WO2022181023A1 - Dispositif d'imagerie, dispositif de traitement d'informations, système d'imagerie et procédé d'observation - Google Patents

Dispositif d'imagerie, dispositif de traitement d'informations, système d'imagerie et procédé d'observation Download PDF

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Publication number
WO2022181023A1
WO2022181023A1 PCT/JP2021/047726 JP2021047726W WO2022181023A1 WO 2022181023 A1 WO2022181023 A1 WO 2022181023A1 JP 2021047726 W JP2021047726 W JP 2021047726W WO 2022181023 A1 WO2022181023 A1 WO 2022181023A1
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Prior art keywords
imaging
image data
imaging device
culture
information processing
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PCT/JP2021/047726
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English (en)
Japanese (ja)
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拓明 山本
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富士フイルム株式会社
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Publication of WO2022181023A1 publication Critical patent/WO2022181023A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M1/00—Apparatus for enzymology or microbiology
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M1/00—Apparatus for enzymology or microbiology
    • C12M1/34—Measuring or testing with condition measuring or sensing means, e.g. colony counters
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B21/00—Microscopes
    • G02B21/24—Base structure
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B21/00—Microscopes
    • G02B21/36—Microscopes arranged for photographic purposes or projection purposes or digital imaging or video purposes including associated control and data processing arrangements

Definitions

  • the technology of the present disclosure relates to an imaging device, an information processing device, an imaging system, and an observation method.
  • An incubator for a fertilized egg is used to culture a fertilized egg that has undergone in vitro fertilization.
  • a fertilized egg (embryo) cultured in an incubator is transferred to the embryo or frozen.
  • embryo refers to a fertilized egg in a state of division.
  • Japanese Patent Application Laid-Open No. 2018-093795 proposes an incubator that enables observation of fertilized eggs being cultured without removing the culture dish.
  • the incubator described in Japanese Patent Application Laid-Open No. 2018-093795 includes a culture section that holds a plurality of culture dishes in a culture environment, and an imaging section provided corresponding to the culture dishes held in the culture section.
  • an incubator that allows fertilized eggs to be observed without removing the culture dish from the culture unit while culturing the fertilized eggs in a culture dish is called a time-lapse incubator. ing.
  • the imaging unit described in JP-A-2018-093795 is an optical camera having a lens, focus is adjusted by moving the lens along the optical axis.
  • a human egg is almost spherical and has a diameter of about 100 to 150 ⁇ m. It is not known in which position of the ovum the position of the pronucleus or the like, which is a clue for judging the fertilization of the ovum, exists. For this reason, the imaging unit described in Japanese Patent Application Laid-Open No. 2018-093795 captures a plurality of images with different focal positions.
  • the time-lapse incubator as described in Japanese Patent Application Laid-Open No. 2018-093795 is expensive because it is an integrated device in which the imaging unit is incorporated in the culturing unit.
  • a problem with such a time-lapse incubator is that it is difficult to introduce in small-scale clinics and the like.
  • the incubator described in Japanese Patent Application Laid-Open No. 2018-093795 uses an optical camera as an imaging unit, so there is a problem that focus adjustment is difficult.
  • An object of the technology of the present disclosure is to provide an imaging device, an information processing device, an imaging system, and an observation method that can be used in an incubator for fertilized eggs, is inexpensive, and does not require focus adjustment. .
  • an imaging device of the present disclosure is an imaging device that includes a light source and an imaging sensor, and generates image data including an interference fringe image by imaging a fertilized egg seeded in a culture container. can be put into and taken out of a culture chamber provided in an incubator for fertilized eggs.
  • a support for supporting the light source is provided, and the height adjustment mechanism is capable of changing the length of the support.
  • the height is less than 10 cm.
  • the incubator is provided with a plurality of culture chambers, and it is preferable that each culture chamber can be taken in and out.
  • the information processing device of the present disclosure receives image data transmitted from the imaging device and performs reconstruction processing based on the received image data, thereby generating a reconstructed image at an arbitrary focus position.
  • the information processing device receives image data periodically transmitted from the imaging device housed in the incubation room, performs reconstruction processing each time it receives image data, and displays a reconstructed image generated by the reconstruction processing. It is preferable to display
  • the light source has a plurality of light emitting points
  • the imaging device generates a plurality of image data by performing a plurality of imaging operations while sequentially causing the light emitting points to emit light.
  • the imaging system of the present disclosure includes an incubator equipped with an imaging device that has a light source and an imaging sensor and generates image data including an interference fringe image by imaging fertilized eggs seeded in a culture container, and image data. and an information processing device that generates a reconstructed image at an arbitrary focus position by performing reconstruction processing based on the image.
  • the information processing device perform reconstruction processing each time the imaging device generates image data, and display the reconstructed image generated by the reconstruction processing on the display.
