Optical measurement device

Abstract

Provided is an optical measurement device including a reaction chamber and a measurement chamber. The reaction chamber: comprises a reaction chamber placement part on which an array plate is placed, and a liquid supply part that supplies a liquid specimen or a prescribed chemical solution to the array plate; and generates a reaction product on the array plate. The measurement chamber comprises: a measurement chamber placement part on which the array plate holding the reaction product thereon is placed; and an optical measurement part that optically measures the reaction product on the array plate. The optical measurement device further includes: an inter-chamber conveyance part that conveys the array plate between the reaction chamber and the measurement chamber; and a partition member that has a passage port allowing the array plate conveyed by the inter-chamber conveyance part to pass therethrough, and that partitions off the reaction chamber and the measurement chamber.

Description

optical measurement device

[0001] The present invention relates to an optical measurement device that performs a reaction step and a measurement step on an array plate.

[0002] Array plates such as protein arrays, peptide arrays, and DNA arrays are known, which have spot areas on a substrate where numerous spots of substances such as proteins, peptides, and nucleic acids are fixed in an array. Using such array plates, interactions between numerous fixed substances and substances in a specimen can be observed simultaneously. This allows comprehensive analysis of interactions between numerous substances and biologically derived liquid specimens such as blood, cell extracts, saliva, and interstitial fluid.

[0003] A known measurement method using an array plate involves selectively fluorescently labeling spots where an interaction of interest has occurred to obtain optical information. A confocal laser microscope is known as a device for observing fluorescently labeled spots. The confocal laser microscope has an illumination optical system, a fluorescence detection optical system, and a two-dimensional scanning system. The fluorescence detection optical system has the function of detecting the amount of fluorescence from spots labeled with fluorescent probes. The two-dimensional scanning system has the function of acquiring a fluorescent image of the spot area on the array plate by two-dimensionally scanning the array plate or the optical system.

[0004] Patent Document 1 discloses an inspection technology that performs a reaction process including labeling a closed cell called a flow cell that holds a liquid reagent and a plate, and a measurement process that optically acquires the labeled pattern. Patent Document 1 also discloses a loading technology that parallelizes the reaction process for the flow cell and sequentially transports the flow cells that have completed the reaction process to an optical measurement area where the measurement process is performed.

[0005] Special Publication No. 2011-501965

[0006] In the inspection technology described in Patent Document 1, part of the measurement light irradiated onto the plate in the measurement process leaves the measurement chamber, is reflected by a component outside the measurement chamber, and returns to the measurement chamber, which may lead to measurement errors in the optical measurement. Furthermore, when the reaction processes of multiple plates are performed in parallel and the reaction processes and measurement processes are performed in series, if part of the measurement light emitted from the measurement chamber hits a plate waiting in the reaction chamber before the measurement process, the waiting plate may be deteriorated.

[0007] The optical measurement device of the present invention is characterized in that it comprises: a reaction chamber mounting section on which an array plate is mounted, the array plate having a plurality of substances fixed in an array on one surface and a storage section for storing a liquid sample or a predetermined chemical solution; a liquid supply section that supplies the liquid sample or the predetermined chemical solution to the storage section, and in which a reaction product is produced on the array plate by a reaction between the liquid sample or the predetermined chemical solution and the plurality of substances; a measurement chamber mounting section on which the array plate holding the reaction product is mounted; and an optical measurement section that optically measures the reaction product on the array plate mounted on the measurement chamber mounting section through the array plate from the other surface opposite to the one surface of the array plate, and in which the reaction product is optically measured; an inter-chamber transport section that transports the array plate between the reaction chamber and the measurement chamber; and a partition member that has a passage through which the array plate held in the inter-chamber transport section can pass, and that separates the reaction chamber from the measurement chamber.

[0008] According to the present invention, by reducing the amount of measurement light that leaks out of the measurement chamber and then returns to the measurement chamber, it is possible to reduce errors in optical measurement. Furthermore, by reducing the amount of light that leaks out of the measurement chamber, it is possible to reduce deterioration of the array plate during standby.

