Imaging device and operating method thereof

Abstract

Provided are an imaging device performing DNA sequencing imaging and an operating method thereof. The imaging device for imaging a DNA signal may: shift, to a unit pixel pitch or less of an image sensor, a position at which emission light emitted from a DNA sample irradiated with a beam is focused on the image sensor; acquire a plurality of images by using the image sensor to receive emission light that is focused at the shifted position on the image sensor; and synthesizing the plurality of acquired images to acquire a result image.

Description

Imaging device and method of operation thereof

[0001] The present disclosure relates to an imaging device and a method of operating the same. Specifically, the present disclosure discloses an imaging device for performing DNA sequencing imaging that images a fluorescent signal excited from a DNA sample, and a method of operating the same.

[0002] DNA sequencing imaging is a method of identifying the type of base by distinguishing and identifying the fluorescent signals of fluorescent substances (fluorophores) that emit different wavelengths (colors) bound to four types of bases. Since the performance of the imaging device (e.g., a fluorescent imaging device) is highly relevant in terms of sequencing accuracy, measurement time, and productivity, the imaging device needs to acquire precise and accurate fluorescent images.

[0003] To improve the accuracy of fluorescence images acquired by imaging devices, methods such as using objective lenses with a high numerical aperture (NA), structured light microscopes, or high-resolution image sensors can be considered, but these require complex optical structures.

[0004] One aspect of the present disclosure provides an imaging device for imaging a DNA signal. The imaging device may include a light source that irradiates a DNA sample with a beam. The imaging device may include an image sensor that receives emitted light emitted from the DNA sample irradiated with the beam. The imaging device may include at least one processor comprising processing circuitry. The imaging device may include a memory that stores one or more instructions.

[0005] By executing one or more instructions individually or collectively by at least one processor, the imaging device can shift the position where the emitted light is focused onto the image sensor by less than the unit pixel pitch of the image sensor. By executing one or more instructions individually or collectively by at least one processor, the imaging device can acquire multiple images by using the image sensor to receive the emitted light whose focused position is shifted onto the image sensor. By executing one or more instructions individually or collectively by at least one processor, the imaging device can synthesize the acquired multiple images to acquire a result image.

[0006] Another aspect of the present disclosure provides a method for an imaging device to image a DNA signal. The method may include the step of shifting the position at which emitted light emitted from a DNA sample irradiated with a beam is focused to an image sensor by a unit pixel pitch or less of the image sensor. The method may include the step of acquiring a plurality of images by receiving the emitted light, at which the position focused to the image sensor is shifted, using the image sensor. The method may include the step of synthesizing the acquired plurality of images to acquire a result image.

[0007] The present disclosure can be easily understood from the combination of the following detailed description and the accompanying drawings, where reference numerals denote structural elements.

[0008] FIG. 1 is a diagram illustrating the operation of an imaging device according to one embodiment of the present disclosure performing DNA sequencing imaging.

[0009] FIG. 2 is a flowchart illustrating a method in which an imaging device according to one embodiment of the present disclosure performs DNA sequencing imaging.

[0010] FIG. 3 is a flowchart illustrating a method for an imaging device according to one embodiment of the present disclosure to perform DNA sequencing imaging.

[0011] FIG. 4 is a block diagram illustrating the components of an imaging device according to one embodiment of the present disclosure.

[0012] FIG. 5 is a diagram showing the operation method of an imaging device according to one embodiment of the present disclosure.

[0013] FIG. 6 is a diagram illustrating the operation of an imaging device according to one embodiment of the present disclosure determining the tilt angle of a tilting plate.

[0014] FIG. 7 is a diagram illustrating the operation of an imaging device according to one embodiment of the present disclosure determining the tilt angle of a tilting plate.

[0015] FIG. 8 is a block diagram of an image synthesis device according to one embodiment of the present disclosure.

[0016] FIG. 9 is a diagram illustrating the relationship between the resolution of an image sensor and a DNA signal that can be identified through the image sensor according to one embodiment of the present disclosure.

[0017] FIG. 10a is a flowchart illustrating an example of a method for an imaging device according to one embodiment of the present disclosure to acquire a result image based on a plurality of fluorescent images.

[0018] FIG. 10b is a reference diagram for explaining an example of a method in which an imaging device according to one embodiment of the present disclosure acquires a result image based on a plurality of fluorescent images.

[0019] FIG. 11a is a flowchart illustrating an example of a method for an imaging device according to one embodiment of the present disclosure to acquire a result image based on a plurality of fluorescent images.

[0020] FIG. 11b is a reference diagram for explaining an example of a method in which an imaging device according to one embodiment of the present disclosure acquires a result image based on a plurality of fluorescent images.

[0021] FIG. 11c is a reference diagram for explaining an example of a method in which an imaging device according to one embodiment of the present disclosure acquires a result image based on a plurality of fluorescent images.

[0022] FIG. 12 is a schematic diagram of an imaging device including a plurality of image sensors according to one embodiment of the present disclosure.

[0023] FIG. 13a is a schematic diagram of an imaging device including a plurality of light sources according to one embodiment of the present disclosure.

[0024] FIG. 13b is a schematic diagram of an imaging device including a plurality of light sources according to one embodiment of the present disclosure.

[0025] FIG. 14 is a schematic diagram of an imaging device including a plurality of light sources and a plurality of image sensors according to one embodiment of the present disclosure.

[0026] FIG. 15a is a flowchart illustrating a method for an imaging device according to one embodiment of the present disclosure to perform DNA sequencing imaging.

[0027] FIG. 15b is a diagram illustrating the operation of an imaging device according to one embodiment of the present disclosure performing DNA sequencing imaging.

[0028] The terms used in the embodiments of this specification have been selected to be as widely used as possible, taking into account the functions of the present disclosure; however, these terms may vary depending on the intent of those skilled in the art, case law, the emergence of new technologies, etc. Additionally, in specific cases, terms have been arbitrarily selected by the applicant, and in such cases, their meanings will be described in detail in the description section of the relevant embodiments. Therefore, terms used in this specification should be defined not merely by their names, but based on their meanings and the overall content of the present disclosure.

[0029] Singular expressions may include plural expressions unless the context clearly indicates otherwise. Terms used herein, including technical or scientific terms, may have the same meaning as generally understood by those skilled in the art as described in this specification.

[0030] In this document, each of the phrases such as "A or B", "at least one of A and B", "at least one of A or B", "A, B or C", "at least one of A, B and C", and "at least one of A, B, or C" may include any one of the items listed together in the corresponding phrase, or all possible combinations thereof.

[0031] The term “and / or” includes a combination of multiple related described components or any of the multiple related described components.

[0032] Terms such as "first," "second," or "first" or "second" may be used simply to distinguish a component from another component and do not limit the components in other aspects (e.g., importance or order).

[0033] Throughout this disclosure, when a part is described as “comprising” a certain component, this means that, unless specifically stated otherwise, it does not exclude other components but may include additional components. Furthermore, terms such as “...part,” “...module,” etc., as used in this specification refer to a unit that processes at least one function or operation, and may be implemented in hardware or software, or as a combination of hardware and software.

[0034] The expression “configured to” as used in this disclosure may be replaced, depending on the context, with, for example, “suitable for,” “having the capacity to,” “designed to,” “adapted to,” “made to,” or “capable of.” The term “configured to” may not necessarily mean only “specifically designed to” in hardware. Instead, in some situations, the expression “system configured to” may mean that the system is “capable of” together with other devices or components. For example, the phrase “a processor configured (or set) to perform A, B, and C” may mean a dedicated processor for performing said operations (e.g., an embedded processor), or a generic-purpose processor (e.g., a CPU or an application processor) capable of performing said operations by executing one or more software programs stored in memory.

[0035] In addition, when a component is described in the present disclosure as being “connected” or “connected” to another component, it should be understood that the component may be directly connected to or directly connected to the other component, but unless otherwise specifically stated, it may also be connected or connected through another component in between.

[0036] All functions or operations described in this disclosure may be processed individually by a single processor and / or collectively by a plurality of processors. A single processor or a combination of a plurality of processors may include circuitry that performs processing, such as an Application Processor (AP), Communication Processor (CP), Graphical Processing Unit (GPU), Neural Processing Unit (NPU), Microprocessor Unit (MPU), System on Chip (SoC), Integrated Chip (IC), etc.

[0037] It should be understood that the blocks and combinations of flowcharts in the flowcharts illustrated in the present disclosure may be performed by one or more computer programs comprising computer-executable instructions. The one or more computer programs may be stored all in a single memory or may be divided and stored in multiple different memories.

[0038] One embodiment of the present disclosure may be represented by functional block configurations and various processing steps. Some or all of these functional blocks may be implemented by various numbers of hardware and / or software configurations that execute specific functions. For example, the functional blocks of the present disclosure may be implemented by one or more microprocessors or by circuit configurations for a specific function. Additionally, for example, the functional blocks of the present disclosure may be implemented in various programming or scripting languages. The functional blocks may be implemented as algorithms executed on one or more processors. Furthermore, the present disclosure may employ prior art for electronic configuration, signal processing, and / or data processing, etc.

[0039] In the present disclosure, 'DNA sequencing imaging' refers to an imaging technique that visually displays the base sequence (A, T, C, G) of DNA. In one embodiment of the present disclosure, DNA sequencing imaging may include a Fluorescence In Situ Hybridization (FISH) method, which involves binding a fluorescent dye to a specific DNA sequence among A, T, C, and G to image the corresponding DNA region in real time using an imaging device such as a microscope.

[0040] In the present disclosure, 'fluorophore' refers to a compound that absorbs light of a specific wavelength and emits light of another wavelength. In the present disclosure, the fluorophore emits fluorescent signals of different wavelengths depending on the DNA base sequence, thereby enabling an imaging device to identify and image the DNA base sequence through the fluorescent signals.

[0041] In the present disclosure, a 'DNA sample' may be a sample or specimen observed by an imaging device (100) and may be an object subject to testing and / or analysis. The DNA sample may contain at least one gene base. For example, the DNA sample may be a genetic biological tissue such as a cell, protein, or tissue. In one embodiment of the present disclosure, the DNA sample may be a sample treated with a plurality of fluorophores. A fluorophor may be a substance that emits a fluorescent signal when irradiated with light of a predetermined wavelength or a predetermined range of wavelengths. A predetermined fluorescent substance may be pre-treated on the DNA sample before the imaging device (100) is used.

[0042] In the present disclosure, the 'sampling interval' may refer to the interval of information that an image sensor can collect during the process of generating a digital image to convert a continuous analog signal into a digital signal. The shorter the sampling interval, the more detailed digital image information can be collected. The sampling interval may correspond to the pixel size or pixel pitch of the image sensor.

[0043] In the present disclosure, 'optical resolution' may be defined as the minimum distance at which an optical device can distinguish two objects or points. Optical resolution may represent the ability of an optical device to capture fine images. Optical resolution may be influenced by the wavelength of light, numerical aperture (NA), etc., and optical devices with higher optical resolution can output images with higher resolution and finer details.

[0044] In the present disclosure, 'NA (numerical aperture)' is a physical parameter that determines the light collection capability and resolution of an optical device (objective lens, microscope, or image sensor, etc.). NA can be determined by the following formula.

[0045] Mathematical formula 1:

[0046]

[0047] In the above mathematical formula 1, n is the refractive index of the medium, and θ represents the maximum half-angle that the optical device can collect. That is, NA is determined by the refractive index of the medium and the maximum angle at which light can be incident on the lens. As NA increases, the size of the point formed by the lens becomes smaller, and as a result, the resolution increases.

[0048] Embodiments of the present disclosure are described below with reference to the attached drawings so that those skilled in the art can easily implement them. However, the present disclosure may be embodied in various different forms and is not limited to the embodiments described herein.

[0049] Embodiments of the present disclosure will be described in detail below with reference to the drawings.

[0050] FIG. 1 is a diagram illustrating the operation of an imaging device (100) according to one embodiment of the present disclosure performing DNA sequencing imaging.

[0051] The imaging device (100) may be an optical device that performs DNA sequencing imaging by using a light source (10) to irradiate a beam toward a DNA sample (200) and imaging the emitted light emitted from the DNA sample (200) by the irradiated beam to obtain an image representing a DNA base sequence (A, T, C, G). In one embodiment of the present disclosure, the imaging device (100) may be implemented as an optical device such as an optical microscope, a fluorescence microscope, a super-resolution imaging system, or a multispectral analysis system.

[0052] In FIG. 1, only essential components for explaining the function and / or operation of the imaging device (100) are illustrated, and the components included in the imaging device (100) are not limited to those illustrated in FIG. 1. The components included in the imaging device (100) will be described in detail with reference to FIG. 3 and FIG. 4.

[0053] Referring to FIG. 1, an imaging device (100) may include a light source (10) and an image sensor (20). The imaging device (100) may irradiate a beam toward a DNA sample (200) using the light source (10). The imaging device (100) may receive the emitted light emitted from the DNA sample (200) by the irradiated beam using the image sensor (20). When the beam is irradiated onto the DNA sample (200), the image sensor (20) may acquire the emitted light generated as the fluorescent material contained in the DNA sample (200) is excited. The imaging device (100) may acquire an image (or also referred to as a fluorescent image) by imaging the emitted light (or converting the emitted light into an electrical signal) using the image sensor (20).

[0054] In one embodiment of the present disclosure, the imaging device (100) can control the position where the emitted light is focused to the image sensor (20) so that it is shifted to a unit pixel pitch or less of the image sensor (20). The position where the emitted light is focused to the image sensor (20) may correspond to the position of the pixel among the pixels of the image sensor (20) where the emitted light is focused. In the present disclosure, the position where the emitted light is focused in the image sensor (20) may also be referred to as the light receiving area of ​​the image sensor (20), the pixel sensor area of ​​the image sensor (20), or the photodiode area of ​​the image sensor (20).

[0055] An imaging device (100) can acquire multiple images (311, 312) for a single DNA sample (200) by receiving emission light in which the position (L1, L2) at which the emission light is focused to the image sensor (20) is shifted one or more times. The imaging device (100) can acquire multiple images (311, 312) corresponding to each of the emission light focused to different positions on the image sensor (20). FIG. 1 is illustrated as acquiring two images (311, 312) by receiving emission light in which the position (L1, L2) at which the emission light is focused to the image sensor (20) is shifted one time, but the present disclosure is not limited thereto. In one embodiment of the present disclosure, the imaging device (100) may acquire three or more multiple images by shifting the position at which the emission light is focused to the image sensor (20) two or more times.

[0056] In one embodiment of the present disclosure, the imaging device (100) may further include a tilting plate (50) positioned between a DNA sample (200) and an image sensor (20). The tilting plate (50) may be positioned in front of the image sensor (20) which is more adjacent to the DNA sample (200). In one embodiment of the present disclosure, the imaging device (100) may use the tilting plate (50) to control the position where the emitted light is concentrated at the image sensor (20). The imaging device (100) may control the position where the emitted light is concentrated at the image sensor (20) by controlling the tilt angle of the tilting plate (50). The tilting plate (50) may be positioned in the middle of the path where the emitted light is concentrated at the image sensor (20). Accordingly, as the emitted light passes through the tilting plate (50) which is tilted at a predetermined angle, the position where it is concentrated at the image sensor (20) may be changed. In the present disclosure, the tilting plate (50) may also be referred to as a micro-light moving element.

[0057] In FIG. 1, an operation of controlling the tilt angle of a tilting plate (50) to shift the position where the emitted light is concentrated on the image sensor (20) is illustrated as an example, but the embodiment is not limited thereto. In one embodiment of the present disclosure, the imaging device (100) may directly shift the position of the image sensor (20) to a unit pixel pitch or less of the image sensor (20) to shift the position where the emitted light is concentrated on the image sensor (20). In this case, the imaging device (100) may not include a tilting plate (50). An embodiment of shifting the position of the image sensor (20) will be described later with reference to FIG. 15a and FIG. 15b.

[0058] An imaging device (100) can obtain a result image (320) by synthesizing (or combining) a plurality of images (311, 312) obtained by varying the positions (L1, L2) at which the emitted light is focused on the image sensor (20). For example, the result image (320) may be data that visually represents a fluorescent signal obtained by analyzing any one of the bases adenine (A), thymine (T), cytosine (C), and guanine (G) in a DNA sample (200). In one embodiment of the present disclosure, the imaging device (100) can obtain a result image (320) having a higher resolution than the resolution of each of the plurality of images (311, 312) by synthesizing (or combining) a plurality of images (311, 312) in which the light-focusing position at the image sensor (20) is moved by a distance smaller than the pixel pitch. An imaging device (100) according to one embodiment of the present disclosure can improve the accuracy of sample observation (e.g., cell structure observation, protein sample detection, or gene sequencing) without complex structural changes.

[0059] FIG. 2 is a flowchart illustrating a method in which an imaging device (100) according to one embodiment of the present disclosure performs DNA sequencing imaging. Hereinafter, the function and / or operation of the imaging device (100) will be described in detail with reference to the flowchart of FIG. 2 together with the embodiment illustrated in FIG. 1.

[0060] Referring to FIG. 2, a method for an imaging device (100) to perform DNA sequencing imaging may include steps S210 to S230. In one embodiment of the present disclosure, steps S210 to S230 may be executed by at least one processor included in the imaging device (100). A method for an imaging device (100) to perform DNA sequencing imaging is not limited to that illustrated in FIG. 2, and in one or more embodiments may further include steps not illustrated in FIG. 2.

[0061] In step S210 of FIG. 2, the imaging device (100) according to one embodiment of the present disclosure can shift the position where the emitted light is focused to the image sensor (20) to a unit pixel pitch or less of the image sensor (20).

[0062] Referring together with FIG. 1, the imaging device (100) can irradiate a beam toward a DNA sample (200) using a light source (10). When the beam is irradiated toward the DNA sample (200), the fluorescent material contained in the DNA sample (200) is excited, and thus the emitted light may be emitted from the DNA sample (200).

