Optical measuring device

Abstract

An optical measuring apparatus has a reaction chamber and a measurement chamber. The reaction chamber includes a reaction chamber stage on which an array plate is placed, and a liquid supply unit that supplies a liquid sample or a predetermined chemical solution to the array plate to generate a reaction product on the array plate. The measurement chamber includes a measurement chamber stage on which the array plate holding the reaction product is placed, and an optical measuring unit that optically measures the reaction product on the array plate. The optical measuring apparatus further includes an inter-chamber conveyor that conveys 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 by the inter-chamber conveyor is allowed to pass, and that partitions a space into the reaction chamber and the measurement chamber.

Description

Technical Field

[0001] The present invention relates to an optical measurement apparatus configured to perform reaction and measurement steps on an array plate. Background Technology

[0002] Array plates, such as protein arrays, peptide arrays, and DNA arrays, are known to have speckled regions where numerous specks of substances such as proteins, peptides, and nucleic acids are immobilized in an array on a substrate. Using such array plates allows for clear observation of the interactions between numerous immobilized substances and substances in the sample. This enables comprehensive analysis of the interactions between numerous substances and biologically derived liquid samples, such as blood, cell extracts, saliva, or tissue fluid.

[0003] One known measurement method using an array plate obtains optical information by selectively fluorescently labeling spots where target interactions occur. A confocal laser microscope is known as an instrument for observing these fluorescently labeled spots. A confocal laser microscope includes an illumination optics system, a fluorescence detection optics system, and a two-dimensional scanning system. The fluorescence detection optics system is capable of detecting the amount of fluorescence from spots labeled with fluorescent probes. The two-dimensional scanning system is capable of acquiring fluorescence images of the spot regions on the array plate by performing a two-dimensional scan of the array plate or the optical system.

[0004] Patent Document 1 discloses an inspection technique comprising a reaction step of marking sealed units, called flow units (each unit containing a liquid reagent and a plate), and a measurement step of optically acquiring the marked pattern. Patent Document 1 also discloses a loading technique that allows the reaction steps to be performed in parallel on the flow units, and sequentially delivers the flow units to an optical measurement area for performing the measurement steps after the reaction steps are completed.

[0005] Existing technical documents

[0006] Patent documents

[0007] Patent Document 1: Japanese Patent Application Publication No. 2011-501965 Summary of the Invention

[0008] The technical problem to be solved by the present invention

[0009] In the inspection technique described in Patent Document 1, during the measurement step, a portion of the measurement light applied to the plate leaks out of the measurement chamber, reflects off a component outside the measurement chamber, and returns to the measurement chamber again, which may lead to measurement errors in optical measurements. Furthermore, if the reaction step is performed in parallel on multiple plates and the reaction step and measurement step are performed serially, if a portion of the measurement light leaking from the measurement chamber strikes a plate waiting in the reaction chamber before the measurement step, the waiting plate may deteriorate.

[0010] Solutions to technical problems

[0011] The optical measuring device of the present invention includes:

[0012] A reaction chamber includes: a reaction chamber stage, an array plate placed on the reaction chamber stage, multiple substances fixed in an array on one surface of the array plate, the array plate having a reservoir configured to store a liquid sample or a predetermined chemical solution; and a liquid supply unit configured to supply the liquid sample or predetermined chemical solution to the reservoir, the reaction chamber being configured to generate reaction products on the array plate through a reaction between the liquid sample or predetermined chemical solution and the multiple substances; and

[0013] A measurement chamber includes: a measurement chamber stage on which an array plate holding the reaction products is placed; and an optical measurement unit configured to perform optical measurements on the reaction products placed on the measurement chamber stage from another surface of the array plate (i.e., a surface opposite to one of the array plates), the measurement chamber being configured to perform optical measurements on the reaction products.

[0014] Intercompartmental delivery system configured to deliver array plates between reaction chamber and measurement chamber; and

[0015] A partition member having a passage port through which an array plate held by an inter-chamber conveyor is allowed to pass, and the partition member dividing the space into a reaction chamber and a measurement chamber.

