Scanning method, scanning system, and position information acquisition method

Abstract

A scanning method for optically scanning an array plate (1) comprising a plurality of spots (3) on a front surface thereof comprises: forming at least one of a solid-gas interface and a solid-solid interface in a first region (1a) of the front surface of the plate by bringing a gas or solid into contact with the first region (1a), and an interface forming step of forming a solid-liquid interface in a second region (1b) of the front surface of the plate by bringing the liquid into contact with the second region (1b), the plurality of spots (3) being included in the second region (1b); a step of optically acquiring first position information on an interface position of at least one of the solid-gas interface and the solid-solid interface; and a step of acquiring second position information on an interface position of the solid-liquid interface on the basis of the first position information.

Description

Technical Field

[0001] The present invention relates to a scanning method, a scanning system, and a position information acquisition method for optically scanning an array plate. Background Art

[0002] Array plates are known in which various substances such as proteins, peptides, and nucleic acids are immobilized in a spot pattern on a substrate. By using the array plate, it is possible to simultaneously observe the interaction between various immobilized substances and substances in a specimen. This enables a comprehensive analysis of the interaction with various substances including biological specimens such as blood, cell extracts, saliva, and interstitial fluid.

[0003] As a method for measuring a specimen, it is known to selectively fluorescently label spots where an interaction of interest has occurred to obtain optical information. As a device for observing a fluorescently labeled specimen, for example, a confocal laser microscope is known.

[0004] Patent Document 1 discloses a confocal microscope device configured to align the rear surface or the front surface of a cover glass holding a specimen with a reference focal position based on reflected light from the rear surface or the front surface of the cover glass.

[0005] In addition, Patent Document 2 discusses a confocal scanning optical microscope including a polarization beam splitter and a λ / 4 plate.

[0006] Citation List

[0007] Patent Documents

[0008] PTL 1: Japanese Patent Laid-Open No. 2009-53578

[0009] PTL 2: Japanese Patent Laid-Open No. 6-214162 Summary of the Invention

[0010] Technical Problem

[0011] When optically scanning an array plate, it is necessary to identify the position of its front surface (the surface where the spots are present) and focus light on it. As discussed in Patent Document 1, there is a method of optically detecting the position of the front surface of the array plate based on reflected light from the front surface.

[0012] However, there may be a situation where the front surface of the array plate comes into contact with a liquid called the observation liquid. In the case where the front surface of the array plate comes into contact with the observation liquid as described above, the refractive index difference at the solid-liquid interface (substrate / observation liquid interface) is small, and reflection is unlikely to occur at this interface, making it difficult to optically detect the position of the front surface of the array plate. For example, when the substrate is glass and the observation liquid is a glycerol solution with a refractive index close to that of glass, the refractive index difference at the solid-liquid interface is significantly small, and it is difficult to optically detect the position of the front surface of the array plate.

[0013] Patent Documents 1 and 2 do not identify the position of the front surface of the eye plate to ensure accurate scanning when the front surface of the array plate is in contact with a liquid.

[0014] The present invention takes into account the above problems and aims to enable accurate scanning in the case where the front surface of the array plate is in contact with a liquid.

[0015] A scanning method according to an embodiment of the present invention is a scanning method for optically scanning an array plate, the array plate including a plurality of spots on its front surface, the scanning method including: an interface forming step of forming at least one of a solid-gas interface and a solid-solid interface in a first region by bringing a gas or a solid into contact with the first region of the front surface of the plate, and forming a solid-liquid interface in a second region by bringing a liquid into contact with the second region of the front surface of the plate, the plurality of spots being included in the second region; a step of optically acquiring first position information on the interface position of at least one of the solid-gas interface and the solid-solid interface; and a step of acquiring second position information on the interface position of the solid-liquid interface based on the first position information.

[0016] In addition, a scanning system according to an embodiment of the present invention is a scanning system for optically scanning an array plate, the array plate including a plurality of spots on its front surface, the scanning system including: a support portion configured to support the array plate such that at least one of a solid-gas interface and a solid-solid interface is formed in a first region by bringing a gas or a solid into contact with a first region of the front surface of the plate, and a solid-liquid interface is formed in a second region by bringing a liquid into contact with a second region of the front surface of the plate, the plurality of spots being included in the second region; an optical system configured to irradiate the spots with primary light and collect secondary light; a scanning unit configured to optically scan the array plate by changing a relative position between the array plate and the primary light; a first position information acquisition unit configured to optically acquire first position information about an interface position of at least one of the solid-gas interface and the solid-solid interface; and a second position information acquisition unit configured to acquire second position information about an interface position of the solid-liquid interface based on the first position information.

[0017] Furthermore, a position information acquisition method according to an embodiment of the present invention is a position information acquisition method for acquiring information about a position of a surface of an array plate including a plurality of spots on at least a part of the plurality of spots in contact with a liquid, the position information acquisition method including: an interface formation step of forming at least one of a solid-gas interface and a solid-solid interface in a first region by bringing a gas or a solid into contact with a first region of the surface, and forming a solid-liquid interface in a second region by bringing a liquid into contact with a second region of the surface, the plurality of spots being included in the second region; a step of optically acquiring first position information about an interface position of at least one of the solid-gas interface and the solid-solid interface; and a step of acquiring second position information about an interface position of the solid-liquid interface based on the first position information.

[0018] Advantages of the Invention

[0019] The present invention enables accurate scanning to be performed when the front surface of the array plate is in contact with a liquid. Description of the Drawings

[0020] Figure 1 is a flowchart illustrating the process of the scanning method.

[0021] Figure 2A is a plan view illustrating an example of the array plate.

[0022] Figure 2B-1 It is a diagram for describing an array board divided into a first region and a second region.

[0023] Figure 2B-2 It is a diagram for describing an array board divided into a first region and a second region.

[0024] Figure 2B-3 It is a diagram for describing an array board divided into a first region and a second region.

[0025] Figure 2B-4 It is a diagram for describing an array board divided into a first region and a second region.

[0026] Figure 2B-5 It is a diagram for describing an array board divided into a first region and a second region.

[0027] Figure 3A It is a diagram schematically showing the configuration of a scanning system according to the first embodiment.

[0028] Figure 3B It is a diagram schematically showing the configuration of a scanning system according to the first embodiment.

[0029] Figure 4A It is a diagram for describing the process for obtaining first position information according to the first embodiment.

[0030] Figure 4B It is a diagram for describing the process for obtaining first position information according to the first embodiment.

[0031] Figure 4C It is a diagram for describing the process for obtaining first position information according to the first embodiment.

[0032] Figure 5A It is a diagram showing an example of the configuration of a one-dimensional scanning mechanism.

[0033] Figure 5B It is a diagram showing an example of the configuration of a one-dimensional scanning mechanism.

[0034] Figure 6 It is a diagram schematically showing the configuration of a modified example of the scanning system according to the first embodiment.

[0035] Figure 7 It is a diagram schematically showing the configuration of a modified example of the scanning system according to the first embodiment.

[0036] Figure 8A It is a diagram for describing the process for obtaining first position information according to the second embodiment.

[0037] Figure 8BThis is a diagram for describing the process of obtaining first position information according to the second embodiment.

[0038] Figure 8C This is a diagram for describing the process of obtaining first position information according to the second embodiment.

