JP4979609B2 - measuring device - Google Patents

Description

  The present invention relates to a measuring apparatus, and in particular, individually supplies a plurality of types of test solutions used for measuring characteristics of the sample substance and a predetermined reference solution as a measurement reference to the sample substance to be measured. The present invention also relates to a measuring apparatus that measures the characteristics of a sample substance by detecting the reaction state of the sample substance.

  2. Description of the Related Art Conventionally, there are known measuring apparatuses that measure characteristics of a sample substance by supplying various solutions to the sample substance to be measured and detecting the reaction state between the sample substance and each solution. .

For example, in Patent Document 1, a liquid flow path is formed so that a liquid can flow, and a liquid flow of a measurement chip provided with an attachment region in which a sample substance to be measured is attached to a wall surface in the liquid flow path. A plurality of kinds of test solutions (described as “analyte” in Patent Document 1) used for measurement of the characteristics of the specimen substance with respect to the channel, and a reference solution (“Buffer” in Patent Document 1) as a measurement reference Measurement) in which screening is performed to identify a test solution that reacts with the sample substance by detecting the reaction state of the sample substance and the test solution in a state where each solution is supplied. An apparatus is disclosed.
JP 2004-136236 A

  By the way, in such screening, the test solution that reacts with the sample substance is a part of a plurality of types.

  For this reason, as described in Patent Document 1, when supplying the test solution and the reference solution alternately is repeated, there is a problem that the processing efficiency is low and the screening processing time is long.

  The present invention has been made to solve the above problems, and an object of the present invention is to provide a measuring apparatus capable of shortening the screening processing time.

In order to achieve the above-mentioned object, the invention described in claim 1 is provided with a plurality of types of test solutions used for measuring the characteristics of the sample substance in the adhesion area of the sample substance to be measured, and a predetermined reference for measurement. Supply means for supplying each of the reference solutions individually, and information indicating reaction states of the specimen substances in a state where the plurality of types of test solutions and the reference solutions are individually supplied by the supply means, respectively When acquiring the acquisition means and each of the plurality of types of test solutions sequentially to the attachment region for each type, any of the test solutions is supplied by the supply means , and the test solutions are supplied. In the state, the presence or absence of interaction between the sample substance and the test solution is determined based on the information indicating the reaction state acquired by the acquisition unit. the reference soluble in And the logic circuit is supplied the following types of the test solution after the reference solution is supplied, if it is determined that there is no interaction, the following types without the reference solution is supplied to the attachment section Control means for controlling the supply means so that the test solution is supplied.

  According to the first aspect of the present invention, the supply means includes a plurality of types of test solutions used for measuring the characteristics of the sample substance and a predetermined reference solution serving as a reference for measurement in the adhesion region of the sample substance to be measured. Each of the information is individually supplied, and the acquisition means acquires information indicating the reaction state of the sample substance in a state where a plurality of types of test solutions and reference solutions are supplied individually by the supply means. Is done.

In the present invention, when the control means sequentially supplies each of the plurality of types of test solutions to the adhesion region for each type, any of the test solutions is supplied by the supply means , and the test solution is whether interaction between the sample substance and the sample solution on the basis of information indicating to the reaction conditions acquired by the acquisition means supplied state is determined, if it is determined that there interactions, the the attachment area When the reference solution is supplied and the next type of test solution is supplied after the reference solution is supplied and it is determined that there is no interaction, the next type is not supplied to the adhesion region. The supply means is controlled so that the test solution is supplied.

  Thus, according to the first aspect of the present invention, the presence or absence of interaction between the sample substance and each test solution is determined. When it is determined that there is no interaction, the reference solution is not supplied to the attachment region. Since the following types of test solutions are supplied, the screening processing time can be shortened.

According to the present invention, as in the second aspect of the invention, the storage means stores the number-of-times information indicating the number of times the test solution has been supplied since the immediately preceding reference solution was supplied by the supply means. further comprising, said control means, when it is determined that there is no interaction with the attachment region when the supply number of the test solution indicated by the count information stored in the storage means is equal to or less than a predetermined threshold value When the next type of test solution is supplied and the number of times of supply of the test solution is larger than the threshold value, the supply means may be controlled so that the reference solution is supplied to the adhesion region.

  According to a second aspect of the present invention, as in the third aspect of the present invention, the control means is acquired by the acquisition means in a state where the reference solution is individually supplied a plurality of times by the supply means. It is preferable to obtain a change in the adhesion state of the specimen substance based on the information indicating the reaction state, and to change the threshold value to a smaller value as the change is larger.

  Further, according to the present invention, as in the invention described in claim 4, when the supplying unit further supplies a cleaning solution for cleaning the specimen substance individually, and the control unit determines that there is an interaction. The supply unit may be controlled so that the cleaning solution is supplied before the reference solution is supplied to the adhesion region.