[0016] The effects of the invention

[0017] According to the present invention, the amount of measurement light that leaks from the measurement chamber to the outside and then returns to the measurement chamber can be reduced, thereby reducing optical measurement errors. Furthermore, the reduction in light leakage from the measurement chamber to the outside allows for less degradation of the array plate during waiting periods. Attached Figure Description

[0018] Figure 1A and Figure 1B The two side views, arranged in pairs, schematically illustrate an example of the structure of the optical measuring device of the present invention, and are top views of the interior of the device when viewed from above.

[0019] Figure 1B and Figure 1A The two side views, arranged in pairs, schematically illustrate an example of the structure of the optical measuring device in this invention, and are shown from one side (from...) Figure 1A (The lower part of the middle) When observing, along Figure 1A The side view of the section cut by line 1B-1B in the diagram.

[0020] Figure 2A It is preferably used for Figure 1A and Figure 1B A schematic diagram of the structure of the framed array plate in the optical measurement device shown.

[0021] Figure 2B From one side (from) Figure 1A (The lower part of the middle) When observing, along Figure 1A The diagram shows a cross-section taken by line 2B-2B in order to illustrate the positional relationship between the array plate placed on the reaction chamber stage and the pipette tip.

[0022] Figure 3A and Figure 3B Formed in pairs Figure 1A and Figure 1B The two side views of the optical measuring device shown schematically illustrate the relationship between the position of the conveyor arm and the position of the through port located in the partition member during optical measurement, and are top views of the interior of the device when viewed from above.

[0023] Figure 3B and Figure 3A Formed in pairs Figure 1A and Figure 1B The two side views of the optical measuring device shown schematically illustrate the relationship between the position of the conveyor arm and the position of the through port located in the partition member during optical measurement (after the array plate is conveyed), and are from one side (from... Figure 1A (The lower part of the middle) along the observation edge Figure 3A The side view of the section cut by line 3B-3B in the diagram.

[0024] Figure 4 It is a schematic illustration of the setting. Figure 1A and Figure 1B A perspective view of the opening and closing mechanism on the separating component of the optical measuring device shown. Detailed Implementation

[0025] Will use Figure 1A , Figure 1B , Figure 2A , Figure 2B , Figure 3A , Figure 3B and Figure 4An embodiment of the optical measuring device according to the present invention is described. Figure 1A This is a schematic plan view of the interior of the housing (outer shell) of the optical measuring device 1000 in this embodiment when viewed from top to bottom in a vertical direction. Figure 1B It is along Figure 1A The vertical sectional view taken by line 1B-1B schematically shows the interior of the device (from the direction indicated by the arrows). Figure 1A (See the lower part of the image). However, for the reaction chamber delivery unit 7 and the linear drive mechanism, Figure 1B Its cross-section is not shown; instead, its appearance from the front of the line of sight is shown.

[0026] Figure 1A and Figure 1B The illustrated optical measuring device 1000 includes a reaction chamber 200 for carrying out a predetermined reaction using a plurality of array plates 2, and a measuring chamber 300 for optically measuring the amount of reaction products generated by the reaction. The reaction chamber 200 and the measuring chamber 300 are housed within a housing (outer shell) and separated from each other by a partition member 40. The housing portion for housing the reaction chamber will be referred to as the reaction chamber housing 220, and the housing portion for housing the measuring chamber will be referred to as the measuring chamber housing 320. The reaction chamber 200 and the measuring chamber 300 are constructed on a common base 100.

[0027] Typically, the array plate 2 has an array region on one surface of a rectangular plate-shaped glass slide, wherein a spot array is formed by multiple substances individually fixed as spots in an array form. A frame member 3 constituting a reservoir for storing liquid reagents is typically attached to the array plate 2 to be mounted on the optical measuring device 1000, so as to surround the array region on the aforementioned one surface (sometimes referred to as the top surface). The array plate 2 with the frame member 3 attached will hereinafter be referred to as "framed array plate 12". Figure 2A This is a schematic diagram illustrating the structure of the framed array plate 12 preferably used in the optical measurement apparatus 1000 of this embodiment. The other surface of the array plate 2 (opposite to the aforementioned surface) will sometimes be referred to as the back surface (or bottom surface). Specifically, the aforementioned surface is the surface in contact with a liquid such as a liquid sample or chemical solution, while the aforementioned other surface is the surface on which primary light from the illumination optics system is incident during optical measurement and from which secondary light is emitted toward the detection optics system. The secondary light is light generated by the reaction products from the reaction between the substance fixed as a spot on the aforementioned surface and the liquid such as a liquid sample or chemical solution when the reaction products are irradiated with the primary light, and typically has a different wavelength than the primary light. Therefore, by detecting this secondary light, the presence or absence of reaction products can be determined, specifically, whether the liquid sample contains a substance that reacts with the fixed substance.

