is possible to measure the SPR signal until detection of the reference level (baseline), reaction state (binding state) of the analyte and ligand, and desorption of the combined analyte and ligand by injection of the buffer solution for measurement. it can.

  As the buffer solution for measurement and the solvent (diluted solution) of the analyte solution 27, for example, various buffer solutions (buffer solutions), physiological salt solutions represented by physiological saline, and pure water are used. Is done. The type of each of these liquids, the pH value, the type of mixture, its concentration, etc. are appropriately determined according to the type of ligand. For example, DMSO (dimethyl-sulfo-oxide) may be included in physiological saline in order to facilitate the dissolution of the analyte. This DMSO greatly affects the signal level. As described above, the measurement buffer solution is used for detection of the reference level. Therefore, when DMSO is contained in the solvent of the analyte, the measurement buffer solution having a DMSO concentration similar to the DMSO concentration should be used. Is preferred.

  The analyte solution 27 is often stored for a long period of time (for example, one year). In such a case, a concentration difference occurs between the initial DMSO concentration and the DMSO concentration at the time of measurement due to a change over time. May end up. When strict measurement is required, such a concentration difference is estimated from the level of the reference signal (ref signal) when the analyte solution 27 is injected, and correction (DMSO concentration correction) is performed on the measurement data. Is called.

  Here, as will be described later, the reference signal (ref signal) is an SPR signal corresponding to a reference region provided on the sensor surface where the ligand is not fixed, and a measurement region where the ligand is fixed and a reaction with the analyte occurs. It is a signal that is compared and referenced with the measurement signal (act signal). At the time of measurement, two signals of the measurement signal and the reference signal are detected, and at the time of data analysis, for example, a difference between the two SPR signals is taken and analyzed as measurement data. By doing so, for example, noise caused by disturbances such as individual differences between a plurality of sensor cells and liquid temperature changes can be canceled, and a signal with a good S / N ratio can be obtained. .

  The correction data for correcting the DMSO concentration is obtained by injecting a plurality of types of measurement buffer solutions having different DMSO concentrations into the sensor cell 17 before injecting the analyte solution 27, and changing the ref according to the change in DMSO concentration at this time. It is obtained by examining the amount of change in each of the signal level and the act signal level.

  The measurement unit 31 includes an illumination unit 32 and a detector (detection means) 33. As described above, since the reaction state between the ligand and the analyte appears as a change in the resonance angle (incident angle of the light irradiated to the light incident surface), the illumination unit 32 can perform various incidents that satisfy the total reflection condition. The light of the corner is irradiated to the light incident surface 13b. The illumination unit 32 includes, for example, a light source 34 and an optical system 36 including a condensing lens, a diffuser plate, and a polarizing plate. The arrangement position and the installation angle satisfy the total reflection condition in terms of the incident angle of illumination light. To be adjusted.

  As the light source 34, for example, a light emitting element such as an LED (Light Emitting Diode), an LD (Laser Diode), or an SLD (Super Luminescent Diode) is used. One such light emitting element is used, and light is emitted from the single light source toward one sensor cell 17. When measuring a plurality of sensor cells 17 at the same time, the light from a single light source may be dispersed and irradiated to the plurality of sensor cells 17, or one light emitting element is provided for each sensor cell 17. A plurality of light emitting elements may be used side by side so as to be allocated. The diffusion plate diffuses light from the light source 34 and suppresses unevenness in the amount of light in the light emitting surface. The polarizing plate allows only p-polarized light that causes SPR to pass through. In addition, when using LD, when the direction of polarization of the light itself emitted from the light source is uniform, the polarizing plate is unnecessary. In addition, even when a light source with uniform polarization is used, if the direction of polarization becomes uneven by passing through the diffusion plate, the direction of polarization is aligned using a polarizing plate. The light thus diffused and polarized is condensed by the condenser lens and irradiated onto the prism 14. As a result, it is possible to cause the light incident surface 13b to enter the light rays having various incident angles without variation in light intensity.

  The detector 33 receives the light reflected by the light incident surface 13b and outputs an electrical signal having a level corresponding to the light intensity. Since light rays are incident on the light incident surface 13b at various angles, the light rays are reflected on the light incident surface 13b at various reflection angles according to respective incident angles. The detector 33 receives light beams having these various reflection angles. When a change occurs in the medium on the sensor surface 13a, the refractive index changes, and the incident angle (resonance angle at which SPR occurs) of the light whose reflected light intensity is attenuated also changes. When the analyte is fed onto the sensor surface 13a, the refractive index on the sensor surface 13a changes according to the reaction state between the analyte and the ligand, and the resonance angle also changes accordingly.

  The detector 33 uses, for example, a CCD area sensor or a photodiode array, receives reflected light reflected at various reflection angles on the light incident surface 13b, photoelectrically converts them, and outputs them as SPR signals. The reaction state of the ligand and the analyte appears as a transition of the attenuation position of the reflected light in the light receiving surface. For example, before and after the analyte contacts the ligand, the refractive index on the sensor surface 13a is different, and the resonance angle at which SPR occurs is different. When the analyte comes into contact with the ligand and starts the reaction, the resonance angle starts to change accordingly and the attenuation position of the reflected light in the light receiving surface starts to move. An SPR signal representing the reaction situation thus obtained is output to the data analyzer. In the data analysis step, the SPR signal obtained by the measuring instrument 11 is analyzed to analyze the characteristics of the analyte.