  Further, according to the present invention, as in the fifth aspect of the present invention, a plurality of the attachment areas of the specimen substance are provided so that the solutions can be supplied individually, and a plurality of the supply means are provided, and each of the attachment areas is provided. Independently supplying each of the plurality of types of test solutions and the reference solution individually, the acquisition unit acquires information indicating the reaction state for each attached region, and the control unit includes: For each adhesion area, the supply means corresponding to each adhesion area may be independently controlled based on the information indicating the reaction state acquired by the acquisition means.

  Further, the present invention further includes a communication unit connected to a network and performing communication through the network as in the sixth aspect of the invention, wherein the control unit includes end information indicating the end of measurement and an abnormality indicating occurrence of an abnormality. At least one of information, progress status information indicating the progress status of measurement, scheduled end time information indicating the scheduled end time of measurement, and request information for requesting replenishment of consumables provided in the apparatus via the communication means. You may make it perform control which transmits to the preset information transmission destination.

  Thus, according to the present invention, the effect that the screening processing time can be shortened can be obtained.

  Hereinafter, embodiments of the present invention will be described with reference to the drawings. In the following, a measurement apparatus that detects the reaction state between a specimen substance and a test solution by detecting the reflection angle at which a dark line is generated due to the occurrence of total reflection attenuation due to surface plasmon resonance (SPR). A case where the present invention is applied will be described.

  The biosensor 10 as a measuring apparatus according to the present embodiment is a so-called surface plasmon sensor that measures the interaction between the protein Ta and the sample A using the surface plasmon resonance phenomenon generated on the surface of the metal film. .

  As shown in FIGS. 1 to 4, the biosensor 10 includes a lower housing 11 and an upper housing 12. The upper housing 12 is made of a heat insulating member and covers the entire upper half of the biosensor 10. The interior of the upper housing 12 is insulated from the outside and the interior of the lower housing 11. The front side of the upper housing 12 can be opened upward, and a handle 13 is attached. A display 14 and an input unit 16 are installed outside the upper housing 12.

  2 is a view showing the inside of the biosensor 10 as seen from the back side of FIG. 1 with the upper housing 12 removed, FIG. 3 is a view of the inside of the housing from the top, and FIG. It is an internal side view seen from this side.

  Disposed inside the upper housing 12 are a dispensing head 20, a measurement unit 30, a sample stock unit 40, a pipette tip stock unit 42, a buffer stock unit 44, a cold insulation unit 46, a waste liquid plate 47, a measurement tip stock unit 48, and a radiator 60. A radiator blower fan 62 and a horizontal blower fan 64 are provided.

  The sample stock unit 40 includes a sample stacking unit 40A and a sample setting unit 40B. In the sample stacking section 40A, a sample plate 40P for stocking a plurality of different types of analyte solutions containing various samples as test solutions used for measuring the characteristics of the specimen substance in each cell is provided in the Z direction (vertical direction). ) And stacked. The plurality of stacked sample plates 40P includes a sample plate 40P that stocks a cleaning solution for cleaning the protein Ta. One sample plate 40P is transported and set from the sample stacking section 40A by a transport mechanism (not shown) to the sample setting section 40B.

  The pipette tip stock portion 42 includes a pipette tip stacking portion 42A and a pipette tip setting portion 42B. In the pipette chip stacking part 42A, pipette chip stockers 42P for holding a plurality of pipette chips are stacked and accommodated in the Z direction. One pipette chip stocker 42P is transported and set from the pipette chip stacking section 42A by a transport mechanism (not shown) to the pipette chip setting section 42B.

  The buffer stock unit 44 includes a bottle storage unit 44A and a buffer supply unit 44B. A plurality of bottles 44C storing a buffer solution as a reference solution serving as a reference for measurement are stored in the bottle storage portion 44A. A buffer plate 44P is set in the buffer supply unit 44B. The buffer plate 44P is partitioned into a plurality of muscles, and buffer solutions having different concentrations are stored in each partition. Further, a hole H into which the pipette tip CP is inserted when the dispensing head 20 is accessed is formed in the upper part of the buffer plate 44P. The buffer liquid is supplied from the bottle 44C to the buffer plate 44P through the hose 44H.

  A correction plate 45 is arranged next to the buffer supply unit 44B, a cold insulation unit 46 is arranged next to it, and a waste liquid plate 47 is arranged next to it. The correction plate 45 is a plate for adjusting the concentration of the buffer solution, and a plurality of cells are formed in a matrix. A sample that needs to be refrigerated is placed in the cold insulation unit 46. The cold insulation part is set to a low temperature, and the sample is kept at a low temperature. The waste liquid plate 47 is connected to a waste liquid tank (not shown) by a hose, and the solution discharged to the waste liquid plate 47 is stored in the waste liquid tank.