[0063] For example, first, the imaging device (100) can focus the emitted light at a first position (L1) of the image sensor (20). In other words, the emitted light can be received by pixels of the image sensor (20) that correspond to the first position (L1) (or first region). FIG. 1 illustrates only the emitted light focused at the first position (L1) corresponding to a single point for convenience of explanation, but a set of one or more pixels that receive the emitted light in the image sensor (20) may correspond to the first position (L1) (or first region).

[0064] Subsequently, the imaging device (100) can focus the emitted light at a second location (L2) of the image sensor (20). In other words, the emitted light can be received by pixels of the image sensor (20) that correspond to the second location (L2) (or second region). The second location (L2) may be a location located at a distance less than or equal to the unit pixel pitch of the image sensor (20) from the first location (L1). FIG. 1 illustrates only the emitted light focused at the second location (L2) corresponding to a single point for convenience of explanation, but a set of one or more pixels receiving the emitted light in the image sensor (20) may correspond to the second location (L2) (or second region).

[0065] The direction in which the imaging device (100) shifts the position where the emitted light is focused at the image sensor (20) is not limited to any one embodiment. In the present disclosure, a direction extending along the X-axis is defined as the first direction (D1), and a direction extending along the Y-axis is defined as the second direction (D2). A direction extending in the opposite direction of the first direction (D1) along the X-axis is defined as the third direction (D3), and a direction extending in the opposite direction of the second direction (D2) along the Y-axis is defined as the fourth direction (D4). The imaging device (100) can shift the position where the emitted light is focused at the image sensor (20) to any one of the first direction (D1), the second direction (D2), the third direction (D3), or the fourth direction (D4). Alternatively, the imaging device (100) may shift the position where the emitted light is focused at the image sensor (20) to a combination of a first direction (D1) or a third direction (D3) extending along the X-axis and a second direction (D2) or a fourth direction (D4) extending along the Y-axis. FIG. 1 illustrates, by way of example, that the second position (L2) is shifted from the first position (L1) to the fourth direction (D4).

[0066] FIG. 1 illustrates, by way of example, that the second position (L2) is shifted from the first position (L1) by a 1 / 2 pixel pitch, but the degree of shifting is not limited to any one embodiment. In one example, the imaging device (100) may shift the position where the emitted light is focused at the image sensor (20) by a 1 / 3 pixel pitch.

[0067] In one embodiment of the present disclosure, the imaging device (100) can control the position where the emitted light is focused to the image sensor (20) by using a tilting plate (50). The imaging device (100) can control the position where the emitted light is focused to the image sensor (20) by controlling the tilt angle of the tilting plate (50). This will be explained in detail with reference to FIG. 3.

[0068] In one embodiment of the present disclosure, the imaging device (100) can control the position of the image sensor (20) to control the position where the emitted light is concentrated on the image sensor (20). The imaging device (100) can directly shift the position of the image sensor (20) to a unit pixel pitch or less of the image sensor (20). This will be explained in detail with reference to FIGS. 15a and FIGS. 15b.

[0069] In step S220 of FIG. 2, an imaging device (100) according to one embodiment of the present disclosure can acquire a plurality of images by using an image sensor (20) to receive emitted light at a position shifted to be focused on the image sensor (20).

[0070] Referring together with FIG. 1, the imaging device (100) can acquire an image by using an image sensor (20) to image the emitted light generated as a fluorescent substance contained in a DNA sample (200) is excited (or by converting the emitted light into an electrical signal). In this case, in one embodiment of the present disclosure, the imaging device (100) can acquire a plurality of images (311, 312) for a single DNA sample (200). The imaging device (100) can acquire a plurality of images (311, 312) by receiving the emitted light emitted from a single DNA sample (200) and focused to the image sensor (20), the position of which is shifted one or more times.

[0071] For example, the imaging device (100) can acquire a first image (311) by focusing the emitted light at a first position (L1) of the image sensor (20). The imaging device (100) can acquire a second image (312) by focusing the emitted light at a second position (L2) of the image sensor (20). Since the second position (L2) corresponds to a position shifted from the first position (L1) by a distance less than or equal to the unit pixel pitch of the image sensor (20), the fluorescence signal imaged in the first image (311) may appear shifted entirely by a distance less than or equal to the unit pixel pitch in the second image (312). Accordingly, corresponding pixels in the first image (311) and the second image (312) may partially overlap.

[0072] In step S230 of FIG. 2, an imaging device (100) according to one embodiment of the present disclosure can synthesize a plurality of acquired images to obtain a result image (320).

[0073] Referring together with FIG. 1, the imaging device (100) can obtain a result image (320) by synthesizing (or combining) a plurality of images (311, 312) each obtained by receiving emitted light that is shifted at a position focused by an image sensor (20) one or more times. The imaging device (100) can obtain a high-resolution result image (320) by synthesizing (or combining) a plurality of images (311, 312) in which corresponding pixels partially overlap. Accordingly, the resolution of the result image (320) may be higher than the resolution of the plurality of images (311, 312).

[0074] In one embodiment of the present disclosure, the imaging device (100) may generate a result image (320) by directly synthesizing (or combining) a plurality of images (311, 312). Meanwhile, the embodiment is not limited thereto, and in one embodiment of the present disclosure, the imaging device (100) may obtain a result image (320) by receiving a result image (320) in which a plurality of images are synthesized (or combined) from an external device (e.g., an image synthesis device). At this time, the external device (e.g., an image synthesis device) may be a computer system or a part of a computer system connected to the imaging device (100) via a wired or wireless communication network. The external device (e.g., an image synthesis device) may receive a plurality of images (311, 312) from the imaging device (100) and transmit the result image (320) to the imaging device (100).

[0075] In one embodiment of the present disclosure, an imaging device (100) can obtain a result image (320) by synthesizing a plurality of images (311, 312) using various image synthesis algorithms. For example, the imaging device (100) can combine a plurality of images by simply integrating and aligning the pixel values ​​of corresponding pixels of a plurality of images. For example, the imaging device (100) can synthesize a plurality of images by calculating the average of the pixel values ​​of corresponding pixels of a plurality of images. For example, the imaging device (100) can synthesize a plurality of images by summing the pixel values ​​of corresponding pixels of a plurality of images, while assigning weights to each image to sum the pixel values. For example, the imaging device (100) can synthesize a plurality of images by using the maximum or minimum value of the pixel values ​​of corresponding pixels of a plurality of images.

[0076] For example, an imaging device (100) can obtain a result image (320) by combining a first image (311) obtained by focusing the emitted light at a first position (L1) and a second image (312) obtained by focusing the emitted light at a second position (L2) shifted from the first position (L1) by a distance of less than or equal to a unit pixel pitch (e.g., 1 / 2 pixel pitch). FIG. 1 illustrates the synthesis of two images (311, 312) as an example, but the number of images synthesized to generate the result image (320) is not limited thereto.

[0077] DNA sequencing imaging is a method of identifying the type of base by distinguishing and identifying the fluorescent signals of fluorescent substances (fluorophores) that emit different wavelengths (colors) bound to four types of bases. Since the performance of the imaging device (100) (e.g., fluorescent imaging device) is highly relevant in terms of sequencing accuracy, measurement time, and productivity, the imaging device (100) needs to acquire a precise and accurate fluorescent image.

[0078] To improve the accuracy of fluorescence images acquired by the imaging device, one could consider using a high numerical aperture (NA) objective lens with high resolution; however, this may result in a trade-off between the depth of focus and the imaging range.

[0079] To increase the accuracy of fluorescence images acquired by an imaging device, one could consider using structured illumination microscopy (SI) technology, which can improve resolution by twofold based on the principle of frequency-space signal synthesis using structured light; however, this may result in a problem where a complex optical configuration including a diffraction element or a spatial light modulator (SLM), digital micromirror device (DMD) is required to generate structured light.

[0080] To improve the accuracy of fluorescence images acquired by an imaging device, one could consider using a high-resolution image sensor with a small unit pixel size and a high pixel count; however, high-pixel image sensors are limited in variety and expensive, and as the unit pixel size becomes too small, the inspection area narrows, which can lead to a problem of reduced sensitivity.

[0081] The present disclosure enables the output of a final high-resolution result image for a specific DNA sample by synthesizing multiple images obtained by different positions at which emitted light is focused from the image sensor (20) when performing DNA sequencing imaging to image a DNA signal. Through this, the imaging device (100) according to one embodiment of the present disclosure can improve the accuracy of DNA sequencing without complex structural changes (e.g., using an expensive high-resolution image sensor, using an objective lens with a high numerical aperture (NA), applying structured illumination microscopy (SI) technology, etc.). Accordingly, the imaging device (100) according to one embodiment of the present disclosure can improve inspection precision (image quality, resolution) in DNA sequencing imaging without complex system design and high costs.

[0082] FIG. 3 is a flowchart illustrating a method in which an imaging device (100) according to one embodiment of the present disclosure performs DNA sequencing imaging. Hereinafter, the function and / or operation of the imaging device (100) will be described in detail with reference to the flowchart of FIG. 3 together with the embodiment illustrated in FIG. 1.

[0083] Referring to FIG. 3, a method for an imaging device (100) to perform DNA sequencing imaging may include step S310. In one embodiment of the present disclosure, step S810 may be executed by at least one processor (30) included in the imaging device (100). The operation of step S310 illustrated in FIG. 3 is a specific embodiment of the operation of S210 illustrated in FIG. 2. After the operation of step S310 illustrated in FIG. 3 is performed, the operation of S220 illustrated in FIG. 2 may be performed.

[0084] In step S310 of FIG. 3, the imaging device (100) according to one embodiment of the present disclosure can adjust the tilt angle of the tilting plate (50) so that the position where the emitted light passes through the tilting plate (50) and is focused to the image sensor (20) is shifted by less than a unit pixel pitch.

[0085] Referring together with FIG. 1, the tilting plate (50) may be positioned in front of the image sensor (20) which is closer to the DNA sample (200). The tilting plate (50) may be positioned in the middle of the path where the emitted light emitted from the DNA sample (200) is concentrated to the image sensor (20). Accordingly, the position where the emitted light emitted from the DNA sample (200) is concentrated at the image sensor (20) may be determined by the tilting angle of the tilting plate (50).

[0086] For example, first, the imaging device (100) can receive emitted light from a DNA sample (200) through an image sensor (20) while the tilting plate (50) is tilted at a first angle. At this time, the emitted light from the DNA sample is focused at a first position (L1) (or first region) among the pixels of the image sensor (20), and the pixel corresponding to the first position (L1) (or first region) can respond and convert the emitted light into an electrical signal.

[0087] Subsequently, for example, the imaging device (100) can change the tilt angle of the tilting plate (50) from a first angle to a second angle. FIG. 1 illustrates, by way of example, that the imaging device (100) further tilts the tilting plate (50) in a fourth direction (D4), but the tilting direction and the tilting angle are not limited to any one embodiment. For example, the first angle or the second angle may be 0 degrees, and the tilting plate (50) with a tilt angle of 0 degrees may be positioned perpendicular to the direction in which light passes.

[0088] Subsequently, the imaging device (100) can receive emitted light from a DNA sample (200) through an image sensor (20) while the tilting plate (50) is tilted at a second angle. At this time, the emitted light emitted from the DNA sample (200) is focused at a second position (L2) (or second region) among the pixels of the image sensor (20), and the pixel corresponding to the second region (or second region) can respond to convert the emitted light into an electrical signal. The emitted light can be received at a second position (L2) (or second region) that is shifted by a distance less than or equal to the unit pixel pitch of the image sensor (20) from a first position (L1) (or first region).

[0089] The imaging device (100) can acquire a first image (311) when the tilting plate (50) is tilted at a first angle. That is, the imaging device (100) can acquire the first image (311) by receiving the emitted light that has passed through the tilting plate (50) tilted at the first angle. The imaging device (100) can acquire a second image (312) when the tilting plate (50) is tilted at a second angle. That is, the imaging device (100) can acquire the second image (312) by receiving the emitted light that has passed through the tilting plate (50) tilted at the second angle. The imaging device (100) can acquire a second image (312) different from the first image (311) as the position where the emitted light is collected at the image sensor (20) is changed by changing the tilt angle of the tilting plate (50).

[0090] According to one embodiment of the present disclosure, the imaging device (100) can obtain a result image (320) with improved resolution without changing the internal structure of the imaging device (100) (e.g., changing to a high numerical aperture objective lens or changing to a structured light microscope) by synthesizing a plurality of images (311, 312) obtained by changing the tilt angle of the tilting plate (50) to generate (or obtain) a result image (320).

[0091] In one embodiment of the present disclosure, the imaging device (100) can determine the tilt angle of the tilting plate (50) based on the refractive index of the tilting plate (50) and the thickness of the tilting plate (50). Based on Snell's law, the imaging device (100) can derive the angle at which the tilting plate (50) must be tilted from the refractive index of the tilting plate (50) and the thickness of the tilting plate (50) so that the position where the emitted light is focused on the image sensor (20) is shifted by a preset distance. In this regard, a detailed explanation will be provided with reference to FIGS. 6 and FIGS. 7.

[0092] In one embodiment of the present disclosure, the imaging device (100) can mechanically adjust the tilt angle of the tilting plate (50). The imaging device (100) may further include a mechanical device for controlling the tilt angle of the tilting plate (50). The imaging device (100) can control the tilt angle of the tilting plate (50) using the mechanical device.

[0093] A mechanical device can control the tilt angle of the tilting plate (50) through mechanical force and structural interaction without using electrical or electronic signals. For example, the mechanical device may include a gear mechanism, a screw adjustment mechanism, a cam mechanism, a lever mechanism, a spring mechanism, or a wheel and pulley system.

[0094] In one embodiment of the present disclosure, the imaging device (100) can electronically adjust the tilt angle of the tilting plate (50). The imaging device (100) may further include an electronic device for controlling the tilt angle of the tilting plate (50). The imaging device (100) can control the tilt angle of the tilting plate (50) using the electronic device.

[0095] The electronic device can control the tilt angle of the tilting plate (50) by using electrical or electronic signals (e.g., conversion and control of electrical signals). The electronic device may include a digital control system for signal processing and control, and this system may be controlled by a microprocessor or a microcontroller. For example, the electronic device may include an actuator and / or a sensor (e.g., an angle sensor or a tilt sensor). Examples of actuators may include a piezo actuator, an electric actuator (e.g., a servo motor), a pneumatic actuator, a hydraulic actuator, etc.

[0096] In one embodiment of the present disclosure, the imaging device (100) can finely control the tilt angle of the tilting plate (50) using a piezo actuator. The piezo actuator can receive an electrical signal and cause deformation of the piezoelectric material (e.g., piezoceramic or piezoceramic polymer) contained in the piezo actuator. The piezo actuator can control the tilt angle of the tilting plate (50) by transmitting this deformation to the tilting plate (50). For example, the piezo actuator can be connected to the tilting plate (50) via a lever system or a hinge structure, and the tilt angle of the tilting plate (50) can be changed by changing the linear deformation of the piezoelectric material of the piezo actuator into an angular deformation. In one embodiment of the present disclosure, it is necessary to finely control the tilt angle of the tilting plate (50) so that the position where the emitted light is focused on the image sensor (20) is shifted by a unit pixel pitch or less. At this time, the piezo actuator can cause a fine linear deformation from the electrical signal, thereby allowing the tilt angle of the tilting plate (50) to be finely controlled. Accordingly, the imaging device (100) can precisely control the position where the emitted light is focused to a level of unit pixel or less, so that the emitted light can be accurately shifted to a preset distance. The imaging device (100) can acquire a plurality of images (311, 312) in which the shift distance of the light-focusing position is precisely controlled, and by generating a result image (320) based on these plurality of images (311, 312), the accuracy of the analysis of the fluorescence signal can be increased.

[0097] FIG. 4 is a block diagram illustrating the components of an imaging device (100) according to one embodiment of the present disclosure.

[0098] The imaging device (100) is an optical device configured to perform DNA sequencing imaging. In the present disclosure, 'DNA sequencing imaging' refers to an imaging technique that visually displays the base sequences (A, T, C, G) of DNA. In one embodiment of the present disclosure, DNA sequencing imaging may include a Fluorescence In Situ Hybridization (FISH) method, which involves binding a fluorescent dye to a specific DNA sequence among A, T, C, and G to image the corresponding DNA region in real time through an imaging device such as a microscope. In one embodiment of the present disclosure, the imaging device (100) may be implemented as an optical device such as an optical microscope, a fluorescence microscope, a super-resolution imaging system, or a multispectral analysis system.

[0099] Referring to FIG. 4, an imaging device (100) according to one embodiment of the present disclosure may include a light source (10), an image sensor (20), a processor (30), a memory (40), and a tilting plate (50). The light source (10), the image sensor (20), the processor (30), the memory (40), and the tilting plate (50) may each be electrically and / or physically connected to each other. Meanwhile, in one embodiment of the present disclosure, the tilting plate (50) may be omitted. FIG. 4 illustrates only essential components for explaining the function and / or operation of the imaging device (100), and the components included in the imaging device (100) are not limited to those illustrated in FIG. 4. Although not illustrated in the drawings, in one embodiment of the present disclosure, if the imaging device (100) includes a tilting plate (50), it may further include a control unit (e.g., an actuator, etc.) for controlling the tilt angle of the tilting plate (50).

[0100] According to one embodiment of the present disclosure, the light source (10) may be a device or component that emits light. The light source (10) may be configured to provide uniform illumination with constant intensity. The light source (10) may include one or more of light sources (10) having various optical characteristics, such as a laser diode, a laser, a light-emitting diode (LED), a halogen lamp, a metal halide lamp, or a fluorescent lamp.

[0101] According to one embodiment of the present disclosure, the light source (10) may be a device or component that emits light. The light source (10) may be a device that irradiates light onto a DNA sample on a flow cell.

[0102] In one embodiment of the present disclosure, the light source (10) may be configured to provide uniform illumination with a constant intensity, such as a uniform beam. However, the embodiment is not limited thereto, and the light source (10) may be configured to provide illumination having a specific pattern, such as a pattern beam, or may be configured to provide illumination spreading in a specific shape, such as a circular beam or a square beam.

