JP4986908B2 - measuring device - Google Patents

Description

  The present invention relates to a measuring apparatus, and in particular, measures characteristics of a specimen material by supplying various solutions to the specimen material to be measured and detecting a reaction state between the specimen material and each solution. It relates to a measuring device.

  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, the applicant of the present application disclosed in Patent Document 1 that a liquid flow path is formed so that a liquid can flow and an attachment region in which a sample substance to be measured is attached to a wall surface in the liquid flow path. Screening that identifies the test solution that reacts with the sample substance by sequentially supplying a plurality of types of test solutions to the liquid flow path of the chip and detecting the reaction state of the sample substance and the test solution A measuring device is disclosed.

  By the way, in the screening, various types of test solutions are prepared at a plurality of concentrations in order to search for test solutions that react with the specimen substance.

  However, when there are many types of test solutions and test solutions with many concentrations are prepared, it is troublesome to separate each test solution manually.

  For this reason, in the case where a plurality of types of test solutions are prepared at a plurality of concentrations, generally, each of the plates (for example, titer plates) provided with a plurality of storage portions (so-called wells) for storing the solutions individually is provided. By creating a master plate that individually stores multiple types of test solutions in the storage section, and dispensing each type of test solution from the master plate to each storage section of different plates using a dispensing device, Each test solution having a different concentration is prepared.

  For example, when 10 kinds of solutions (concentration 1 to 10) are prepared for each test solution using a 384 well plate, as shown in FIG. 15, 10 plates (40P-1 to 40P) are prepared. -10) is prepared, and each test solution having a concentration of 1 to 10 is prepared by dispensing the solution from the master plate to each plate using a dispensing device.

In the measurement apparatus described above, a plurality of plates in which a plurality of types of test solutions are individually stored for each concentration are set in this manner, and a plurality of types of test solutions stored in the storage section of each plate are stored in the measurement chip. Screening is performed by sequentially supplying the liquid channel and detecting the reaction state between the sample substance and the test solution.
JP 2007-198768 A

  By the way, since the state of the sample substance adhering to the adhesion region in the liquid channel changes as the number of times the test solution is supplied to the measurement chip, the number of times that the test solution can be supplied is limited. For this reason, in the measurement apparatus described above, when the supply frequency reaches a predetermined limit number (hereinafter also referred to as “reuse frequency”), the measurement chip is replaced and the screening is continued.

  However, when screening is performed by sequentially supplying the test solution stored in each reservoir of each plate to the liquid flow path of the measurement chip in the plate order, the number of times of supply becomes the number of reuses and the measurement chip is replaced. Thus, even in the same type of test solution, if the concentration is different, the reaction state may be detected by a different measurement chip.

  For example, due to the number of times of reuse, four types of test objects (concentration 1 to concentration 10) stored in 10 plates of 384 well shown in FIG. 15 are used by four measurement chips (50-1 to 50-4). When the screening is performed by sequentially supplying the test solution to the liquid flow path of the measuring chip in the order of the plate, as shown in FIG. 18, the middle of the plate of concentration 3, between the plates of concentration 5 and 6, and the concentration In the middle of the eight plates, the measurement chips are respectively exchanged, and the measurement chips used in the ten plates are separated and detected. In FIG. 18, wells for supplying an analyte solution to four measurement chips 50 (50-1 to 50-4) in 10 plates are provided, and the regions are shown by changing the type of shading. Yes.

  However, this measurement chip has a difference in the adhesion state of the sample substance for each measurement chip. For this reason, in this type of measuring apparatus, when the reaction state of a test solution having a different concentration is detected with a different measurement chip even with the same type of test solution, the accuracy of data indicating the reaction state obtained by the detection is low. There was a problem.

  The present invention has been made to solve the above problems, and improves the accuracy of data indicating the reaction state when screening is performed to detect the reaction state with the sample substance by changing the concentration of the test solution. An object of the present invention is to provide a measuring apparatus that can perform the above-described measurement.