[0039] Figure 9A This is a diagram for describing the process of obtaining first position information and third position information according to the third embodiment.

[0040] Figure 9B This is a diagram for describing the process of obtaining first position information and third position information according to the third embodiment.

[0041] Figure 9C This is a diagram for describing the process of obtaining first position information and third position information according to the third embodiment.

[0042] Figure 10 This is a diagram illustrating a schematic configuration of a scanning system according to the fourth embodiment.

[0043] Figure 11 This is a diagram illustrating a schematic configuration of a modified example of the scanning system according to the fourth embodiment.

[0044] Figure 12A This is a diagram illustrating a modified example of a first region of an array plate.

[0045] Figure 12B This is a diagram illustrating a modified example of a first region of an array plate.

[0046] Figure 12C This is a diagram illustrating a modified example of a first region of an array plate. Detailed Description of the Invention

[0047] Preferred embodiments of the present invention will be described below with reference to the accompanying drawings.

[0048] First, the following will be described with reference to Figure 1 、 Figure 2A and Figures 2B-1 to 2B-5 an overview of a scanning method to which the present invention is applied.

[0049] [Array Plate]

[0050] Figure 2A This is a plan view showing an example of an array plate 1. A plurality of spots 3 aligned both vertically and horizontally are located in a region 4 on the surface of a substrate 2 such as a glass slide of the array plate 1. Biomolecules containing peptide bonds are fixed at each spot 3. A single type of biomolecule is fixed at each spot. The array plate is also referred to as a microarray (microchip), protein array (protein chip), peptide array (protein chip), or DNA array (DNA chip).

[0051] As described above, the array plate 1 includes spots 3 containing multiple types of biomolecules on a substrate 2 and is used for comprehensive analysis of specimens. For example, Agilent Technologies and Ray Biotech offer microarray plates, and commercially available array plates can be used. Alternatively, an array plate can be prepared. The immobilization of biomolecules is also referred to as adsorption and includes immobilization by hydrophobic interaction, electrostatic interaction, van der Waals interaction, hydrogen bonding, and covalent bonding. The substrate 2 is preferably transparent. Examples of the material of the substrate 2 include glass, synthetic quartz, quartz, borosilicate glass. Examples of the material of the substrate also include resins such as polystyrene, polypropylene, (meth)acrylic resin, polyamide, polyimide, melamine, acrylonitrile butadiene styrene (ABS), polyphenylene ether polyurethane, silicone, epoxy resin, and polydimethylsiloxane.

[0052] [Observation liquid]

[0053] The plate surface of the array plate 1 (the front surface where the spots 3 are located, hereinafter simply referred to as the front surface) can be brought into contact with a liquid called the observation liquid. The observation liquid is also referred to as a cleaning liquid because it replaces the optical background noise components, i.e., cleans them. When acquiring optical information, the observation liquid is brought into contact with at least some of the spots 3 of the array plate 1. The observation liquid preferably exhibits good affinity for the liquid used in the array plate 1 in the immediately preceding process. Additionally, the observation liquid desirably has a refractive index comparable to that of the substrate 2 and prevents oxidation of the substances (especially labeled substances) on the array plate 1. Additionally, the observation liquid preferably does not emit fluorescence when irradiated with excitation light for optical information acquisition. Although a glycerol solution is suitable as a liquid satisfying the above conditions, an appropriate liquid can be selected based on the nature of the labeled substance, biomolecule, and / or specimen. The observation liquid preferably contains at least one selected from the group consisting of glycerol, water, and Tris-buffered saline with Tween 20 (TBST).

[0054] [Scanning method]

[0055] When applying the present invention, the front surface of the array plate 1 (substrate 2) is divided into a first region 1a in contact with a gas (air) and a second region 1b in contact with a liquid (observation liquid) 6, as Figures 2B-1 to 2B-5 shown. The second region 1b is a region including a plurality of spots 3, and the first region 1a does not include a region overlapping with the plurality of spots 3. Although specific examples will be described below, a frame 5 for holding the liquid is placed on the array plate 1 to separate the first region 1a in contact with air and the second region 1b where the observation liquid 6 is in contact with the spots 3. It should be noted that in Figures 2B-1 to 2B-5The illustration of spot 3 is omitted. It should be noted that not all regions on the front surface of the array plate 1 other than the second region 1b need to be the first region 1a, and only some of the regions other than the second region 1b can be the first region 1a.

[0056] Figure 1 The scanning method process is illustrated.

[0057] In step S1, the array plate 1 is arranged such that air contacts the first region 1a and the observation liquid 6 contacts the second region 1b, thereby forming a solid-gas interface in the first region 1a and a solid-liquid interface in the second region 1b.

[0058] The following will refer to Figures 2B-1 to 2B-5 Describe the arrangement of the array plate 1. The short side direction and the long side direction of the array plate 1 are respectively defined as the main scanning direction and the sub-scanning direction, and X, Y, and Z are respectively defined as the main scanning direction, the sub-scanning direction, and the direction perpendicular to the XY plane (the plane including the main scanning direction and the sub-scanning direction of the array plate 1).

[0059] Figures 2B-1 to 2B-3 is a plan view (a view seen from the front surface side in the Z direction) illustrating the array plate 1, and a first region 1a having a solid-gas interface (substrate / air interface) and a second region 1b having a solid-liquid interface (substrate / observation liquid interface) exist on the front surface of the array plate 1. It should be noted that it is sufficient for the first region 1a and the second region 1b to exist on the front surface of the array plate 1, and the shape of the frame 5 is not limited. For example, as Figure 2B-1 shown, a frame 5 having a rectangular shape with dimensions approximately the same as those of region 4 (refer to Figure 2A ) can be used, where the inner side and the outer side of the frame 5 are respectively defined as the second region 1b and the first region 1a. Additionally, as Figure 2B-2 shown, the first region 1a can be located within the second region 1b. Additionally, as Figure 2B-3 shown, the shape of the frame 5 is not limited to rectangular, for example, the first region 1a can extend into the second region 1b.

[0060] Figure 2B-4 and Figure 2B-5 are views illustrating the array plate 1 seen from the X direction. As Figure 2B-4 shown, holding the observation liquid 6 inside the frame 5 is a typical example. Additionally, as Figure 2B-5 shown, the array plate 1 can be placed in the observation liquid 6, and a cup-shaped frame 5 can be used to ensure the first region 1a.

[0061] It should be noted that the solid-liquid interface corresponds to the interface where a solid and a gas with a refractive index difference n (n_solid>n_gas) are in contact, and is the interface for obtaining reflected light corresponding to the refractive index difference of the interface. As the gas forming the solid-gas interface, the surrounding gas from the environment where the optical system for fluorescence measurement is placed is used, and includes the atmosphere at 1 atm, nitrogen with a specified partial pressure or diluted nitrogen, carbon dioxide, and oxygen. The solid forming the solid-gas interface includes an array plate with a refractive index higher than that of the gas in contact with the solid, and a thin film on the array plate.