  In the measurement chip stock portion 48, a measurement chip accommodation plate 48P is set. A plurality of measurement chips 50 are accommodated in the measurement chip accommodation plate 48P.

  A measurement chip transport mechanism 49 is provided between the measurement chip stock unit 48 and the measurement unit 30. The measuring chip transport mechanism 49 includes a holding arm 49A that sandwiches and holds the measuring chip 50 from both sides, a ball screw 49B that moves the holding arm 49A in the Y direction by rotation, and a transport rail on which the measuring chip 50 is placed. 49C. At the time of measurement, one measurement chip 50 is placed on the transport rail 49C from the measurement chip storage plate 48P by the measurement chip transport mechanism 49, and is moved and set to the measurement unit 30 while being held by the holding arm 49A. .

  As shown in FIGS. 5 and 6, the measurement chip 50 includes a dielectric block 52, a flow path member 54, and a holding member 56.

  The dielectric block 52 is made of a transparent resin or the like that is transparent to the light beam, and has a prism portion 52A having a trapezoidal cross section, and the prism portion 52A integrally with both ends of the prism portion 52A. A formed held portion 52B is provided. A metallic thin film 57 is formed on the upper surface on the wider side of the two parallel surfaces of the prism portion 52A. The dielectric block 52 functions as a so-called prism. When the measurement is performed by the biosensor 10, a light beam is incident from one of two opposing non-parallel sides of the prism portion 52A and the thin film 57 is incident from the other. A light beam totally reflected at the interface is emitted.

  On the surface of the thin film 57, there is formed a linker layer 57A for attaching protein Ta on the thin film 57 as a sample substance to be measured. Protein Ta is attached on this linker layer 57A.

  Engaging convex portions 52C that are engaged with the holding member 56 are formed along the upper side edge on both side surfaces of the prism portion 52A. Further, a flange portion 52D that is engaged with the transport rail 49C is formed along the side end side below the prism portion 52A.

  As shown in FIG. 6, the flow path member 54 includes six base portions 54A, and four cylindrical members 54B are erected on each of the base portions 54A. In the base portion 54A, for each of the three base portions 54A, one upper portion of the standing cylindrical members 54B is connected by a connecting member 54D. The channel member 54 is made of a soft and elastically deformable material, for example, an amorphous polyolefin elastomer. In this manner, by configuring the flow path member 54 with a material that can be elastically deformed, the adhesion with the dielectric block 52 is enhanced, and the sealing performance of the liquid flow path 55 configured between the dielectric block 52 is improved. Secured.

  The holding member 56 is long and has a shape in which the upper surface member 56A and the two side plates 56B are formed in a lid shape. The side plate 56B is formed with an engagement hole 56C to be engaged with the engagement protrusion 52C of the dielectric block 52, and a window 56D at a portion corresponding to the optical path of the light beam. The holding member 56 is attached to the dielectric block 52 with the engagement hole 56 </ b> C and the engagement protrusion 52 </ b> C engaged. The flow path member 54 is integrally formed with the holding member 56 and is disposed between the holding member 56 and the dielectric block 52. A receiving portion 59 is formed on the upper surface member 56A at a position corresponding to the cylindrical member 54B of the flow path member 54. The receiving part 59 is substantially cylindrical.

  As shown in FIG. 7, the base portion 54A has two substantially S-shaped channel grooves 54C formed on the bottom surface side. Each of the end portions of the flow channel 54C communicates with the hollow portion of one cylindrical member 54B. The bottom surface of the base portion 54A is in close contact with the upper surface of the dielectric block 52, and the liquid channel 55 is configured by the space formed between the channel groove 54C and the upper surface of the dielectric block 52 and the hollow portion. The

  Two liquid channels 55 are formed in one base portion 54A. In each liquid channel 55, an entrance / exit 53 of the liquid channel 55 is formed on the upper end surface of the cylindrical member 54B.

  Here, one of the two liquid channels 55 is used as the measurement channel 55A, and the other one is used as the reference channel 55R. The measurement is performed in a state where the protein Ta is attached on the thin film 57 (on the linker layer 57A) of the measurement channel 55A and the protein Ta is not attached on the thin film 57 (on the linker layer 57A) of the reference channel 55R.

  As shown in FIG. 7, light beams L1 and L2 are incident on the measurement channel 55A and the reference channel 55R, respectively. As shown in FIG. 8, the light beams L1 and L2 are applied to an S-shaped bent portion disposed on the center line M of the base portion 54A. Hereinafter, the irradiation region of the light beam L1 in the measurement channel 55A is referred to as a measurement region E1, and the irradiation region of the light beam L2 in the reference channel 55R is referred to as a reference region E2. The reference area E2 is an area for performing measurement for correcting data obtained from the measurement area E1 to which the protein Ta is attached.