[0009] 1A and 1B, it constitutes a two-sided diagram showing an example of the structure of the optical measurement device of the present invention, and is a top view of the inside of the device. In combination with FIG. 1A, it constitutes a two-sided diagram showing an example of the structure of the optical measurement device of the present invention, and is a side view (bottom view in FIG. 1A) of a cross section cut along line 1B-1B in FIG. 1A. It is a schematic view of the structure of a framed array plate suitably used in the optical measurement device shown in FIGS. 1A and 1B, seen from above. It is a schematic view of a cross section cut along line 2B-2B in FIG. 1A, seen from the side (bottom view in FIG. 1A) to show the positional relationship between the array plate and the pipette tip placed on the reaction chamber mounting section. In combination with FIG. 3B, it constitutes a two-sided diagram showing the relationship between the position of the transport arm and the position of the passage opening provided in the partition member during optical measurement (after transporting the array plate) of the optical measurement device shown in FIGS. 1A and 1B, and is a top view of the inside of the device, seen from above. 3A, which constitutes a two-sided diagram that, in combination with Fig. 3A, schematically shows the relationship between the position of the transport arm and the position of the passage opening provided in the partition member during optical measurement (after transporting the array plate) of the optical measurement device shown in Fig. 1A and Fig. 1B, and is a side view (from the side in Fig. 3A) of a cross section cut along line 3B-3B in Fig. 3A. Fig. 3B is a perspective view that schematically shows an opening closing member provided in the partition member of the optical measurement device shown in Fig. 1A and Fig. 1B.

[0010] An embodiment of an optical measurement device according to the present invention will be described with reference to FIGS. 1A, 1B, 2A, 2B, 3A, 3B, and 4. FIG. 1A is a plan view schematically showing the interior of the housing (enclosure) of an optical measurement device 1000 of this embodiment, viewed vertically downward from above. FIG. 1B is a vertical cross-sectional view schematically showing the interior of the device, cut along line 1B-1B in FIG. 1A (as shown by the arrow, viewed from below in FIG. 1A). However, the reaction chamber transport unit 7 and the linear drive mechanism are shown in external appearance from the near side, rather than in cross section.

[0011] 1A and 1B includes a reaction chamber 200 in which a predetermined reaction is carried out using a plurality of array plates 2, and a measurement chamber 300 in which the amount of reaction product produced by the reaction is optically measured. The reaction chamber 200 and the measurement chamber 300 are housed inside a housing (enclosure) and are separated from each other by a partition member 40. The housing portion that houses the reaction chamber will be referred to as the reaction chamber housing 220, and the housing portion that houses the measurement chamber will be referred to as the measurement chamber housing 320. The reaction chamber 200 and the measurement chamber 300 are built on a common base portion 100.

[0012] Generally, the array plate 2 has an array region on one surface of a rectangular flat glass slide, where a plurality of substances are individually fixed as spots in an array to form a spot array. The array plate 2 placed on the optical measurement device 1000 typically has a frame member 3 attached to the one surface (sometimes referred to as the top surface) that surrounds the array region. The frame member 3 forms a reservoir for storing a liquid reagent. The array plate 2 with the frame member 3 attached will be referred to as a "framed array plate 12" below. FIG. 2A is a schematic diagram showing the structure of a framed array plate 12 suitable for use in the optical measurement device 1000 of this embodiment. The other surface of the array plate 2 (opposite to the one surface) is sometimes referred to as the back surface (or bottom surface). That is, the one surface is the surface that comes into contact with a liquid, such as a liquid sample or a chemical solution, and the other surface is the surface onto which primary light from the illumination optical system is incident and secondary light is emitted to the detection optical system during optical measurement. The secondary light is generated when the primary light is irradiated onto a reaction product formed by a reaction between the substance fixed as a spot on one surface and a liquid specimen or a drug solution, and generally has a different wavelength from that of the primary light. Therefore, by detecting this secondary light, it is possible to determine whether or not the reaction product is present, i.e., whether or not a substance that reacts with the fixed substance is contained in the liquid specimen.