In order to achieve the above object, the invention according to claim 1 stores a plurality of measurement chips each attached with a sample substance to be measured, and a test solution used for measuring characteristics of the sample substance individually. In addition, a plurality of plates each having a plurality of storage portions each individually addressed, and the plurality of storage portions in the same plate store the test solutions having the same concentration and different types. In addition, in the storage section having the same address in a plurality of plates, the plurality of plates in which the test solutions of the same type and different concentrations are stored, and each storage of the plates for each of the plates in correspondence with the part of the address, storage means for the type and the information indicating the concentration of each of the test solution stored in each storage part of each plate is stored in advance as a sample solution information, the plurality of play It said supply means for supplying to one of the storage portion of the plurality of measuring chips separately each test solution of each concentration that is stored separately in, reads the test solution information stored in the storage means, the same Control means for controlling the supply means so as to supply the test solution of each concentration of each kind to the same measurement chip.

The invention of claim 1, wherein is deposited analyte substance to each measurement into a plurality of measurement chips, each storing the test solution used to measure the characteristics of individual said sample substance, and is individually addressed Due to the plurality of plates having a plurality of defined reservoirs , the plurality of reservoirs in the same plate store the test solutions having the same concentration and different types, and the same in the plurality of plates In the storage section of the address, the test solutions of the same type and different concentrations are stored , and by the storage means, for each plate, corresponding to the address of each storage section of the plate, wherein stored in the storage portion of the plate information indicating each type and concentration of the test solution is stored in advance as the test solution information, by supply means, it is stored separately in the storage unit of the plurality of plates Each test solution of each concentration is assumed to be supplied to one of said plurality of measuring chips separately.

In the present invention, the control unit reads out the test solution information stored in the storage unit, and the supply unit controls the test solution of the same type with each concentration to be supplied to the same measurement chip. Is done.

  As described above, according to the first aspect of the present invention, a plurality of types of test solutions having a plurality of types and a plurality of concentrations stored individually in each storage section across a plurality of plates are subjected to a plurality of measurements in which specimen substances are attached. When supplying to the chip, control is performed so that the same type of test solution of each concentration is supplied to the same measurement chip, so screening that detects the reaction state with the sample substance by changing the concentration of the test solution It is possible to improve the accuracy of the data indicating the reaction state when performing.

  In the present invention, as in the invention described in claim 2, it is preferable that the control means controls the supply means so as to supply the test solution of the same type with each concentration in ascending order.

  In the present invention, as in the invention described in claim 3, the plurality of types of test solutions may be stored in separate plates for each concentration.

  Further, according to the present invention, as in the fourth aspect of the invention, in the state where the test solution is supplied from the supply means to the measurement chip, the total reflection is performed on the specimen substance adhesion region of the measurement chip. The apparatus may further comprise detection means for detecting a reaction state between the specimen substance and the test solution based on a light intensity distribution of the light beam that is incident at a plurality of angles and totally reflected in the adhesion region.

  According to a fourth aspect of the present invention, as in the fifth aspect of the present invention, the number of times that the measurement chip can supply the test solution is limited to a predetermined limit number, and the detection means Transport means for individually transporting the measurement chip to a position where the reaction state can be detected, and the control means supplies each of the following types from the supply means to the measurement chip at the detectable position: If the number of times of supply of the test solution of the measurement chip when the test solution having a concentration is supplied is larger than the limit number of times, the transport unit may be controlled to replace the measurement chip.

  As described above, according to the present invention, a plurality of types and a plurality of concentrations of test solutions individually stored in each storage section across a plurality of plates are supplied to a plurality of measurement chips to which the sample substance is attached. In this case, since the control is performed so that the same type of test solution of each concentration is supplied to the same measurement chip, screening was performed to detect the reaction state with the sample substance by changing the concentration of the test solution. The effect that the precision of the data which show the reaction state in the case can be improved is acquired.