[0103] In one embodiment of the present disclosure, the light source (10) may include one or more of the following light sources having various optical characteristics: a laser diode, an LED (Light Emitting Diode), a halogen lamp, a metal halide lamp, or a fluorescent lamp.

[0104] In one embodiment of the present disclosure, the light emitted from the light source (10) may be a laser. The wavelength of the laser emitted by the light source (10) may be within a certain range. For example, the wavelength of the laser emitted by the light source (10) may be within the range of the excitation wavelength of the fluorescent dye treated on the DNA sample.

[0105] In one embodiment of the present disclosure, the light source (10) may emit polychromatic light. The light emitted by the light source (10) may be broadband light or light whose wavelength changes over time. The wavelength band of the broadband light may be controlled and adjusted to within the range of the excitation wavelength of the fluorescent material treated on the DNA sample. Additionally, the wavelength range of the light whose wavelength changes over time may be controlled and adjusted to within the range of the excitation wavelength of the fluorescent material treated on the DNA sample.

[0106] In one embodiment of the present disclosure, the light source (10) may emit single-wavelength or multi-wavelength light and may be combined with a filter or a spectrometer to irradiate light having specific spectral characteristics.

[0107] In one embodiment of the present disclosure, the imaging device (100) may include a plurality of light sources (10). An embodiment in which the imaging device (100) includes a plurality of light sources (10) will be described in detail with reference to FIG. 13a, FIG. 13b, and FIG. 14.

[0108] In one embodiment of the present disclosure, the image sensor (20) can detect emitted light (e.g., a fluorescent signal). The image sensor (20) can obtain information about the composition of the DNA sample (200) based on the detected fluorescent signal. For example, the image sensor (20) can obtain a plurality of images containing information about the location where the fluorescent signal was emitted from the DNA sample (200) based on at least one beam.

[0109] A fluorescent substance contained in a DNA sample (200) can be excited by a beam irradiated through a light source (10). The beam irradiated from the light source (10) may correspond to the excitation light of the DNA sample (200). When the beam corresponding to the excitation light is irradiated onto the DNA sample (200), emission light of a wavelength different from the wavelength of the irradiated excitation light may be generated. The emission light may have a longer wavelength than the beam corresponding to the excitation light. An image sensor (20) can receive the emission light emitted from the DNA sample (200).

[0110] In one embodiment of the present disclosure, an image sensor (20) can acquire at least one emitted light emitted from a DNA sample (200) as at least one beam is irradiated toward the DNA sample (200). The image sensor (20) can acquire a plurality of images corresponding to each of the at least one emitted light. The plurality of images can be acquired by receiving the emitted light that has passed through a tilting plate (50) tilted at different angles.

[0111] In one embodiment of the present disclosure, the imaging device (100) may include a plurality of image sensors (20). An embodiment in which the imaging device (100) includes a plurality of image sensors (20) will be described in detail with reference to FIG. 12 and FIG. 14.

[0112] In one embodiment of the present disclosure, a tilting plate (50) may be positioned between a DNA sample (200) and an image sensor (20). The tilting plate (50) may be positioned in front of the image sensor (20) that is closer to the DNA sample (200). The tilting plate (50) may be positioned in front of the image sensor (20) adjacent to the DNA sample (200). The tilting plate (50) may be positioned facing the pixels of the image sensor (20) where the emitted light is focused. The tilting plate (50) may be positioned between the image sensor (20) and a lens (e.g., a tube lens) that focuses the emitted light. The tilting plate (50) may be positioned in the middle of the path where the emitted light is focused to the image sensor (20).

[0113] In one embodiment of the present disclosure, the tilting plate (50) may have the form of a flat plate with a constant thickness. The tilting plate (50) may be composed of a material through which light can pass.

[0114] In one embodiment of the present disclosure, the tilting plate (50) may include a low-dispersion material. By including a low-dispersion material in the tilting plate (50), chromatic aberration can be reduced (or corrected), so that an image with minimized distortion can be provided even when the emitted light passes through the tilting plate (50). Chromatic aberration refers to a phenomenon in which some colors of an image appear blurry or unclear as the focus changes depending on the wavelength (or color) of the light.

[0115] In one embodiment of the present disclosure, the tilting plate (50) may include a high refractive index material. The tilting plate (50) may include a material with a high Abbe number. By strengthening the degree of refraction of light passing through the tilting plate (50), fine focus setting and fine light path control may be possible. Accordingly, image clarity may be maintained even when the emitted light passes through the tilting plate (50).

[0116] In one embodiment of the present disclosure, the tilting plate (50) may include glass. The tilting plate (50) may be a glass substrate. Since the glass corresponds to a low-dispersion material and a high-refractive index material, when the imaging device (100) includes a tilting plate (50) of a glass substrate, a high-clarity image can be obtained.

[0117] In one embodiment of the present disclosure, the tilt angle of the tilting plate (50) may be mechanically adjusted. The imaging device (100) may further include a mechanical device for controlling the tilt angle of the tilting plate (50). Since the mechanical device has been described in detail with reference to FIG. 3, a redundant description will be omitted.

[0118] In one embodiment of the present disclosure, the tilt angle of the tilting plate (50) may be electronically adjusted. The imaging device (100) may further include an electronic device for controlling the tilt angle of the tilting plate (50). For example, the imaging device (100) may further include a piezo actuator for controlling the tilt angle of the tilting plate (50). The imaging device (100) can precisely control the tilt angle of the tilting plate (50) to a level of unit pixel pitch or less by using the piezo actuator. Since the electronic device has been described in detail with reference to FIG. 3, a redundant description will be omitted.

[0119] In one embodiment of the present disclosure, the tilting plate (50) may include a plurality of tilting plates (50). For example, if the imaging device (100) includes a plurality of image sensors (20), the tilting plate (50) may also include a plurality of tilting plates (50) corresponding to each of the plurality of image sensors (20). An embodiment in which the imaging device (100) includes a plurality of tilting plates (50) will be described in detail with reference to FIGS. 12 and FIGS. 14.

[0120] The processor (30) can execute one or more instructions of a program stored in memory (40). The processor (30) may be composed of hardware components that perform arithmetic, logic, and input / output operations and image processing. Although the processor (30) is depicted as a single element in FIG. 4, it is not limited thereto. In one embodiment of the present disclosure, the processor (30) may be composed of one or more elements.

[0121] The processor (30) may include various processing circuits and / or multiple processors. For example, the term 'processor' as used in the present disclosure, including in the claims, may include at least one processor (30) and various processing circuits. In the at least one processor (30), one or more processors may be configured to perform the various functions described herein in a distributed manner, individually and / or collectively. As used in the present disclosure, 'processor', 'at least one processor', and 'one or more processors' may be configured to perform various functions. However, these terms cover, without limitation, situations where one processor performs some of the functions and other processor(s) perform other parts of the functions, and situations where a single processor can perform all functions. Additionally, the at least one processor (30) may include a combination of processors performing various functions of the disclosed functions in a distributed manner. The at least one processor (30) may execute program instructions to achieve or perform various functions.

[0122] The processor (30) may be implemented as a general-purpose processor such as a CPU (Central Processing Unit), AP (Application Processor), DSP (Digital Signal Processor), a graphics-dedicated processor such as a GPU (Graphic Processing Unit) or VPU (Vision Processing Unit), or an artificial intelligence-dedicated processor such as an NPU (Neural Processing Unit). The processor (30) may be controlled to process input data according to predefined operation rules or an artificial intelligence model. Alternatively, if the processor (30) is an artificial intelligence-dedicated processor, the artificial intelligence-dedicated processor may be designed with a hardware structure specialized for processing a specific artificial intelligence model.

[0123] The memory (40) may be composed of at least one type of storage medium, such as a flash memory type, a hard disk type, a multimedia card micro type, a card type memory (e.g., SD or XD memory), RAM (Random Access Memory), SRAM (Static Random Access Memory), ROM (Read-Only Memory), EEPROM (Electrically Erasable Programmable Read-Only Memory), PROM (Programmable Read-Only Memory), or an optical disk.

[0124] The memory (40) may store instructions related to functions and / or operations in which the imaging device (100) shifts the position where the emitted light is focused to the image sensor (20) by less than the unit pixel pitch of the image sensor (20), acquires a plurality of images by receiving the emitted light whose position is shifted to the image sensor (20), and performs DNA sequencing imaging by combining the plurality of images. In one embodiment of the present disclosure, the memory (40) may store at least one of instructions, an algorithm, a data structure, a program code, and an application program that can be read by the processor (30). The instructions, algorithm, data structure, and program code stored in the memory (40) may be implemented in a programming or scripting language such as, for example, C, C++, Java, assembler, etc.

[0125] The processor (30) can be implemented by executing instructions or program code stored in memory (40). Hereinafter, the functions and / or operations performed by the processor (30) by executing instructions or program code stored in memory (40) will be described in detail.

[0126] In one embodiment of the present disclosure, the processor (30) can adjust the tilt angle of the tilting plate (50) so that the position where the emitted light passes through the tilting plate (50) and is focused to the image sensor (20) is shifted by less than a unit pixel pitch.

[0127] In one embodiment of the present disclosure, the processor (30) can control the tilt angle of the tilting plate (50) using a piezo actuator.

[0128] In one embodiment of the present disclosure, the processor (30) can determine the tilt angle of the tilting plate (50) based on the refractive index of the tilting plate (50) and the thickness of the tilting plate (50).

[0129] In one embodiment of the present disclosure, the processor (30) can acquire four different images by adjusting the tilt angle of the tilting plate (50) to four different angles so that the position where the emitted light is focused on the image sensor (20) is shifted by half of the unit pixel pitch. The processor (30) can acquire a result image by combining the four images. By combining the four images, the processor (30) can acquire a result image with a resolution improved by four times.

[0130] In one embodiment of the present disclosure, the processor (30) can acquire nine different images by adjusting the tilt angle of the tilting plate (50) to nine different angles so that the position where the emitted light is focused to the image sensor (20) is shifted by one-third of the unit pixel pitch. The processor (30) can acquire a result image by combining the nine images. By combining the nine images, the processor (30) can acquire a result image with a resolution improved nine times.

[0131] In one embodiment of the present disclosure, the processor (30) can adjust the position of the image sensor (20) so that it is shifted by a unit pixel pitch or less of the image sensor (20). That is, the imaging device (100) can shift the position where the emitted light is focused to the image sensor (20) by moving the position of the image sensor (20). At this time, the imaging device (100) may not include a tilting plate (50).

[0132] Hereinafter, with reference to FIG. 5, a series of operations in which an imaging device (100) according to one embodiment of the present disclosure irradiates a beam onto a DNA sample (200) and receives emitted light emitted from the DNA sample (200) will be described.

[0133] FIG. 5 is a diagram showing the operation method of an imaging device (100) according to one embodiment of the present disclosure.

[0134] Referring to FIG. 5, an imaging device (100) according to one embodiment of the present disclosure may include a light source (10), a collimator lens (510), a dichroic filter (520), an objective lens (530), a band-pass filter (540), a tube lens (550), a tilting plate (50), an image sensor (20), and an image synthesis device (not shown). However, not all components shown in FIG. 5 are essential components. The imaging device (100) may be implemented with more components than shown, or with fewer components. A detailed description of the components described above with reference to FIG. 1 through 4 is omitted.

[0135] The collimator lens (510) performs the function of aligning light in parallel in an optical system. The collimator lens (510) collects the emitted light and adjusts it in a certain direction to generate parallel light (parallel beam). The collimator lens (510) can maintain a constant path of light by performing the function of converging or adjusting the light emitted by the light source (10) to be parallel.

[0136] According to one embodiment of the present disclosure, a collimator lens (510) can convert a beam emitted from a light source (10) into a parallel beam. The beam emitted from the light source (10) can be converted into a parallel beam through the collimator lens (510) and incident on a dichroic filter (520). An imaging device (100) can uniformly adjust the illuminance distribution of the light source by passing the light emitted from the light source (10) through the collimator lens (510).

[0137] The dichroic filter (520) may be a component of an optical system having the characteristic of selectively reflecting or transmitting light of a specific wavelength. For example, the dichroic filter (520) may be a dichroic mirror or a polarization splitter.

[0138] In one embodiment of the present disclosure, a dichroic filter (520) can separate a beam emitted from a light source (10) from emitted light from a DNA sample (200). For example, the dichroic filter (520) can irradiate the beam onto the DNA sample (200) by transmitting the beam emitted from the light source (10), and the emitted light generated by the beam being irradiated onto the DNA sample (200) can be reflected toward a bandpass filter (540).

[0139] For example, the dichroic filter (520) may reflect light of a wavelength longer than the cutoff wavelength and transmit light of a wavelength shorter than the cutoff wavelength. Alternatively, for example, the dichroic filter (520) may reflect light of a wavelength shorter than the cutoff wavelength and transmit light of a wavelength longer than the cutoff wavelength. In one embodiment of the present disclosure, a fluorescent signal emitted from a DNA sample (200) may pass through a bandpass filter (540) as it is reflected by the dichroic filter (520).

[0140] In one embodiment of the present disclosure, a dichroic filter (520) transmits excitation light toward a DNA sample (200) and reflects emission light having a relatively long wavelength emitted from the DNA sample (200), thereby enabling the acquisition of a fluorescent image of the DNA sample (200) through an image sensor (20). In one embodiment of the present disclosure, the excitation light is light that excites a fluorescent substance contained in the DNA sample (200) to emit light, and may have short wavelength (high energy) characteristics. The emission light is light emitted by the fluorescent substance contained in the DNA sample (200) after being excited, and may have a longer wavelength (lower energy) than the excitation light.

[0141] The objective lens (530) may be a component that performs the function of collecting a fluorescent signal emitted from a DNA sample (200). The objective lens (530) may include at least one lens. In one embodiment of the present disclosure, the objective lens (530) may be positioned between a light source (10) and a DNA sample (200). The objective lens (530) may condense a beam emitted from the light source (10) onto the DNA sample (200). As the objective lens (530), a lens capable of creating a small focusing area may be used. The objective lens (530) may temporarily bring the energy of the DNA sample (200) into an excited state by irradiating the DNA sample (200) with excitation light. The DNA sample (200) may emit emission light, which is a constant fluorescent light, as it returns to a stable state by releasing the absorbed energy again.

[0142] The emitted light has a wavelength that is shifted slightly toward the red direction compared to the excitation light, and this change can be called Stokes Shift. That is, according to Stokes Shift, the emitted light may have a slightly longer wavelength compared to the excitation light (or the beam emitted from the light source (10)).

[0143] In one embodiment of the present disclosure, the bandpass filter (540) can selectively transmit (or pass) only the wavelength specified by the dichroic filter (520) and transmit it to the image sensor (20). The bandpass filter (540) can selectively transmit only light of the emission wavelength band. The bandpass filter (540) can selectively transmit only light of the first emission wavelength band and block (or absorb or reflect) light of the second emission wavelength band.

[0144] A bandpass filter (540) can be placed between the dichroic filter (520) and the image sensor (20). A fluorescent signal emitted from the DNA sample (200) can pass through the bandpass filter (540) and be incident on the tube lens (550).

[0145] In one embodiment of the present disclosure, the emitted light emitted from the DNA sample (200) and reflected by the dichroic filter (520) may contain some form of optical noise. The bandpass filter (540) can remove the optical noise contained in the emitted light and transmit only the emitted light of the desired wavelength to the image sensor (20). Through this, the resolution of the image obtained by the image sensor (20) can be improved.

[0146] The tube lens (550) can perform the function of converting the intermediate image formed by the objective lens (530) into a focused image. The tube lens (550) can transmit the converted image to the image sensor (20). The tube lens (550) can focus the emitted light that has passed through the bandpass filter (540) to the image sensor (20). The emitted light (e.g., a fluorescent signal) that has passed through the tube lens (550) can be focused to the focus of the tube lens (550). The tube lens (550) may be a lens for consistently correcting the focus of the emitted light (e.g., a fluorescent signal). In one embodiment of the present disclosure, the emitted light (e.g., a fluorescent signal) that has passed through the tube lens (550) can be focused to the focus of the tube lens (550). The image sensor (20) can detect the emitted light (e.g., a fluorescent signal) that has passed through the tube lens (550).

[0147] In one embodiment of the present disclosure, a tilting plate (50) may be positioned between a tube lens (550) and an image sensor (20). The tilting plate (50) may be positioned in the middle of the path where the emitted light passes through the tube lens (550) and is concentrated at the focal point of the tube lens (550). Accordingly, depending on the tilt angle of the tilting plate (50), the degree of refraction of the emitted light as it passes through the tilting plate (50) changes, thereby shifting the position of the focal point concentrated at the image sensor (20).

[0148] In one embodiment of the present disclosure, a space of about 150 mm to about 300 mm corresponding to the focal length (555) of the tube lens (550) may exist between the tube lens (550) and the image sensor (20). According to one embodiment of the present disclosure, the tilting plate (50) can be mounted in a sufficient space between the tube lens (550) and the image sensor (20), so that the imaging device (100) can improve the accuracy of sample observation (e.g., cell structure observation, protein sample detection, or gene sequencing) without complex structural changes.

[0149] In one embodiment of the present disclosure, an image synthesis device may generate a result image based on a plurality of images acquired by an image sensor (20). The image synthesis device may be a component included in the imaging device (100) or may exist as a separate electronic device.

[0150] The image synthesis device may be a computer system or part of a computer system connected to the imaging device (100) via a wired or wireless communication network. The image synthesis device may include a processor comprising one or more cores. The image synthesis device will be described in more detail with reference to FIG. 8.

[0151] In one embodiment of the present disclosure, the DNA sample (200) may be a sample treated with a plurality of fluorescent substances. The fluorescent substance may be a substance that emits a fluorescent signal when irradiated with light of a predetermined wavelength or a predetermined range of wavelengths. The predetermined fluorescent substance may be pre-treated on the DNA sample (200) before the imaging device (100) is used.