[0013] The reaction chamber 200 is provided with a plurality of reaction chamber mounting sections 4 (five in FIG. 1A ) so that a plurality of framed array plates 12 (four in FIG. 1A , 12-1 to 12-4) can be mounted thereon. Note that 12-i in FIG. 2A indicates one of the framed array plates 12, and 2-i and 3-i respectively indicate the array plate 2 and frame member 3 constituting the framed array plate 12-i. In FIG. 1A , the framed array plate 12-4 is shown to be composed of the array plate 2-4 and frame member 3-4, while in FIG. 1B , the framed array plate 12-1 is shown to be composed of the array plate 2-1 and frame member 3-1. Each reaction chamber mounting section 4 is equipped with a shaking section (not shown) capable of shaking the framed array plate 12 individually. The shaking section applies vibrations to the framed array plate 12 mounted on the reaction chamber mounting section 4, thereby applying mechanical energy to the chemical solution 11 stored in the storage section. This serves to homogenize the reaction between the chemical solution 11 stored in the reservoir and the multiple substances immobilized in the array region. A heat transfer unit 5 is provided on each reaction chamber mounting unit 4, and the heat transfer unit 5 is in thermal contact with the framed array plate 12 mounted on the reaction chamber mounting unit 4. The heat transfer unit 5 may also be said to be in thermal contact with the framed array plate 12. Therefore, shaking and temperature control can be performed individually for each framed array plate 12 mounted on each reaction chamber mounting unit 4. In other words, the heat transfer unit 5 and the shaking unit can be considered a reaction adjustment unit that adjusts the reaction on the framed array plate 12. The multiple reaction chamber mounting units 4 are installed on a reaction chamber transport unit 7 that transports the framed array plate 12. The reaction chamber transport unit 7 can be moved relative to the base unit 100 in the X direction by a linear drive mechanism 8 provided on the base unit 100.

[0014] The optical measurement device 1000 shown in FIGS. 1A and 1B has five reaction chamber mounting sections 4, with framed array plates 12-1 to 12-4 mounted on the four reaction chamber mounting sections on the left side when viewed from the reaction chamber side (left). In the reaction chamber 200, a drainage area 20, where a liquid reagent is discharged from the framed array plate 12, and a liquid supply area 21, where a liquid reagent is supplied to the framed array plate 12, are located at predetermined positions within the device. When discharging (draining) a liquid reagent, the linear drive mechanism 8 is driven to move the reaction chamber transport section 7 so that the framed array plate 12 to be drained is positioned in the drainage area 20. When supplying (supplying) a liquid reagent, the linear drive mechanism 8 is driven to move the reaction chamber transport section 7 so that the framed array plate 12 to be supplied is positioned in the liquid supply area 21. For example, while a liquid supply operation is being performed on a framed array plate 12, the temperature of the other framed array plates 12 can be adjusted and shaken, allowing reactions to continue in their respective reservoirs. That is, the framed array plates 12 can be moved so that selected framed array plates 12-i are positioned in the liquid supply region or the liquid drainage region at different times. At the end of the reaction, a liquid reagent containing glycerol, which has a higher viscosity than water, is introduced into the framed array plate 12 to prevent drying and fading. As described above, the reaction chamber 200 has a reaction adjustment region 25 consisting of multiple reaction chamber mounting sections 4, where the reaction on the framed array plate 12 is adjusted by a reaction adjustment section (shaking section and heat transfer section). The reaction chamber transport section 7 is configured to transport the framed array plate 12, together with the reaction adjustment region 25, between the liquid drainage region 20 and the liquid supply region 21 (and the relay region 22 described below). That is, the relative positions of the liquid drainage region 20, the liquid supply region 21, and the relay region 22 with respect to the base section 100 are each fixed. On the other hand, the reaction adjustment area 25 is fixed to the reaction chamber transport part 7 , moves integrally with the reaction chamber transport part 7 in the X direction, and moves relative to the base part 100 together with the reaction chamber transport part 7 .