  FIG. 9 shows a detailed configuration of the dispensing head 20.

  The dispensing head 20 includes 12 dispensing tubes 20A. Each dispensing tube 20A is held by a holding member 20B so as to be arranged in a line along an arrow Y direction orthogonal to the X direction. Two adjacent pipes 20A are used as a pair, one for supplying liquid and the other for discharging liquid. A pipette tip CP is attached to the tip of the dispensing tube 20A. The pipette tip CP is stocked in the pipette tip stocker 42P and can be exchanged as necessary.

  As shown in FIG. 2, the dispensing head 20 is provided in the upper part of the upper housing 12 and can be moved in the arrow X direction by the horizontal drive mechanism 22. The horizontal drive mechanism 22 includes a ball screw 22A, a motor 22B, and a guide rail 22C. The ball screw 22A and the guide rail 22C are arranged in the X direction. Two guide rails 22C are arranged in parallel, and one of them is arranged below the ball screw 22A at a predetermined interval. The dispensing head 20 is moved in the X direction along the guide rail 22C when the ball screw 22A is rotated by the rotational drive of the motor 22B. By this movement in the X direction, the dispensing head 20 causes the waste liquid plate 47, the cold insulation unit 46, the correction plate 45, the buffer supply unit 44B (buffer plate 44P), the measurement unit 30 (measurement chip 50), and the sample setting unit 40B (sample). The plate 40P) and the pipette tip set part 42B (pipette tip stocker 42P) can be moved to positions facing each other.

  As shown in FIG. 9, the dispensing head 20 is provided with a vertical drive mechanism 24 that moves the dispensing head 20 in the arrow Z direction. The vertical drive mechanism 24 includes a motor 24A and a drive shaft 24B disposed in the Z direction, and the drive shaft 24B is rotated by the rotational drive of the motor 24A, thereby moving the dispensing head 20 in the Z direction. By this movement in the Z direction, the dispensing head 20 has a pipette tip stocker 42P set in the pipette tip setting portion 42B, a sample plate 40P set in the sample setting portion 40B, a buffer plate 44P set in the buffer supply portion 44B, The correction plate 45, the plate set in the cold insulation unit 46, the measurement chip 50 set in the measurement unit 30, and the like can be accessed.

  As shown in FIG. 10, a suction / discharge drive unit 26 is connected to the dispensing head 20. The intake / exhaust drive unit 26 includes a first pump 27 and a second pump 28. The first pump 27 and the second pump 28 are provided corresponding to the pair of dispensing pipes 20A described above. The first pump 27 includes a syringe pump, and includes a first cylinder 27A, a first piston 27B, and a first motor 27C that drives the first piston 27B. The first cylinder 27A is connected to the dispensing head 20 via a pipe 27H. The second pump 28 is also a syringe pump, and includes a second cylinder 28A, a second piston 28B, and a second motor 28C that drives the second piston 28B. The second cylinder 28A is connected to the dispensing head 20 via a pipe 28H.

  The dispensing head 20 controls the rotational drive of the first motor 27C and the second motor 28C, and controls the drive of the first piston 27B and the second piston 28B. In addition, the speed of the solution when sucking and discharging is adjustable.

  On the other hand, as shown in FIG. 4, the measuring unit 30 includes an optical surface plate 32, a light emitting unit 34, and a light receiving unit 36. The optical surface plate 32 has an upper base 32A composed of a horizontal plane in the upper center as viewed from the side, an outgoing inclined portion 32B that decreases in a direction away from the upper base 32A, and an outgoing slope across the upper base 32A. A light receiving inclined portion 32C disposed on the side opposite to the portion 32B is formed. The measurement chip 50 is set on the upper base 32A along the Y direction. A light emitting portion 34 that emits the light beams L 1 and L 2 toward the measurement chip 50 is installed on the emission inclined portion 32 B of the optical surface plate 32. In addition, a light receiving portion 36 is installed in the light receiving inclined portion 32C. Next to the optical surface plate 32, a water cooling jacket 32J for cooling the optical surface plate 32 is provided.

  As shown in FIG. 11, the light emitting unit 34 includes a light source 34A and a lens unit 34B. Further, the light receiving unit 36 includes a lens unit 36A and a CCD 36B.

  A divergent light beam L is emitted from the light source 34A. The lens unit 34B has a built-in polarization beam splitter, which separates the P-polarized component and the S-polarized component of the light beam L incident from the light source 34A. The P-polarized component of the light beam L has a certain width with respect to the Z direction. Are divided into two relatively thick parallel light beams L1 and L2. The lens unit 34B then applies the two parallel light beams L1 and L2 at various incident angles that are greater than the total reflection angle with respect to the measurement region E1 and the reference region E2 at the interface between the thin film 57 and the dielectric block 52. Incident light is incident on the measurement region E1 and the reference region E2 so as to be in a convergent light state. Therefore, the light beams L1 and L2 incident on the measurement region E1 and the reference region E2 are totally reflected at various reflection angles at the interface between the dielectric block 52 and the thin film 57. The totally reflected light beams L1 and L2 are focused on the CCD 36B through the lens unit 36A. The CCD 36B is an area sensor having a light receiving surface having an area capable of receiving both of the totally reflected light beams L1 and L2, and generates and outputs image information indicating an image formed on the light receiving surface. .