[0028] The reaction chamber 200 is equipped with multiple reaction chamber platforms 4 ( Figure 1A There are five in the middle, so that multiple framed array plates 12 can be placed on them. Figure 1A There are four in total, from 12-1 to 12-4. Figure 2A In the above, 12-i represents one of a plurality of framed array plates 12, and 2-i and 3-i represent the array plate 2 and the frame member 3 constituting the framed array plate 12-i, respectively. Figure 1A A framed array plate 12-4, consisting of array plates 2-4 and frame members 3-4, is shown. Figure 1B A framed array plate 12-1, consisting of an array plate 2-1 and a frame member 3-1, is shown. Each reaction chamber stage 4 is equipped with a vibrator (not shown) capable of individual vibration. The vibrator causes the framed array plate 12 placed on the reaction chamber stage 4 to vibrate, thereby applying mechanical energy to the chemical solution 11 stored in the reservoir. Thus, the vibrator functions to homogenize the reaction between the chemical solution 11 stored in the reservoir and the various substances fixed in the array region. Furthermore, each reaction chamber stage 4 is equipped with a heat transfer unit 5. The heat transfer unit 5 is in thermal contact with the framed array plate 12 placed on the reaction chamber stage 4. In other words, the heat transfer unit 5 contacts the framed array plate 12 in a thermally conductive manner. Therefore, each framed array plate 12 placed on each reaction chamber stage 4 can be individually vibrated and temperature regulated. In summary, the heat transfer unit 5 and the vibrator can be considered as reaction regulating units configured to regulate the reaction on the framed array plate 12. Multiple reaction chamber platforms 4 are mounted on reaction chamber conveying units 7 configured as conveyor belt frame array plates 12. The reaction chamber conveying units 7 can be moved relative to the base 100 in the X direction via a linear drive mechanism 8 mounted on the base 100.

[0029] Figure 1A and Figure 1BThe illustrated optical measuring device 1000 includes five reaction chamber platforms 4, and framed array plates 12-1 to 12-4 are placed on four left-side reaction chamber platforms viewed from the reaction chamber side (left side). In the reaction chamber 200, a draining region 20 for discharging liquid reagents from the framed array plate 12 and a supply region 21 for supplying liquid reagents to the framed array plate 12 are located at predetermined positions within the device. To discharge liquid reagents (liquid discharge), a linear drive mechanism 8 is driven to move the reaction chamber delivery unit 7, such that the framed array plate 12 to be drained is located in the draining region 20. Simultaneously, to supply liquid reagents (liquid supply), the linear drive mechanism 8 is driven to move the reaction chamber delivery unit 7, such that the framed array plate 12 to be supplied is located in the supply region 21. For example, while one framed array plate 12 is undergoing a liquid supply operation, another framed array plate 12 can undergo temperature regulation and vibration operation, allowing their reactions to continue in their respective reservoirs. In other words, multiple plates can be moved such that each framed array plate 12-i selected from the plurality of framed array plates 12 can be located in the supply region or the drainage region at different points in time. At the end of the reaction, a liquid reagent containing glycerol and more viscous than water is introduced into the framed array plate 12 to prevent drying and discoloration. The reaction chamber 200 has a reaction conditioning region 25, which includes a plurality of reaction chamber platforms 4, and in this region, the reaction on each framed array plate 12 is regulated by the reaction conditioning unit (vibrator and heat transfer unit) as described above. The reaction chamber delivery unit 7 is then configured to transport the framed array plate 12 together with the reaction conditioning region 25 between the drainage region 20 and the supply region 21 (and the relay region 22 described below). Specifically, the positions of the drainage region 20, the supply region 21, and the relay region 22 relative to the base 100 are fixed. On the other hand, the reaction adjustment region 25 is fixed to the reaction chamber delivery unit 7, moves together with the reaction chamber delivery unit 7 in the X direction, and moves together with the reaction chamber delivery unit 7 relative to the base 100.