[0015] After the reaction, the framed array plate 12 is moved to the relay region 22 in the apparatus by the reaction chamber transport unit 7 driven by the linear drive mechanism 8, and then transferred to the inter-chamber transport unit 9, which is provided in the plate transport unit 24 and moves at least in the Y direction. The relay region 22 may be located at the same position as or different from the liquid supply region 21 or the liquid drainage region 20. When the liquid supply region 21 and the relay region are located at the same position, the above-described reaction chamber transport unit 7 is not required to move the relay region 22, and the plate is directly transferred to the inter-chamber transport unit 9. The reason for locating the relay region 22 at a different position from the liquid supply region 21 is that the passage opening 41 provided in the partition member 40 is located between the relay region 22 and the optical measurement unit 30, and the partition member 40 can at least partially block the space between the liquid supply region 21 and the optical measurement unit 30. Furthermore, as shown in FIGS. 1A and 1B, it is preferable that the distance between the relay region 22 and the passage opening 41 is shorter than the distance between the liquid supply region 21 and the passage opening 41. In this configuration, the liquid supply region 21, which has a higher probability of generating aerosols than the relay region 22, is positioned away from the passage port 41 by the amount of dispensing operation that is performed. By adopting such an arrangement, it is possible to reduce the probability that aerosols of the liquid to be dispensed will enter the measurement chamber 300 from the reaction chamber 200 via the passage port 41.

[0016] The delivered framed array plate 12 is transported in the Y direction to the measurement region 23 by the inter-chamber transport unit 9 provided in the plate transport unit 24, where the reaction products generated in the reservoir are detected and their amounts are optically measured. Figures 3A and 3B show the state after the framed array plate 12-1 has been transported from the relay region 22 in the reaction chamber 200 to the measurement region 23 in the measurement chamber 300 (during optical measurement). That is, Figures 1A and 1B and Figures 3A and 3B are identical except for the position of the array plate 12-1 and the state of the inter-chamber transport unit 9. As shown in Figures 1A and 3A, the inter-chamber transport unit 9 has a base 24b installed in either the reaction chamber 200 or the measurement chamber 300 (on the measurement chamber 300 side in the figure), and a moving unit 24m that moves relative to the base 24b. The transfer unit 24m has a passing portion 24t, which is a portion that passes through a passing opening 41 provided in a partition member 40 provided between the reaction chamber 200 and the measurement chamber 300, and a non-passing portion 24u, which is a portion that does not pass through the passing opening 41. When the inter-chamber transfer unit 9 transfers the framed array plate 12 from the relay region 22 to the measurement region 23, the passing portion 24t of the inter-chamber transfer unit 9 passes through the passing opening 41 while holding the framed array plate 12. Note that the inter-chamber transfer unit 9 is also referred to as a measurement chamber loading unit because it is the portion on which the framed array plate 12 is loaded while the optical measurement unit 30 scans the framed array plate 12 (upper array region) in the measurement chamber 300. The inter-chamber transfer unit 9 can move the multiple framed array plates 12 in cooperation with the reaction chamber transfer unit 7 so that a selected framed array plate 12-i from the multiple framed array plates 12 is positioned in the measurement region 23 or the relay region 22 at different times.