[0152] The wavelength range of the fluorescence signal emitted from the DNA sample (200) may be independent of the wavelength range of the light irradiated onto the sample. For example, the fluorescent material of the DNA sample (200) may absorb light within a specific absorption wavelength range. As light within a specific absorption wavelength range is absorbed by the fluorescent material, the fluorescent material may emit a fluorescence signal within a specific emission wavelength range. The absorption wavelength range of the light absorbed by the fluorescent material and the emission wavelength range of the fluorescence signal emitted by the fluorescent material may be different from each other. In one embodiment of the present disclosure, the absorption wavelength range of the light absorbed by the fluorescent material may be the range of the excitation wavelength of the fluorescent material. The range of the excitation wavelength of the fluorescent material may vary depending on the type of fluorescent material.

[0153] FIG. 6 is a drawing for explaining the operation of an imaging device (100) according to one embodiment of the present disclosure determining the tilt angle of a tilting plate (50).

[0154] In one embodiment of the present disclosure, the imaging device (100) can determine the tilt angle of the tilting plate (50) based on the refractive index of the tilting plate (50) and the thickness of the tilting plate (50). The imaging device (100) can derive the tilt angle of the tilting plate (50) from the refractive index of the tilting plate (50) and the thickness of the tilting plate (50) based on Snell's Law.

[0155] From the angle of incidence (601) at which a ray is incident on the tilting plate (50), the refractive index of the tilting plate (50), and the thickness (602) of the tilting plate (50), a distance (603) (hereinafter referred to as shift distance (603)) can be derived in which the path of a ray emitted from the tilting plate (50) is shifted with respect to the path of a ray incident on the tilting plate (50). In one embodiment of the present disclosure, the shift distance (603) may correspond to the distance in which the focusing position in the image sensor (20) is shifted as the ray passes through the tilting plate (50) having a predetermined angle of inclination.

[0156] In addition, conversely to what was previously described, the angle of incidence (601) of a ray incident on the tilting plate (50) may be derived from the shift distance (603) of the ray, the refractive index of the tilting plate (50), and the thickness (602) of the tilting plate (50). At this time, since the tilt angle (604) of the tilting plate (50) is the same as the angle of incidence (601) of the ray incident on the tilting plate (50), the angle of tilt (604) of the tilting plate (50) may be derived from the shift distance (603) of the light, the refractive index of the tilting plate (50), and the thickness (602) of the tilting plate (50).

[0157] Below, we will explain a mathematical formula for deriving the shift distance (603) of a ray from the angle of incidence (601) of a ray incident on the tilting plate (50), the refractive index of the tilting plate (50), and the thickness (602) of the tilting plate (50).

[0158] First, based on Snell's law, the relationship between the refractive index of air, the angle of incidence of the light ray (601), the refractive index of the tilting plate (50), and the angle of refraction of the light ray (605) can be expressed as Equation 2 below.

[0159] Mathematical formula 2:

[0160]

[0161] In Equation 2, θ represents the angle of incidence (601) of the ray, n represents the refractive index of the tilting plate (50), and θ' represents the angle of refraction (605) of the ray. In Equation 2, the refractive index of air is expressed as 1.

[0162] Based on the Sine Law, which represents the relationship between the angles of a triangle and their corresponding sides, the relationship between the first side (611), the second side (612), the first angle (621) facing the first side (611), and the second angle (622) facing the second side (612) can be expressed as Equation 3 below. At this time, the first side (611) is " It can be expressed as ", and the first angle (621) can be expressed as "90-θ", and the second angle (622) can be expressed as "θ-θ'".

[0163] Mathematical formula 3:

[0164]

[0165] In mathematical formula 3, x represents the second side (612).

[0166] By rearranging the above mathematical formulas 2 and 3, the second side (612) can be expressed using only the angle of incidence of the ray (601), the refractive index of the tilting plate (50), and the thickness (602) of the tilting plate (50). At this time, since the shift distance (603) of the ray is equivalent to multiplying the second side (612) by "sin(90-θ)", that is, "cosθ", based on the definition of a sine function, the shifted distance (603) of the ray can be expressed using only the angle of incidence of the ray (601), the refractive index of the tilting plate (50), and the thickness (602) of the tilting plate (50), as shown in the following mathematical formula 4.

[0167] Mathematical formula 4:

[0168]

[0169] Mathematical formula 4 can also be expressed as mathematical formula 5 below.

[0170] Mathematical formula 5:

[0171]

[0172] In one embodiment of the present disclosure, the angle of incidence (601) of a ray, i.e., the tilt angle (604) of the tilting plate (50), can be derived from the shift distance (603) of the ray using the above mathematical formula 4 or mathematical formula 5. When the imaging device (100) intends to shift the path of the ray by a specific distance, it can determine the tilt angle (604) at which the tilting plate (50) should be tilted based on the distance to be shifted (603), the refractive index of the tilting plate (50), and the thickness (602) of the tilting plate (50).

[0173] FIG. 7 is a drawing for explaining the operation of an imaging device (100) according to one embodiment of the present disclosure determining the tilt angle of a tilting plate (50).

[0174] In one embodiment of the present disclosure, the imaging device (100) may store a graph showing the relationship between the amount of light shift and the tilt angle of the tilting plate (50) for a tilting plate (50) having a specific thickness and a specific refractive index. The amount of light shift may correspond to the distance over which the light is shifted. In one embodiment of the present disclosure, the amount of light shift may correspond to the distance over which the position where the emitted light is focused in the image sensor (20) is shifted.

[0175] The imaging device (100) can derive the distance at which a ray is shifted (i.e., the shift distance of the ray) for a specific tilt angle of the tilting plate (50) by referring to a graph showing the relationship between the amount of ray movement and the tilt angle of the tilting plate (50). Alternatively, the imaging device (100) can derive the tilt angle of the tilting plate (50) for shifting the ray by a predetermined distance by referring to a graph showing the relationship between the amount of ray movement and the tilt angle of the tilting plate (50).

[0176] FIG. 7 illustrates an exemplary graph between the tilt angle of a tilting plate (50) and the amount of light ray movement for a tilting plate (50) having a thickness of 2 mm and a refractive index of 1.5.

[0177] For example, it can be assumed that the tilting plate (50) included in the imaging device (100) has a thickness of 2 nm and a refractive index of 1.5, and the image sensor (20) has a unit pixel pitch of 3.45 µm (micrometer). In this case, if the light beam is to be moved by 1 / 2 unit pixel pitch from the image sensor (20), the amount of light beam movement must be 1.725 µm. Referring to the graph, it can be seen that in order for the amount of light beam movement to be 1.725 µm, the angle at which the tilting plate (50) must be tilted must be 0.14825°. That is, if the imaging device (100) is to move the light beam by 1 / 2 unit pixel pitch from the image sensor (20), the tilt angle of the tilting plate (50) is determined to be 0.14825°, and the tilting plate (50) can be tilted at an angle of 0.14825°.

[0178] In one embodiment of the present disclosure, the imaging device (100) may store a lookup table that maps or indexes the relationship between the tilt angle of a tilting plate (50) and the amount of light ray shift for a tilting plate (50) having a specific thickness and a specific refractive index. The imaging device (100) may derive the distance at which a light ray is shifted (i.e., the shift distance of the light ray) for a specific tilt angle of the tilting plate (50) by referring to the lookup table. Alternatively, the imaging device (100) may derive the tilt angle of the tilting plate (50) for shifting the light ray by a predetermined distance by referring to the lookup table.

[0179] Meanwhile, in one embodiment of the present disclosure, the imaging device (100) may receive a tilt angle calculated from an external device. In this case, a graph or lookup table regarding the relationship between the tilt angle of the tilting plate (50) and the amount of light movement may be stored in the external device.

[0180] FIG. 8 is a block diagram of an image synthesis device (800) according to one embodiment of the present disclosure.

[0181] According to one embodiment of the present disclosure, an image synthesis device (800) can generate a result image based on a plurality of fluorescent images acquired by an image sensor (20). The image synthesis device (800) may be a component included in the imaging device (100) or may exist as a separate electronic device. With reference to FIG. 8, we will examine the components in the case where the image synthesis device (800) is implemented as an electronic device capable of synthesizing images.

[0182] In one embodiment of the present disclosure, the image synthesis device (800) may represent various types of electronic devices capable of synthesizing images. The image synthesis device (800) may represent various hardware and / or software elements that perform the function of generating a result image based on fluorescent image data.

[0183] In one embodiment of the present disclosure, the image synthesis device (800) may include devices capable of synthesizing images, such as a PC, server, smartphone, tablet PC, laptop PC, etc., but is not limited thereto. In one embodiment of the present disclosure, the image synthesis device (800) may synthesize a plurality of images based on artificial intelligence technology and output a result image.

[0184] In one embodiment of the present disclosure, the image synthesis device (800) may be implemented in the form of a graphics-dedicated processor such as a GPU (Graphics Processing Unit) or a VPU (Vision Processing Unit), an artificial intelligence-based processor such as an NPU (neural processing unit), or a FPGA (Field-Programmable Gate Array), but is not limited thereto.

[0185] In one embodiment of the present disclosure, whether the image synthesis device (800) is implemented as a hardware / software element or as an electronic device, the image synthesis device (800) may be connected to an image sensor (20) via a wired or wireless connection to receive a fluorescent image. The image synthesis device (800) may synthesize a result image based on a plurality of fluorescent images obtained from the image sensor (20). In one embodiment of the present disclosure, the result image may represent an image with a higher resolution than the plurality of fluorescent images.

[0186] In one embodiment of the present disclosure, the image synthesis device (800) may include a communication interface, a memory (810), and a processor (820). However, not all of the illustrated components are essential components. The image synthesis device (800) may be implemented with more components than those illustrated, or with fewer components.

[0187] The memory (810) is electrically connected to the processor (820) and can store one or more modules, algorithms, operation rules, models, programs, instructions, or data related to the operation of the components included in the image synthesis device (800). For example, the memory (810) can store one or more modules, algorithms, operation rules, models, programs, instructions, or data for processing and control of the processor (820).

[0188] The memory (810) may include at least one type of storage medium among flash memory type, hard disk type, multimedia card micro type, card type memory (e.g., SD or XD memory, etc.), RAM (Random Access Memory), SRAM (Static Random Access Memory), ROM (Read-Only Memory), EEPROM (Electrically Erasable Programmable Read-Only Memory), PROM (Programmable Read-Only Memory), magnetic memory, magnetic disk, and optical disk, but is not limited thereto.

[0189] The processor (820) is electrically connected to the components included in the image synthesis device (800) and can perform operations or data processing regarding the control and / or communication of the components included in the image synthesis device (800). In one embodiment of the present disclosure, the processor (820) can load a request, command, or data received from at least one of the other components into memory for processing and store the processing result data in memory.

[0190] According to one embodiment of the present disclosure, the processor (820) may include at least one of a general-purpose processor such as a CPU (central processing unit), AP (application processor), DSP (Digital Signal Processor), a graphics-dedicated processor such as a GPU (graphic processing unit) or VPU (Vision Processing Unit), or an artificial intelligence-dedicated processor such as an NPU (neural processing unit).

[0191] The processor (820) can process input data or control other configurations to process it according to data, operation rules, algorithms, methods, or models stored in memory (810). The processor (820) can perform operations of predefined operation rules, algorithms, methods, or models stored in memory (810) using the input data.

[0192] The processor (820) may include various processing circuits and / or multiple processors. For example, the term "processor" as used herein, including in the claim, may include at least one processor and various processing circuits. In at least one processor, one or more processors may be configured to perform the various functions described herein in a distributed manner, individually and / or collectively. As used herein, "processor," "at least one processor," and "one or more processors" may be configured to perform various functions. However, these terms cover, for example but without limitation, situations where one processor performs some of the functions and other processor(s) perform other parts of the functions, and situations where a single processor can perform all functions. Additionally, at least one processor may include a combination of processors performing various functions of the disclosed functions in a distributed manner. At least one processor may execute program instructions to achieve or perform various functions.

[0193] In an embodiment of the present disclosure, the processor (820) may store one or more instructions in an internally provided memory and control the operation of the image synthesis device (800) to be performed by executing one or more instructions stored in the internally provided memory. That is, the processor (820) may perform a predetermined operation by executing at least one instruction or program stored in an internal memory or memory (810) provided within the processor (820).

[0194] In one embodiment of the present disclosure, the processor (820) can perform the operation of the image synthesis device (800) disclosed in the present disclosure by executing one or more instructions stored in memory (810).

[0195] A processor (820) according to one embodiment of the present disclosure can receive a plurality of fluorescent images obtained by receiving emission light at an image sensor (20) at a shifted position by executing one or more instructions stored in memory (810).

[0196] A processor (820) according to one embodiment of the present disclosure can generate a result image based on a plurality of fluorescent images by executing one or more instructions stored in memory (810). A processor (820) according to one embodiment of the present disclosure can generate a result image by synthesizing (or combining) a plurality of images obtained from an image sensor by executing one or more instructions stored in memory (810). In a plurality of images, corresponding pixels may partially overlap. Accordingly, the image synthesis device can generate a result image having a higher resolution than the resolution of the plurality of images.

[0197] In one embodiment of the present disclosure, the image synthesis device (800) may include a communication interface (not shown). The communication interface may connect the image synthesis device (800) to an image sensor (20) under the control of a processor (820). The communication interface may connect the image synthesis device (800) to a peripheral device, an external device, a server, a mobile terminal, etc., under the control of a processor (820). For example, the communication interface may include at least one of a communication module, a communication circuit, a communication device, an input / output port, and an input / output plug for performing wired or wireless communication with at least one image sensor or at least one external device.

[0198] For example, the communication interface may include at least one short-range communication module that performs communication according to wireless communication standards such as Bluetooth, Wi-Fi, BLE (Bluetooth Low Energy), NFC / RFID, Wi-Fi Direct, UWB, or ZIGBEE. Alternatively, the communication interface may further include a communication module that performs communication with a server to support long-range communication according to long-range communication standards. For example, the communication interface may include a communication module that performs communication through a network for internet communication. Additionally, the communication interface may include a wireless internet module that performs communication through a communication network according to communication standards such as 3G, 4G, 5G, and / or 6G.

[0199] For example, the communication interface may include at least one port for connecting to the image sensor (20) or an external device via a wired cable in order to communicate with the image sensor (20) or an external device via a wired connection. For example, the communication interface may include at least one of an HDMI port (High-Definition Multimedia Interface port), a component jack, a PC port, a USB port, or a LAN port. The communication interface may communicate with the image sensor or an external device connected via a wired connection through at least one port. Here, a port may refer to a physical device configuration into which a cable, a communication line, or a plug can be connected or inserted.

[0200] As described above, the communication interface may include at least one support element to support communication between the image synthesis device (800) and the image sensor (20) or an external device. Here, the support element may include the aforementioned communication module, communication circuit, communication device, port (for input / output of data), cable port (for input / output of data), plug (for input / output of data), etc. For example, the at least one support element included in the communication interface may be an Ethernet communication module, a Wi-Fi communication module, a Bluetooth communication module, an IR communication module, a USB port, a LAN port, an HDMI port, etc. A wireless communication module of the image synthesis device (800) according to one embodiment of the present disclosure may include at least one of a short-range communication module or a wireless internet module.

[0201] With reference to FIGS. 9 to 11c below, the operation of an imaging device acquiring a result image by synthesizing a plurality of fluorescent images will be described in detail.

[0202] FIG. 9 is a diagram for explaining the relationship between the resolution of an image sensor (931, 932) according to one embodiment of the present disclosure and a DNA signal (911, 912) that can be identified through the image sensor (931, 932).

[0203] Referring to FIG. 9, a situation can be assumed in which an imaging device (100) detects adjacent first DNA signals (911) (or first DNA fluorescence signals) and second DNA signals (912) (or second DNA fluorescence signals) using image sensors (931, 932). FIG. 9 describes a situation in which adjacent first DNA signals (911) and second DNA signals (912) are imaged using image sensors (931, 932) having different resolutions. For example, adjacent first DNA signals (911) and second DNA signals (912) can be imaged using a first image sensor (931) having a first unit pixel pitch (941) and a second image sensor (932) having a second unit pixel pitch (942). At this time, since the second unit pixel pitch (942) is shorter than the first unit pixel pitch (941), the second image sensor (932) can have a higher resolution than the first image sensor (931). Since the resolution of the image is proportional to the pixel size of the image sensor, the image output through the second image sensor (932) can have a higher resolution than the image output through the first image sensor (931).

[0204] First, in the first image sensor (931), as the emitted light corresponding to the first DNA signal (911) is focused on two adjacent pixels in the Y-axis direction of the first image sensor (931), an equal amount of light can be delivered to the two pixels. As the emitted light corresponding to the second DNA signal (912) is focused on two adjacent pixels in the Y-axis direction of the first image sensor (931), an equal amount of light can be delivered to the two pixels. At this time, the pixels where the first DNA signal (911) is detected and the pixels where the second DNA signal (912) is detected may be adjacent to each other. Accordingly, in the first fluorescent image (951) output from the first image sensor (931), the first DNA signal (911) and the second DNA signal (912) are not distinguished and can be recognized as a single signal. That is, the first image sensor (931) may output a fluorescent image with lost details because it does not have a sufficient sampling interval (941) for the first DNA signal (911) and the second DNA signal (912).

[0205] Image sensors can generate digital images by sampling optical information. In this case, according to the Nyquist Sampling Theorem, for a fluorescence image to sufficiently represent optical resolution (ρ), the sampling interval (i.e., unit pixel size or unit pixel pitch) must be at least twice as small as the optical resolution. Here, optical resolution refers to the minimum distance between two distinguishable points (e.g., two distinguishable signals) in an optical system.

[0206] The second image sensor (932) is subjected to the Nyquist sampling theory, so that the sampling interval (942) (i.e., unit pixel size or unit pixel pitch) of the second image sensor (932) can be at least twice as small as the distance (920) between the first DNA signal (911) and the second DNA signal (912). For example, as shown in FIG. 9, at least one entire pixel can be placed between the first DNA signal (911) and the second DNA signal (912) in the second image sensor (932), so that the second image sensor (932) can output a second fluorescence image (952) in which the first DNA signal (911) and the second DNA signal (912) are separated. That is, the second image sensor (932) can output a high-resolution fluorescence image by having a sufficient sampling interval for the first DNA signal (911) and the second DNA signal (912) based on the Nyquist sampling theory.