[0030] After the reaction is complete, the framed array plate 12 is moved to the relay region 22 in the device by the reaction chamber transport unit 7 driven by the linear drive mechanism 8, and then transferred to the inter-chamber conveyor 9, which is located in the plate transport unit 24 and moves at least in the Y direction. The relay region 22 can be located at a different location from or at the same location as the liquid supply region 21 or the liquid discharge region 20. When the liquid supply region 21 and the relay region are located at the same location, the framed array plate 12 is directly transferred to the inter-chamber conveyor 9 without the aforementioned movement by the reaction chamber transport unit 7. The significance of setting the relay region 22 at a different location from the liquid supply region 21 is that the liquid supply region 21 and the optical measurement unit 30 can be at least partially spatially isolated from each other by the partition member 40, while the through port 41 provided in the partition member 40 is located between the relay region 22 and the optical measurement unit 30. Furthermore, as Figure 1A and Figure 1B As shown, preferably, the distance between the relay region 22 and the through port 41 is shorter than the distance between the liquid supply region 21 and the through port 41. In this configuration, the liquid supply region 21 (where the likelihood of aerosol generation due to the dispensing operation is higher than in the relay region 22) is arranged further away from the through port 41. This arrangement reduces the probability that aerosols from the dispensed liquid will enter the measuring chamber 300 from the reaction chamber 200 via the through port 41.

[0031] The framed array plate 12 is transferred to the measurement area 23 along the Y direction by the intercom 9 provided in the plate delivery unit 24, in which the reaction products generated in the reservoir are detected and their amount is measured optically. Figure 3A and Figure 3B This illustrates the state after the framed array plate 12-1 has been transferred from relay region 22 in reaction chamber 200 to measurement region 23 in measurement chamber 300 (during optical measurement). That is, Figure 1A and Figure 1B and Figure 3A and Figure 3B Except for the position of the array plate 12-1 and the state of the inter-chamber conveyor 9, they are the same. Figure 1A or Figure 3AAs shown, the intercompartment conveyor 9 has: a base section 24b, which is mounted in the reaction chamber 200 or the measurement chamber 300 (shown on the measurement chamber 300 side in the figure); and a moving section 24m, which is configured to move relative to the base section 24b. The moving section 24m includes a through portion 24t (which is the portion passing through a through port 41 provided in the partition member 40 installed between the reaction chamber 200 and the measurement chamber 300) and a non-through portion 24u (which is the portion that does not pass through the through port 41). When the intercompartment conveyor 9 conveys the framed array plate 12 from the relay area 22 to the measurement area 23, the through portion 24t of the intercompartment conveyor 9 holds the framed array plate 12 and passes through the through port 41. The intercompartment conveyor 9 is the section on which the framed array plate 12 is placed while the optical measurement unit 30 scans the framed array plate 12 (upper array area) in the measurement chamber 300, and is therefore sometimes referred to as the measurement chamber stage. In conjunction with the reaction chamber delivery unit 7, the inter-chamber delivery unit 9 can move multiple framed array plates 12 such that each framed array plate 12-i selected from the multiple framed array plates 12 is located in the measurement area 23 or the relay area 22 at different time points.

[0032] Figure 2B This is a plan view of the optical measuring device 1000 according to this embodiment. Figure 1A The image shown is a vertical sectional view taken along line 2B-2B, viewed in the direction indicated by the arrow. However, Figure 2B The diagram shows the reaction chamber stage 4 moved in the X direction such that the framed array plate 12-1 is positioned in the liquid supply region 21 located on line 2B-2B. Furthermore, the diagram also shows the reaction chamber delivery unit 7 and the linear drive mechanism 8 (and the dispensing pipette 10, which will be described below). Figure 2B Its cross-section is not shown, but its appearance from the front of the line of sight is shown. The dispensing pipette 10 is, for example, a disposable pipette tip for an automated dispensing pipette and constitutes a supply unit. In the supply area, it supplies liquid samples or chemical solutions 11 from the top of the reaction chamber delivery unit 7, which houses the framed array plate 12, which opens to the top side. Such chemical solutions contain buffer solutions, observation solutions, primary antibodies, secondary antibodies, terminators, etc. On the other hand, as... Figure 1B As shown, the measurement system (optical measurement unit 30) for optical measurements is positioned lower than the framed array plate 12 and performs reciprocating scans in the X direction. During optical measurements, the framed array plate 12, held by the inter-chamber conveyor (measurement chamber stage) 9, is scanned in the Y direction above the measurement system by the inter-chamber conveyor 9, while the measurement system performs reciprocating scans in the X direction below the framed array plate 12. After measurement, the inter-chamber conveyor 9 returns the framed array plate 12 from the measurement area 23 to the relay area 22 through the through port 41 provided in the partition member 40.