[0062] In addition, the solid-liquid interface corresponds to the interface where a solid and a liquid with a small refractive index difference n (n_solid≈n_liquid) are in contact, and is the interface where it is difficult to obtain the light intensity of reflected light corresponding to the refractive index difference of the interface. The liquid forming the solid-liquid interface includes an observation liquid such as a buffer solution or a cleaning solution applied to or remaining on the array plate during fluorescence measurement. The solid forming the solid-liquid interface includes the array plate and a thin film on the array plate. The thin film on the array plate includes spots where biomolecules such as proteins or peptides are immobilized.

[0063] In addition, when considering the solid-liquid interface, for the thickness of each spot on the array plate, a value sufficiently smaller than the depth of focus determined by the numerical aperture of the objective optical system is generally used. In other words, for the measurement, an objective lens with a specification that allows the depth of focus to overlap sufficiently larger than the thickness of each spot on the array plate on the optical axis is used. The depth of focus DOF depending on the numerical aperture NA and the wavelength λ of light can be determined using the Berek formula.

[0064] In step S2, first position information on the interface position of the solid-gas interface in the first region 1a is optically acquired.

[0065] This step acquires the first position information by irradiating the array plate 1 with focused light from a confocal optical system. As the first position information, information on the position of the solid-gas interface in the first region 1a in the Z direction (i.e., the position of the front surface of the array plate 1 in the first region 1a in the Z direction) is acquired. It should be noted that the positions in the X, Y, and Z directions will be referred to as the X, Y, and Z positions, respectively. By irradiating with focused light while changing the irradiation position in the Z direction and detecting the peak in the reflected light intensity, the Z position of the solid-gas interface in the first region 1a can be detected. The details of step S2 will be described in each of the embodiments described below.

[0066] In step S3, second position information on the interface position of the solid-liquid interface in the second region 1b is acquired based on the first position information acquired in step S2.

[0067] In this step, information on the Z position of the solid-liquid interface in the second region 1b that is in contact with the observation liquid 6 and is difficult to optically detect (i.e., information on the Z position of the front surface of the array plate 1 in the second region 1b) is obtained as second position information. Here, an equation for calculating the Z position of the solid-liquid interface in the second region 1b is set as a straight line or a curve. Details of step S3 will be described in each of the embodiments described below.

[0068] It should be noted that although the step of setting an equation for calculating the interface position of the solid-liquid interface in the second region 1b based on the first position information is described as being included in step S3, this is not a limitation. Instead of or in addition to the step of setting the equation, a step of making a determination related to focusing on the solid-liquid interface based on the first position information and / or a step of referring to previous information on the interface position of the solid-liquid interface may be included.

[0069] In step S4, position adjustment information regarding position adjustment within the scanning range of the second region 1b is obtained based on the second position information obtained in step S3.

[0070] In this step, based on the second position information obtained in step S3 (the equation for calculating the Z position of the solid-liquid interface in the second region 1b), a change in the Z position of the solid-liquid interface within the scanning range of the second region 1b in the Y direction is detected, and the Z position adjustment amount is calculated as the position adjustment information. Step S4 will be described in each of the embodiments described below.

[0071] Steps S2 to S4 constitute a pre-scan, followed by a main scan (main scan) performed in step S5. In the main scan, the confocal optical system optically and three-dimensionally scans the second region 1b by irradiating the array plate 1 with focused light based on the position adjustment information obtained in step S4 and obtains optical information on the target.

[0072] The main scan includes a scanning step of forming an irradiation spot in the second region 1b by irradiating the second region 1b with primary light including focused light and moving the irradiation spot relative to the array plate 1. In the scanning step, a focusing step of adjusting the depth reference position (focus position) of the focal depth with respect to the solid-liquid interface in the optical axis direction of the primary light based on the position adjustment information is included. The focusing step is performed by adjusting at least one of the working distance between the array plate 1 and the emission end of the primary light and the focal length of the objective optical system including the emission end. The scanning step is performed at the depth reference position adjusted by the focusing step.

[0073] As described above, when the front surface of the array plate 1 is in contact with the observation liquid 6, the position of the front surface of the second region 1b in contact with the observation liquid 6 is identified based on the first position information obtained from the first region 1a in contact with air, thereby enabling accurate scanning.

[0074] Specific examples of the scanning method and the scanning system to which the present invention is applied will be described below.

[0075] <First Embodiment>

[0076] Figure 3A and Figure 3B is a diagram showing a schematic configuration of a scanning system according to the first embodiment. Figure 3A is a diagram showing a schematic configuration of the scanning system, and Figure 3B is a diagram showing a functional configuration of the information processing device 400. The scanning system according to the first embodiment is a fluorescence-based confocal scanning system.

[0077] The scanning system includes a support portion 100 configured to support the array plate 1, a Y-direction (sub-scanning direction) scanning mechanism 150, and a height adjustment mechanism 160 configured to adjust the position in the Z-direction (height direction).

[0078] The array plate 1 is as described above, and biomolecules containing peptide bonds are fixed at each spot 3 on the glass slide serving as the substrate 2. A single type of biomolecule is fixed at each spot. In addition, a fluorescent label responsive to the characteristics and state of the fixed biomolecule is applied to the spot 3. The surface of the array plate 1 is divided into a first region 1a in contact with air and a second region 1b in contact with the observation liquid 6. The array plate 1 as described above is placed on the support portion 100, thereby being supported, and is arranged such that air is in contact with the first region 1a and the observation liquid 6 is in contact with the second region 1b. The support portion 100 is connected to the Y-direction scanning mechanism 150 corresponding to the sub-scanning direction and the height adjustment mechanism 160 for adjusting the Z-position corresponding to the height position, and can be moved in the Y-direction and the Z-direction. The scanning mechanism 150 and the height adjustment mechanism 160 are scanning units configured to optically scan the array plate 1 by changing the relative position between the array plate 1 and the primary light irradiated by the observation optical system 200.

[0079] In addition, the scanning system includes an observation optical system 200, which is a confocal optical system. The observation optical system 200 is an optical system configured to irradiate the spot 3 with primary light and collect secondary light.

[0080] The observation optical system 200 includes a semiconductor laser 201, a collimating lens 202, a band-pass filter 203, a polarization beam splitter 204, a λ / 4 wave plate 205, a long-pass filter 206, an objective lens 207, and a one-dimensional scanning mechanism 208. The semiconductor laser 201 emits light with a wavelength of 670 nm. The band-pass filter 203 is a filter that transmits light with a wavelength close to 670 nm. The long-pass filter 206 is a long-pass filter with a cut-off wavelength of 685 nm. The λ / 4 wave plate 205 is a λ / 4 wave plate whose slow axis is inclined at 45 degrees with respect to the polarization direction of the polarization beam splitter 204.

[0081] The light emitted from the semiconductor laser 201 passes through the collimating lens 202, the band-pass filter 203, and the polarization beam splitter 204, and becomes circularly polarized when passing through the λ / 4 wave plate 205. The light passing through the λ / 4 wave plate 205 is reflected by the long-pass filter 206 and focused by the objective lens 207 onto the front surface of the array plate 1. The configuration of irradiating the focused light through the rear surface of the array plate 1 as described above is adopted.