[0207] Accordingly, in an imaging device (100) that performs DNA sequencing imaging, the smaller the sampling interval (i.e., unit pixel size or unit pixel pitch) of the image sensor (931, 932), the higher the imaging precision of the DNA signal.

[0208] However, if the pixel size in the image sensor becomes too small, sampling may be excessive, causing the data to increase unnecessarily, and consequently, the system efficiency of the imaging device (100) may be reduced when performing DNA sequencing imaging. Additionally, if the pixel size in the image sensor becomes too small, the inspection area may become narrower, which may result in a longer image acquisition time. Accordingly, the image sensor (932) may determine the pixel size to be half the optical resolution level to minimize the loss of detail while simultaneously maximizing the density of the signal within the image based on the Nyquist sampling theory, so that no sampling error occurs. However, even in this case, there may still be a possibility of errors in the detection of DNA signals due to accumulated errors caused by system noise, depth of focus, illumination non-uniformity, alignment problems, etc.

[0209] According to one embodiment of the present disclosure, an imaging device (100) can acquire a plurality of images by shifting the position where emitted light is focused from the image sensor (20, 932) to a level less than or equal to a unit pixel pitch without further reducing the pixel size of the image sensor (20, 932), and can acquire a result image with improved resolution by synthesizing the acquired plurality of images. Since it is not necessary to reduce the pixel size to increase the resolution of the image sensor (20, 932), the problem of increasing image acquisition time as the inspection area becomes narrower can be avoided. The imaging device (100) can improve the resolution of the final image through post-processing of the image while maintaining the existing optical structure. Accordingly, an imaging device (100) can be provided that can resolve the trade-off problem between image resolution and quality and inspection area and inspection time.

[0210] FIG. 10a is a flowchart illustrating an example of a method for an imaging device (100) according to one embodiment of the present disclosure to acquire a result image based on a plurality of fluorescent images.

[0211] Referring to FIG. 10a, a method for an imaging device (100) to perform DNA sequencing imaging may include steps S1010 and S1020. In one embodiment of the present disclosure, steps S1010 and S1020 may be executed by at least one processor (30) included in the imaging device (100). The operation of step S1010 illustrated in FIG. 10a is a specific operation of step S220 illustrated in FIG. 2, and the operation of step S1020 illustrated in FIG. 10a is a specific operation of step S230 illustrated in FIG. 2. The operation of step S1010 illustrated in FIG. 10a may be performed after the operation of S210 illustrated in FIG. 2 has been performed.

[0212] In step S1010 of FIG. 10a, the imaging device (100) can acquire four different images by adjusting the tilt angle of the tilting plate (50) to four different angles so that the position where the emitted light is focused on the image sensor (20) is shifted by half of the unit pixel pitch. That is, the imaging device (100) can acquire four different images by receiving the emitted light that is shifted three times by a distance of half of the unit pixel pitch to the position where the emitted light is focused on the image sensor (20).

[0213] In step S1020 of FIG. 10a, the imaging device (100) can obtain a result image by combining four multiple images. As the imaging device (100) obtains four multiple images based on emitted light shifted by half a unit pixel pitch from the image sensor, corresponding pixels in the four multiple images may partially overlap. Accordingly, the imaging device (100) can obtain a result image with improved resolution by combining these four multiple images. Hereinafter, with reference to FIG. 10b, the operation of obtaining and combining four multiple images will be described in detail.

[0214] FIG. 10b is a reference diagram for explaining an example of a method in which an imaging device (100) according to one embodiment of the present disclosure acquires a result image based on a plurality of fluorescent images.

[0215] Referring to FIG. 10b, the imaging device (100) can acquire a first image (1021) by receiving emitted light focused at a first position (1011a, 1011b) of the image sensor (1010) while the tilting plate (50) is tilted at a first angle. For example, the image sensor (1010) can detect a first DNA signal (1001) and a second DNA signal (1002). When acquiring the first image (1021), as the first DNA signal (1001) is focused in the center of four pixels, an equal amount of light can be delivered to four pixels. When acquiring the first image (1021), as the second DNA signal (1002) is focused in the center of four pixels, an equal amount of light can be delivered to four pixels. In the first image (1021), the first DNA signal (1001) and the second DNA signal (1002) may not be distinguishable.

[0216] The imaging device (100) can change the tilting plate (50) from a state where it is tilted at a first angle to a state where it is tilted at a second angle by further tilting it in a third direction (D3) (e.g., left) by a predetermined angle. The second angle of the tilting plate (50) can be determined as an angle such that the position where the emitted light is focused from the image sensor (1010) can be shifted in the third direction (D3) (e.g., left) by a 1 / 2 unit pixel pitch. The imaging device (100) can receive the emitted light focused at the second position (1012a, 1012b) of the image sensor (1010) while the tilting plate (50) is tilted at the second angle, and acquire a second image (1022). The second position (1012a, 1012b) may correspond to a position shifted in a third direction (D3) (e.g., left) by a distance of half the unit pixel pitch of the image sensor (1010) from the first position (1011a, 1011b). The second image (1022) may be identical to the image acquired when the image sensor (1010) is shifted in a first direction (D1) (e.g., right) by half the unit pixel pitch after acquiring the first image (1021).

[0217] When acquiring the second image (1022), as the first DNA signal (1001) is focused in the center of two adjacent pixels along the Y-axis (e.g., vertically), an equal amount of light can be transmitted to two adjacent pixels along the Y-axis. When acquiring the second image (1022), as the second DNA signal (1002) is focused in the center of two adjacent pixels along the Y-axis, an equal amount of light can be transmitted to two adjacent pixels along the Y-axis. In the second image (1022), the first DNA signal (1001) and the second DNA signal (1002) can be distinguished.

[0218] The imaging device (100) can change the tilting plate (50) from a state where it is tilted at a second angle to a state where it is tilted at a third angle by further tilting it in a second direction (D2) (e.g., upward). The third angle of the tilting plate (50) can be determined as an angle at which the position where the emitted light is focused from the image sensor (1010) can be shifted in the second direction (D2) (e.g., upward) by a 1 / 2 unit pixel pitch. The imaging device (100) can receive the emitted light focused at the third position (1013a, 1013b) of the image sensor (1010) while the tilting plate (50) is tilted at the third angle, and acquire a third image (1023). The third position (1013a, 1013b) may correspond to a position shifted in the second direction (D2) (e.g., upward) by a distance of half the unit pixel pitch of the image sensor (1010) from the second position (1012a, 1012b). Additionally, the third position (1013a, 1013b) may correspond to a position shifted in the third direction (D3) and the second direction (D2) (e.g., left and upward), respectively, by a distance of half the unit pixel pitch of the image sensor (1010) from the first position (1011a, 1011b). The third image (1023) may be identical to the image acquired when the image sensor (1010) is shifted in the fourth direction (D4) (e.g., downward) by a distance of half the unit pixel pitch after acquiring the second image (1022).

[0219] When the third image (1023) is acquired, light can be transmitted to only one pixel as the first DNA signal (1001) is focused on the center of one pixel. When the third image (1023) is acquired, light can be transmitted to only one pixel as the second DNA signal (1002) is focused on the center of one pixel. In the third image (1023), the first DNA signal (1001) and the second DNA signal (1002) can be distinguished.

[0220] The imaging device (100) can change the tilting plate (50) from a state where it is tilted at a third angle to a state where it is tilted at a fourth angle by further tilting it at a predetermined angle in a first direction (D1) (e.g., to the right). The fourth angle of the tilting plate (50) can be determined as an angle at which the position where the emitted light is focused from the image sensor (1010) can be shifted in the first direction (D1) (e.g., to the right) by a 1 / 2 unit pixel pitch. The imaging device (100) can receive the emitted light focused at the fourth position (1014a, 1014b) of the image sensor (1010) while the tilting plate (50) is tilted at the fourth angle, and acquire a fourth image (1024). The fourth position (1014a, 1014b) may correspond to a position shifted in the first direction (D1) (e.g., to the right) by a distance of half the unit pixel pitch of the image sensor (1010) from the third position (1013a, 1013b). Additionally, the fourth position (1014a, 1014b) may correspond to a position shifted in the second direction (D2) (e.g., upward) by a distance of half the unit pixel pitch of the image sensor (1010) from the first position (1011a, 1011b). The fourth image (1024) may be identical to the image acquired when the image sensor (1010) is shifted in the first direction (D1) (e.g., to the left) by a distance of half the unit pixel pitch after acquiring the third image (1023).

[0221] When acquiring the fourth image (1024), as the first DNA signal (1001) is focused in the center of two adjacent pixels along the X-axis (e.g., left and right), an equal amount of light can be transmitted to the two pixels. When acquiring the fourth image (1024), as the second DNA signal (1002) is focused in the center of two adjacent pixels along the X-axis, an equal amount of light can be transmitted to the two pixels. In the fourth image (1024), the first DNA signal (1001) and the second DNA signal (1002) may not be distinguishable.

[0222] An imaging device (100) can obtain a result image (1030) by combining first to fourth images (1021, 1022, 1023, 1024) in which the positions where the emitted light from the image sensor (1010) is focused are different. The first to fourth images (1021, 1022, 1023, 1024) may have corresponding pixels that partially overlap. For example, each of the first to fourth images (1021, 1022, 1023, 1024) may represent at least a portion of a specific DNA sample in corresponding pixels. For example, each of the first to fourth images (1021, 1022, 1023, 1024) may represent at least a portion of a first DNA signal (1001) in a pixel in row 1, column 1. For example, each of the first to fourth images (1021, 1022, 1023, 1024) can represent at least a portion of the second DNA signal (1002) in a pixel of row 3, column 1.

[0223] In one embodiment of the present disclosure, the imaging device (100) can synthesize (or combine) the first to fourth images (1021, 1022, 1023, 1024) with corresponding pixels. For example, at a specific pixel, the pixel value of the corresponding pixel of the first image (1021) can be written at the (0, 0) position (1031), and the pixel value of the corresponding pixel of the second image (1022) can be written at the (0.5, 0) position (1032), which is shifted in the first direction (D1) by 1 / 2 unit pixel from the (0, 0) position (1031). At the (0.5, 0.5) position (1033), which is shifted by 1 / 2 unit pixel in the fourth direction (D4) from the (0.5, 0) position (1032), the pixel value of the corresponding pixel of the third image (1023) can be written, and at the (0.5, 0) position (1034), which is shifted by 1 / 2 unit pixel in the second direction (D2) from the (0.5, 0.5) position (1033), the pixel value of the corresponding pixel of the fourth image (1024) can be written.

[0224] According to one embodiment of the present disclosure, a plurality of images capturing different details can be obtained by shifting the position where the emitted light is focused among the pixels of the image sensor (1010) by a portion of the unit pixel pitch. The imaging device (100) can combine these details by synthesizing (or combining) the plurality of images, thereby improving the overall image quality and obtaining a result image (1030) with high clarity and improved resolution.

[0225] However, FIG. 10b illustrates an example of a result image (1030) obtained (or generated) through the synthesis of the first to fourth images (1021, 1022, 1023, 1024), and the result image (1030) may vary depending on the image synthesis algorithm adopted by the imaging device (100). For example, the first to fourth images (1021, 1022, 1023, 1024) may be compared for each pixel, and the pixel value from the image with higher resolution (or clarity) may be adopted. Alternatively, different weights may be set for multiple images according to the quality of each image, and a pixel value obtained by taking a weighted average from the pixel values ​​of the first to fourth images (1021, 1022, 1023, 1024) may be adopted.

[0226] As shown in the first image (1021) and the fourth image (1024), adjacent DNA signals (1001, 1002) may not be detected separately depending on the position where the emitted light is focused from the image sensor (1010). However, according to one embodiment of the present disclosure, the imaging device (100) may obtain an image in which adjacent DNA signals are detected separately by acquiring a plurality of images in which the position where the emitted light is focused from the image sensor (1010) is shifted by a portion of a unit pixel. The imaging device (100) may obtain a high-resolution result image (1030) in which adjacent DNA signals can be more clearly distinguished by synthesizing these plurality of images to generate a result image (1030).

[0227] Accordingly, the imaging device (100) can improve inspection precision (image quality, resolution) in DNA sequencing imaging without incurring complex system design and high costs, such as changing the internal structure (e.g., changing to a high numeric aperture objective lens or changing to a structured light microscope).

[0228] FIG. 11a is a flowchart illustrating an example of a method for an imaging device (100) according to one embodiment of the present disclosure to acquire a result image based on a plurality of fluorescent images.

[0229] Referring to FIG. 11a, a method for an imaging device (100) to perform DNA sequencing imaging may include steps S1110 and S1120. In one embodiment of the present disclosure, steps S1110 and S1120 may be executed by at least one processor (30) included in the imaging device (100). The operation of step S1110 illustrated in FIG. 11a is a specific operation of step S220 illustrated in FIG. 2, and the operation of step S1120 illustrated in FIG. 11a is a specific operation of step S230 illustrated in FIG. 2. The operation of step S1110 illustrated in FIG. 11a may be performed after the operation of S210 illustrated in FIG. 2 has been performed.

[0230] In step S1110 of FIG. 11a, the imaging device (100) can acquire nine different images by adjusting the tilt angle of the tilting plate (50) to nine different angles so that the position where the emitted light is focused on the image sensor (20) is shifted by one-third of the unit pixel pitch. That is, the imaging device (100) can acquire nine different images by receiving the emitted light that is shifted nine times by a distance of one-third of the unit pixel pitch to the position where the emitted light is focused on the image sensor (20).

[0231] In step S1120 of FIG. 11a, the imaging device (100) can combine nine multiple images to obtain a result image. As the imaging device (100) obtains nine multiple images based on emitted light shifted by 1 / 3 of a unit pixel pitch from the image sensor, corresponding pixels in the nine multiple images may partially overlap. Accordingly, the imaging device (100) can obtain a result image with improved resolution by combining these nine multiple images. Hereinafter, with reference to FIG. 11b, the operation of obtaining and combining nine multiple images will be described in detail.

[0232] FIG. 11b is a reference diagram for explaining an example of a method in which an imaging device (100) according to one embodiment of the present disclosure acquires a result image based on a plurality of fluorescent images. FIG. 11c is a reference diagram for explaining an example of a method in which an imaging device (100) according to one embodiment of the present disclosure acquires a result image based on a plurality of fluorescent images. FIG. 11b illustrates the location where emitted light is collected at an image sensor (1110), and FIG. 11c illustrates a plurality of images (1121 to 1129) acquired at each image sensor (1110) and a result image (1130) acquired based on the plurality of images (1121 to 1129).

[0233] Referring to FIG. 11b and FIG. 11c together, the imaging device (100) can acquire a first image (1121) by receiving emitted light focused at a first position (1111a, 1111b) of the image sensor (1110) while the tilting plate (50) is tilted at a first angle. For example, the image sensor (1110) can detect a first DNA signal (1101) and a second DNA signal (1102). When acquiring the first image (1121), as the first DNA signal (1101) is focused in the center of four pixels, an equal amount of light can be delivered to four pixels. When acquiring the first image (1121), as the second DNA signal (1102) is focused in the center of four pixels, an equal amount of light can be delivered to four pixels. In the first image (1121), the first DNA signal (1101) and the second DNA signal (1102) may not be distinguishable.

[0234] The imaging device (100) can acquire a second image (1122) by receiving emitted light focused at a second position (1112a, 1112b) shifted in a third direction (D3) by a 1 / 3 unit pixel pitch from a first position (1111a, 1111b) while the tilt angle of the tilting plate (50) is changed from a first angle to a second angle. The imaging device (100) can acquire a third image (1123) by receiving emitted light focused at a third position (1113a, 1113b) shifted in a third direction (D3) by a 1 / 3 unit pixel pitch from a second position (1112a, 1112b) while the tilt angle of the tilting plate (50) is changed from a second angle to a third angle. In the second image (1122) and the third image (1123), as each of the first DNA signal (1101) and the second DNA signal (1102) is focused in the center of two pixels adjacent to the Y-axis, an equal amount of light can be transmitted to the two pixels. In the second and third images (1123), the first DNA signal (1101) and the second DNA signal (1102) can be distinguished.

[0235] The imaging device (100) can acquire a fourth image (1124) by receiving emitted light focused at a fourth position (1114a, 1114b) shifted in the second direction (D2) by a 1 / 3 unit pixel pitch from a third position (1113a, 1113b) while the tilt angle of the tilting plate (50) is changed from a third angle to a fourth angle. The imaging device (100) can acquire a fifth image (1125) by receiving emitted light focused at a fifth position (1115a, 1115b) shifted in the first direction (D1) by a 1 / 3 unit pixel pitch from a fourth position (1114a, 1114b) while the tilt angle of the tilting plate (50) is changed from a fourth angle to a fifth angle. In the fourth image (1124) and the fifth image (1125), as the first DNA signal (1101) and the second DNA signal (1102) are each focused within one pixel, light can be transmitted to only one pixel. In the fourth and fifth images (1124, 1125), the first DNA signal (1101) and the second DNA signal (1102) can be distinguished.

[0236] The imaging device (100) can acquire a sixth image (1126) by receiving emission light focused at a sixth position (1116a, 1116b) shifted in the first direction (D1) by a 1 / 3 unit pixel pitch from a fifth position (1115a, 1115b) while the tilt angle of the tilting plate (50) is changed from a fifth angle to a sixth angle. The imaging device (100) can acquire a seventh image (1127) by receiving emission light focused at a seventh position (1117a, 1117b) shifted in the second direction (D2) by a 1 / 3 unit pixel pitch from a sixth position (1116a, 1116b) while the tilt angle of the tilting plate (50) is changed from a sixth angle to a seventh angle. In the sixth image (1126) and the seventh image (1127), as each of the first DNA signal (1101) and the second DNA signal (1102) is focused in the center of two pixels adjacent to each other along the X-axis, an equal amount of light can be transmitted to the two pixels. In the sixth and seventh images (1126, 1127), the first DNA signal (1101) and the second DNA signal (1102) may not be distinguishable.