  FIG. 12 shows the configuration of the electrical system of biosensor 10 according to the present embodiment.

  As shown in the figure, the biosensor 10 includes a CPU 70A, a ROM 70B, a RAM 70C, an HDD 70D, and the like. The biosensor 10 controls the operation of the entire apparatus, the rotational drive of the motor 22B and the motor 24A, and the first By controlling the rotational drive of the first motor 27C and the second motor 28C, the dispensing head 20 is moved in the X and Z directions, and the pipette tip CP attached to each dispensing tube 20A of the dispensing head 20 A dispensing head drive control unit 72 for controlling the suction and discharge of each type of analyte solution, buffer solution, and cleaning solution, and the rotation of a motor (not shown) that operates the holding arm 49A and rotates the ball screw 49B. As a result, the measurement chip conveyance control unit 74 that controls the operation of the measurement chip conveyance mechanism 49 and the imaging operation of the CCD 36B are controlled. A CCD controller 76 that controls the power supply to the light source 34A, a lighting controller 78 that controls the lighting of the light source 34A, and a terminal device such as a server connected to the network 90 and connected to the network 90. And a communication control unit 80 that communicates with 92.

  A dispensing head drive controller 72, a measurement chip transport controller 74, a CCD controller 76, a lighting controller 78, a display 14, an input unit 16, and a communication controller 80 are connected to the controller 70.

  Therefore, the control unit 70 controls the movement of the dispensing head 20 via the dispensing head drive control unit 72, the suction and discharge of the analyte solution, the buffer solution, and the cleaning solution to the pipette tip CP, and the measurement chip conveyance control. Control of the conveyance of the measurement chip 50 via the unit 74, control of the imaging operation of the CCD 36B via the CCD control unit 76, control of lighting of the light source 34A via the lighting control unit 78, and operation screen on the display 14 Control of display of various information such as various messages and control of transmission / reception of various information to / from the terminal device 92 via the communication control unit 80 can be performed. Further, the control unit 70 can grasp the operation content for the input unit 16.

  The control unit 70 performs predetermined processing based on the image information input via the CCD control unit 76, and derives refractive index change data in the measurement region E1 and the reference region E2.

The refractive index change data is obtained by individually supplying an analyte solution and a buffer solution to the measurement chip 50 and emitting the light beam L from the light emitting unit 34 to irradiate the measurement region E1 and the reference region E2 with the light beams L1 and L2. Then, it is obtained based on the angle difference between the reflection angle at which the dark line of the light beam L1 totally reflected in the measurement region E1 is generated and the reflection angle at which the dark line of the light beam L2 totally reflected in the reference region E2 is generated. is there. The light beams L1 and L2 incident on the interface between the thin film 57 and the dielectric block 52 at a specific incident angle excite surface plasmons on the interface, thereby reflecting the light beams L1 and L2 incident on the specific incident angle. The intensity of light sharply decreases and is observed as a dark line. The incident angles of the light beams L1 and L2, which are dark lines, are the total reflection attenuation angle θ _SP , and the total reflection attenuation angle θ _SP detected in the measurement region E1 and the reference region E2 when the buffer liquid is supplied to the measurement chip 50. and the angle difference, the difference between the angle difference of the attenuated total reflection angle theta _SP detected in the measurement region E1 and the reference region E2 of the case of supplying the analyte solution to the measurement chip 50 is the refractive index change data.

  Further, the biosensor 10 according to the present embodiment can designate a cleaning mode in which the protein Ta is washed with the washing solution when the protein Ta reacts with the analyte solution. When designating the cleaning mode, the user performs a predetermined operation for designating the cleaning mode on the input unit 16. Information indicating whether or not to execute the cleaning mode may be stored in the HDD 70D, and the cleaning mode may be executed based on the information.

  Further, the control unit 70 according to the present embodiment is configured to measure the processing status of the measurement process of the characteristics of the protein Ta, the number of pipette tips CP accommodated in the pipette tip stock portion 42, and the measurement accommodated in the measurement tip stock portion 48. The number of chips 50 and the remaining amount of consumables such as the remaining amount of buffer liquid stored in the bottle 44C are monitored at any time, indicating end information indicating the end of measurement, abnormal information indicating the occurrence of abnormality, and the progress of measurement. Control is performed to transmit to the terminal device 92 progress status information, scheduled end time information indicating a scheduled measurement end time, and request information for requesting replenishment of consumables. Note that, for example, the measurement operator sets the mail address of his / her mobile phone in the control unit 70 from the input unit 16, so that the control unit 70 registers end information, abnormality information, progress status information, Various types of information such as scheduled end time information may be transmitted.