[0033] The partition member 40 installed between the reaction chamber 200 and the measurement chamber 300 has a through port 41 serving as a path connecting the relay area 22 and the measurement area 23, but it is essentially installed to shield the reaction chamber 200 and the measurement chamber 300 from each other. This partition member 40 ensures that the operator is protected from the atmosphere inside the detection chamber, the laser used in the optical measurement unit 30, and the like. Furthermore, the partition member 40 reduces leakage of the measurement light (primary light) applied in the measurement chamber 300 to the reaction chamber 200 side, thereby preventing the framed array plate 12 waiting before measurement from fading due to leakage of the measurement light applied to another framed array plate 12 being measured. Even in the absence of a waiting framed array plate 12, the installation of the partition member 40 reduces the possibility of measurement light leakage into the reaction chamber 200, reflection on the partition member 40, and return to the measurement chamber 300, which could lead to detection errors. Therefore, the surface of the partition member 40 facing the measurement chamber 300 is preferably provided with a low-reflectivity surface color or surface texture (such as black) to reduce the reflection of measurement light and thus reduce measurement error. For example, the surface of the partition member facing the measurement chamber preferably has a spectral reflectance of less than 10% for primary light. Here, preferably, the average reflectance of the inner wall of the measurement chamber for primary light is lower than the average emissivity of the inner wall of the reaction chamber.

[0034] The partition member 40 is primarily designed to reduce leakage of the measuring light applied in the measuring chamber 300 into the reaction chamber 200. When the measuring light is applied, the passage port 41 of the partition member 40 is preferably closed or at least narrowed to reduce its opening area. Figure 4 A mechanism for changing the opening area of ​​the passage port (opening) 41 of the partition member 40 is shown. The mechanism includes an opening / closing member 50 attached to a movable section 51 configured to move in the Z direction, and actuating an actuator in a fixed section 52 to open and close the passage port 41 or adjust its opening area. As the actuator, a ball screw, cylinder, solenoid, etc., can be used. Figure 4 The mechanism in the middle can at least partially close the through port 41 of the partition member 1 when the measuring light is applied to the measuring chamber, thereby more strictly preventing the measuring light from leaking to the outside of the measuring chamber.

[0035] This invention is not limited to the embodiments described above, and various modifications and variations can be made without departing from the spirit and scope of the invention. Therefore, the following claims are appended to publicly disclose the scope of the invention.

[0036] This application claims priority based on Japanese Patent Application No. 2024-030443, filed on February 29, 2024, the entire contents of which are incorporated herein by reference.

[0037] Explanation of reference numerals in the attached figures

[0038] 1000 Optical Measurement Device

[0039] 2 Array board

[0040] 3. Frame components

[0041] 4. Reaction chamber placement platform

[0042] 5 heat transfer units

[0043] 7. Reaction Chamber Transport Unit

[0044] 8. Linear drive mechanism

[0045] 9-chamber conveyor

[0046] 10 Dispensing pipettes

[0047] 11. Liquid reagents supplied on the array plate

[0048] 12-frame array board

[0049] 20 Drainage area

[0050] 21 Liquid Supply Area

[0051] 22 Relay Area

[0052] 23 Measurement Area

[0053] 24-plate conveyor unit

[0054] 25 Reaction Regulation Region

[0055] 30 optical measurement units

[0056] 40. Separating components

[0057] 41. Through the port (opening)