  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. As shown in FIG. 5, the sample stacking section 40 </ b> A according to the present embodiment is capable of accommodating a total of 12 sample plates 40 </ b> P in two rows. Numbers are assigned in order from 1 to each accommodating portion that accommodates the sample plate 40P of the sample stacking portion 40A. In FIG. 5, numbers assigned by numbers in parentheses are shown.

  In the sample setting section 40B (see FIG. 3), one sample plate 40P is transported and set from the sample stacking section 40A by a transport mechanism (not shown). This sample plate 40P is provided with a plurality of wells for storing solutions individually in a two-dimensional form. In this embodiment, as shown in FIG. 6, a plate of 384 wells (16 rows × 24 columns) is used. ing. In the sample plate 40P, alphabets A to P are assigned to each row, and numbers 1 to 24 are assigned to each column. In the sample plate 40P, each well can be specified by specifying a row and a column by a combination of assigned alphabet and number, and the combination of this alphabet and number is an address of each well.

  On the other hand, the pipette tip stock portion 42 (see FIG. 3) 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. 7 and 8, 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. 8, 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. 9, two substantially S-shaped channel grooves 54 </ b> C are formed on the bottom surface side of the base portion 54 </ b> A. 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. The measurement chip 50 according to the present embodiment is thus provided with six measurement channels including the pair of measurement flow paths 55A and the reference flow path 55R.

  As shown in FIG. 9, light beams L1 and L2 are incident on the measurement channel 55A and the reference channel 55R, respectively. As shown in FIG. 10, the light beams L1 and L2 are applied to an S-shaped bent portion arranged 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. 11 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. 11, 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.

  Furthermore, the dispensing head 20 is provided with a dispensing tube lowering mechanism (not shown) that moves six dispensing tubes 20A for supplying liquid out of the 12 dispensing tubes 20A by a predetermined distance in the vertical direction. . The dispensing head 20 can lower the six dispensing tubes 20A for supplying liquid by a predetermined distance in the vertical direction by the dispensing tube lowering mechanism.

  When the dispensing head 20 aspirates the solution from the sample plate 40P, the buffer plate 44P, the correction plate 45, the plate set in the cold insulation section 46, etc., the six dispensing pipes for supplying liquid by the dispensing pipe lowering mechanism. The pipe 20A is lowered, and only the pipette tip CP attached to the six dispensing pipes 20A for supplying liquid is accessed to suck the solution. In addition, when supplying the sucked solution to the measuring chip 50 or discharging it to the waste liquid plate 47, the dispensing head 20 raises the six dispensing tubes 20A for supplying liquid by the dispensing tube lowering mechanism to 12 Only the pipette tips CP attached to the twelve pipes 20A are accessed with the pipes 20A having the same height.

  As shown in FIG. 12, 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 light beams L 1 and L 2 to 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.

  FIG. 13 shows a schematic configuration of the light emitting unit 34 and the light receiving unit 36. Note that FIG. 13 shows the configuration of only the portion that emits the light beams L1 and L2 to one measurement channel of the measurement chip 50, but the light beam L1 is simultaneously applied to the six measurement channels of the measurement chip 50. , Six light emitting portions 34 and six light receiving portions 36 are provided in parallel so as to be able to emit L2 and receive reflected light.

  As shown in the figure, the light emitting section 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. 14 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 By controlling the dispensing head drive control unit 72 that controls the suction and discharge of each type of analyte solution and buffer solution, and the rotation of a motor (not shown) that operates the holding arm 49A and rotates the ball screw 49B. , Controlling the operation of the measurement chip transport control unit 73 for controlling the operation of the measurement chip transport mechanism 49 and the transport mechanism (not shown) Thus, by controlling the operation of the plate transport control unit 74 that controls the transport of each sample plate 40P stored in the sample stacking unit 40A to the sample setting unit 40B and the transport mechanism (not shown), the pipette chip stacking unit 42A is controlled. The stocker transport control unit 75 that controls the transport of each pipette chip stocker 42P accommodated in the pipette chip set unit 42B, the CCD control unit 76 that controls the imaging operation of the CCD 36B, and the power supply to the light source 34A. Thus, a lighting control unit 78 that controls lighting of the light source 34A and a communication control unit 80 that is connected to the network 90 and communicates with a terminal device 92 such as a server connected to the network 90 are provided.