  Next, the operation of the biosensor 10 according to the present embodiment will be described.

  When measuring the characteristics of the protein Ta, the control unit 70 performs a solution supply control process, which will be described later, and controls the dispensing head 20 via the dispensing head drive control unit 72 to measure the measurement chip as a measurement target. 50, a buffer solution of a predetermined concentration, various types of analyte solutions, and cleaning solutions are individually supplied from the dispensing head 20.

  When the buffer solution or the analyte solution is supplied to the measurement chip 50 to be measured, the control unit 70 controls the measurement chip conveyance mechanism 49 via the measurement chip conveyance control unit 74 and performs the measurement every predetermined measurement cycle. Then, the measurement chip 50 supplied with the buffer solution or the analyte solution is conveyed to the upper base 32A, and the measurement region E1 of the measurement channel 55A to be measured and the reference region E2 of the reference channel 55R are respectively light beams L1 and L2. It arrange | positions in the position which enters. Then, the control unit 70 controls the lighting control unit 78 to turn on the light source 34A, emits a light beam from the light emitting unit 34, and applies the light beams L1 and L2 to the measurement region E1 and the reference region E2, respectively. Irradiate. These light beams L1 and L2 are totally reflected by the measurement region E1 and the reference region E2, and are emitted to the outside through the prism surface of the dielectric block 52 while diverging. The light beams L1 and L2 emitted to the outside are focused on the light receiving surface of the CCD 36B through the lens unit 36A.

  The control unit 70 controls the imaging operation of the CCD 36B via the CCD control unit 76, causes the image formed on the light receiving surface of the CCD 36B to be captured, and outputs image information indicating the image from the CCD 36B. The output image information is input to the control unit 70 via the CCD control unit 76.

  When the image information is input, the control unit 70 performs a predetermined process based on the input image information, and derives refractive index change data in the measurement region E1 and the reference region E2.

  Next, FIG. 13 shows a flowchart showing the flow of the solution supply control process executed by the control unit 70 when measuring the characteristics of the protein Ta. Hereinafter, the solution supply control process will be described with reference to FIG.

  In step 100 in the figure, a buffer solution having a predetermined concentration is supplied from the dispensing head 20 to the measurement chip 50 to be measured. Further, the control unit 70 stores, for each measurement chip 50, the number of times of supply of the buffer solution and the number of times of supply of the analyte solution since the immediately preceding buffer solution is supplied in the HDD 70D. In this step 100, the value of the buffer supply frequency information indicating the supply frequency of the supply of the buffer solution of the measurement chip 50 to be measured is counted up, and the supply frequency of supplying the analyte solution after the previous buffer solution is supplied. Is initialized to zero.

  When the buffer solution is supplied to the measurement chip 50 to be measured, the control unit 70 conveys the measurement chip 50 to the upper base 32A and measures the measurement region E1 of the measurement channel 55A to be measured and the reference channel 55R. The reference area E2 is arranged at a position where the light beams L1 and L2 are incident, and the light source 34A is turned on to perform image capturing to acquire image information. Then, the control unit 70 identifies the reflection angle at which the dark line is generated in the measurement region E1 and the reference region E2 from the image indicated by the acquired image information, and the reflection angle at which the dark line is generated in the measurement region E1 and the dark line in the reference region E2. The angle difference between the reflection angles at which is generated is obtained.

  In the next step 102, it is determined whether or not the buffer liquid has been supplied to the measurement chip 50 to be measured a plurality of times based on the buffer supply count information stored in the HDD 70D. If the result of determination is negative, the process proceeds to step 104.

  In step 104, the threshold value N at which the analyte solution can be continuously supplied is set to a predetermined initial value (for example, 5). The initial value of the threshold value N is stored in advance in the ROM 70B or the HDD 70D.

  On the other hand, in step 106, the threshold N is set to a smaller value as the difference between the angle difference between the reflection angles obtained when the buffer solution is supplied last time and the angle difference between the reflection angles obtained when the buffer solution is supplied this time is larger. Change to

  Here, in this type of biosensor 10, the attachment state of the protein Ta is changed by flowing a solution through the liquid channel 55, and the film thickness of the protein Ta is decreased with time, and the refraction of the protein Ta. A phenomenon called drift may occur in which the reflection angle at which dark lines are generated changes as the rate changes over time.

  FIG. 14 shows an example of a change in reflection angle at which a dark line is generated when, for example, a buffer solution (reference solution) and an analyte solution (test solution) are alternately and individually supplied to the measurement channel 55A. Yes.