  For the sake of convenience, in FIG. 1, the direction of the incident light beam on the light incident surface 13 b and the reflected light beam reflected there is the flow direction of the liquid in the flow channel 16 so that the configuration of the measurement unit 31 becomes clear. Although the illumination unit 32 and the detector 33 are arranged so as to be parallel to each other, as shown in FIG. 2, the directions of the incident light beam and the reflected light beam are actually orthogonal to the flow direction. The illumination unit 32 and the detector 33 are arranged so as to be irradiated. Of course, the measurement unit 31 may be arranged and measured as shown in FIG.

  As shown in FIG. 2, on the linker film 22, a measurement region (act region) 22 a where a ligand is immobilized and a reaction between the analyte and the ligand occurs, and the ligand is not immobilized. A reference region (ref region) 22b for obtaining a reference signal is formed. The ref region 22b is formed when the linker film 22 described above is formed. As a formation method, for example, the linker film 22 is subjected to a surface treatment, and a binding group that binds to a ligand is deactivated in a region about half of the linker film 22. Thereby, half of the linker film 22 becomes the act region 22a, and the other half becomes the ref region 22b.

  The detector 33 outputs an SPR signal corresponding to the act region 22a as an act signal, and outputs an SPR signal corresponding to the ref region 22b as a ref signal. The act signal and the ref signal are measured almost simultaneously from the detection of the reference level to the desorption through the binding reaction. Data analysis is performed by obtaining the difference or ratio between the act signal and the ref signal thus obtained. For example, the data analyzer obtains difference data between the act signal and the ref signal, uses the difference data as measurement data, and performs analysis based on the difference data. By doing this, as described above, noise caused by disturbances such as individual differences between sensor units and sensor cells, mechanical fluctuations of the device, and temperature changes of the liquid can be canceled. Is possible.

  The illumination unit 32 and the detector 33 are configured so as to be able to measure two channels of these act signals and ref signals. For example, the illuminating unit 32 splits one light emitting element into a plurality of light beams incident on the act region 22a and the ref region 22b using a reflection mirror or the like. Each light beam is received by a detector 33 constituted by a plurality of photodiode arrays for each channel.

  When a CCD area sensor is used as the detector 33, the reflected light of each channel simultaneously received can be recognized as an act signal and a ref signal by image processing. However, when such a method using image processing is difficult, the timings of incidence on the act region 22a and the ref region 22b may be shifted by a minute time to receive the signal of each channel. As a method of shifting the incident timing, for example, a disk with two holes formed at a position shifted by 180 degrees on the optical path is arranged, and this disk is rotated to rotate the incident timing of each channel. Is shifted. Each hole is arranged at a position where the distance from the center is different by the distance between the regions 22a and 22b, so that when one hole enters the optical path, a light beam enters the act region 22a and the other When the hole enters the optical path, the light beam enters the ref region 22b.

  FIG. 3 is an exploded perspective view of the sensor unit 12. The sensor unit 12 is held in a state in which the flow path member 41 in which the flow path 16 is formed, the prism 14 with the metal film 13 formed on the upper surface, and the bottom surface of the flow path member 41 and the upper surface of the prism 14 are joined. And a lid member 43 disposed above the holding member 42.

  In the flow path member 41, for example, three flow paths 16 are formed. The flow path member 41 is formed in an elongated shape, and the three flow paths 16 are arranged along the longitudinal direction thereof. This flow path 16 constitutes a sensor cell 17 (see FIG. 1) together with the metal film 13 bonded to the bottom surface thereof. Therefore, the flow path member 41 is formed of an elastic material such as rubber or PDMS (polydimethylsiloxane) in order to improve the adhesion with the metal film 13. As a result, when the bottom surface of the flow path member 41 is pressed against the top surface of the prism 14, the flow path member 41 is elastically deformed to fill the gap between the joint surfaces with the metal film 13, and the open bottom of each flow path 16 is the prism. The upper surface of 14 is covered with water. In this example, the example in which the number of the flow paths 16 is three has been described. Of course, the number of the flow paths 16 is not limited to three, and may be one or two, or four or more. But you can.

  A metal film 13 is formed on the upper surface of the prism 14 by vapor deposition. The metal film 13 is formed in a strip shape so as to face the plurality of channels 16 formed in the channel member 41. Furthermore, a linker film 22 is formed on the upper surface (sensor surface 13 a) of the metal film 13 at a site corresponding to each flow path 16. Engaging claws 14 a that engage with the engaging portions 42 a of the holding member 42 are provided on both side surfaces of the prism 14 in the longitudinal direction. By these engagements, the flow path member 41 is sandwiched between the holding member 42 and the prism 14, and is held in a state where the bottom surface and the top surface of the prism 14 are in pressure contact with each other. Thus, the flow path member 41, the metal film 13, and the prism 14 are integrated.