[0237] The imaging device (100) can acquire an 8th image (1128) by receiving emission light focused at an 8th position (1118a, 1118b) shifted in a 3rd direction (D3) by a 1 / 3 unit pixel pitch from a 7th position (1117a, 1117b) while the tilt angle of the tilting plate (50) is changed from a 7th angle to an 8th angle. The imaging device (100) can acquire a 9th image (1129) by receiving emission light focused at a 9th position (1119a, 1119b) shifted in a 3rd direction (D3) by a 1 / 3 unit pixel pitch from an 8th position (1118a, 1118b) while the tilt angle of the tilting plate (50) is changed from a 8th angle to a 9th angle. In the eighth image (1128) and the ninth image (1129), as the first DNA signal (1101) and the second DNA signal (1102) are each focused within one pixel, light can be transmitted to only one pixel. In the eighth and ninth images (1128, 1129), the first DNA signal (1101) and the second DNA signal (1102) can be distinguished.

[0238] The imaging device (100) can obtain a result image (1130) by combining first to ninth images (1121 to 1129) in which the positions where the emitted light from the image sensor (1110) is focused are different. The first to ninth images (1121 to 1129) may have corresponding pixels that partially overlap. For example, each of the first to ninth images (1121 to 1129) may represent at least a portion of a specific DNA sample in corresponding pixels. For example, each of the first to ninth images (1121 to 1129) may represent at least a portion of a first DNA signal (1101) in a pixel in row 1, column 1. For example, each of the first to ninth images (1121 to 1129) may represent at least a portion of a second DNA signal (1102) in a pixel in row 3, column 1.

[0239] In one embodiment of the present disclosure, the imaging device (100) can synthesize (or combine) the first to ninth images (1121 to 1129) with corresponding pixels. For example, at a specific pixel, the pixel value of the corresponding pixel of the first image (1121) can be written at the (0, 0) position, the pixel value of the corresponding pixel of the second image (1122) can be written at the (1 / 3, 0) position which is shifted by 1 / 3 pixel in the first direction (D1) from the (0, 0) position, and the pixel value of the corresponding pixel of the third image (1123) can be written at the (2 / 3, 0) position which is shifted by 1 / 3 pixel in the first direction (D1) from the (1 / 3, 0) position.

[0240] At the position (2 / 3, 1 / 3), which is shifted by 1 / 3 pixel in the fourth direction (D4) from the position (2 / 3, 0), the pixel value of the corresponding pixel of the fourth image (1124) can be written; at the position (1 / 3, 1 / 3), which is shifted by 1 / 3 pixel in the third direction (D3) from the position (2 / 3, 1 / 3), the pixel value of the corresponding pixel of the fifth image (1125) can be written; and at the position (0, 1 / 3), which is shifted by 1 / 3 pixel in the third direction (D3) from the position (1 / 3, 1 / 3), the pixel value of the corresponding pixel of the sixth image (1126) can be written.

[0241] At the (0, 2 / 3) position, which is shifted by 1 / 3 pixels in the fourth direction (D4) from the (0, 1 / 3) position, the pixel value of the corresponding pixel of the 7th image (1127) can be written; at the (1 / 3, 2 / 3) position, which is shifted by 1 / 3 pixels in the first direction (D1) from the (0, 2 / 3) position, the pixel value of the corresponding pixel of the 8th image (1128) can be written; and at the (2 / 3, 2 / 3) position, which is shifted by 1 / 3 pixels in the first direction (D1) from the (1 / 3, 2 / 3) position, the pixel value of the corresponding pixel of the 9th image (1129) can be written.

[0242] To summarize, in one example, the imaging device (100) can combine the first to ninth images (1121 to 1129) by aligning the pixel values ​​of corresponding pixels in the first to ninth images (1121 to 1129) to generate a result image (1130).

[0243] According to one embodiment of the present disclosure, a plurality of images capturing different details can be obtained by shifting the position where the emitted light is focused among the pixels of the image sensor (1110) by a portion of the unit pixel pitch. The imaging device (100) can combine these details by synthesizing (or combining) the plurality of images, thereby improving the overall image quality and obtaining a result image (1130) with high clarity and improved resolution.

[0244] However, FIG. 11b illustrates an example of a result image (1130) obtained (or generated) through the synthesis of the first to ninth images (1121 to 1129), and the result image (1130) may vary depending on the image synthesis algorithm adopted by the imaging device (100).

[0245] As shown in the first image (1121), the sixth image (1126), and the seventh image (1127), adjacent DNA signals (1101, 1102) may not be detected separately depending on the position where the emitted light is focused from the image sensor (1110). However, according to one embodiment of the present disclosure, the imaging device (100) may obtain an image in which adjacent DNA signals are detected separately by acquiring a plurality of images in which the position where the emitted light is focused from the image sensor (1110) is shifted by a portion of a unit pixel. The imaging device (100) may obtain a high-resolution result image (1130) in which adjacent DNA signals can be more clearly distinguished by synthesizing these plurality of images to generate a result image (1130).

[0246] Accordingly, the imaging device (100) can improve inspection precision (image quality, resolution) in DNA sequencing imaging without incurring complex system design and high costs, such as changing the internal structure (e.g., changing to a high numeric aperture objective lens or changing to a structured light microscope).

[0247] FIG. 12 is a schematic diagram of an imaging device (1200) including a plurality of image sensors according to one embodiment of the present disclosure.

[0248] The imaging device (1200) described with reference to FIG. 12 may correspond to the imaging device (100). In one embodiment of the present disclosure, the imaging device (1200) may include a plurality of image sensors (1291, 1292). For example, the image sensor (20) described with reference to FIG. 2 may include a plurality of image sensors (1291, 1292).

[0249] In one embodiment of the present disclosure, the imaging device (1200) may include a plurality of tilting plates (1281, 1282). For example, the tilting plate (50) described with reference to FIG. 2 may include a plurality of tilting plates (1281, 1282). Each of the plurality of tilting plates (1281, 1282) may be positioned corresponding to a plurality of image sensors (1291, 1292).

[0250] Since the description of the imaging device (100) described above with reference to FIGS. 1 to 11 can be applied to the operation of the imaging device (1200), the description of FIG. 12 will focus on the operation of the plurality of image sensors (1291, 1292), and further detailed descriptions will be omitted below.

[0251] In one embodiment of the present disclosure, a beam emitted by an imaging device (1200) through a light source (1210) may be irradiated onto a DNA sample (2200) by passing through a collimator lens (1220), a first dichroic filter (1230), and an objective lens (1240) in sequence. As the fluorescent material of the DNA sample (2200) is excited, emitted light may be generated from the DNA sample (2200). The emitted light may exhibit light having a wavelength longer than the beam. The imaging device (1200) may acquire the emitted light.

[0252] In one embodiment of the present disclosure, the imaging device (1200) can acquire a plurality of emission lights having different wavelengths. For example, it can acquire a plurality of emission lights emitted from a plurality of fluorescent materials contained in a DNA sample (2200). For example, a plurality of fluorescent materials contained in a DNA sample (2200) can absorb the same excitation light and emit emission lights of different wavelengths.

[0253] For example, fluorescent material A in the DNA sample (2200) may absorb excitation light provided by the light source (1210) and then emit first emission light having a first emission wavelength. Another fluorescent material B contained in the DNA sample (2200) may absorb the same excitation light but emit second emission light having a second emission wavelength different from the first emission wavelength. In this way, the imaging device (1200) can individually detect multiple fluorescent materials while using a single light source (1210), and each emission light may provide specific biomolecule or structural information.

[0254] Emitted light (e.g., first emitted light and second emitted light) may pass through an objective lens (1240) and be incident on a first dichroic filter (1230). In one embodiment of the present disclosure, the first dichroic filter (1230) may transmit excitation light shorter than a first threshold wavelength and reflect emission light longer than a first threshold wavelength. In one embodiment of the present disclosure, when the first dichroic filter (1230) reflects emission light emitted from a DNA sample (2200), the emission light may be incident on a second dichroic filter (1250).

[0255] In one embodiment of the present disclosure, the second dichroic filter (1250) can transmit a first emission light shorter than a second threshold wavelength and reflect a second emission light longer than a second threshold wavelength among the incident emission light. When the second dichroic filter (1250) transmits the first emission light, the first emission light can be incident on the first image sensor (1291). When the second dichroic filter (1250) reflects the second emission light, the second emission light can be incident on the second image sensor (1292). The first emission light can be incident on the first image sensor (1291) via a first bandpass filter (1261), a first tube lens (1271), and a first tilting plate (1281). The second emitted light may pass through the second bandpass filter (1262), the second tube lens (1272), and the second tilting plate (1282) to enter the second image sensor (1292). However, the embodiments are not limited thereto, and in one embodiment of the present disclosure, the second dichroic filter (1250) may reflect the first emitted light shorter than the second threshold wavelength and transmit the second emitted light longer than the second threshold wavelength among the emitted light.

[0256] In one embodiment of the present disclosure, a first image sensor (1291) may receive a first emitted light to generate a first wavelength image. In one embodiment of the present disclosure, a second image sensor (1292) may receive a second emitted light to generate a second wavelength image. Thus, the imaging device (1200) may generate a plurality of wavelength images based on emitted light having a plurality of wavelengths through a plurality of image sensors (1291, 1292).

[0257] The imaging device (1200) can acquire images corresponding to multiple wavelengths by independently detecting fluorescence signals of different wavelengths through the first image sensor (1291) and the second image sensor (1292). Additionally, the imaging device (1200) can improve the analysis speed by using multiple image sensors (1291, 1292) and can improve the efficiency and accuracy of the fluorescence microscope compared to the existing single image sensor-based fluorescence detection method. Furthermore, since the imaging device (1200) can accurately distinguish signals of different wavelengths emitted from different fluorescent markers by using multiple image sensors (1291, 1292), it can perform multi-channel fluorescence analysis. By performing multi-channel fluorescence analysis, the imaging device (1200) can individually distinguish and observe gene bases, specific proteins or structures within a cell, and can increase the accuracy of analysis by reducing cross-talk between fluorescence signals.

[0258] According to one embodiment of the present disclosure, in an imaging device (1200) comprising a plurality of image sensors (1291, 1292), the imaging device (1200) can shift the position where emitted light is focused from the image sensors (1291, 1292) by adjusting the tilt angle of a plurality of tilting plates (1281, 1282), and can acquire a plurality of images corresponding to the plurality of focused positions. For example, the imaging device (1200) can shift the position where a first emitted light is focused from the first image sensor (1291) by controlling the tilt angle of a first tilting plate (1281). Accordingly, the imaging device (1200) can acquire a plurality of first wavelength images in which the focused positions of the first emitted light are different by using the first image sensor (1291). For example, the imaging device (1200) can shift the position where the second emitted light is focused at the second image sensor (1292) by controlling the tilt angle of the second tilting plate (1282). Accordingly, the imaging device (1200) can acquire multiple second wavelength images with different focusing positions of the second emitted light by using the second image sensor (1292).

[0259] The imaging device (1200) can acquire multiple wavelength images corresponding to each wavelength and synthesize (or combine) the multiple wavelength images to acquire multiple result images with improved resolution. By acquiring result images with improved resolution for each wavelength, the imaging device (1200) can more accurately identify different gene bases, specific proteins or structures within a cell. For example, if a first fluorescent material emitting a first emission of light is attached to a guanine (G) base included in a DNA sample (2200), and a second fluorescent material emitting a second emission of light is attached to a cytosine (C) base included in the DNA sample (2200), the first image sensor (1291) of the imaging device (1200) can receive the first emission of light to identify the guanine (G) base, and the second image sensor (1292) can receive the second emission of light to identify the cytosine (C) base.

[0260] FIG. 12 illustrates, by way of example, that an imaging device (1200) includes two image sensors (1291, 1292) that receive emission light corresponding to two wavelengths based on a single light source (1210) through a second dichroic filter (1250). However, the embodiment is not limited thereto, and the imaging device (1200) may include three or more image sensors. For example, if a third dichroic filter is added to the imaging device (1200), emission light corresponding to three wavelengths based on a single light source may be identified. If a fourth dichroic filter is added to the imaging device (1200), emission light corresponding to four wavelengths based on a single light source may be identified, but the embodiment of the present disclosure is not limited to that described.

[0261] In one embodiment of the present disclosure, the number of image sensors (1291, 1292) included in the imaging device (1200) may be determined in correspondence with the number of fluorescent materials having different wavelengths included in the DNA sample (2200). In one embodiment of the present disclosure, at least one of the number of band-pass filters (1261, 1262), the number of tube lenses (1271, 1272), or the number of tilting plates (1281, 1282) included in the imaging device (1200) may be determined in correspondence with the number of fluorescent materials having different wavelengths included in the DNA sample (2200).

[0262] In FIG. 12, it is illustrated that two tilting plates (1281, 1282) are provided corresponding to each of the plurality of image sensors (1291, 1292), but the embodiment is not limited thereto. In one embodiment of the present disclosure, the tilting plates may be positioned corresponding to only some of the image sensors among the plurality of image sensors (1291, 1292). For example, based on the fluorescent material to be analyzed in each of the plurality of image sensors (1291, 1292), the tilting plates may be provided only to some of the image sensors that image the fluorescent material requiring a high-resolution image.

[0263] FIG. 13a is a schematic diagram of an imaging device (1300) including a plurality of light sources according to one embodiment of the present disclosure.

[0264] The imaging device (1300) described with reference to FIG. 13a may correspond to the imaging device (100) described above. According to one embodiment of the present disclosure, the imaging device (1300) may include a plurality of light sources (1311, 1312). For example, the light source (10) described with reference to FIG. 2 may include a plurality of light sources (1311, 1312).

[0265] Since the description of the imaging device (100) described above with reference to FIGS. 1 to 11 can be applied to the operation of the imaging device (1300), the description of FIG. 13a will focus on the operation of the plurality of light sources (1312, 1322), and further detailed descriptions will be omitted below.

[0266] In one embodiment of the present disclosure, the imaging device (1300) may emit beams of different wavelengths through a first light source (1311) and a second light source (1312), respectively. The first beam emitted by the imaging device (1300) through the first light source (1311) and the second beam emitted through the second light source (1312) may be emitted simultaneously from the first light source (1311) and the second light source (1312), may be emitted sequentially with a predetermined time difference, or may be emitted in time-slicing. The first beam may be irradiated onto a DNA sample (2300) by passing through a first collimating lens (1321), a first dichroic filter (1331), a second dichroic filter (1332), and an objective lens (1340) in sequence. The second beam may be irradiated onto a DNA sample (2300) by passing through a second collimating lens (1322), a first dichroic filter (1331), a second dichroic filter (1332), and an objective lens (1340) in sequence. In one embodiment of the present disclosure, the first dichroic filter (1331) may transmit the first beam and reflect the second beam. In one embodiment of the present disclosure, the second dichroic filter (1332) may transmit the first beam and the second beam, transmit excitation light shorter than the first threshold wavelength, and reflect emission light longer than the first threshold wavelength.

[0267] The imaging device (1300) can acquire a first emission light emitted from a DNA sample (2300) by a first beam. The imaging device (1300) can receive the first emission light emitted from the DNA sample (2300) by the first beam, reflected by a second dichroic filter (1332) and a mirror (1350), and passed through a bandpass filter (1360), a tube lens (1370), and a tilting plate (1380) using an image sensor (1390). The first emission light may have a first wavelength range.

[0268] The imaging device (1300) can acquire second emission light emitted from a DNA sample (2300) by a second beam. The imaging device (1300) can receive second emission light emitted from a DNA sample (2300) by a second beam using an image sensor (1390), reflected by a second dichroic filter (1332) and a mirror (1350), and passed through a bandpass filter (1360), a tube lens (1370), and a tilting plate (1380). The second emission light may have a second wavelength range different from the first wavelength range.

[0269] In one embodiment of the present disclosure, the bandpass filter (1360) may be a multi-band pass filter capable of passing light of a plurality of wavelength ranges. For example, the multi-band pass filter may selectively transmit light of a first wavelength range and light of a second wavelength range different from the first wavelength range.

[0270] In one embodiment of the present disclosure, the imaging device (1300) can acquire a plurality of first wavelength images based on a first emitted light. The imaging device (1300) can acquire a plurality of first wavelength images corresponding to a plurality of positions where the emitted light is focused at the image sensor (1390) by controlling the tilt angle of the tilting plate (1380) while acquiring the first wavelength images.

[0271] In one embodiment of the present disclosure, the imaging device (1300) can acquire a plurality of second wavelength images based on a second emitted light. The imaging device (1300) can acquire a plurality of second wavelength images corresponding to a plurality of positions where the emitted light is focused at the image sensor (1390) by controlling the tilt angle of the tilting plate (1380) while acquiring the second wavelength images.

[0272] According to one embodiment of the present disclosure, an imaging device (1300) may acquire a plurality of wavelength images corresponding to each wavelength and synthesize (or combine) the plurality of wavelength images to acquire a plurality of result images with improved resolution. By acquiring result images with improved resolution for each wavelength, the imaging device (1300) can more accurately identify different gene bases, specific proteins or structures within a cell.

[0273] Unlike what is depicted, the imaging device (1300) may include three or more light sources. In this case, each light source may emit a beam of the same wavelength or a different wavelength.

[0274] FIG. 13b is a schematic diagram of an imaging device (1300) including a plurality of light sources according to one embodiment of the present disclosure.

[0275] FIG. 13b illustrates an exemplary embodiment in which an imaging device (1300) includes four light sources (1311, 1312, 1313, 1314). Since the operation of the imaging device (1300) can be similarly applied to the imaging device (100) described above with reference to FIG. 13a, the description of FIG. 13b will focus on the operation of the imaging device (1300) including four light sources (1311, 1312, 1313, 1314), and further detailed descriptions will be omitted below.