[0082] The one-dimensional scanning mechanism 208 is a mechanism for performing main scanning (scanning in the X direction). The following will refer to Figure 5A and Figure 5B to describe an example of the configuration of the one-dimensional scanning mechanism 208. The one-dimensional scanning mechanism 208 is preferably configured to perform scanning at a high speed to reduce the measurement time. For example, as shown in Figure 5A , the one-dimensional scanning mechanism 208 is composed of a unit 218 placed on a linear guide 216 parallel to the X direction. The unit 218 includes a combination of the objective lens 207 and a mirror 217 positioned at a 45-degree angle with respect to the linear guide 216. By moving the unit 218 along the linear guide 216, it becomes possible to scan the focused irradiation light in the X direction. The unit 218 is composed of, for example, a piston-crank mechanism that converts the rotational motion of an electric actuator or a motor into a linear motion.

[0083] In addition, as shown in Figure 5B , the one-dimensional scanning mechanism 208 can be composed of a combination of a galvanometer scanner 219 and a focusing lens 220. As the focusing lens 220, a telecentric lens or an fθ lens can be used.

[0084] Returning to the description with reference to Figure 3A and Figure 3B , the observation optical system 200 includes a band-pass filter 211, a fluorescence imaging lens 209, a pinhole 210, and a photomultiplier tube 213. The band-pass filter 211 is a filter that transmits light with a wavelength close to 716 nm.

[0085] The fluorescence emitted from the spot 3 of the array plate 1 passes through the objective lens 207 and the long-pass filter 206 and is focused by the imaging lens 209, and the light passing through the pinhole 210 is detected by the photomultiplier 213.

[0086] In addition, the observation optical system 200 includes an imaging lens 214 for reflecting light, a pinhole 215, and a light detection device 212.

[0087] The excitation light reflected by the substrate 2 of the array plate 1 passes through the objective lens 207 and is reflected by the long-pass filter 206. Since the direction of the circular polarization of the reflected light is reversed due to the reflection on the substrate 2, the light passing through the λ / 4 wave plate 205 is in a state of being rotated 90 degrees from the linear polarization of the irradiation light and is reflected by the polarization beam splitter 204. The light reflected by the polarization beam splitter 204 is focused by the imaging lens 214, and the light passing through the pinhole 215 is detected by the light detection device 212.

[0088] The observation optical system 200 configured as described above can separate fluorescence and reflected light and acquire them simultaneously. Here, adjustment is made so that the excitation light spot focused by the objective lens 207 is in a confocal relationship with the pinholes 210 and 215. In this case, when the intensity of the reflected light from the array plate 1 detected by the light detection device 212 reaches its maximum value, the fluorescence intensity detected by the photomultiplier 213 also reaches its maximum value. In addition, even when there is a deviation from the confocal relationship, by previously measuring the deviation amount and storing it as an offset value, the position where the fluorescence intensity reaches its maximum value can be determined based on the position where the reflected light intensity is at its maximum value.

[0089] In addition, the scanning system includes an information processing device 400. The information processing device 400 controls the driving of the scanning mechanism 150, the height adjustment mechanism 160, and the one-dimensional scanning mechanism 208, and performs the pre-scanning and main scanning described above. The reflected light information from the array plate 1 detected during the pre-scanning is stored in the storage medium 450.

[0090] As Figure 3B shown, the information processing device 400 includes a first position information acquisition unit 401, a second position information acquisition unit 402, and a position adjustment information acquisition unit 403. The information processing device 400 is composed of, for example, a computer device including a CPU, a ROM, and a RAM, and the CPU executes a predetermined program stored in the ROM, for example, to perform the functions of the units 401 to 403.

[0091] Next, the scanning method according to the first embodiment will be described with reference to Figure 1 the flowchart shown in.

[0092] This embodiment is applicable to cases where there are variations in the array plate 1 and variations in the thickness of the substrate 2 between the array plates 1. More specifically, it is applicable to cases where when the array plate 1 is replaced, the difference in the surface height of the array plate 1 (difference in Z position) caused by the variation in the thickness of the substrate 2 may not fall within the depth of focus. On the other hand, it is assumed that there are neither variations in the thickness of a single array plate 1 nor tilts of the array plate 1 placed on the support portion 100. More specifically, it is applicable to cases where the difference in the surface height of the array plate 1 caused by the variation in the thickness of a single array plate 1 or the tilt of the array plate 1 falls within the depth of focus.

[0093] In step S1, the array plate 1 is placed on the support portion 100 and arranged such that air contacts the first region 1a and the observation liquid 6 contacts the second region 1b.

[0094] In step S2, the first position information acquisition unit 401 optically acquires first position information regarding the interface position of the solid-gas interface in the first region 1a.

[0095] The following will refer to Figure 4A 、 Figure 4B and Figure 4C to describe the processing of step S2. Figure 4A 、 Figure 4B and Figure 4C are diagrams for describing the processing for acquiring the first position information, Figure 4A is a characteristic diagram illustrating the relationship between the amount of height movement (amount of movement in the Z direction) and the reflected light intensity, Figure 4B is a diagram illustrating the state where the light is focused on the rear surface of the array plate 1, and Figure 4C is a diagram illustrating the state where the light is focused on the front surface of the array plate 1. It should be noted that the illustration of the speckle 3 is omitted in Figure 4B and Figure 4C .

[0096] The information processing device 400 controls the scanning mechanism 150 and positions the objective lens 207 at the Y position Y1 below the first region 1a of the array plate 1. By controlling the height adjustment mechanism 160 at the Y position Y1 and irradiating with focused light while changing the irradiation position in the Z direction, the reflected light distribution shown in Figure 4A is obtained. When the excitation light is focused on the rear surface (Z position Z1') of the array plate 1, a peak P1 appears in the reflected light intensity. Thereafter, when the excitation light is focused on the front surface (Z position Z1) of the array plate 1, a peak P2 appears in the reflected light intensity. The first position information acquisition unit 401 records the Z position Z1 at which the peak P2 in the reflected light intensity appears as the Z position of the solid-gas interface in the first region 1a.

[0097] ​​In step S3, the second position information acquisition unit 402 acquires second position information regarding the interface position of the solid-liquid interface in the second region 1b based on the first position information acquired in step S2.

[0098] In the present embodiment, the second position information acquisition unit 402 determines that the Z position Z of the solid-liquid interface in the second region 1b is Z1 based on the Z position Z1 acquired as the first position information, regardless of the Y position. This can be expressed as the equation Z = Z1.

[0099] In step S4, the position adjustment information acquisition unit 403 acquires position adjustment information regarding position adjustment within the scanning range of the second region 1b based on the second position information acquired in step S3.

[0100] In the present embodiment, the position adjustment information acquisition unit 403 acquires Z position adjustment information for scanning such as the irradiation position in the Z direction within the scanning range in the Y direction of the second region 1b as Z1.

[0101] It should be noted that in the case where there is a known offset between the equation set in step S3 and the relative position between the array plate 1 and the observation optical system 200, the Z position Z of the solid-liquid interface in the second region 1b is determined as Z = Z1 + A using the offset value A.

[0102] As described above, position adjustment information for relatively moving the array plate 1 and the observation optical system 200 can be acquired.

[0103] In step S5, the information processing device 400 performs main scanning. The information processing device 400 simultaneously controls the scanning mechanism 150 and the height adjustment mechanism 160 based on the position adjustment information acquired in step S4 through step control or constant speed control to adjust the relative position between the array plate 1 and the observation optical system 200. By combining this with the main scanning performed by the one-dimensional scanning mechanism 208, main scanning is performed, thereby enabling the acquisition of a focused fluorescence image across the entire measurement region. In the case of the present embodiment, since the Z position is maintained constant (Z position Z1) within the scanning range of the second region 1b, the height adjustment mechanism 160 remains stationary and does not operate during the main scanning.