  • the incubator has a culture chamber for accommodating culture vessels and a lid for keeping the culture chamber airtight, and the light source is provided on the lid.
  • the imaging sensor is preferably provided at the bottom of the culture chamber in which the culture vessel is placed.
  • the light source has a plurality of light emitting points
  • the imaging device generates a plurality of image data by performing a plurality of imaging operations while sequentially causing the light emitting points to emit light.
  • the information processing device preferably generates high-resolution image data based on a plurality of image data, and performs reconstruction processing based on the generated high-resolution image data.
  • the observation method of the present disclosure generates image data including an interference fringe image by imaging a fertilized egg seeded in a culture vessel, and performs reconstruction processing based on the generated image data to obtain an arbitrary focal point.
  • An observation method for observing a fertilized egg by generating a reconstructed image at a position, wherein the fertilized egg has a diameter of 100 ⁇ m or more and less than 200 ⁇ m.
  • the fertilized egg floats in the culture solution dropped into the culture vessel, and the height of the culture solution is preferably 1 mm or more and less than 20 mm.
  • an imaging device and an information processing device that can be used in an incubator for fertilized eggs, are inexpensive, and do not require focus adjustment.
  • FIG. 3 is a side view of an imaging device on which a culture container is placed; It is a figure which shows an example of a structure of an imaging sensor.
  • FIG. 10 is a diagram showing how an interference fringe image is generated when illumination light is incident on a fertilized egg; 1 is a schematic diagram showing an example of the configuration of a time-lapse imaging system;
  • FIG. It is a block diagram showing an example of an internal configuration of an imaging device and an information processing device. It is a block diagram which shows an example of the functional structure of an information processing apparatus.
  • FIG. 3 is a side view of an imaging device on which a culture container is placed; It is a figure which shows an example of a structure of an imaging sensor.
  • FIG. 10 is a diagram showing how an interference fringe image is generated when illumination light is incident on a fertilized egg;
  • 1 is a schematic diagram showing an example of the configuration of a time-lapse imaging system;
  • FIG. It is a block diagram showing an example of an internal configuration of an imaging device and an information processing
  • FIG. 4 is a diagram showing an example of reconstructed positions; 4 is a flow chart showing an example of the overall operation of the time-lapse imaging system; It is a side view of the imaging device concerning a modification. It is a figure explaining height adjustment of the imaging device concerning a modification. It is a schematic diagram which shows the structure of the light emission surface of the light source which concerns on a modification.
  • FIG. 11 is a schematic diagram showing the configuration of a time-lapse imaging system according to a modification;
  • FIG. 10 is a schematic diagram showing the configuration of an incubator according to a modification;
  • FIG. 4 is a diagram for explaining the diameter of a fertilized egg and the height of a culture medium;
  • FIG. 1 shows an example of an imaging device.
  • the imaging device 10 has a light source 11 , an imaging sensor 12 , a support 13 , a base 14 and a stage 15 .
  • the light source 11 is, for example, a laser diode.
  • the imaging device 10 performs so-called lens-free imaging, in which an observation target is imaged without using an optical lens.
  • the light source 11 may be configured by combining a light emitting diode and a pinhole.
  • the light source 11 emits radial illumination light 16 toward the stage 15 .
  • the illumination light 16 is coherent light.
  • the wavelength of the illumination light 16 is 640 nm, 780 nm, or the like.
  • the light source 11 is connected to one end of a substantially L-shaped support 13 .
  • the other end of the support 13 is connected to the base 14 .
  • the base 14 has a flat plate shape, and a stage 15 is provided substantially in the center.
  • the stage 15 is provided with a recessed mounting portion 15A on which a culture container 20 for culturing the fertilized egg is mounted.
  • the column 13 supports the light source 11 so that the light source 11 faces the imaging surface 12A of the imaging sensor 12 .
  • the direction in which the light source 11 and the imaging surface 12A face each other is hereinafter referred to as the Z direction.
  • the Z direction is also the irradiation direction of the illumination light 16 .
  • a direction orthogonal to the Z direction is called an X direction.
  • a direction orthogonal to the Z direction and the X direction is called the Y direction.
  • the imaging surface 12A is orthogonal to the Z direction and parallel to the X and Y directions.
  • the imaging sensor 12 is composed of, for example, a monochrome CMOS (Complementary Metal Oxide Semiconductor) image sensor.
  • a culture container 20 is placed on the imaging surface 12A of the imaging sensor 12 .
  • the culture container 20 is a shallow cylindrical container and is also called a culture dish.
  • the culture container 20 is used together with a lid (not shown).
  • the culture container 20 is transparent and allows the illumination light 16 to pass therethrough.
  • the diameter of the culture vessel 20 is about 30 to 60 mm.