  In addition, protrusions 14 b are provided at both ends in the short side direction of the prism 14. The sensor unit 12 is set in the fixing device 10 or the measuring device 11 in a state of being housed in a holder (not shown). The protrusion 14b is for positioning the sensor unit 12 at a predetermined storage position in the holder by fitting with a slit formed in the holder.

  The prism 14 is made of, for example, optical glass such as borosilicate crown (BK7) or barium crown (Bak4), polymethyl methacrylate (PMMA), polycarbonate (PC), amorphous polyolefin (APO), or the like. Representative optical plastics can be used.

  On the upper surface of the holding member 42, a receiving port 42b into which the tip of the pipette (19a, 19b, 26a, 26b) enters is formed at a position corresponding to the inlet 16a and the outlet 16b of each channel 16. The receiving port 42b has a funnel shape so that the liquid discharged from the pipette is guided to each inlet 16a. When the holding member 42 sandwiches the channel member 41 and engages with the prism 14, the lower surface of the receiving port 42 b is joined to the inlet 16 a and the outlet 16 b, and the receiving port 42 b and the channel 16 are connected.

  In addition, cylindrical bosses 42c are provided on both sides of each receiving port 42b. These bosses 42 c are for fitting the holes 43 a formed in the lid member 43 to position the lid member 43. The lid member 43 is affixed to the upper surface of the holding member 42 by a double-sided tape 44 having a hole in a position corresponding to the receiving port 42b and the boss 42c.

  The lid member 43 covers the receiving port 42 b communicating with the flow path 16, thereby preventing the liquid in the flow path 16 from evaporating. The lid member 43 is formed of, for example, an elastic material such as rubber or plastic, and a cross-shaped slit 43b is formed at a position corresponding to each receiving port 42b. Since the lid member 43 is for preventing evaporation of the liquid in the flow path 16, it is necessary to cover the receiving port 42b, but if it is completely covered, the pipette is inserted into the receiving port 42b. I can't. Therefore, by forming the slit 43b, the pipette can be inserted, and the receiving port 42b is closed when the pipette is not inserted. When the pipette is pushed into the slit 43b, the periphery of the slit 43b is elastically deformed (see FIG. 1), and the mouth of the slit 43b is wide open to receive the pipette. Then, when the pipette is pulled out, the slit 43b returns to the initial state by the elastic force and closes the receiving port 42b.

  For example, an RFID (Radio Frequency IDentification) tag that is a non-contact type IC memory may be attached to the prism 14 or the holding member 42 of the sensor unit 12. For example, the sensor unit 12 can be identified by writing a unique ID number for each sensor unit 12 in a read-only RFID tag and reading this ID number before performing each process. Thereby, even when fixing and measuring the plurality of sensor units 12 at the same time, it is possible to prevent the occurrence of problems such as erroneous injection of analytes and mistaken measurement results. Furthermore, using a readable / writable RFID tag, for example, the type of immobilized ligand, the date and time when the ligand was immobilized, and the type of analyte reacted may be written for each step. .

  FIG. 4 is a configuration diagram schematically showing the configuration of the fixing device 10. The fixing machine 10 is configured to detachably hold a pipette tip 50 formed in a substantially conical cylindrical shape, and to suck or discharge liquid into the pipette tip 50 by pressurizing or depressurizing the inside of the pipette tip 50. A pump 52 that drives the pump 52, a head moving mechanism 54 that moves the pipette head 51 in three directions, front, rear, left, right, and up, and a controller 55 that controls each part of the fixing machine 10 in an integrated manner. Have.

  The pipette head 51 is formed with two nozzles 60 protruding in a substantially cylindrical shape. The outer diameter of each nozzle 60 substantially matches the inner diameter of the pipette tip 50. When the pipette tip 50 is inserted into each nozzle 60, it is held by the pipette head 51 by mechanical fitting with the nozzle 60. That is, each pipette 19a, 19b is configured by inserting the pipette tip 50 into each nozzle 60. The pipette head 51 is provided with a release mechanism (not shown), and the pipette tip 50 inserted into each nozzle 60 is pushed down to remove the pipette tip 50 from the pipette head 51. Since the pipette tip 50 is in direct contact with the liquid to be fed, the pipette tip 50 is exchanged every time the liquid is fed so as not to cause a mixed liquid of different kinds of liquids through the pipette tip 50.

  As the two pumps 52 provided for each pipette 19a, 19b, for example, a so-called syringe pump composed of a cylinder and a piston can be used. Each pump 52 is connected to each nozzle 60 via pipes 61 and 62 and a pipette head 51. Each pump 52 causes the pipettes 19a and 19b to suck the liquid by depressurizing the inside of the pipe path leading to each nozzle 60, and discharges the liquid sucked to each pipette 19a and 19b by pressurizing the inside of the pipe path. Let A trifurcated branch pipe 63 is provided between the pipe 61 and the pipe 62. Each branch pipe 63 divides pressure fluctuations by the respective pumps 52 in two directions, and transmits one to the pipette head 51 via the pipe 62 and the other to the pressure sensors 65 via the pipe 64.