  As shown in the figure, a drift phenomenon occurs in which the reflection angle decreases with time due to the supply of the buffer solution or the analyte solution.

  When the change in the reflection angle due to the drift is small, the change in the attachment state of the protein Ta is small. Therefore, the refractive index change data is derived by supplying the buffer solution every time the analyte solution is supplied a plurality of times. The error of the refractive index change data is small.

  On the other hand, when the change in the reflection angle due to drift is large, an error in the refractive index change data increases if the buffer liquid is supplied and the refractive index change data is derived every time the nalite solution is supplied a plurality of times.

  For this reason, in this Embodiment, when the change of the angle difference of a reflection angle is large, the threshold value N is changed into the small value.

  In the next step 108, the analyte solution is supplied from the dispensing head 20 to the measuring chip 50 to be measured. In step 108, the value of the analyte supply frequency information indicating the supply frequency of supplying the analyte solution after the buffer solution of the measurement chip 50 to be measured is supplied is counted up.

  When the analyte solution is supplied to the measurement chip 50 to be measured, the control unit 70 obtains image information by performing the same control as described above in step 100, and obtains the reflection angle of the dark line generated. Find the angle difference. Then, the control unit 70 derives, as refractive index change data, the difference between the angle difference between the reflection angles when the immediately preceding buffer solution is supplied and the angle difference between the reflection angles when the analyte solution is supplied this time.

  In the next step 110, it is determined whether or not all types of analyte solutions to be measured are supplied to the measuring chip 50 to be measured. If the determination is affirmative, the solution supply control process is terminated. If a negative determination is made, the routine proceeds to step 112.

  In the next step 112, it is determined whether or not there is an interaction between the protein Ta and the analyte solution supplied in step 108 from the derived refractive index change data. If it is determined that there is an interaction, the process proceeds to step 114. If it is determined that there is no interaction, the process proceeds to step 120.

  Here, in the present embodiment, it is determined that there is an interaction when the difference in the angle difference of the reflection angles indicated by the refractive index change data is equal to or greater than a predetermined value. This predetermined value is determined as an appropriate value for the determination of the presence or absence of the interaction through experiments or the like.

  In step 114, it is determined whether or not the cleaning mode is designated. If the determination is affirmative, the process proceeds to step 116. If the determination is negative, the process proceeds to step 100 and the buffer solution is supplied. Later, the next type of analyte solution is supplied.

  In step 116, the cleaning solution is supplied from the dispensing head 20 to the measuring chip 50 to be measured, and after supplying the cleaning solution, the process proceeds to step 100 to supply the buffer solution, and then the supply of the next type of analyte solution. I do.

  On the other hand, in step 120, it is determined whether or not the number of times of supply of the analyte solution indicated by the analyte supply number information stored in the HDD 70D is equal to or less than the threshold value N. If the determination is affirmative, the process proceeds to step 108. Then, the next type of analyte solution is supplied. If the determination is negative, the process proceeds to step 100 to supply the buffer solution, and then the next type of analyte solution is supplied.

  As a result, when the number of times the analyte solution has been supplied since the immediately previous buffer solution is supplied is equal to or less than the threshold value N, the supply of the buffer solution is omitted, and the processing time can be shortened. Further, when the number of times the analyte solution has been supplied since the immediately preceding buffer solution is supplied is greater than the threshold value N, an increase in the refractive index change data error can be suppressed by supplying the buffer solution. it can.

  By the way, in this embodiment, as shown in FIGS. 5 to 8, six measurement channels each including a pair of measurement flow paths 55 </ b> A and reference flow paths 55 </ b> R are provided in one measurement chip 50. .

  For this reason, the control unit 70 according to the present embodiment independently controls the first pump 27 and the second pump 28 of the suction / exhaust drive unit 26 corresponding to each measurement channel, and the solution supply control process described above As shown in FIG. 15, the presence / absence of an interaction is determined for each measurement channel, and when it is not necessary to supply a washing solution or a buffer solution in the measurement channel, the measurement channel 55A and the reference flow of the measurement channel Supply of the solution to the path 55R is stopped. In FIG. 15, the period for supplying the solution is indicated by a solid line, and the stop period for stopping the supply of the solution is indicated by a broken line.

  As described above, according to the present embodiment, the presence or absence of interaction between the protein Ta and the supplied analyte solution is determined, and when it is determined that there is an interaction, the following is performed after the buffer solution is supplied. When it is determined that there is no interaction when a type of analyte solution is supplied, the next type of analyte solution is supplied without supplying a buffer solution, so that the screening processing time can be shortened.

  Note that the configuration of the biosensor 10 described in the present embodiment (see FIGS. 1 to 12) is merely an example, and it is needless to say that the configuration can be appropriately changed without departing from the gist of the present invention.