  The control unit 70 includes a dispensing head drive control unit 72, a measurement chip transfer control unit 73, a plate transfer control unit 74, a stocker transfer control unit 75, a CCD control unit 76, a lighting control unit 78, a display 14, an input unit 16, And the communication control part 80 is connected.

  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 conveyance of the measurement chip 50 via the unit 73, control of conveyance of the sample plate 40P via the plate conveyance control unit 74, control of conveyance of the pipette chip stocker 42P via the stocker conveyance control unit 75, and CCD Control of the imaging operation of the CCD 36B via the control unit 76, control of lighting of the light source 34A via the lighting control unit 78, control of display of various information such as operation screens and various messages on the display 14, and communication control Control of transmission and reception of various types of information with the terminal device 92 can be performed via the unit 80. 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 supplied to the measurement chip 50 by separately supplying an analyte solution and a buffer solution, and the light beam L is emitted from the light emitting unit 34, and the light beam L1 is supplied to the measurement region E1 and the reference region E2 of each measurement channel. , L2 and 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. This is required for each measurement channel. 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.

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

  When performing screening to measure the characteristics of protein Ta, the user creates a master plate in which different types of analyte solutions containing various samples are individually stored in each well of the sample plate 40P as a test solution. Then, each type of analyte solution is dispensed from the master plate to each well of the different sample plate 40P using a dispensing device, and each analyte solution having a different concentration is prepared. For example, when a 384 well sample plate 40P is used as in the present embodiment, a master plate in which 384 types of analyte solutions are individually stored in each well of the sample plate 40P is prepared. Dispensing into 10 sample plates 40P using a dispensing device, as shown in FIG. 15, a plurality of types of concentrations 1 to 10 are provided on 10 sample plates 40P (40P-1 to 40P-10). Prepare an analyte solution.

  In each sample plate 40P dispensed in this way, the same type of analyte solution is stored at different concentrations in wells of the same address.

  The user sets each sample plate 40P prepared in this way in the sample stacking portion 40A.

  In addition, the user prepares a plurality of measurement chips 50 to which the protein Ta to be measured is attached on the thin film 57 of each measurement channel 55A, and stores the prepared plurality of measurement chips 50 in the measurement chip storage plate 48P. And set in the measurement chip stock section 48.

  The user corresponds to the number of times the measuring chip 50 is reused from the input unit 16 and the address of each well of the sample plate 40P for each sample plate 40P, and each well of each sample plate 40P set in the sample stacking unit 40A. The type of the analyte solution stored in the column and the concentration of the analyte solution are registered as test solution information. The number of reuses and the test solution information may be registered from a terminal device 92 such as a server connected via the network 90.

  The control unit 70 stores the registered number of reuses and test solution information in the HDD 70D.

  When instructing the start of screening, the user performs a predetermined instruction operation on the input unit 16.

  In addition, the biosensor 10 according to the present embodiment can select the accuracy priority mode or the speed priority mode as the measurement mode when performing screening. When instructing the start of screening, the user selects either the accuracy priority mode or the speed priority mode as the measurement mode.

  When a predetermined instruction operation for instructing the start of screening is performed, the control unit 70 performs a supply order determination process described later, and determines each measurement chip 50 based on the number of reuses and the test solution information stored in the HDD 70D. In addition, the supply order of the analyte solution from each sample plate 40P to the measurement chip 50 is determined, and supply order information indicating the determined supply order is generated.