  Each pressure sensor 65 converts the pressure applied to each pipe by each pump 52 into an electrical signal, and outputs this electrical signal (hereinafter referred to as “pressure measurement signal”) to the controller 55. The pressure sensor 65 may be a known pressure sensor such as a semiconductor diaphragm pressure sensor or a capacitance pressure sensor.

  The controller 55 transmits a drive signal for each pump 52 to the pump driver 53, and controls the suction and discharge timing, the suction amount and the discharge amount, and the like. The pump driver 53 drives each pump 52 independently based on a drive signal from the controller 55, and causes each pipette 19a, 19b to suck and discharge liquid. That is, the drive control means described in the claims includes the pump driver 53 and the controller 55. At this time, the controller 55 applies feedback to the drive signal of each pump 52 based on the pressure measurement signal from each pressure sensor 65. As a result, it is possible to cause each pipette 19a, 19b to accurately suck and discharge the liquid at the target pressure value.

  Further, the controller 55 determines whether or not the pressure in each pipette 19a, 19b is abnormal based on the pressure measurement signal from each pressure sensor 65. For example, when liquid leakage occurs at each insertion portion of the pipette tip 50, a pressure value that is considerably lower than the target pressure value is measured. On the contrary, when the pipette tip 50 is clogged, a pressure value higher than the target pressure value is measured. In this manner, by measuring the pressure measurement signal, it is possible to detect liquid feeding abnormality such as liquid leakage. In addition, the pressure abnormality of each pipette 19a, 19b should just investigate whether the measured pressure value exists in the predetermined | prescribed error range with respect to the target pressure value, for example.

  The controller 55 is connected to a warning light (notification means) 66 and an operation input unit (release instruction input means) 67. When the controller 55 determines that the measured pressure value is abnormal, the controller 55 turns on the warning lamp 66 to notify that the pressure in each pipette 19a, 19b has become abnormal. The warning light 66 is preferably provided with, for example, two light sources corresponding to the pipettes 19a and 19b so that it can be determined which of the pipettes 19a and 19b is abnormal. The operation input unit 67 is a well-known input unit such as a keyboard, a mouse, and a touch panel, for example, and inputs various operation instructions to the fixed machine 10.

  The head moving mechanism 54 is a known moving mechanism including, for example, a conveyance belt, a pulley, a carriage, and a motor, and moves the pipette head 51 in three directions, front, back, left, right, up and down, under the control of the controller 55. The fixing device 10 includes a plurality of liquid storage units for storing various liquids (ligand solution, washing solution, fixing buffer solution, anti-drying solution, activation solution, blocking solution, etc.) to be injected into the flow path 16. A pipette chip storage section for storing the pipette chip 50 (all of which are not shown) is installed, and the head moving mechanism 54 attaches the pipette head 51 to each of these sections, the sensor unit 12 set in the fixing machine 10, and the like. Make it accessible.

  Next, the operation of the fixing machine 10 having the above configuration will be described with reference to the flowchart shown in FIG. When performing the fixing process on the sensor unit 12, first, the sensor unit 12 is stored in a holder (not shown), and the holder is set in a predetermined placement space of the fixing machine 10. After the sensor unit 12 is set, when a fixing start instruction is input from the operator via the operation input unit 67, the fixing machine 10 starts the fixing process.

  The controller 55 drives the head moving mechanism 54 in response to the input of the fixation start instruction, and moves the pipette head 51 to the liquid storage unit that stores the activation liquid of the linker film 22. The controller 55 having accessed the pipette head 51 to the liquid storage unit drives the pump 52 of the pipette 19a via the pump driver 53, and causes the pipette 19a to suck a predetermined amount of the activation liquid. The controller 55 that has caused the pipette 19a to suck the activation liquid moves the pipette head 51 to the sensor unit 12, and inserts the pipette pair 19 into the inlet 16a and outlet 16b of the flow path 16.

  The controller 55 having the pipette pair 19 inserted into the flow path 16 drives each pump 52 so that the pipette 19a discharges and the pipette 19b sucks. The pipette 19a discharges the activation liquid held in the pipette tip 50 and injects it into the flow path 16, and the pipette 19b sucks the air in the flow path 16 or the previously injected cleaning liquid, etc. 16 is discharged. As a result, the fluid in the flow path 16 is replaced with the activation liquid from the air or the cleaning liquid, and the linker film 22 is activated. At this time, as shown in the section indicated by an arrow A in FIG. 6, the suction force of the pipette pair 19b on the discharge side may be slightly increased to actively suck out air, cleaning liquid, or the like in the flow path. As a result, the fluid in the flow path is surely discharged, so that, for example, the liquid such as the cleaning liquid cannot be completely sucked out and remains in the flow path and is mixed with the liquid to be fed next. It is prevented.