[0104] As described above, main scanning is performed after identifying the Z position of the front surface of the second region 1b. In the present embodiment, even in the presence of variability of the array plate 1 and variations in the thickness of the substrate 2 between the array plates 1, a fluorescence image can be acquired by aligning the focal position without causing a decrease in fluorescence intensity, thereby enabling accurate scanning.

[0105] It should be noted that although this embodiment describes an example of a configuration in which the scanning mechanism 150 and the height adjustment mechanism 160 are connected to the support portion 100, this is not a limitation, and any configuration capable of adjusting the relative position between the array plate 1 and the observation optical system 200 can be used.

[0106] As Figure 6 shown, the scanning mechanism 151 and the height adjustment mechanism 161 can be connected to the observation optical system 200.

[0107] In addition, as Figure 7 shown, the scanning mechanism 152 can be connected to the observation optical system 200, and the height adjustment mechanism 162 can be connected to the support portion 100.

[0108] <Second Embodiment>

[0109] Next, the second embodiment will be described below. The difference between the second embodiment and the first embodiment lies in the processing of steps S2 to S4. The schematic configuration and the basic operation processing of the scanning system are similar to those in the first embodiment, and the differences from the first embodiment will be mainly described below.

[0110] The scanning method according to the second embodiment will be described below with reference to Figure 1 the flowchart in.

[0111] This embodiment is applicable to cases where there are variations in the array plate 1 and variations in the thickness of the substrate 2 between the array plates 1. More specifically, it is applicable to cases where the difference in the surface height (difference in Z position) of the array plate 1 caused by the change in the thickness of the substrate 2 when replacing the array plate 1 may not fall within the depth of focus. In addition, it is applicable to cases where the difference in the surface height of the array plate 1 caused by the change in the thickness of a single array plate 1 in the Y direction or the tilt of the array plate 1 placed on the support portion 100 in the Y direction may not fall within the depth of focus.

[0112] In step S2, the first position information acquisition unit 401 optically acquires first position information regarding the interface position of the solid-gas interface in the first region 1a. In the first embodiment, the first position information is acquired at one Y position. On the other hand, in this embodiment, the first region 1a exists on both sides of the second region 1b, and the first position information is acquired at the Y positions on both sides of the second region 1b.

[0113] The processing of step S2 will be described below with reference to Figure 8A , Figure 8B and Figure 8C describe the processing of step S2. Figure 8A , Figure 8B and Figure 8C are diagrams for describing the processing for acquiring the first position information.Figure 8A and Figure 8B is a characteristic diagram showing the relationship between the amount of height movement (the amount of movement in the Z direction) of the illustration and the intensity of the reflected light, and Figure 8C is a diagram showing the state where the light is focused on the front surface of the array plate 1. It should be noted that in Figure 8C the illustration of the spot 3 is omitted.

[0114] The information processing device 400 controls the scanning mechanism 150 and positions the objective lens 207 at the Y position Y2 below the first region 1a of the array plate 1. By controlling the height adjustment mechanism 160 at the Y position Y2 and irradiating with the focused light while changing the irradiation position in the Z direction, similar to those described with reference to Figure 4A 、 Figure 4B and Figure 4C the peaks P1 and P2 in the reflection intensity appear, as shown in Figure 8A . The first position information acquisition unit 401 records the Z position Z2 where the peak P2 in the reflected light intensity appears as the Z position of the solid-gas interface in the first region 1a.

[0115] In addition, the information processing device 400 controls the scanning mechanism 150 and positions the objective lens 207 at the Y position Y3 below the first region 1a of the array plate 1. The Y positions Y2 and Y3 correspond to the Y positions on both sides of the second region 1b. By controlling the height adjustment mechanism 160 at the Y position Y3 and irradiating with the focused light while changing the irradiation position in the Z direction, similar to those described with reference to Figure 4A 、 Figure 4B and Figure 4C the peaks P1 and P2 in the reflection intensity appear, as shown in Figure 8A . The first position information acquisition unit 401 records the Z position Z3 where the peak P2 in the reflected light intensity appears as the Z position of the solid-gas interface in the first region 1a.

[0116] It should be noted that at the Y position Y2, the Z position of the solid-gas interface in the first region 1a can be detected at a single X position, or the Z position of the solid-gas interface in the first region 1a can be detected at multiple X positions, and then its average value can be calculated, for example. Although this also applies to the Y position Y3, it is preferable to match the X position for the Y position Y3 with the X position for the Y position Y2.

[0117] In step S3, the second position information acquisition unit 402 acquires second position information regarding the interface position of the solid-liquid interface in the second region 1b based on the first position information acquired in step S2.

[0118] In this embodiment, the second position information acquisition unit 402 performs linear interpolation based on the Z positions Z2 and Z3 at the Y positions Y2 and Y3 obtained as the first position information, and the Z position Z of the solid-liquid interface in the second region 1b at the Y position is expressed by the following equation (1):

[0119] Z = {(Z2 - Z3) / (Y2 - Y3)}*(Y - Y2) + Z2 (1),

[0120] where (Z2 - Z3) / (Y2 - Y3) indicates the inclination of the front surface of the array plate 100.

[0121] In step S4, the position adjustment information acquisition unit 403 acquires position adjustment information regarding position adjustment within the scanning range of the second region 1b based on the second position information acquired in step S3.

[0122] In this embodiment, the position adjustment information acquisition unit 403 calculates the Z positions Zs and Ze at the end positions Ys and Ye within the scanning range of the second region 1b in the Y direction by using equation (1). As described above, since the Z position of the solid-liquid interface in the second region 1b changes from Zs to Ze within the scanning range of the second region 1b in the Y direction, the position adjustment information acquisition unit 403 acquires position adjustment information of the scanning to be performed by adjusting the irradiation position in the Z direction from Zs to Ze within the scanning range of the second region 1b in the Y direction.

[0123] As described above, the main scan is performed after identifying the Z position of the front surface of the second region 1b. In this embodiment, even in the case where there are variations in the array plate 1 and variations in the thickness of the substrate 2 between the array plates 1, and in the case where there are thickness variations of a single array plate 1 in the Y direction or an inclination of the array plate 1 in the Y direction, a fluorescence image can be acquired by aligning the focal position without reducing the fluorescence intensity, thereby enabling accurate scanning.

[0124] Although the first position information is acquired at two points in the first region 1a and the second position information is acquired by linear interpolation, this is not a limitation. The first position information can be acquired at three or more points in the first region 1a, and the second position information can be acquired by fitting a higher-order function.

[0125] <Third Embodiment>

[0126] Next, the third embodiment will be described below. The third embodiment is different from the first embodiment in the processing of steps S2 to S4. The schematic configuration and basic operation processing of the scanning system are similar to those in the first embodiment, and the differences from the first embodiment will be mainly described below.