  Thereafter, the control unit 70 controls the measurement chip transport mechanism 49 via the measurement chip transport control unit 73 according to the supply order indicated by the supply order information, and transports the measurement chip 50 to be measured to the upper base 32A. Thus, the measurement chip 50 is disposed at a measurement position where the light beams L1 and L2 are incident on the measurement region E1 of the measurement channel 55A of each measurement channel and the reference region E2 of the reference channel 55R. The control unit 70 controls the conveyance of the sample plate 40P via the plate conveyance control unit 74 according to the supply sequence indicated by the supply sequence information, and controls the dispensing head 20 via the dispensing head drive control unit 72. Control is performed from the dispensing head 20 to the measurement flow channel 55A and the reference flow channel 55R of each measurement channel of the measurement chip 50 to be measured in the determined supply order. Supply light solution and cleaning solution separately.

  When the buffer solution or the analyte solution is supplied to the measurement chip 50 to be measured, the control unit 70 controls the lighting control unit 78 to turn on the light source 34A and emit the light beam from the light emitting unit 34. Each of the measurement region E1 and the reference region E2 of each measurement channel is irradiated with the light beams L1 and L2. 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 predetermined processing based on the input image information, and derives refractive index change data in the measurement region E1 and the reference region E2 for each measurement channel.

  Next, FIG. 16 shows a flowchart showing a flow of supply order determination processing executed by the control unit 70 when a predetermined instruction operation for instructing the start of screening is performed. Hereinafter, the supply order determination process will be described with reference to FIG.

  In step 100 in the figure, the number of reuses and the test solution information stored in the HDD 70D are read out.

  In the next step 102, there is an analyte solution having the same type and different concentration in each analyte solution stored in each well of each sample plate 40P set in the sample stacking portion 40A based on the test solution information. If the determination is affirmative, the process proceeds to step 106. If the determination is negative, the process proceeds to step 104.

  In step 104, since the types of the analyte solutions stored in the wells of the sample plates 40P set in the sample stacking unit 40A are all different, the sample plates 40P set in the sample stacking unit 40A are used as the sample stacking unit 40A. The sample solution is conveyed to the sample setting unit 40B in the order of the number of the storage units, and the analyte solution is supplied to each measurement chip 50 in the address order of each well of the sample plate 40P until the number of times of supply of the analyte solution reaches the number of reuses. Determine the supply sequence of the analyte solution. In this embodiment, since a 384 well plate is used as the sample plate 40P, for example, as indicated by the arrows in FIG. 17, one well in the column direction for each column in the column order. The supply order of the analyte solution is determined on the assumption that the analyte solution is supplied four times at different positions. As described above, when the solution is sucked from the sample plate 40P, the six dispensing tubes 20A for liquid supply are lowered by the dispensing tube lowering mechanism. For this reason, in FIG. 17, one pipette tip CP out of the pair of pipette tips CP corresponding to each measurement channel is shown.

  For example, when the number of times of reuse of the measurement chip 50 is 160, since there are six measurement channels in one measurement chip 50, the analyte solution can be measured 960 times with one measurement chip 50. Therefore, in the case of the 384-well sample plate 40P, 2.5 (= 960/384) sample plates 40P can be measured per one measurement chip 50. For example, each sample plate 40P includes 10 384-well sample plates 40P. When different types of analyte solutions are stored, measurement is performed with the four measurement chips 50. In FIG. 18, in this case, in each of the ten sample plates 40P, wells for supplying the analyte solution to the four measurement chips 50 (50-1 to 50-4) are provided, and the areas are shaded. Shown changed.

  On the other hand, in step 106, the analyte solutions having the same type and different concentrations are grouped from the analyte solutions stored in each well of each sample plate 40P set in the sample stacking section 40A. FIG. 19 schematically shows the result of grouping.