[0017] FIG. 2B is a vertical cross-sectional view of the optical measurement device 1000 according to this embodiment, taken along line 2B-2B in FIG. 1A, which is a plan view of the device. However, FIG. 2B shows the state in which the reaction chamber mounting unit 4 has been moved in the X direction so that the framed array plate 12-1 is positioned in the liquid supply area 21, which is located on line 2B-2B. Furthermore, the reaction chamber transport unit 7 and the linear drive mechanism 8 (and the dispensing pipette 10, described below) are shown as their external appearances, rather than cross-sectional views, from the front side. The dispensing pipette 10, which may be a disposable tip for an automatic dispensing pipette, constitutes a liquid supply unit that supplies a liquid sample or a chemical solution 11 to the framed array plate 12 from above the reaction chamber transport unit 7, on which the framed array plate 12, which has an open top, is installed. Such chemical solutions include buffer solutions, observation solutions, primary antibodies, secondary antibodies, and stop drugs. 1B, the measurement system (optical measurement unit 30) used for optical measurement is located lower than the framed array plate 12 and performs reciprocating scanning in the X direction. During optical measurement, the framed array plate 12 held by the inter-chamber transport unit (measurement chamber mounting unit) 9 is scanned in the Y direction by the inter-chamber transport unit 9 above the measurement system, which is scanning reciprocatingly in the X direction below it. After measurement, the framed array plate 12 is returned by the inter-chamber transport unit 9 from the measurement region 23 to the relay region 22 through a passage 41 provided in the partition member 40.

[0018] The partition member 40 between the reaction chamber 200 and the measurement chamber 300 has a passageway 41 connecting the relay region 22 and the measurement region 23, but is primarily provided to isolate the reaction chamber 200 and the measurement chamber 300. This ensures the safety of the operator from the atmosphere in the detection chamber and the laser light used in the optical measurement unit 30. The partition member 40 also reduces leakage of measurement light (primary light) irradiated in the measurement chamber 300 into the reaction chamber 200, preventing a framed array plate 12 waiting before measurement from fading due to leakage of measurement light onto another framed array plate 12 during measurement. Even when there are no waiting framed array plates 12, the partition member 40 reduces the possibility that measurement light leaking into the reaction chamber 200 will be reflected back into the measurement chamber 300, leading to detection errors. Therefore, it is preferable to use a low-reflectivity surface color or texture, such as black, on the surface of the partition member 40 facing the measurement chamber 300 to reduce reflection of measurement light and reduce measurement errors. For example, the spectral reflectance of the surface of the partition member facing the measurement chamber to the primary light is preferably 10% or less. The average reflectance of the interior wall of the measurement chamber to the primary light is preferably lower than the average reflectance of the interior wall of the reaction chamber.

[0019] The primary purpose of the partition member 40 is to reduce leakage of measurement light irradiated in the measurement chamber 300 toward the reaction chamber 200. It is preferable to close or at least narrow the passage opening 41 of the partition member 40 to reduce its opening area while the measurement light is being irradiated. FIG. 4 shows a mechanism for changing the opening area of ​​the passage opening (opening) 41 of the partition member 40. In this mechanism, an opening closing member 50 is attached to a movable part 51 that moves in the Z direction, and the opening opening 41 is opened or closed or the opening area is adjusted by driving an actuator in a fixed part 52. Examples of actuators that can be used include a ball screw, a cylinder, and a solenoid. The mechanism shown in FIG. 4 can at least partially close the passage opening 41 of the partition member 1 while the measurement light is being irradiated in the measurement chamber, thereby more strictly preventing the measurement light from leaking outside the measurement chamber.

[0020] The present invention is not limited to the above-described embodiments, and various modifications and variations can be made without departing from the spirit and scope of the present invention. Therefore, the following claims are appended to apprise the public of the scope of the present invention.

[0021] This application claims priority based on Japanese Patent Application No. 2024-030443, filed February 29, 2024, the entire contents of which are incorporated herein by reference.

[0022] 1000: Optical measurement device 2: Array plate 3: Frame member 4: Reaction chamber mounting section 5: Heat transfer section 7: Reaction chamber transport section 8: Linear drive mechanism 9: Inter-chamber transport section 10: Dispensing pipette 11: Liquid reagent supplied onto array plate 12: Framed array plate 20: Liquid drainage area 21: Liquid supply area 22: Relay area 23: Measurement area 24: Plate transport section 25: Reaction adjustment area 30: Optical measurement section 40: Partition member 41: Passage port (opening) 50: Opening closing member 51: Movable section 52: Fixed section 100: Base section 200: Reaction chamber 220: Reaction chamber housing 300: Measurement chamber 320: Measurement chamber housing