  • the thickness of the culture vessel 20 is approximately 10 to 20 mm.
  • a fertilized egg 21 that has undergone in vitro fertilization is seeded in the culture container 20 .
  • In vitro fertilization treatment includes microinsemination treatment performed under a microscope and normal in vitro fertilization treatment in which ovum and sperm are combined in a predetermined container.
  • the method of fertilization of the fertilized egg 21 to be cultured does not matter.
  • the fertilized egg 21 is, for example, a human fertilized egg.
  • the fertilized egg 21 is almost spherical and has a diameter of about 100 to 200 ⁇ m.
  • the fertilized egg 21 floats in the culture solution 22 that has been dropped into the culture container 20 .
  • the culture medium 22 is covered with oil 23 filled in the culture container 20 .
  • the oil 23 suppresses evaporation and pH change of the culture solution 22 .
  • the fertilized egg 21 in the divided state is also called an embryo.
  • a fertilized egg 21 in the present disclosure includes an embryo.
  • the base 14 is a flat member having sides parallel to the X direction and the Y direction. Let Xi be the length of the base 14 in the X direction, and let Yi be the length in the Y direction. In this embodiment, the length Xi is the maximum length of the imaging device 10 in the X direction, and the length Yi is the maximum length of the imaging device 10 in the X direction.
  • FIG. 2 is a side view of the imaging device 10 on which the culture container 20 is placed.
  • the length from the bottom surface of the base 14 to the upper end of the light source 11 is Zi.
  • the length Zi is the maximum length of the imaging device 10 in the Z direction.
  • the length Zi is also referred to as the height of the imaging device 10 . That is, the size of the imaging device 10 is defined by the lengths Xi, Yi, and Zi.
  • the imaging sensor 12 detects the illumination light 16 emitted from the light source 11 and transmitted through the culture container 20 . Specifically, the illumination light 16 is incident on the culture container 20 and diffracted by the fertilized egg 21 , thereby producing an interference fringe image reflecting the shape and internal structure of the fertilized egg 21 . An interference fringe image is also called a hologram image. The imaging sensor 12 captures an interference fringe image generated by the fertilized egg 21 .
  • FIG. 3 shows an example of the configuration of the imaging sensor 12.
  • the imaging sensor 12 has a plurality of pixels 12B arranged on an imaging surface 12A.
  • the pixel 12B is a photoelectric conversion element that outputs a pixel signal corresponding to the amount of incident light by photoelectrically converting incident light.
  • the pixels 12B are arranged at equal pitches along the X and Y directions.
  • the arrangement of the pixels 12B is a so-called square arrangement.
  • the X direction is a direction perpendicular to the Z direction.
  • the Y direction is a direction orthogonal to the X and Z directions.
  • the pixels 12B are arranged at a first arrangement pitch ⁇ x in the X direction and arranged at a second arrangement pitch ⁇ y in the Y direction.
  • the imaging sensor 12 captures light incident on the imaging surface 12A and outputs image data composed of pixel signals output from each of the pixels 12B.
  • FIG. 4 shows how an interference fringe image is generated when the illumination light 16 is incident on the fertilized egg 21 .
  • a part of the illumination light 16 incident on the culture container 20 is diffracted by the fertilized egg 21 . That is, the illumination light 16 is divided into diffracted light 30 diffracted by the fertilized egg 21 and transmitted light 31 not diffracted by the fertilized egg 21 but transmitted through the incubation container 20 .
  • the transmitted light 31 is a spherical wave or a plane wave.
  • the diffracted light 30 and the transmitted light 31 pass through the bottom surface of the culture container 20 and enter the imaging surface 12A of the imaging sensor 12 .
  • the diffracted light 30 and the transmitted light 31 interfere with each other to generate an interference fringe image 33 .
  • the interference fringe image 33 is composed of bright portions 36 and dark portions 38 .
  • the interference fringe image 33 is illustrated with circular bright portions 36 and dark portions 38 , but the shape of the interference fringe image 33 changes according to the shape and internal structure of the fertilized egg 21 .
  • the imaging sensor 12 captures an optical image including the interference fringe image 33 formed on the imaging surface 12A and outputs image data including the interference fringe image 33 .
  • FIG. 5 shows an example of the configuration of the time-lapse imaging system.
  • the time-lapse imaging system 2 includes an imaging device 10, an incubator 40, and an information processing device 50.
  • the incubator 40 is a multi-room incubator for fertilized eggs and is also called an embryo culture device.
  • the fertilized egg 21 is cultured within the incubator 40 for a predetermined period (for example, seven days).
  • the incubator 40 has a plurality of culture chambers 41, unlike a general incubator for culturing cells other than fertilized eggs. This is because the imaging device 10 is accommodated in each of the culture chambers 41 so that the fertilized egg 21 is managed individually so as not to be mistaken for someone else's fertilized egg 21 .