  The controller 55 causes the pipette pair 19 to suck and discharge, and simultaneously monitors the pressure measurement signal from each pressure sensor 65, and discharges the pipette 19a and sucks the pipette 19b at the target pressure value. Apply feedback to the drive signal. As a result, the suction and discharge of the liquid by the pipettes 19a and 19b are accurately performed at the target pressure value, and the flow rate of the liquid to be fed and the liquid feeding time can be strictly managed. Further, the controller 55 determines whether or not the pressure in each pipette 19a, 19b is abnormal based on the pressure measurement signal from each pressure sensor 65, and detects a liquid feeding abnormality such as liquid leakage.

  At this time, the controller 55 that has detected an abnormality in one of the pipettes 19a and 19b instructs the pump driver 53 to stop each pump 52, stops liquid feeding to the flow path 16, and turns on the warning lamp 66. The operator is notified that an abnormality has occurred. That is, the controller 55 functions as a drive control unit and a determination unit, and also functions as an abnormality detection processing unit.

  In this way, by performing the abnormality detection process and causing the operator to recognize the abnormality, it is possible to prevent the fixing process from being completed without noticing that the abnormality has occurred. In addition, since it is possible to quickly take measures such as inspection and repair of each part, it is possible to prevent time from being used meaninglessly. It should be noted that each pump 52 may be provided with a limiter for controlling the upper limit of the pressure so that an excessive pressure is not applied to each pipette 19a, 19b or the flow path 16.

  When the injection of the activation liquid into the flow path 16 is completed, the controller 55 applies a weak suction force to both the pipettes 19a and 19b as shown by the arrow B section in FIG. And the flow path 16 is brought into a reduced pressure state. The controller 55 drives the head moving mechanism 54 in a state where each part is in a reduced pressure state, and pulls out the pipettes 19 a and 19 b from the flow path 16. Since a suction force is applied to each pipette 19a, 19b, liquid is prevented from leaking from the tip of each pipette 19a, 19b when it is pulled out. In addition, when the flow path 16 in the reduced pressure state returns to the atmospheric pressure, the liquid level in each flow path 16 is pushed down by the air, so that the liquid with the pipettes 19a and 19b is improved and the liquid adhering to the outer surface is improved. Can also be suppressed.

  The controller 55 that has pulled out the pipettes 19a and 19b from the flow path 16 moves the pipette head 51 to the discarding section, and releases the pipette tips 50 immersed in the activation liquid. The controller 55 that has released each pipette tip 50 moves the pipette head 51 to the pipette tip storage section, inserts an unused pipette tip 50 into each nozzle 60, and then pipettes the ligand solution 21 to be injected next. The chip 50 is replaced. When each pipette tip 50 is released, each pipette tip 50 may be returned to the pipette tip storage unit, and a dedicated pipette tip 50 may be provided for each liquid to be injected.

  The controller 55 that has exchanged the pipette tip 50 moves the pipette head 51 to the liquid storage section that stores the ligand solution 21 and causes each pipette 19a to aspirate the ligand solution 21. The controller 55 that has aspirated the ligand solution 21 moves the pipette head 51 to the sensor unit 12 and inserts it into the channel 16 of each pipette 19a, 19b in the same procedure as the activation liquid, An immobilization process for immobilizing the ligand 21a on the linker film 22 is performed by detecting an abnormality in liquid feeding and extracting the pipettes 19a and 19b from the flow path 16. Before pulling out each pipette 19a, 19b, it is preferable to stir the ligand solution 21 injected into the flow path 16 by alternately sucking and discharging each pipette 19a, 19b. By doing so, the binding between the ligand and the linker film 22 is promoted, and the amount of the ligand immobilized can be increased.

  FIG. 7 is an explanatory diagram showing an example in which a plurality of pipette pairs 19 as a pipette group are provided. Note that the same functions and configurations as those of the above embodiment are denoted by the same reference numerals, and detailed description thereof is omitted. 7 includes a pipette head 102 having three pairs of pipettes 19 matched to each flow path 16 of the sensor unit 12, and a pump 52 that causes each pipette 19a, 19b to suck and discharge liquid. A pump driver 53 that drives each of these pumps 52, a head moving mechanism 54 that moves the pipette head 102 in three directions, front, rear, left, right, and up, and a controller 104 that comprehensively controls each part of the fixing machine 100. It has been. Moreover, the warning lamp 66 and the operation input part 67 are connected to the controller 104 like the said embodiment.

  The controller 104 of the fixing machine 100 to which the fixing start instruction is input via the operation input unit 67 activates the linker film 22 and fixes the ligand as described above. At this time, the fixing machine 100 inserts each pipette pair 19 into each flow path 16 included in the sensor unit 12, and simultaneously performs the fixing process on each sensor cell 17. In the above embodiment, only one pipette pair 19 is provided on the pipette head 51. On the other hand, in this example, since the immobilization process can be simultaneously performed on each sensor cell 17, the time required for the immobilization process can be shortened.

  The controller 104 determines whether or not the pressure in each pipette 19a, 19b is abnormal based on the pressure measurement signal from each pressure sensor 65 when liquid is supplied to each flow path 16, and supplies liquid leakage or the like. Detect liquid abnormality. The controller 104 that has detected the abnormality stops the liquid feeding of the pipette pair 19 including the pipettes 19a and 19b in which the abnormality is detected, and the abnormality is caused by turning on the warning lamp 66. To the operator or the like.