Claims

1. An optical measurement device comprising: a reaction chamber mounting section on which an array plate having a plurality of substances fixed in an array on one surface and a reservoir section for storing a liquid sample or a predetermined chemical solution is mounted; and a liquid supply section for supplying the liquid sample or the predetermined chemical solution to the reservoir section, wherein a reaction product is produced on the array plate by a reaction between the liquid sample or the predetermined chemical solution and the plurality of substances; a measurement chamber mounting section on which the array plate holding the reaction product is mounted; and an optical measurement section for optically measuring the reaction product on the array plate mounted on the measurement chamber mounting section through the array plate from the other side opposite to the one side of the array plate, wherein the reaction product is optically measured; an inter-chamber transport section for transporting the array plate between the reaction chamber and the measurement chamber; and a partition member having a passage through which the array plate held in the inter-chamber transport section can pass, which separates the reaction chamber from the measurement chamber.

2. The optical measuring device according to claim 1, wherein the inter-chamber transport section has a portion that passes through the passage opening.

3. An optical measuring device as described in claim 1 or 2, wherein the optical measuring unit is configured to irradiate primary light of a predetermined wavelength onto the array plate, and measure secondary light of a wavelength different from the primary light emitted from the array plate by irradiation, and the spectral reflectance of the surface of the partition member facing the measurement chamber for the primary light is 10% or less.

4. An optical measurement device according to any one of claims 1 to 3, wherein the inter-chamber transport unit is configured to transport the array plate between the reaction chamber mounting unit and the measurement chamber mounting unit.

5. An optical measuring device according to any one of claims 1 to 4, wherein the reaction chamber has a relay area for transferring the array plate between the reaction chamber mounting section and the inter-chamber transport section.

6. The optical measurement device according to claim 5, wherein the reaction chamber further comprises a reaction chamber transport unit that moves the array plate via the reaction chamber mounting unit.

7. The optical measurement device according to claim 6, wherein the reaction chamber has a liquid supply area, to which the liquid is supplied by the liquid supply unit, at a position different from the relay area.

8. The optical measuring device according to claim 7, wherein the distance between the relay area and the passage port is shorter than the distance between the liquid supply area and the passage port.

9. An optical measuring device as described in claim 7 or 8, wherein the passage port is located between the relay area and the optical measuring section, and the portion between the liquid supply area and the optical measuring section is blocked by the partition member.

10. The optical measurement device according to any one of claims 7 to 9, wherein the reaction chamber transport unit transports the array plate between the liquid supply area and the relay area.

11. An optical measurement device described in any one of claims 6 to 10, wherein the reaction chamber has a reaction adjustment area that adjusts the reaction on the array plate using a reaction adjustment unit that applies thermal or mechanical energy to the array plate.

12. The optical measuring device according to claim 11, wherein the reaction adjusting unit includes at least one selected from a heat transfer unit that adjusts the array plate to a predetermined temperature, and a shaking unit that applies vibrations to the array plate.

13. The optical measuring device according to claim 11 or 12, wherein the distance between the relay area and the passage port is shorter than the distance between the reaction adjustment area and the passage port.

14. An optical measuring device as claimed in any one of claims 11 to 13, wherein the passage opening is located between the relay area and the optical measuring unit, and the area between the reaction adjustment area and the optical measuring unit is blocked by the partition member.

15. The optical measurement device according to any one of claims 11 to 14, wherein the reaction chamber transport unit transports the array plate between the reaction adjustment area and the relay area.

16. An optical measurement device according to any one of claims 1 to 15, wherein the inter-chamber transport unit has a base that is installed in either the reaction chamber or the measurement chamber, and a moving unit that moves relative to the base and has a portion that passes through the passage opening between the reaction chamber and the measurement chamber.

17. The optical measurement device according to claim 3, wherein the measurement chamber has an interior wall with a lower average reflectance to the primary light than the reaction chamber.

18. An optical measuring device according to any one of claims 1 to 17, comprising a mechanism for changing the opening area of ​​the passage opening.

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