[0276] In one embodiment of the present disclosure, the imaging device (1300) may emit beams of different wavelengths through a first light source (1311), a second light source (1312), a third light source (1313), and a fourth light source (1314), respectively. The first beam emitted through the first light source (1311) may be irradiated onto a DNA sample (2300) by passing through a first collimating lens (1321), a first-1 dichroic filter (1331a), a first-2 dichroic filter (1331b), a first-3 dichroic filter (1331c), a second dichroic filter (1332), and an objective lens (1340) in sequence. A second beam emitted through a second light source (1312) can be irradiated onto a DNA sample (2300) by passing through a second collimating lens (1322), a first-1 dichroic filter (1331a), a first-2 dichroic filter (1331b), a first-3 dichroic filter (1331c), a second dichroic filter (1332), and an objective lens (1340) in sequence.

[0277] A third beam emitted through a third light source (1313) can be irradiated onto a DNA sample (2300) by passing through a third collimating lens (1323), a first-second dichroic filter (1331b), a first-third dichroic filter (1331c), a second dichroic filter (1332), and an objective lens (1340) in sequence. A fourth beam emitted through a fourth light source (1314) can be irradiated onto a DNA sample (2300) by passing through a fourth collimating lens (1324), a first-third dichroic filter (1331c), a second dichroic filter (1332), and an objective lens (1340) in sequence. In one embodiment of the present disclosure, a first-first dichroic filter (1331a) can transmit the first beam and reflect the second beam. The first-second dichroic filter (1331b) can transmit the first and second beams and reflect the third beam. The first-third dichroic filter (1331c) can transmit the first to third beams and reflect the fourth beam.

[0278] The imaging device (1300) can acquire a first emission light having a first wavelength range emitted from a DNA sample (2300) by a first beam. The imaging device (1300) can acquire a second emission light having a second wavelength range emitted from a DNA sample (2300) by a second beam. The imaging device (1300) can acquire a third emission light having a third wavelength range emitted from a DNA sample (2300) by a third beam. The imaging device (1300) can acquire a fourth emission light having a fourth wavelength range emitted from a DNA sample (2300) by a fourth beam.

[0279] In one embodiment of the present disclosure, the bandpass filter (1360a) may be a multi-bandpass filter capable of passing light of a plurality of wavelength ranges. For example, the multi-bandpass filter (1360a) may selectively transmit light of different first wavelength ranges, second wavelength ranges, third wavelength ranges, and fourth wavelength ranges.

[0280] In one embodiment of the present disclosure, if a DNA sample (2300) contains four types of gene bases (A, T, G, C) and a specific fluorescent substance is attached to each base, each fluorescent substance has different excitation wavelengths and emission wavelengths. At this time, the imaging device (1400) can identify the distribution, structure, or presence of each gene base contained in the DNA sample (2300) by using four light sources (1411, 1412, 1413, 1414) and a multi-band pass filter (1360a). That is, the first to fourth wavelength ranges may each correspond to the fluorescence wavelength of the fluorescent substance attached to the four types of gene bases.

[0281] FIG. 14 is a schematic diagram of an imaging device (1400) including a plurality of light sources and a plurality of image sensors according to one embodiment of the present disclosure.

[0282] The imaging device (1400) described with reference to FIG. 14 may correspond to at least one of the imaging device (100), the imaging device (1200) described with reference to FIG. 12, or the imaging device (1300) described with reference to FIG. 13. According to one embodiment of the present disclosure, the imaging device (1400) may include a plurality of light sources (1411, 1412). According to one embodiment of the present disclosure, the imaging device (1200) may include a plurality of image sensors (1491, 1492, 1493, 1494).

[0283] Since the operation of the imaging device (1400) can be similarly applied to the description of the imaging device described above with reference to FIGS. 1 to 13, the description of FIG. 14 will focus on the operation of the imaging device (1400) including a plurality of light sources (1411, 1412) and a plurality of image sensors (1491, 1492, 1493, 1494), and a more detailed description will be omitted below.

[0284] The first dichroic filter (1431), the second dichroic filter (1432), the third-1 dichroic filter (1451), the third-2 dichroic filter (1452), and the third-3 dichroic filter (1453) can separate light based on their respective threshold wavelengths. For example, at least one of the first dichroic filter (1431), the second dichroic filter (1432), the third-1 dichroic filter (1451), the third-2 dichroic filter (1452), and the third-3 dichroic filter (1453) can reflect light shorter than the threshold wavelength and transmit light longer than the threshold wavelength. For example, at least one of the first dichroic filter (1431), the second dichroic filter (1432), the third-1 dichroic filter (1451), the third-2 dichroic filter (1452), and the third-3 dichroic filter (1453) may reflect light longer than a critical wavelength and transmit light longer than a critical wavelength. The critical wavelengths of the first dichroic filter (1431), the second dichroic filter (1432), the third-1 dichroic filter (1451), the third-2 dichroic filter (1452), and the third-3 dichroic filter (1453) may be different from each other or the same from each other. The critical wavelength of the first dichroic filter (1431) is referred to as the first critical wavelength, the critical wavelength of the second dichroic filter (1432) as the second critical wavelength, the critical wavelength of the third-1 dichroic filter (1451) as the third critical wavelength, the critical wavelength of the third-2 dichroic filter (1452) as the fourth critical wavelength, and the critical wavelength of the third-3 dichroic filter (1453) as the fifth critical wavelength.

[0285] In one embodiment of the present disclosure, a first beam emitted by an imaging device (1400) through a first light source (1411) may be irradiated onto a DNA sample (2400) by passing through a first collimator lens (1421), a first dichroic filter (1431), a second dichroic filter (1432), and an objective lens (1440) in sequence. As the fluorescent material of the DNA sample (2400) is excited, a first emitted light may be generated. The first emitted light may pass through the objective lens (1440) and be incident on the second dichroic filter (1432).

[0286] The second dichroic filter (1432) transmits a first excitation light (e.g., a first beam) shorter than a first threshold wavelength and can reflect a first emission light shorter than a first threshold wavelength. The first emission light may be incident on the third-1 dichroic filter (1451) and reflected toward the third-2 dichroic filter (1452). The third-2 dichroic filter (1452) can transmit the first-1 emission light among the first emission light, which is longer than the fourth threshold wavelength of the third-2 dichroic filter (1452). The imaging device (1400) can receive the first-1 emission light through the fourth image sensor (1494) to generate a first wavelength image. The third-2 dichroic filter (1452) can reflect the first-2 emission light among the first emission light, which is shorter than the fourth threshold wavelength of the third-2 dichroic filter (1452). The imaging device (1400) can generate a second wavelength image by receiving the first and second emitted light through the third image sensor (1493).

[0287] For example, the first-1 emission light may be emitted as the first-1 fluorescent material contained in the DNA sample (2400) is excited, and the first-2 emission light may be emitted as the first-2 fluorescent material contained in the DNA sample (2400) is excited. The first-1 fluorescent material and the first-2 fluorescent material are excited by a first beam emitted through an excitation light of the same wavelength, but may emit emission light having different wavelengths (e.g., the first-1 emission light and the first-2 emission light).

[0288] In one embodiment of the present disclosure, a second beam emitted by an imaging device (1400) through a second light source (1412) may be irradiated onto a DNA sample (2400) by passing through a second collimator lens (1422), a first dichroic filter (1431), a second dichroic filter (1432), and an objective lens (1440) in sequence. As the fluorescent material of the DNA sample (2400) is excited, a second emitted light may be generated. The second emitted light may pass through the objective lens (1440) and be incident on the second dichroic filter (1432).

[0289] The second dichroic filter (1432) can transmit a second excitation light (e.g., a second beam) shorter than the first threshold wavelength and reflect a second emission light shorter than the first threshold wavelength. The second emission light can be incident on the third-1 dichroic filter (1451) and transmitted toward the third-3 dichroic filter (1453). The third-3 dichroic filter (1453) can transmit the second-1 emission light among the second emission light, which is longer than the fifth threshold wavelength of the third-3 dichroic filter (1453). The imaging device (1400) can receive the second-1 emission light through the second image sensor (1492) to generate a third wavelength image. The third-3 dichroic filter (1453) can transmit the second-2 emission light among the second emission light, which is shorter than the fifth threshold wavelength of the third-3 dichroic filter (1453). The imaging device (1400) can generate a fourth wavelength image by receiving the second-2 emission light through the first image sensor (1491).

[0290] For example, the second-1 emission light may be emitted as the second-1 fluorescent material contained in the DNA sample (2400) is excited, and the second-2 emission light may be emitted as the second-2 fluorescent material contained in the DNA sample (2400) is excited. The second-1 fluorescent material and the second-2 fluorescent material may be excited by a second beam emitted through an excitation light of the same wavelength, but may emit emission light having different wavelengths (e.g., the second-1 emission light and the second-2 emission light). In summary, according to one embodiment of the present disclosure, the imaging device (1400) may be designed to detect fluorescent signals of different wavelengths.

[0291] For example, when a first beam emitted from a first light source (1411) irradiates a DNA sample (2400), a specific fluorescent substance present in the DNA sample (2400) is excited and emits a fluorescent signal. The imaging device (1400) can detect fluorescent signals of different wavelengths (first-1 emission light and first-2 emission light) using a third image sensor (1493) and a fourth image sensor (1494). The imaging device (1400) can detect the first-1 emission light emitted by the first-1 fluorescent substance through the fourth image sensor (1494), and the first-2 emission light emitted by the first-2 fluorescent substance through the third image sensor (1493).

[0292] Likewise, when a second beam emitted from a second light source (1412) irradiates a DNA sample (2400), another fluorescent material is excited and emits a fluorescent signal. The imaging device (1400) can detect fluorescent signals of different wavelengths (second-1 emission light and second-2 emission light) using a first image sensor (1491) and a second image sensor (1492). The imaging device (1400) can detect the second-1 emission light emitted by the second-1 fluorescent material through the second image sensor (1492), and the second-2 emission light emitted by the second-2 fluorescent material through the first image sensor (1491).

[0293] In this way, the imaging device (1400) can detect fluorescent signals emitted from a plurality of fluorescent substances contained in a DNA sample (2400) and analyze the distribution, structure, or presence of biomaterials (e.g., gene bases, proteins, cell structures, etc.) corresponding to each fluorescent substance.

[0294] For example, if a sample contains four types of gene bases (A, T, G, C) and a specific fluorescent substance is attached to each base, each fluorescent substance will have different excitation and emission wavelengths. At this time, the imaging device (1400) can identify the distribution, structure, or presence of each gene base contained in the DNA sample (2400) by using two light sources (1412, 1412) and a plurality of image sensors (1491, 1492, 1493, 1494).

[0295] Accordingly, the imaging device (1400) according to one embodiment of the present disclosure can accurately separate and analyze fluorescent signals, so it can be utilized in various life science and medical diagnostic fields such as gene sequence analysis, protein detection, and cell structure research.

[0296] In one embodiment of the present disclosure, the imaging device (1400) may include a plurality of tilting plates (1481, 1482, 1483, 1484). For example, the plurality of tilting plates (1481, 1482, 1483, 1484) may include a first tilting plate (1481) corresponding to a first image sensor (1491), a second tilting plate (1482) corresponding to a second image sensor (1492), a third tilting plate (1483) corresponding to a third image sensor (1493), and a fourth tilting plate (1484) corresponding to a fourth image sensor (1494).

[0297] The imaging device (1400) can acquire a plurality of first wavelength images corresponding to a plurality of positions where the first-1 emission light is focused at the fourth image sensor (1494) by controlling the tilt angle of the fourth tilting plate (1484) while acquiring the first wavelength image. The imaging device (1400) can acquire a plurality of second wavelength images corresponding to a plurality of positions where the first-2 emission light is focused at the third image sensor (1493) by controlling the tilt angle of the third tilting plate (1483) while acquiring the second wavelength image. The imaging device (1400) can acquire a plurality of second wavelength images corresponding to a plurality of positions where the second-1 emission light is focused at the second image sensor (1492) by controlling the tilt angle of the second tilting plate (1482) while acquiring the third wavelength image. The imaging device (1400) can acquire a plurality of fourth wavelength images corresponding to a plurality of positions where the second-second emission light is focused from the first image sensor (1491) by controlling the tilt angle of the first tilting plate (1481) while acquiring the fourth wavelength image.

[0298] The imaging device (1300) can acquire multiple wavelength images corresponding to each wavelength and synthesize (or combine) the multiple wavelength images to acquire multiple result images with improved resolution. By acquiring result images with improved resolution for each wavelength, the imaging device (1300) can more accurately identify different gene bases, specific proteins or structures within a cell.

[0299] Meanwhile, FIG. 14 illustrates that four tilting plates (1481, 1482, 1483, 1484) are provided corresponding to each of the plurality of image sensors (1491, 1492, 1493, 1494), but the embodiment is not limited thereto. In one embodiment of the present disclosure, the tilting plates may be positioned to correspond to only some of the image sensors among the plurality of image sensors (1491, 1492, 1493, 1494). For example, based on the fluorescent material to be analyzed in each of the plurality of image sensors (1491, 1492, 1493, 1494), the tilting plates may be provided only to the image sensors that detect the fluorescent material requiring high-resolution imaging.

[0300] FIG. 15a is a flowchart illustrating a method in which an imaging device (1500) according to one embodiment of the present disclosure performs DNA sequencing imaging. FIG. 15b is a diagram illustrating an operation in which an imaging device (1500) according to one embodiment of the present disclosure performs DNA sequencing imaging.

[0301] Since the operation of the imaging device (1500) can be similarly applied to the imaging device described above with reference to FIGS. 1 to 14, the description of FIGS. 15a and 15b will focus on the operation of the imaging device (1500) as the imaging device (1500) does not include a tilting plate, and a more detailed description will be omitted below.

[0302] Referring to FIG. 15a, a method for an imaging device (1500) to perform DNA sequencing imaging may include step S1510. In one embodiment of the present disclosure, step S1510 may be executed by at least one processor (30) included in the imaging device (1500). The operation of step S1510 illustrated in FIG. 15a is a specification of the operation of S210 illustrated in FIG. 2. After the operation of step S1510 illustrated in FIG. 15a is performed, the operation of S220 illustrated in FIG. 2 may be performed.

[0303] In step S1510 of FIG. 15a, an imaging device (100) according to one embodiment of the present disclosure can adjust the position of an image sensor (1530) so that it is shifted by a unit pixel pitch or less of the image sensor (1530). That is, the imaging device (1500) can directly shift the position of the image sensor (1530) by a unit pixel pitch or less of the image sensor (1530) in order to shift the position where the emitted light is concentrated on the image sensor (1530). As an example, the image sensor (1530) may be a pixel shift camera. In this case, the imaging device (1500) may not include a tilting plate.

[0304] Referring together with FIG. 15b, in the imaging device (1500), light that has passed through a band-pass filter (1510) among the emitted light emitted from a DNA sample (200) can be focused to an image sensor (1530) by a tube lens (1520). In one embodiment of the present disclosure, the imaging device (1500) may move the position of the image sensor (1530) itself to shift the path through which the emitted light is focused to the image sensor (1530). In one embodiment of the present disclosure, the imaging device (1500) may not change the path through which the emitted light is focused to the image sensor (1530), but may shift the position of the image sensor (1530) to change the position among the pixels of the image sensor (1530) where the emitted light is focused. The imaging device (1500) can move the position of the image sensor (1530) by a unit pixel pitch or less so that the position where the emitted light is focused on the image sensor (1530) is shifted by a unit pixel pitch or less.

[0305] For example, first, the imaging device (1500) can receive emitted light emitted from a DNA sample (200) through the image sensor (1530) while the image sensor (1530) is positioned at a location corresponding to a first coordinate. At this time, the emitted light emitted from the DNA sample is focused at a first location (L1) (or a first region) among the pixels of the image sensor (1530), and the pixel corresponding to the first location (L1) (or a first region) can respond and convert the emitted light into an electrical signal.

[0306] Subsequently, for example, the imaging device (1500) may move the position of the image sensor (1530) from a first coordinate to a position corresponding to a second coordinate. The distance between the first coordinate and the second coordinate may be less than or equal to the unit pixel pitch of the image sensor (1530) (e.g., 1 / 2 unit pixel pitch or 1 / 3 unit pixel pitch). FIG. 15b illustrates, as an example, that the imaging device (1500) shifts the image sensor (1530) upward, but the direction in which the image sensor (1530) is moved is not limited to any one embodiment. FIG. 15b illustrates, as an example, that the imaging device (1500) shifts the image sensor (1530) upward by 1 / 2 unit pixel pitch, but the distance the image sensor (1530) is moved is not limited to any one embodiment.

[0307] Subsequently, the imaging device (1500) can receive emitted light emitted from the DNA sample (200) through the image sensor (1530) while the image sensor (1530) is positioned at a location corresponding to a second coordinate. At this time, the emitted light emitted from the DNA sample is focused at a second location (L2) (or second region) among the pixels of the image sensor (1530), and the pixel corresponding to the second location (L1) (or second region) can respond and convert the emitted light into an electrical signal. As the position of the image sensor (1530) shifts upward, the emitted light can be received at a second location (L2) (or second region) that is shifted downward by a distance less than or equal to the unit pixel pitch (e.g., 1 / 2 pixel pitch or 1 / 3 pixel pitch) of the image sensor (1530) from the first location (L1) (or first region).

[0308] The imaging device (1500) can acquire a first image when the image sensor (1530) is positioned at a first coordinate, and acquire a second image when the image sensor (1530) is positioned at a second coordinate. The imaging device (1500) can acquire a second image different from the first image when the position at which the emitted light is collected from the image sensor (1530) is changed as the position of the image sensor (1530) is changed. FIG. 15b illustrates, as an example, that the imaging device (1500) acquires two images by shifting the image sensor (1530) once, and the imaging device (1500) can acquire more images by shifting the image sensor (1530) further.

[0309] The imaging device (1500) can generate a result image by synthesizing a plurality of images obtained by shifting the position of the image sensor (1530) by a unit pixel pitch or less. In the plurality of images, corresponding pixels may partially overlap. The resolution of the result image may be higher than the resolution of the plurality of images.