  In the next step 108, the number of times the analyte solution is supplied is counted for each compound group grouped in step 106. In this step 108, the number of times of supply of the analyte solution for each compound group is added in order. If the number of times of supply of the addition result is equal to or less than the number of reuse, the analyte solution of the compound group to which the number of times of supply is added immediately before When the supply frequency of the addition result exceeds the reuse count, the analyte solution of the compound group to which the supply count has been added immediately before is supplied to the next measurement chip 50. The measurement chip 50 is assigned to. FIG. 19 shows a result of assigning four measurement chips 50 (50-1 to 50-4) to each compound group. Thereby, a compound group comes to be supplied to the same measurement chip 50.

  For example, when the measurement chip 50 is reused 160 times, the analyte solution can be measured 960 times with one measurement chip 50 as described above. Thus, for example, as shown in FIG. 15, when multiple types of analyte solutions having concentrations 1 to 10 are prepared on 10 sample plates 40P (40P-1 to 40P-10), one type of analyte is prepared. In order to measure 10 concentrations per solution, 96 (= 960/10) kinds of analyte solutions are measured with one measuring chip 50, and 384 kinds of analyte solutions are measured with four measuring chips 50. become. Further, as described above, ten sample plates 40P as shown in FIG. 15 have the same type of analyte solution stored in different concentrations in wells of the same address. Therefore, each sample plate 40P is measured with 1/4 (= 96/386) different measurement chips 50. In FIG. 20, in this case, the wells for supplying the analyte solution to the four measurement chips 50 in the ten sample plates 40P are provided, and the regions are shown in different shaded types.

  In the next step 110, it is determined whether or not the speed priority mode is designated as the measurement mode. If the determination is affirmative, the process proceeds to step 112. If the determination is negative, the process proceeds to step 114.

  In step 112, for each measurement chip 50, the sample plate 40P set in the sample stacking section 40A is transported to the sample setting section 40B in the order of the accommodating part of the sample stacking section 40A, and each compound group assigned to the measurement chip 50 is transferred. The analyte solution supply order is determined so that the analyte solution of each compound group is supplied to the same measurement channel in the order of addresses of each well of the sample plate 40P.

  Therefore, in this speed priority mode, when all the analyte solutions in each well in the shaded area corresponding to the measurement chip 50 of the sample plate 40P shown in FIG. 20 are supplied to the measurement chip 50, the sample plate 40P is replaced, When the supply of the analyte solution in all the sample plates 40P is completed, the measurement chip 50 is replaced. Thereby, since the frequency | count of replacement | exchange of the sample plate 40P can be reduced, the measurement time required for a screening can be shortened.

  On the other hand, in step 114, the supply order of the analyte solution is determined for each measurement chip 50 so that the analyte solution is supplied to the same measurement channel in descending order of the concentration of the analyte solution of each compound group assigned to the same measurement chip 50. .

  Therefore, in this accuracy priority mode, for each compound group, the sample plate 40P set in the sample stacking portion 40A is transported to the sample setting portion 40B in order of decreasing concentration, and each time the analyte solution is supplied, the sample plate When 40P is exchanged and supply of the analyte solution of all the compound groups assigned to the measurement chip 50 is completed, the measurement chip 50 is exchanged. Thereby, since the concentration change of the analyte solution in the measurement chip 50 can be suppressed, the measurement accuracy is further improved.

  As described above, according to the present embodiment, a plurality of types of analyte solutions individually stored in each well across a plurality of sample plates 40P are applied to a plurality of protein solutions to which protein Ta is attached. When supplying to the measuring chip 50, the control is performed so that the same type of each concentration of the analyte solution is supplied to the same measuring chip 50. Therefore, the concentration of the analyte solution is changed to change the reaction state with the protein Ta. The accuracy of the data indicating the reaction state when screening for detection is performed can be improved.

  In addition, according to the present embodiment, when detecting the reaction state by supplying the same type of analyte solution of each concentration to the measurement chip 50, the detection region for detecting the reaction state without the measurement chip 50 being replaced. Therefore, the accuracy of the data indicating the reaction state can be improved.