  Further, the controller 104 continues the abnormality detection process until a cancel instruction is input from the operation input unit 67, and keeps the pipette pair 19 in which the abnormality is detected stopped. Thereby, for example, when immobilization processing is performed subsequently to the plurality of sensor units 12, it is possible to prevent inadvertent liquid feeding by the abnormal pipette pair 19. If liquid feeding is performed by the pipette pair 19 having an abnormality, the liquid is fed into the flow channel 16 until the abnormality is again determined by the controller 104, and the bonding group of the linker film 22 is denatured by the liquid. There is a risk of inactivity.

  If the bonding group of the linker film 22 is denatured or deactivated, measurement cannot be performed normally even if the immobilization process is performed again later. Thus, by leaving the pipette pair 19 in which an abnormality is detected to be stopped, measurement defects can be prevented in advance, and the highly reliable fixing device 100 can be provided. The cancellation instruction may be input by the operator via the operation input unit 67 after the abnormality is resolved.

  In this example, when the controller 104 determines a pressure abnormality, only the liquid feeding of the pipette pair 19 including the pipettes 19a and 19b in which the abnormality is detected is stopped. However, at least one pipette 19a , 19b, all pipette pairs 19 may be stopped in response to the detection of an abnormality. However, as shown in this example, by stopping only the liquid feeding of the pipette pair 19 including the pipettes 19a and 19b in which the abnormality is detected, the other pipette pairs 19 that are operating normally are not affected. Since the immobilization process can proceed, the process can proceed more quickly than in the case where all the pipette pairs 19 are stopped.

  In this example, the abnormality detection process is canceled in response to the input of the cancellation instruction via the operation input unit 67. However, the present invention is not limited to this. For example, the abnormality of each pipette 19a, 19b is detected. It is also possible to perform a return process for returning the error to the controller 104 and cause the controller 104 to cancel the abnormality detection process after performing the return process. At this time, examples of the return process include replacement of the pipette tip 50 and cleaning of each piping path from the pump 52 to the nozzle 60.

  If the pressure abnormality of each pipette 19a, 19b is due to clogging of the pipette tip 50, poor mounting of the pipette tip 50, etc., the abnormality can be restored by replacing the pipette tip 50. On the other hand, if the pressure abnormality of each pipette 19a, 19b is due to foreign matter or the like adhering to the piping path, the abnormality can be recovered by cleaning the piping path. For example, the pipe path may be washed by sucking a cleaning liquid from the pipettes 19a and 19b, flowing through the pipes, and discharging the pipettes 19a and 19b again.

  By performing the return process in this manner, the pressure abnormality of each pipette 19a, 19b is automatically recovered without troublesome operator, and the next sensor unit 12 or the like is normally fixed. Will be able to. Note that the timing of performing the return process may be immediately after the controller 104 determines a pressure abnormality, or may be after the immobilization process on the sensor unit 12 in which the abnormality has been determined. Further, the cancellation of the abnormality detection process by the return process and the cancellation of the abnormality detection process by the operation input unit 67 may be alternatively selected.

  In each of the above embodiments, when the controller determines that the measured pressure value is abnormal, the abnormality detection process is to stop driving each pump 52 and stop the liquid supply to the flow path 16. However, the present invention is not limited to this, and for example, recording of information such as a pipette in which an abnormality has occurred, time, operation timing (which liquid was being delivered), and the like may be performed as an abnormality detection process. If recording is made in this way so that the sensor cell 17 having an abnormality can be identified later, it is possible to prevent the fixing process from being terminated without noticing that an abnormality has occurred, as described above. be able to.

  In each of the above embodiments, the warning light 66 is shown as the notification means. However, the present invention is not limited to this. For example, a warning sound may be emitted from a speaker or a warning message may be displayed on a liquid crystal display or the like. You may make it display.

  In each of the above embodiments, the flow channel 16 having two inlets and outlets 16a and 16b is used, and the pipette pair 19 having two pipettes 19a and 19b is shown as a pipette group. The number of entrances / exits included in and the number of pipettes included in the pipette group are not limited to this. For example, as shown in FIG. 8, three entrances and three pipettes may be provided. The flow path member 121 of the sensor unit 120 is formed with a flow path 122 having three entrances 122a, 122b, and 122c. On the other hand, the pipette head 123 is provided with three nozzles 124, and a pipette tip 125 is inserted into each nozzle 124 to form a pipette group 126 including three pipettes 126a, 126b, and 126c. . In the sensor unit 120, two linker films 127 are formed so as to be positioned between the respective inlets / outlets 122a, 122b, 122c, and each linker film 127 is formed at a time by a combination of the pipettes 126a, 126b, 126c. The liquid can be sent or can be sent individually.

  Further, in each of the above-described embodiments, the example in which the present invention is applied to the pipette pair 19 of the stationary machine has been shown, but the present invention may of course be applied to the pipette pair 26 of the measuring machine 11. Furthermore, the present invention may be applied to other liquid feeding devices using a pipette tip, such as a hand-held pipetter as shown in FIG.