  Further, the process flow of the solution supply control process (see FIG. 13) described in the present embodiment is also an example, and it is needless to say that the process flow can be appropriately changed without departing from the gist of the present invention.

  In addition, in the present embodiment, a surface plasmon sensor that detects the reaction state of the analyte substance from the difference between the reflection angle difference when the buffer solution is supplied and the reflection angle difference when the analyte solution is supplied is provided. Although described as an example, the measuring apparatus for measuring the characteristics of the specimen substance is not limited to this.

It is a perspective view of the whole biosensor which concerns on embodiment. It is a perspective view inside the biosensor which concerns on embodiment. It is a top view inside the biosensor which concerns on embodiment. It is an internal side view of the biosensor which concerns on embodiment. It is a perspective view of the measurement chip concerning an embodiment. It is a disassembled perspective view of the measuring chip concerning an embodiment. It is a figure which shows the state in which the light beam is injecting into the measurement area | region and reference area of the measurement chip which concerns on embodiment. It is the figure which looked at the flow path member of the measurement chip concerning an embodiment from the lower side. It is a perspective view which shows the vertical drive mechanism of the dispensing head of the biosensor which concerns on embodiment. It is a schematic block diagram of the liquid suction / discharge part of the biosensor according to the embodiment. It is the schematic of the optical measurement part vicinity of the biosensor which concerns on embodiment. It is a block diagram which shows the structure of the electric system of the biosensor which concerns on embodiment. It is a flowchart which shows the flow of the solution supply control process which concerns on embodiment. It is a graph which shows an example in the state where the drift phenomenon occurred. It is the schematic diagram which showed typically the liquid feeding state for every measurement channel.

Explanation of symbols

10 Biosensor 20 Dispensing head (supplying means)
30 Measurement unit (acquisition means)
70 Control unit (control means)
70D HDD (storage means)
80 Communication control unit (communication means)
90 Network 92 Terminal device

Claims (6)

Supply means for individually supplying a plurality of types of test solutions used for measuring the characteristics of the sample substance and a predetermined reference solution serving as a measurement reference to the adhesion area of the sample substance to be measured;
Acquisition means for acquiring information indicating a reaction state of the specimen substance in a state where the plurality of types of test solutions and the reference solution are individually supplied by the supply means;
When each of the plurality of types of test solutions is sequentially supplied to the adhesion region for each type , any of the test solutions is supplied by the supply unit, and the acquisition unit is supplied with the test solution being supplied. And determining whether or not there is an interaction between the sample substance and the test solution based on the information indicating the reaction state acquired by the step, and supplying the reference solution to the attachment region when it is determined that there is an interaction. When the next type of test solution is supplied after the reference solution is supplied and it is determined that there is no interaction, the next type of test is not performed without supplying the reference solution to the adhesion region. Control means for controlling the supply means such that a solution is supplied;
Measuring device. The apparatus further comprises storage means for storing number-of-times information indicating the number of times the test solution has been supplied since the immediately preceding reference solution was supplied by the supply means,
Wherein when it is determined that no interaction, the following types to the attachment region when the supply number of the test solution indicated by the count information stored in the storage means is equal to or less than a predetermined threshold value The measuring device according to claim 1, wherein when the test solution is supplied and the number of times the test solution is supplied is greater than the threshold value, the supply means is controlled so that the reference solution is supplied to the adhesion region. . The control means obtains a change in the adhesion state of the specimen substance based on information indicating the reaction state respectively acquired by the acquisition means in a state where the reference solution is individually supplied a plurality of times by the supply means, The measurement apparatus according to claim 2, wherein the threshold value is changed to a smaller value as the change is larger. The supply means further individually supplies a cleaning solution for cleaning the specimen material;
The control unit controls the supply unit so that the cleaning solution is supplied before the reference solution is supplied to the adhesion region when it is determined that there is an interaction. The measurement apparatus according to any one of the above. A plurality of the specimen substance adhering regions are provided so that each can supply a solution individually,
A plurality of the supply means are provided, and supply each of the plurality of types of test solutions and the reference solution individually to each adhesion region,
The acquisition means acquires information indicating the reaction state for each adhesion region,
The control means independently controls the supply means corresponding to each adhesion area based on information indicating the reaction state acquired by the acquisition means for each adhesion area. 5. The measuring apparatus according to any one of 4 above. A communication means connected to the network and performing communication through the network;
The control means includes end information indicating the end of measurement, abnormality information indicating occurrence of abnormality, progress status information indicating the progress status of measurement, scheduled end time information indicating a scheduled measurement end time, and replenishment of consumables provided in the apparatus The measurement apparatus according to any one of claims 1 to 5, wherein control is performed to transmit at least one of request information for requesting to a preset information transmission destination via the communication unit.

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