  Note that the biosensor 10 described in the present embodiment further supplies an individual cleaning solution for cleaning the specimen substance to the measurement chip 50 when a highly concentrated compound is measured in order to perform a more accurate measurement. As a matter of course, a mechanism for changing the liquid feeding pattern such as increasing the cleaning time / increasing the number of times of cleaning may be provided.

  In the biosensor 10 described in the present embodiment, a plurality of measurement channels are provided in the measurement chip 50 and a plurality of measurement channels are measured simultaneously. However, the present invention is not limited to this.

  Moreover, although the biosensor 10 described in the present embodiment has been described for the case where each type of analyte solution is stored in a separate sample plate 40P for each concentration, the present invention is not limited to this. For example, each type of analyte solution having a plurality of concentrations may be stored in one sample plate 40P. Further, each type of analyte solution having a certain concentration may be stored across a plurality of sample plates 40P. Furthermore, each type of analyte solution of each concentration may be stored across a plurality of sample plates 40P.

  Furthermore, the configuration of the biosensor 10 described in the present embodiment (see FIGS. 1 to 14) 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 flow of the solution supply control process (see FIG. 16) 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 the front view which expanded and showed the sample lamination | stacking part which concerns on embodiment. It is a perspective view of the sample plate 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 figure which shows the state which prepared the multiple types of analyte solution of the density | concentration 1-the density | concentration 10 on ten sample plates. It is a flowchart which shows the flow of the solution supply control process which concerns on embodiment. It is a schematic diagram which shows the supply order of the analyte solution stored by the sample plate which concerns on embodiment. It is a schematic diagram which shows the area | region where the well of the sample plate which supplies an analyte solution to each measurement chip | tip is provided. It is a schematic diagram which shows the result of having allocated each compound group which concerns on embodiment to a measurement chip | tip. It is a schematic diagram which shows the area | region where the well of the sample plate which supplies an analyte solution to each measuring chip which concerns on embodiment is provided.

Explanation of symbols

10 Biosensor 20 Dispensing head (supplying means)
30 Measurement unit (detection means)
40P Each sample plate (plate)
49 Measuring chip transport mechanism (transport means)
50 Measuring chip 70 Control unit (control means)

Claims (5)

A plurality of measuring chips each having a specimen substance to be measured attached thereto;
Each test solution were pooled for use in the measurement of the characteristics of individual said sample substance, and a plurality of plates that individually having a plurality of reservoir the address is determined, a plurality of the reservoir within the same plate The test solutions of the same concentration and different types are stored, and the test solutions of the same type and different concentrations are stored in the storage section at the same address in a plurality of plates. And multiple plates,
For each plate, information indicating the type and concentration of the test solution stored in each storage section of each plate is stored in advance as test solution information in association with the address of each storage section of the plate. Storage means,
A supply means for individually supplying each test solution of each concentration stored in the storage section of the plurality of plates to any of the plurality of measurement chips;
Control means for reading the test solution information stored in the storage means and controlling the supply means so as to supply the test solution of each concentration of the same type to the same measurement chip;
Measuring device. The measurement apparatus according to claim 1, wherein the control unit controls the supply unit to supply the test solution having the same type of each concentration in ascending order of concentration. The measuring apparatus according to claim 1, wherein the plurality of types of test solutions are stored in different plates for each concentration.   In a state where the test solution is supplied to the measurement chip from the supply means, a light beam is incident at a plurality of angles so as to be totally reflected at the specimen substance adhesion region of the measurement chip, and is totally reflected at the adhesion region. The measuring apparatus according to claim 1, further comprising a detecting unit that detects a reaction state between the specimen substance and the test solution based on a light intensity distribution of the light beam. The measurement chip is limited to a predetermined limit number of times that the test solution can be supplied,
Transport means for individually transporting the measurement chip to a position where the reaction state can be detected by the detection means;
The control means supplies the test solution of the measurement chip when the test solution having the following concentrations is supplied from the supply means to the measurement chip at the detectable position. The measuring apparatus according to claim 4, wherein when the number of times is greater than the limit number, the transport unit is controlled to replace the measuring chip.