  FIG. 9 is an external perspective view showing the configuration of the pipetter 140. The pipetter 140 includes a head part 142 in which six nozzles 141 for sucking and discharging liquid are formed, a main body part 144 for storing a controller 143 for controlling suction and discharge of each nozzle 141, and the like. A connecting portion 145 for connecting the portion 144. The connecting portion 145 is formed in a substantially cylindrical shape, mechanically connects the head portion 142 and the main body portion 144, and houses various wirings therein to electrically connect the head portion 142 and the main body portion 144. Also connect.

  Each nozzle 141 is inserted with a pipette tip 146 having a substantially conical cylindrical shape. Each pipette tip 146 is fitted into each nozzle 141 and is detachably held by the head portion 142. A syringe pump 147 including a cylinder 148 and a piston 149 is provided inside the head portion 142 so as to correspond to each nozzle 141. A slide movement mechanism (not shown) is connected to the piston 149. The slide moving mechanism slides the piston 149 in accordance with a drive signal from the controller 143, and changes the pressure in the cylinder 148. The nozzle 141 performs liquid suction / discharge according to the pressure fluctuation. A known mechanism such as a rack and pinion may be used as the slide movement mechanism. Each syringe pump 147 is connected to each nozzle 141 via a trifurcated branch pipe 150. Each branch pipe 150 divides the pressure fluctuation by each syringe pump 147 into two directions, and transmits one to the nozzle 141 and the other to the pressure sensor 151. The pressure sensor 151 converts the pressure applied by the syringe pump 147 into an electrical signal and outputs this signal to the controller 143.

  The main body 144 is provided with an operation input unit 155, a start button 156, and an LCD panel 157. Various buttons 155a are arranged in the operation input unit 155, and setting items such as an operation mode of the pipetter 140 can be input by pressing these buttons 155a. The operation mode of the pipetter 140 includes, for example, a pipetting mode in which a set volume of liquid is sucked into the pipette tip 146 and discharged at one time, or an equal amount in which the liquid in the pipette tip 146 is dispensed into equal amounts. There is a continuous dispensing mode.

  A menu list or the like is displayed on the LCD panel 157. The operator can set the above-described operation mode while looking at the LCD panel 157. The start button 156 inputs the start of the liquid feeding operation to the controller 143 according to the pressing operation. In response to the pressing operation of the start button 156, the controller 143 controls the driving of each syringe pump 147 based on a preset operation mode. Further, a hook 158 is formed on the main body 144 in order to prevent accidental dropping when the operator holds the main body 144 by hand and causes the pipetter 140 to perform a liquid feeding operation.

  For example, by inserting the tip of each pipette tip 146 into each flow path 16 of the sensor unit 12 and performing a liquid feeding operation, the same effect as the above-described fixing machine 10 can be obtained even with the pipetter 140 configured in this way. Can do.

  In each of the above-described embodiments, the prism 14 is shown as the dielectric block. However, the dielectric block may be a plate of optical glass or optical plastic, or a plate of these. And a prism integrated with an optical surface smoothing agent (for example, optical matching oil).

  In each of the above embodiments, an SPR measurement device is shown as an example of a measurement device using total reflection attenuation. However, for example, a leak mode sensor is known as a measurement device using total reflection attenuation. It has been. The leakage mode sensor is composed of a dielectric, and a thin film composed of a clad layer and an optical waveguide layer that are sequentially layered thereon. One surface of the thin film serves as a sensor surface, and the other surface receives light. It becomes a surface. When light is incident on the light incident surface so as to satisfy the total reflection condition, a part of the light is transmitted through the cladding layer and taken into the optical waveguide layer. In this optical waveguide layer, when the waveguide mode is excited, the reflected light at the light incident surface is greatly attenuated. The incident angle at which the waveguide mode is excited changes according to the refractive index of the medium on the sensor surface, similar to the resonance angle of SPR. By detecting the attenuation of the reflection angle, the chemical reaction on the sensor surface is measured.

It is explanatory drawing of a SPR measuring method. It is explanatory drawing which extracts and demonstrates one sensor cell. It is a disassembled perspective view which shows schematic structure of a sensor unit. It is a block diagram which shows the structure of a fixing machine roughly. It is a flowchart which shows the procedure of a fixing process. It is a graph which shows an example of the output signal of a pressure sensor. It is explanatory drawing which shows the example which provided multiple pipette pairs. It is explanatory drawing which shows the other example of a pipette head and a sensor unit. It is an external appearance perspective view which shows the structure of a pipettor.