[0127] The following will refer to Figure 1 the flowchart in

[0128] to describe the scanning method according to the third embodiment. [[ / END]]

[0129] In step S2, the first position information acquisition unit 401 optically acquires first position information on the interface position of the solid-gas interface in the first region 1a. In addition to the first position information, the first position information acquisition unit 401 also optically acquires third position information on the position of the rear surface of the array plate 1.

[0130] The following will refer to Figure 9A , Figure 9B and Figure 9C to describe the process of step S2. Figure 9A , Figure 9B and Figure 9C are diagrams for describing the process of acquiring the first position information and the third position information, Figure 9A and Figure 9B are characteristic diagrams showing the relationship between the amount of height movement (the amount of movement in the Z direction) and the reflected light intensity, and Figure 9C is a diagram showing the state where the light is focused on the rear surface of the array plate 1. It should be noted that the illustration of the speckle 3 is omitted in Figure 9C .

[0131] The information processing device 400 controls the scanning mechanism 150 and positions the objective lens 207 at the Y position Y4 below the first region 1a of the array plate 1. By controlling the height adjustment mechanism 160 at the Y position Y4 and irradiating with the focused light while changing the irradiation position in the Z direction, similar to those described above with reference to Figure 4A , Figure 4B and Figure 4C , peaks P1 and P2 in the reflected intensity appear, as shown in Figure 9AAs shown in []. The first position information acquisition unit 401 records the Z position Z4' where the peak P1 in the reflected light intensity appears as the Z position of the rear surface of the first region 1a, and records the Z position Z4 where the peak P2 in the reflected light intensity appears as the Z position of the solid-gas interface in the first region 1a.

[0132] In addition, the information processing device 400 controls the scanning mechanism 150 and positions the objective lens 207 at the Y position Y5 below the second region 1b of the array plate 1. By controlling the height adjustment mechanism 160 at the Y position Y5 and irradiating with the focused light while changing the irradiation position in the Z direction, similar to those described above with reference to Figure 4A 、 Figure 4B and Figure 4C the peak P1 in the reflected intensity due to reflection on the rear surface appears as shown in Figure 9B . However, the peak P2 due to reflection on the front surface in contact with the observation liquid does not appear (or is significantly small). The first position information acquisition unit 401 records the Z position Z5' where the peak P1 in the reflected light intensity appears as the Z position of the rear surface of the second region 1b.

[0133] It should be noted that at the Y position Y4, the Z positions of the rear surface and the solid-gas interface of the first region 1a can be detected at a single X position, or can be detected at multiple X positions, and then for example, its average value can be calculated. Although this also applies to the Y position Y5, it is preferable to match the X position for the Y position Y5 with the X position for the Y position Y4.

[0134] In step S3, the second position information acquisition unit 402 acquires second position information about the interface position of the solid-liquid interface in the second region 1b based on the first position information and the third position information acquired in step S2.

[0135] As Figure 9A 、 Figure 9B and Figure 9C shown in [], the difference d between the Z positions Z4' and Z4 where the peaks P1 and P2 appear respectively at the Y position Y4 becomes thickness information corresponding to the thickness of the array plate 1. It should be noted that this thickness information is different from the actual thickness because it includes the refractive index information of the substrate 2 used in the array plate 1. At the Y position Y5, the Z position of the rear surface of the second region 1b is obtained. Since the difference in the surface height of the array plate 1 caused by the change in the thickness of a single array plate 1 in the Y direction falls within the depth of focus, the Z position Z5 of the front surface of the second region 1b at the Y position Y5 can be calculated using the following equation (2):

[0136] Z5 = Z5' + d (2).

[0137] The second position information acquisition unit 402 performs linear interpolation based on the Z positions Z4 and Z5 at the Y positions Y4 and Y5, and the Z position Z of the solid-liquid interface in the second region 1b at the Y position is expressed by the following equation (3):

[0138] Z = {(Z4 - Z5) / (Y4 - Y5)} * (Y - Y4) + Z4 (3), where (Z4 - Z5) / (Y4 - Y5) indicates the inclination of the front surface of the array plate 100.

[0139] In step S4, the position adjustment information acquisition unit 403 acquires position adjustment information regarding position adjustment within the scanning range of the second region 1b based on the second position information acquired in step S3.

[0140] In the present embodiment, as in the second embodiment, the position adjustment information acquisition unit 403 calculates the Z positions Zs and Ze at the end positions Ys and Ye within the scanning range in the Y direction of the second region 1b by using equation (3). As described above, since the Z position of the solid-liquid interface in the second region 1b changes from Zs to Ze within the scanning range in the Y direction of the second region 1b, the position adjustment information acquisition unit 403 acquires position adjustment information of the scan to be performed by adjusting the irradiation position in the Z direction from Zs to Ze within the scanning range in the Y direction of the second region 1b.

[0141] As described above, the main scan is performed after identifying the Z position of the front surface of the second region 1b. In the present embodiment, even in the case where there are variations in the array plate 1 and variations in the thickness of the substrate 2 between the array plates 1 and in the case where there is an inclination of the array plate 1 in the Y direction, a fluorescence image can be acquired by aligning the focal position without causing a reduction in fluorescence intensity, thereby enabling accurate scanning. In addition, since the Z position in the second region 1b, which is used as the image acquisition region, is used as a reference, the accuracy of the position adjustment information is improved.

[0142] It should be noted that, as described in the second embodiment above, the second position information can be acquired by fitting a higher-order function instead of linear interpolation.

[0143] <Fourth Embodiment>

[0144] Next, the fourth embodiment will be described below with reference to Figure 10 The fourth embodiment describes a reflective confocal scanning system.

[0145] Figure 10The figure illustrates a schematic configuration of a scanning system according to a fourth embodiment. It should be noted that components similar to those of the scanning system according to the first embodiment are assigned the same reference numerals, and their descriptions are omitted. In a fluorescence-based confocal scanning system, fluorescence from the speckle is detected, while in a reflective confocal scanning system, light reflected from the speckle is detected.

[0146] The reflective confocal scanning system includes an observation optical system 500, which is a confocal optical system.

[0147] The observation optical system 500 includes a semiconductor laser 501, a collimating lens 502, a band-pass filter 503, a polarization beam splitter 504, a λ / 4 wave plate 505, an objective lens 507, and a one-dimensional scanning mechanism 508. The semiconductor laser 501 emits light with a wavelength of 670 nm. The band-pass filter 503 is a filter that transmits light with a wavelength close to 670 nm.

[0148] The light emitted from the semiconductor laser 501 passes through the collimating lens 502, the band-pass filter 503, and the polarization beam splitter 504. The light passing through the λ / 4 wave plate 505 is focused by the objective lens 507 onto the front surface of the array plate 1. The configuration of irradiating the focused light through the rear surface of the array plate 1 as described above is adopted.

[0149] The one-dimensional scanning mechanism 508 is a mechanism for performing main scanning in the X direction and is similar to the one-dimensional scanning mechanism 208.

[0150] In addition, the observation optical system 500 includes an imaging lens 514 for reflecting light, a pinhole 515, and a light detection device 512.

[0151] The reflected light from the speckle 3 on the array plate 1 passes through the objective lens 507 and the λ / 4 wave plate 505 and is reflected by the polarization beam splitter 504. The light reflected by the polarization beam splitter 504 is focused by the imaging lens 514, and the light passing through the pinhole 515 is detected by the light detection device 512.