[0310] According to one embodiment of the present disclosure, the imaging device (1500) can acquire a result image with improved resolution without changing the internal structure of the imaging device (1500) (e.g., changing to a high numerical aperture objective lens or changing to a structured light microscope). Since the imaging device (1400) according to one embodiment of the present disclosure can accurately separate and analyze fluorescence signals, it can be utilized in various life science and medical diagnostic fields, such as gene sequence analysis, protein detection, and cell structure research.

[0311] According to one embodiment of the present disclosure, an imaging device (100) for imaging a DNA signal may be provided.

[0312] According to one embodiment of the present disclosure, an imaging device (100) may include a light source (10) that irradiates a beam onto a DNA sample. According to one embodiment of the present disclosure, the imaging device (100) may include an image sensor (20) that receives emitted light emitted from the DNA sample irradiated by the beam. According to one embodiment of the present disclosure, the imaging device (100) may include at least one processor (30) that includes processing circuitry. According to one embodiment of the present disclosure, the imaging device (100) may include. According to one embodiment of the present disclosure, the imaging device (100) may include a memory (40) that stores one or more instructions.

[0313] According to one embodiment of the present disclosure, by executing one or more instructions individually or collectively by at least one processor (30), the imaging device (100) can shift the position where the emitted light is focused to the image sensor (20) to a unit pixel pitch or less of the image sensor (20).

[0314] According to one embodiment of the present disclosure, by executing one or more instructions individually or collectively by at least one processor (30), the imaging device (100) can acquire a plurality of images by receiving emitted light with a shifted position focused to the image sensor (20) using an image sensor (20).

[0315] According to one embodiment of the present disclosure, by executing one or more instructions individually or collectively by at least one processor (30), the imaging device (100) can synthesize a plurality of acquired images to obtain a result image.

[0316] According to one embodiment of the present disclosure, in a plurality of images, corresponding pixels may be partially overlapped.

[0317] According to one embodiment of the present disclosure, the resolution of the resulting image may be higher than the resolution of a plurality of images.

[0318] According to one embodiment of the present disclosure, the imaging device may further include a tilting plate (50) disposed between a DNA sample and an image sensor (20).

[0319] According to one embodiment of the present disclosure, by executing one or more instructions individually or collectively by at least one processor (30), the imaging device (100) can adjust the tilt angle of the tilting plate (50) so that the position where the emitted light passes through the tilting plate (50) and is focused to the image sensor (20) is shifted by less than a unit pixel pitch.

[0320] According to one embodiment of the present disclosure, by executing one or more instructions individually or collectively by at least one processor (30), the imaging device (100) can determine the tilt angle of the tilting plate (50) based on the refractive index of the tilting plate (50) and the thickness of the tilting plate (50).

[0321] According to one embodiment of the present disclosure, by executing one or more instructions individually or collectively by at least one processor (30), the imaging device (100) can acquire four different images by adjusting the tilt angle of the tilting plate (50) to four different angles so that the position where the emitted light is focused to the image sensor (20) is shifted by half of a unit pixel pitch.

[0322] According to one embodiment of the present disclosure, by executing one or more instructions individually or collectively by at least one processor (30), the imaging device (100) can synthesize four plurality of images to obtain a result image.

[0323] According to one embodiment of the present disclosure, by executing one or more instructions individually or collectively by at least one processor (30), the imaging device (100) can acquire nine different images by adjusting the tilt angle of the tilting plate (50) to nine different angles so that the position where the emitted light is focused to the image sensor (20) is shifted by one-third of the unit pixel pitch.

[0324] According to one embodiment of the present disclosure, by executing one or more instructions individually or collectively by at least one processor (30), the imaging device (100) can synthesize nine plurality of images to obtain a result image.

[0325] According to one embodiment of the present disclosure, the imaging device (100) may further include a piezo actuator that controls the tilt angle of the tilting plate (50).

[0326] According to one embodiment of the present disclosure, the tilting plate (50) may be characterized by including glass.

[0327] According to one embodiment of the present disclosure, the imaging device (100) may further include a dichroic filter (520) that separates a beam directed toward a DNA sample from the emitted light emitted from the DNA sample. According to one embodiment of the present disclosure, the imaging device (100) may further include a band-pass filter (540) that selectively passes light of a specific wavelength range that emits fluorescence. According to one embodiment of the present disclosure, the imaging device (100) may further include a tube lens (550) that focuses light of a specific wavelength range. According to one embodiment of the present disclosure, a tilting plate (50) may be characterized by being positioned between the tube lens (550) and the image sensor (20).

[0328] According to one embodiment of the present disclosure, by executing one or more instructions individually or collectively by at least one processor (30), the imaging device (100) can reflect emitted light emitted from a DNA sample toward a bandpass filter (540) using a dichroic filter (520).

[0329] According to one embodiment of the present disclosure, by executing one or more instructions individually or collectively by at least one processor (30), the imaging device (100) can pass only light of a specific wavelength range among the reflected emitted light using a bandpass filter (540).

[0330] According to one embodiment of the present disclosure, by executing one or more instructions individually or collectively by at least one processor (30), the imaging device (100) can focus light of a specific wavelength range that has passed through a bandpass filter (540) to an image sensor (20) using a tube lens (550).

[0331] According to one embodiment of the present disclosure, by executing one or more instructions individually or collectively by at least one processor (30), the imaging device (100) can adjust the position of the image sensor (20) so that it is shifted to a unit pixel pitch or less of the image sensor (20).

[0332] According to one embodiment of the present disclosure, the imaging device (100) may further include a multi-band pass filter (1360, 1360a) that selectively passes light of different first wavelength ranges and second wavelength ranges that emit fluorescence.

[0333] According to one embodiment of the present disclosure, the light source (10) may be characterized by including a first light source (1311) that emits a first beam of a first emission wavelength and a second light source (1312) that emits a second beam of a second emission wavelength different from the first emission wavelength.

[0334] According to one embodiment of the present disclosure, by executing one or more instructions individually or collectively by at least one processor (30), the imaging device (100) can acquire a plurality of first images by receiving light of a first wavelength range emitted from a DNA sample irradiated with a first beam and passed through a multi-band pass filter (1360, 1360a).

[0335] According to one embodiment of the present disclosure, by executing one or more instructions individually or collectively by at least one processor (30), the imaging device (100) can acquire a plurality of second images by receiving light of a second wavelength range emitted from a DNA sample irradiated with a second beam and passed through a multi-band pass filter (1360, 1360a).

[0336] According to one embodiment of the present disclosure, by executing one or more instructions individually or collectively by at least one processor (30), the imaging device (100) can synthesize a plurality of acquired first images to obtain a first result image.

[0337] According to one embodiment of the present disclosure, by executing one or more instructions individually or collectively by at least one processor (30), the imaging device (100) can synthesize a plurality of acquired second images to obtain a second result image.

[0338] According to one embodiment of the present disclosure, the image sensor (20) may be characterized by including a first image sensor (1291) that receives light in a first wavelength range and a second image sensor (1292) that receives light in a second wavelength range different from the first wavelength range.

[0339] According to one embodiment of the present disclosure, the tilting plate (50) may be characterized by including at least one of a first tilting plate (1281) corresponding to a first image sensor (1291) or a second tilting plate (1282) corresponding to a second image sensor (1292).

[0340] According to one embodiment of the present disclosure, a method for imaging a DNA signal by an imaging device (100) may be provided.

[0341] According to one embodiment of the present disclosure, the method may include a step (S210) of shifting the position at which emitted light emitted from a DNA sample irradiated with a beam is focused to an image sensor (20) by a unit pixel pitch or less of the image sensor (20). According to one embodiment of the present disclosure, the method may include a step (S220) of acquiring a plurality of images by receiving the emitted light, at which the position focused to the image sensor (20) is shifted, using the image sensor (20). According to one embodiment of the present disclosure, the method may include a step (S230) of acquiring a result image by synthesizing the acquired plurality of images.

[0342] According to one embodiment of the present disclosure, the step (S210) of controlling the position where the emitted light is focused to the image sensor (20) to be shifted to a unit pixel pitch or less of the image sensor (20) may include the step (S310) of adjusting the tilt angle of the tilting plate (50) so that the position where the emitted light passes through the tilting plate (50) and is focused to the image sensor (20) is shifted to a unit pixel pitch or less.

[0343] According to one embodiment of the present disclosure, the method may include the step of determining the tilt angle of the tilting plate (50) based on the refractive index of the tilting plate (50) and the thickness of the tilting plate (50).

[0344] According to one embodiment of the present disclosure, the step of acquiring a plurality of images (S220) may include the step of acquiring four different plurality of images (S1010) by adjusting the tilt angle of the tilting plate (50) to four different angles so that the position where the emitted light is focused on the image sensor (20) is shifted by half of the unit pixel pitch.

[0345] According to one embodiment of the present disclosure, the step of obtaining a result image (S230) may include the step of obtaining a result image (S1020) by synthesizing four plurality of images.

[0346] According to one embodiment of the present disclosure, the step of acquiring a plurality of images (S220) may include the step of acquiring nine different plurality of images (S1110) by adjusting the tilt angle of the tilting plate (50) to nine different angles so that the position where the emitted light is focused on the image sensor (20) is shifted by 1 / 3 of the unit pixel pitch.

[0347] According to one embodiment of the present disclosure, the step of obtaining a result image (S230) may include the step of obtaining a result image (S1120) by synthesizing nine plurality of images.

[0348] According to one embodiment of the present disclosure, the method may include the step of using a dichroic filter (520) to separate a beam irradiated toward a DNA sample from an emitted light emitted from the DNA sample and reflecting the emitted light toward a bandpass filter (540).

[0349] According to one embodiment of the present disclosure, the method may include the step of using a bandpass filter (540) to pass only light of a specific wavelength range that emits fluorescence among the reflected emitted light.

[0350] According to one embodiment of the present disclosure, the method may include the step of using a tube lens (550) to focus light of a specific wavelength range that has passed through a band-pass filter (540) through a tilting plate (50) to an image sensor (20).

[0351] A program executed by the imaging device (100) described in the present disclosure may be implemented as a hardware component, a software component, and / or a combination of a hardware component and a software component. The program may be executed by any system capable of executing computer-readable instructions.

[0352] Software may include a computer program, code, instructions, or a combination of one or more of these, and may configure a processing unit to operate as desired or command the processing unit independently or collectively.

[0353] Software can be implemented as a computer program containing instructions stored on a computer-readable storage medium. Examples of computer-readable recording media include magnetic storage media (e.g., ROM (read-only memory), RAM (random-access memory), floppy disks, hard disks, etc.) and optical reading media (e.g., CD-ROMs, DVDs (Digital Versatile Discs)). Computer-readable recording media can be distributed across networked computer systems, allowing computer-readable code to be stored and executed in a distributed manner. The medium is readable by a computer, stored in memory, and can be executed by a processor.

[0354] Computer-readable storage media may be provided in the form of non-transitory storage media. Here, 'non-transitory' means only that the storage medium does not contain a signal and is tangible, and does not distinguish between cases where data is stored semi-permanently or temporarily on the storage medium. For example, a 'non-transitory storage medium' may include a buffer in which data is stored temporarily.

[0355] In addition, the program according to the embodiments disclosed herein may be provided by being included in a computer program product. The computer program product may be traded between a seller and a buyer as a product.

[0356] A computer program product may include a software program and a computer-readable storage medium on which the software program is stored. For example, the computer program product may include a product in the form of a software program (e.g., a downloadable application) that is distributed electronically through the manufacturer of the imaging device (100) or an electronic market (e.g., Samsung Galaxy Store™). For electronic distribution, at least a portion of the software program may be stored on a storage medium or temporarily created. In this case, the storage medium may be a server of the manufacturer of the imaging device (100), a server of the electronic market, or a storage medium of a relay server that temporarily stores the software program.

[0357] A computer program product may include a storage medium of a server or a storage medium of an imaging device (100) in a system composed of an imaging device (100) and / or a server. Alternatively, if there is a third device that is communicationally connected to the imaging device (100), the computer program product may include a storage medium of the third device. Alternatively, the computer program product may include a software program itself that is transmitted from the imaging device (100) to the third device or from the third device to the imaging device.

[0358] In this case, either the imaging device (100) or one of the third devices may execute a computer program product to perform the method according to the disclosed embodiments. Alternatively, at least one of the imaging device (100) and the third device may execute a computer program product to perform the method according to the disclosed embodiments in a distributed manner.

[0359] For example, the imaging device (100) can execute a computer program product stored in memory (140, see FIG. 3) to control another imaging device that is communicationally connected to the imaging device (100) to perform a method according to the disclosed embodiments.

[0360] As another example, a third device may execute a computer program product to control an imaging device that is communicationally connected to the third device to perform the method according to the disclosed embodiment.

[0361] When the third device executes a computer program product, the third device may download the computer program product from the imaging device (100) and execute the downloaded computer program product. Alternatively, the third device may execute a computer program product provided in a pre-loaded state to perform the method according to the disclosed embodiments.

[0362] Although the embodiments have been described above with reference to limited examples and drawings, those skilled in the art can make various modifications and variations from the description above. For example, appropriate results can be achieved even if the described techniques are performed in a different order than described, and / or components such as the described computer system or module are combined or assembled in a form different from described, or replaced or substituted by other components or equivalents.

Claims

In an imaging device (100) for imaging DNA signals, A light source (10) that irradiates a beam onto a DNA sample; An image sensor (20) that receives emitted light emitted from the DNA sample irradiated by the beam; At least one processor (30) including processing circuitry; and It includes memory (40) for storing one or more instructions, and By executing the above one or more instructions individually or collectively by the at least one processor (30), the imaging device (100) The position where the emitted light is focused on the image sensor (20) is shifted to a unit pixel pitch or less of the image sensor (20), and By using the image sensor (20), a plurality of images are obtained by receiving the emitted light, the position at which it is focused to the image sensor (20) is shifted. An imaging device (100) that synthesizes a plurality of images obtained above to obtain a result image. In Article 1, An imaging device (100) in which corresponding pixels in the above plurality of images are partially overlapped. In any one of paragraphs 1 to 2, An imaging device (100) in which the resolution of the above result image is higher than the resolution of the above plurality of images. In any one of paragraphs 1 to 3, It further includes a tilting plate (50) disposed between the DNA sample and the image sensor (20), and By executing the above one or more instructions individually or collectively by the at least one processor (30), the imaging device (100) An imaging device (100) that adjusts the tilt angle of the tilting plate (50) so that the position where the emitted light passes through the tilting plate (50) and is focused on the image sensor (20) is shifted to less than the unit pixel pitch. In Paragraph 4, By executing the above one or more instructions individually or collectively by the at least one processor (30), the imaging device (100) An imaging device (100) that determines the tilt angle of the tilting plate (50) based on the refractive index of the tilting plate (50) and the thickness of the tilting plate (50). In any one of paragraphs 4 to 5, By executing the above one or more instructions individually or collectively by the at least one processor (30), the imaging device (100) The tilt angle of the tilting plate (50) is adjusted to four different angles so that the position where the emitted light is focused on the image sensor (20) is shifted by half of the unit pixel pitch, thereby acquiring four different images. An imaging device (100) that synthesizes the above four multiple images to obtain the above result image. In any one of paragraphs 4 to 5, By executing the above one or more instructions individually or collectively by the at least one processor (30), the imaging device (100) The tilt angle of the tilting plate (50) is adjusted to nine different angles so that the position where the emitted light is focused on the image sensor (20) is shifted by 1 / 3 of the unit pixel pitch, thereby acquiring nine different images. An imaging device (100) that synthesizes the above nine multiple images to obtain the above result image. In any one of paragraphs 4 through 7, Imaging device (100) further comprising a piezo actuator for controlling the tilt angle of the tilting plate (50). In any one of paragraphs 4 through 8, The above tilting plate (50) is an imaging device (100) comprising glass. In any one of paragraphs 4 through 9, A dichroic filter (520) that separates the beam directed toward the DNA sample and the emitted light emitted from the DNA sample; A band-pass filter (540) that selectively passes light of a specific wavelength range that emits fluorescence; and It further includes a tube lens (550) that focuses light within the above specific wavelength range, and The tilting plate (50) is positioned between the tube lens (550) and the image sensor (20), and By executing the above one or more instructions individually or collectively by the at least one processor (30), the imaging device (100) Using the dichroic filter (520), the emitted light emitted from the DNA sample is reflected toward the bandpass filter (540), and By using the bandpass filter (540) above, only light within the specific wavelength range among the reflected emitted light is passed through, and An imaging device (100) that uses the above tube lens (550) to focus light of the above specific wavelength range that has passed through the above band-pass filter (540) to the above image sensor (20). In any one of paragraphs 1 to 3, By executing the above one or more instructions individually or collectively by the at least one processor (30), the imaging device (100) An imaging device (100) that adjusts the position of the image sensor (20) so that it is shifted to a unit pixel pitch less than or equal to that of the image sensor (20). In a method for imaging a DNA signal using an imaging device (100), Step (S210) of shifting the position where the emitted light emitted from the DNA sample irradiated by the beam is focused to the image sensor (20) to a unit pixel pitch or less of the image sensor (20); A step (S220) of acquiring a plurality of images by receiving the emitted light, the position at which it is focused to the image sensor (20), using the image sensor (20); and A method comprising the step (S230) of synthesizing a plurality of images obtained above to obtain a result image. In Article 12, In the plurality of images above, corresponding pixels partially overlap, and A method in which the resolution of the above result image is higher than the resolution of the above plurality of images. In any one of paragraphs 12 to 13, The step (S210) of controlling the position where the emitted light is focused on the image sensor (20) so that it is shifted to a unit pixel pitch or less of the image sensor (20) is, A method comprising the step (S310) of adjusting the tilt angle of the tilting plate (50) so that the position where the emitted light passes through the tilting plate (50) and is focused on the image sensor (20) is shifted to less than the unit pixel pitch. In Article 14, The above method is, A method further comprising the step of determining the tilt angle of the tilting plate (50) based on the refractive index of the tilting plate (50) and the thickness of the tilting plate (50).

Images