Explanation of symbols

10, 100 Fixing machine 11 Measuring machine 12, 80 Sensor unit 13 Metal film (thin film layer)
14 Prism (dielectric block)
16, 82 Channel 16a Inlet (entrance / exit)
16b Outlet (entrance / exit)
19 Pipette pairs (Pipettes)
19a Pipette 19b Pipette 32 Illumination part 33 Detector (detection means)
34 Light source 52 Pump 53 Pump driver (drive control means)
55, 104 controller (drive control means, determination means, abnormality detection processing means)
65 Pressure sensor 66 Warning light (notification means)
67 Operation input section (release instruction input means)
126 Pipette group 126a Pipette 126b Pipette 126c Pipette 140 Pipetter 143 Controller 147 Syringe pump 151 Pressure sensor

Claims (12)

A sensor unit having a flow path having a plurality of inlets and outlets and a sensor surface for detecting the reaction of the sample facing each other is detachably set, and the sample solution in which the sample is dissolved is sent to the flow path. Then, in the liquid feeding device for contacting the sensor surface,
A group of pipettes consisting of a plurality of pipettes inserted into the doorways;
A plurality of pumps provided corresponding to each of the pipettes, pressurizing or depressurizing the inside of the pipettes, and sucking or discharging the sample solution to the pipettes;
A plurality of pressure sensors for converting the pressure applied to each of the pipettes into an electrical signal;
Drive control means for driving each pump independently and controlling each corresponding pump according to the electrical signal from each pressure sensor ;
A determination means for determining whether or not the pressure in each pipette is abnormal based on the electrical signal from each pressure sensor when liquid is supplied to the flow path;
When the determination means determines an abnormality for at least one of the pipettes, an abnormality detection process is performed, and following the abnormality detection process, a return process for recovering an abnormality in the pressure in each pipette is performed. An abnormality detection processing means for canceling the abnormality detection process after performing the process . The pipette is formed on a head that holds the pipette, and includes a pipe connected to the pump via a pipe and the head, and a pipette tip that is detachably attached to the nozzle.
2. The liquid feeding device according to claim 1, wherein the return processing performed by the abnormality detection processing means is replacement of the pipette tip or cleaning of a piping path from the pump to the nozzle. Claims wherein the abnormality detecting processing means the abnormality detection processing carried out, the stopping of the pump directs to the drive control means, and characterized in that to stop feeding liquid to the flow path by the pipette unit 3. The liquid feeding device according to 1 or 2 . The sensor unit is provided with a plurality of the flow paths,
4. The liquid feeding device according to claim 1 , wherein a plurality of the pipette groups are provided corresponding to the respective flow paths. 5. The abnormality detection processing unit, among the plurality of the pipettes group, according to claim 4, characterized in that the abnormality detection processing only on the pipette group including the pipette which the determination means determines an abnormality Liquid delivery device. The informing means according to any one of claims 1 to 5 , further comprising an informing means for informing that an abnormality has occurred in the pressure in each pipette when the judging means judges an abnormality. Liquid delivery device. A cancellation instruction input means for inputting the abnormality detection processing cancellation instruction to the abnormality detection processing means;
The liquid feeding device according to claim 1, wherein the abnormality detection processing unit continues the abnormality detection processing until the cancellation instruction is input. Said drive control means, when withdrawing the respective pipette from each doorway claim 1, wherein within each pipette and the flow channel is characterized by controlling the respective pump so that the vacuum state 8. The liquid feeding device according to any one of 7 above . It is a liquid feeding method of the liquid feeding apparatus in any one of Claim 1 to 8, Comprising:
The pipette is inserted into each of the inlets and outlets to discharge the sample solution from the at least one pipette into the flow path, and at least one of the remaining pipettes uses air in the flow path or After sucking the liquid and feeding the sample solution to the sensor surface,
A liquid feeding method, wherein each pipette is aspirated to reduce the pressure in each pipette and the flow path, and each pipette is pulled out from each inlet / outlet. 10. The liquid feeding according to claim 9 , wherein the suction of air or liquid in the flow path is stronger than the discharge of the sample solution, and the sample solution is fed in a reduced pressure state in the flow path. Method. After feeding the sample solution to the flow channel, wherein the discharge and suction of the pipette repeatedly alternately, claim 9 or 10, wherein the agitating said sample solution in the channel Liquid feeding method. For a sensor unit provided with a flow path having a plurality of entrances and a dielectric block having a thin film layer for detecting the reaction of the sample on one surface, light is transmitted so as to satisfy the total reflection condition. In a measuring device using total reflection attenuation, comprising: a light source that irradiates light; and a detecting means that receives reflected light from the sensor unit and photoelectrically converts the reflected light into an electrical signal.
A group of pipettes consisting of a plurality of pipettes inserted into the doorways;
A plurality of pumps provided corresponding to each of the pipettes, pressurizing or depressurizing the inside of the pipettes, and sucking or discharging the sample solution to the pipettes;
A plurality of pressure sensors for converting the pressure applied to each of the pipettes into an electrical signal;
Drive control means for driving each pump independently and controlling each corresponding pump according to the electrical signal from each pressure sensor ;
A determination means for determining whether or not the pressure in each pipette is abnormal based on the electrical signal from each pressure sensor when liquid is supplied to the flow path;
When the determination means determines an abnormality for at least one of the pipettes, an abnormality detection process is performed, and following the abnormality detection process, a return process for recovering an abnormality in the pressure in each pipette is performed. A measuring apparatus using total reflection attenuation , comprising: an abnormality detection processing means for canceling the abnormality detection processing after performing the processing .

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