[0152] In the observation optical system 500 configured as described above, the light detection device 512 has two functions, which are to detect the position of the array plate 1 and to acquire a two-dimensional image based on the reflected light from the speckle 3, so that optical information about the speckle 3 can be obtained with a simpler configuration. In addition, since the observation liquid 6 in contact with the front surface of the array plate 1 has a refractive index closer to that of the array plate 1 than air, the light emitted from the optical system is less likely to be reflected at the interface between the array plate 1 and the observation liquid 6, so that optical information with a higher signal-to-noise ratio can be obtained.

[0153] It should be noted that although in this embodiment, the λ / 4 wave plate 505 and the polarization beam splitter 504 are used to guide the reflected light to the light detection device 512, this is not a limitation.

[0154] As Figure 11 shown, the half mirror 521 can be used to guide the reflected light to the light detection device 512. With this configuration, the light detection device 512 can acquire a two-dimensional image of the reflected light based on the speckles 3 from the array plate 1 with a simpler configuration.

[0155] <Fifth Embodiment>

[0156] Next, the fifth embodiment will be described below with reference to Figure 12A 、 Figure 12B and Figure 12C The fifth embodiment describes a modification example of the first region in the array plate 1. Figure 12A 、 Figure 12B and Figure 12C are diagrams illustrating modification examples of the first region in the array plate 1.

[0157] Although in Figures 2B-1 to 2B-5 a first region 1a having a solid-gas interface (substrate / air interface) exists on the front surface of the array plate 1, this is not a limitation. The present invention is also applicable to cases where, as Figure 12A 、 Figure 12B and Figure 12C shown, a first region 1c having a solid-solid interface (substrate / solid interface) exists.

[0158] For example, as Figure 12A shown, a reflective film 7 such as a dielectric multilayer film or a metal film is provided on the front surface of the array plate 1. In this case, a solid-solid interface is formed between the array plate 1 and the reflective film 7 in the first region 1c. To improve the measurement accuracy, the reflectivity of the reflective film 7 is preferably higher than the reflectivity of the solid-gas interface, and the reflectivity is preferably 10% or higher.

[0159] In addition, as Figure 12B shown, a resin coating film 8 is provided on the front surface of the array plate 1 to prevent measurement errors caused by dirt. In this case, a solid-solid interface is formed between the array plate 1 and the resin coating film 8 in the first region 1c. A resin coating film 8 having a large refractive index difference from the array plate 1 is preferred, and a resin coating film 8 having a refractive index difference of 0.1 or more from the array plate 1 is preferred.

[0160] In addition, as Figure 12CAs shown, the solid-solid interface can be located within the region of the observation liquid 6 or the buffer solution. In this case, the first region 1c is located within a part of the second region 1b, but the present invention still applies.

[0161] It should be noted that the solid-solid interface formed in the first region 1c includes the front surface of the array plate 1 and the interface in contact with the front surface of the array plate 1, deposited on the front surface of the array plate 1, or formed on the front surface of the array plate 1 and in contact with the solid material.

[0162] Although the present invention has been described in conjunction with its embodiments, the above embodiments merely illustrate examples of the embodiments for implementing the present invention, and these should not be construed as limiting the technical scope of the present invention. In other words, the present invention can be implemented in various forms without departing from its technical concept or main features.

[0163] (Other Embodiments)

[0164] The present invention can also be implemented by a process in which a program for implementing one or more functions of the above embodiments is supplied to a system or device via a network or a storage medium, and one or more processors of a computer of the system or device read the program and execute the processed program. Additionally, the present invention can also be implemented by a circuit (e.g., ASIC) configured to implement one or more functions.

[0165] The disclosure of this embodiment includes the following method.

[0166] (Method 1)

[0167] A scanning method for optically scanning an array plate that includes a plurality of spots on its front surface, the scanning method including: an interface forming step of forming at least one of a solid-gas interface and a solid-solid interface in a first region by bringing a gas or a solid into contact with the front surface of the plate, and forming a solid-liquid interface in a second region by bringing a liquid into contact with the front surface of the plate, the plurality of spots being included in the second region; a step of optically obtaining first position information regarding the interface position of at least one of the solid-gas interface and the solid-solid interface; and a step of obtaining second position information regarding the interface position of the solid-liquid interface based on the first position information.

[0168] (Method 2)

[0169] The scanning method according to Method 1 further includes a scanning step of forming an irradiation spot in the second region by irradiating the second region with primary light including focused light and moving the irradiation spot relative to the array plate.

[0170] (Method 3)

[0171] According to the scanning method of Method 2, it further includes a focusing step of adjusting a depth reference position of a focal depth with respect to the solid-liquid interface in the optical axis direction of the primary light based on the second position information.

[0172] (Method 4)

[0173] According to the scanning method of Method 3, wherein the scanning step is performed at the depth reference position adjusted by the focusing step.

[0174] (Method 5)

[0175] According to the scanning method of Method 3 or 4, wherein the focusing step is performed by adjusting at least one of a working distance between the array plate and an emission end of the primary light and a focal length of an objective optical system including the emission end.

[0176] (Method 6)

[0177] According to the scanning method of any one of Methods 1 to 5, wherein the first region does not include a region overlapping with the plurality of spots.

[0178] (Method 7)

[0179] According to the scanning method of any one of Methods 2 to 5, wherein the primary light is irradiated by a confocal optical system.

[0180] (Method 8)

[0181] According to the scanning method of any one of Methods 1 to 7, wherein the step of optically obtaining the first position information optically obtains the first position information about an interface position of one of the solid-gas interface and the solid-solid interface.

[0182] (Method 9)

[0183] According to the scanning method of any one of Methods 1 to 8, wherein the step of obtaining the second position information includes at least one of a step of setting an equation for calculating an interface position of the solid-liquid interface based on the first position information, a step of making a determination related to focusing on the solid-liquid interface, and a step of referring to previous information.

[0184] (Method 10)

[0185] A scanning method according to any one of Methods 1 to 9, wherein the solid-gas interface includes the interface between the front surface of the plate and the surrounding gas, and wherein the solid-solid interface includes the interface between the front surface of the plate and the solid material that contacts, deposits on, or forms on the front surface of the plate.

[0186] (Method 11)

[0187] A scanning method according to any one of Methods 1 to 10, wherein the step of obtaining the second position information sets an equation for calculating the interface position of the solid-liquid interface as the second position information.

[0188] (Method 12)

[0189] A scanning method according to any one of Methods 1 to 11, further comprising obtaining position adjustment information regarding position adjustment within the scanning range of the second region based on the second position information.

[0190] (Method 13)

[0191] A scanning method according to Method 12, wherein the main scan is performed based on the position adjustment information to optically scan the second region.

[0192] (Method 14)

[0193] A scanning method according to Method 13, wherein the main scan optically scans the second region by irradiating the array plate with focused light using a confocal optical system.

[0194] (Method 15)

[0195] A scanning method according to any one of Methods 1 to 14, wherein the step of obtaining the first position information obtains the first position information by irradiating the array plate with focused light using a confocal optical system.

[0196] (Method 16)

[0197] A scanning method according to any one of Methods 1 to 15, wherein the step of obtaining the first position information obtains information regarding the position of at least one of the solid-gas interface and the solid-solid interface in a direction perpendicular to a plane including the main scan direction and the sub-scan direction of the array plate as the first position information.