[0058] 50 Opening and closing components

[0059] 51 Movable Section

[0060] 52 Fixed Section

[0061] 100 base

[0062] 200 reaction chamber

[0063] 220 Reaction Chamber Shell

[0064] 300 Measurement Room

[0065] 320 Measuring Chamber Shell

Claims

1. An optical measuring device, comprising: A reaction chamber comprising: a reaction chamber stage on which an array plate is placed, multiple substances fixed in an array on one surface of the array plate, the array plate having a reservoir configured to store a liquid sample or a predetermined chemical solution; and a liquid supply unit configured to supply the liquid sample or predetermined chemical solution to the reservoir, the reaction chamber being configured to generate reaction products on the array plate through a reaction of the liquid sample or predetermined chemical solution with the multiple substances; A measurement chamber comprising: a measurement chamber stage on which the array plate holding the reaction product is placed; and an optical measurement unit configured to perform optical measurements on the reaction product placed on the measurement chamber stage from another surface of the array plate, the other surface of the array plate being the opposite surface to one surface of the array plate, the measurement chamber being configured to perform optical measurements on the reaction product; Intercompartmental conveyor, configured to convey the array plate between the reaction chamber and the measurement chamber; and A partition member having a passage port through which the array plate held by the inter-chamber conveyor is allowed to pass, and the partition member dividing the space into the reaction chamber and the measurement chamber.

2. The optical measuring apparatus of claim 1, wherein the intercompressor includes a portion configured to pass through the through port.

3. The optical measuring device according to claim 1 or 2, wherein... The optical measurement unit is configured to illuminate the array plate with primary light of a predetermined wavelength so that the primary light enters the array plate, and to measure secondary light of a different wavelength from the primary light, the secondary light being emitted from the array plate under the illumination. The surface of the partition member facing the measurement chamber has a spectral reflectance of less than 10% for the primary light.

4. The optical measuring apparatus according to any one of claims 1 to 3, wherein the inter-chamber conveyor is configured to convey the array plate between the reaction chamber stage and the measuring chamber stage.

5. The optical measuring apparatus according to any one of claims 1 to 4, wherein the reaction chamber includes a relay region, at which the array plate is transferred between the reaction chamber stage and the inter-chamber conveyor.

6. The optical measuring apparatus of claim 5, wherein the reaction chamber further comprises a reaction chamber transport unit configured to move the array plate via the reaction chamber stage.

7. The optical measuring device according to claim 6, wherein the reaction chamber further includes a liquid supply area, wherein the array plate is supplied with liquid by the liquid supply unit in the liquid supply area, and the liquid supply area is located at a different position from the relay area.

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

9. The optical measuring device according to claim 7 or 8, wherein The port is located between the relay area and the optical measurement unit, and The liquid supply area and the optical measurement unit are partially spatially isolated from each other by the separating member.

10. The optical measuring apparatus according to any one of claims 7 to 9, wherein the reaction chamber delivery unit delivers the array plate between the liquid supply region and the relay region.

11. The optical measuring apparatus according to any one of claims 6 to 10, wherein the reaction chamber further comprises a reaction conditioning region, wherein the reaction on the array plate is regulated by a reaction conditioning unit configured to apply thermal or mechanical energy to the array plate.

12. The optical measuring apparatus of claim 11, wherein the reaction conditioning unit comprises at least one selected from a heat transfer unit configured to condition the array plate to a predetermined temperature and a vibrator configured to vibrate the array plate.

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

14. The optical measuring apparatus according to any one of claims 11 to 13, wherein: The port is located between the relay area and the optical measurement unit, and The reaction conditioning region and the optical measurement unit are partially spatially isolated from each other by the separating member.

15. The optical measuring apparatus according to any one of claims 11 to 14, wherein the reaction chamber delivery unit delivers the array plate between the reaction conditioning region and the relay region.

16. The optical measuring apparatus according to any one of claims 1 to 15, wherein the intercompressor comprises: A base section installed in the reaction chamber or the measuring chamber, and a movable section configured to move relative to the base section and having a portion passing through the through port between the reaction chamber and the measuring chamber.

17. The optical measuring apparatus of claim 3, wherein the average reflectivity of the inner wall of the measuring chamber for the primary light is lower than the average reflectivity of the reaction chamber for the primary light.

18. The optical measuring apparatus according to any one of claims 1 to 17, comprising a mechanism configured to change the opening area of ​​the through port.

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