[0198] (Method 17)

[0199] The scanning method according to Method 16, wherein the step of obtaining the second position information obtains information about the position of the solid-liquid interface in the vertical direction as the second position information.

[0200] (Method 18)

[0201] The scanning method according to Method 17 further includes the step of obtaining position adjustment information for position adjustment in the vertical direction within the scanning range of the second region based on the second position information.

[0202] (Method 19)

[0203] The scanning method according to any one of Methods 1 to 18, wherein the step of obtaining the first position information obtains the first position information at two or more points in the first region.

[0204] (Method 20)

[0205] The scanning method according to Method 19, wherein the first region is present on both sides of the second region, and the first position information is obtained at positions on both sides of the second region.

[0206] (Method 21)

[0207] The scanning method according to any one of Methods 1 to 20, wherein the step of obtaining the first position information optically obtains third position information about the position of the rear surface of the array plate in addition to the first position information.

[0208] The present invention is not limited to the above embodiments, and various changes and modifications can be made without departing from the spirit and scope of the present invention. Therefore, the appended claims are attached to disclose the scope of the present invention.

[0209] This application claims priority based on Japanese Patent Application No. 2022-180542 filed on November 10, 2022, and Japanese Patent Application No. 2023-186775 filed on October 31, 2023, and incorporates the entire contents of these applications by reference.

[0210] Description of reference numerals

[0211] 1 Array plate

[0212] 1a, 1c First region

[0213] 1b Second region

[0214] 2 Substrate

[0215] 3 Spot

[0216] 5 Frame

[0217] 6 Observation liquid

[0218] 7 Reflective film

[0219] 8 Resin-coated film

[0220] 100 Support part

[0221] 200, 500 Observation optical system

[0222] 400 Information processing device

[0223] 401 First position information acquisition unit

[0224] 402 Second position information acquisition unit

[0225] 403 Position adjustment information acquisition unit.

Claims

1. A scanning method for optically scanning an array plate, the array plate including a plurality of spots on its front surface, the scanning method comprising: An interface forming step of forming at least one of a solid-gas interface and a solid-solid interface in a first region by bringing a gas or a solid into contact with the first region of the front surface of the plate, and forming a solid-liquid interface in a second region by bringing a liquid into contact with the second region of the front surface of the plate, the plurality of spots being included in the second region; A step of optically obtaining first position information on the interface position of at least one of the solid-gas interface and the solid-solid interface; And A step of obtaining second position information on the interface position of the solid-liquid interface based on the first position information.

2. The scanning method according to claim 1, further comprising a scanning step of forming an irradiation spot in the second region by irradiating the second region with primary light including focused light and moving the irradiation spot relative to the array plate.

3. The scanning method according to claim 2, further comprising a focusing step of adjusting a depth reference position of a depth of focus in the optical axis direction of the primary light relative to the solid-liquid interface based on the second position information.

4. The scanning method according to claim 3, wherein the scanning step is performed at the depth reference position adjusted by the focusing step.

5. The scanning method according to claim 3 or 4, wherein the focusing step is performed by adjusting at least one of a working distance between the array plate and an emission end of the primary light and a focal length of an objective optical system including the emission end.

6. The scanning method according to claim 1 or 2, wherein the first region does not include a region overlapping with the plurality of spots.

7. The scanning method according to claim 2 or 3, wherein the primary light is irradiated by a confocal optical system.

8. The scanning method according to claim 1 or 2, wherein the step of optically obtaining the first position information optically obtains the first position information on the interface position of one of the solid-gas interface and the solid-solid interface.

9. The scanning method according to claim 1 or 2, wherein the step of obtaining the second position information includes at least one of a step of setting an equation for calculating the interface position of the solid-liquid interface based on the first position information, a step of making a determination related to focusing on the solid-liquid interface, and a step of referring to previous information.

10. The scanning method according to claim 1 or 2, wherein the solid-gas interface includes an interface where the front surface of the plate contacts the surrounding gas, and wherein the solid-solid interface includes an interface where the front surface of the plate contacts a solid material, the solid material contacting, depositing on, or forming on the front surface of the plate.

11. The scanning method according to claim 1 or 2, wherein the step of obtaining the second position information is configured to calculate an equation for the interface position of the solid-liquid interface as the second position information.

12. The scanning method according to claim 1 or 2, further comprising obtaining position adjustment information for position adjustment within the scanning range of the second region based on the second position information.

13. The scanning method according to claim 12, wherein the main scan is performed based on the position adjustment information to optically scan the second region.

14. The scanning method according to claim 13, wherein the main scan optically scans the second region by irradiating the array plate with focused light using a confocal optical system.

15. The scanning method according to claim 1 or 2, wherein the step of obtaining the first position information obtains the first position information by irradiating the array plate with focused light using a confocal optical system.

16. The scanning method according to claim 1 or 2, wherein the step of obtaining the first position information obtains information about the position of at least one of the solid-gas interface and the solid-solid interface in a direction perpendicular to a plane, the plane including the main scan direction and the sub-scan direction of the array plate, as the first position information.

17. The scanning method according to claim 16, wherein the step of obtaining the second position information obtains information about the position of the solid-liquid interface in the perpendicular direction as the second position information.

18. The scanning method according to claim 17, further comprising a step of obtaining position adjustment information for position adjustment in the perpendicular direction within the scanning range of the second region based on the second position information.

19. The scanning method according to claim 1 or 2, wherein the step of obtaining the first position information obtains the first position information at two or more points in the first region.

20. The scanning method according to claim 19, wherein the first region exists on both sides of the second region, and the first position information is obtained at positions on both sides of the second region.

21. The scanning method according to claim 1 or 2, wherein the step of obtaining the first position information optically obtains third position information about the position of the rear surface of the array plate in addition to the first position information.

22. A scanning system for optically scanning an array plate, the array plate including a plurality of spots on its front surface, the scanning system comprising: a support portion configured to support the array plate such that at least one of a solid-gas interface and a solid-solid interface is formed in a first region by bringing a gas or a solid into contact with the first region of the front surface of the plate, and a solid-liquid interface is formed in a second region by bringing a liquid into contact with the second region of the front surface of the plate, the plurality of spots being included in the second region; an optical system configured to irradiate the spots with primary light and collect secondary light; A scanning unit configured to optically scan the array plate by changing a relative position between the array plate and the primary light; A first position information acquisition unit configured to optically acquire first position information about an interface position of at least one of the solid-gas interface and the solid-solid interface; And A second position information acquisition unit configured to acquire second position information about an interface position of the solid-liquid interface based on the first position information.

23. A position information acquisition method for acquiring information about a position of a surface of an array plate including a plurality of spots on the surface in a state where at least a part of the plurality of spots is in contact with a liquid, the position information acquisition method including: An interface formation step of forming at least one of a solid-gas interface and a solid-solid interface in a first region by bringing a gas or a solid into contact with the first region of the surface and forming a solid-liquid interface in a second region by bringing a liquid into contact with the second region of the surface, the plurality of spots being included in the second region; A step of optically acquiring first position information about an interface position of at least one of the solid-gas interface and the solid-solid interface; And A step of acquiring second position information about an interface position of the solid-liquid interface based on the first position information.

Images