  • the incubation room 41 is also referred to as an incubation chamber. Although two culture chambers 41 are provided in the incubator 40 shown in FIG. 5, the number of culture chambers 41 is not limited to this and can be changed as appropriate.
  • Each of the culture chambers 41 is provided with an openable lid 42 .
  • the incubator 40 is provided with a switch 43 for opening and closing the lid 42 for each culture chamber 41 .
  • the lid 42 is opened and closed by a driving mechanism (not shown).
  • the lid 42 may be configured to be manually opened and closed.
  • the incubation chamber 41 is kept airtight when the lid 42 is closed.
  • a mixed gas obtained by mixing carbon dioxide (CO 2 ) gas and nitrogen (N 2 ) gas with outside air (air) from an external gas cylinder (not shown) is passed through a HEPA filter (High Efficiency Particulate Air Filter). supplied via Heaters (not shown) are provided on the side and bottom surfaces of the culture chamber 41 .
  • the incubation chamber 41 is controlled so that the concentration, temperature, and humidity of the mixed gas are kept constant, thereby maintaining a constant culture environment.
  • the imaging device 10 has a size that allows it to be taken in and out of the culture room 41 . As shown in FIG. 5, one imaging device 10 is inserted into one incubation chamber 41 . That is, the lid 42 can be closed while the imaging device 10 with the culture container 20 placed thereon is inserted into the culture chamber 41 . As a result, while culturing the fertilized egg 21 in the culture chamber 41 , the image of the fertilized egg 21 can be captured by the imaging device 10 without removing the culture container 20 from the culture chamber 41 .
  • the culture chamber 41 is a substantially rectangular parallelepiped space.
  • Xc be the length of the incubation chamber 41 in the X direction
  • Yc be the length in the Y direction
  • Zc be the length in the Z direction.
  • the length Zc is hereinafter also referred to as the height of the culture chamber 41 .
  • the height Zc of the culture chamber 41 is the same as that of a general incubator for culturing cells other than fertilized eggs. It is lower than the height of the chamber, for example less than 10 cm. Therefore, the height Zi of the imaging device 10 preferably satisfies the relationship of Zi ⁇ Zc and the relationship of Zi ⁇ 10 cm.
  • the lengths Xi and Yi of the imaging device 10 satisfy the relationship of Xi ⁇ Xc and the relationship of Yi ⁇ Yc. Also, the lengths Xi and Yi of the imaging device 10 are each about 10 cm.
  • the information processing device 50 is, for example, a desktop personal computer.
  • a display 51 , a keyboard 52 , a mouse 53 and the like are connected to the information processing device 50 .
  • the keyboard 52 and mouse 53 constitute an input device 54 for the user to enter information.
  • the input device 54 also includes a touch panel and the like.
  • the information processing device 50 exchanges data with the imaging devices 10 accommodated in each incubation room 41 by wireless communication.
  • the imaging device 10 performs imaging periodically (for example, every 5 to 15 minutes).
  • the information processing device 50 periodically receives image data including the interference fringe image 33 (see FIG. 4) from the imaging device 10, performs reconstruction processing based on the received image data, and reproduces the reconstruction generated by the reconstruction processing. View the composition image.
  • a reconstructed image is also called a tomographic image.
  • FIG. 6 shows an example of the internal configuration of the imaging device 10 and the information processing device 50.
  • the imaging device 10 includes a processor 60, a storage device 61, a communication unit 62, a power supply unit 63, and a battery 64 in addition to the light source 11 and the imaging sensor 12. These are connected via a bus line 65. are interconnected.
  • the processor 60 is, for example, an FPGA (Field Programmable Gate Array), and controls the operation of each unit in the imaging device 10.
  • the storage device 61 is RAM (Random Access Memory), flash memory, or the like. The storage device 61 stores image data generated by the imaging device 10 and various data.
  • the communication unit 62 is a communication circuit that performs wireless communication with the information processing device 50 .
  • Processor 60 transmits image data to information processing device 50 via communication unit 62 .
  • the battery 64 is a secondary battery such as a lithium polymer battery.
  • the power supply unit 63 includes a power supply circuit and a charging control circuit.
  • the power supply unit 63 supplies power supplied from the battery 64 to the processor 60 and the like. Further, the power supply unit 63 controls charging of the battery 64 with electric power supplied from the outside. Note that the power supply unit 63 may be configured to wirelessly charge the battery 64 .
  • the information processing device 50 includes a processor 55 , a storage device 56 and a communication section 57 , which are interconnected via a bus line 58 . Also, the display 51 and the input device 54 are connected to the bus line 58 .
  • the processor 55 is composed of, for example, a CPU (Central Processing Unit), and implements various functions by reading the operating program 56A and various data stored in the storage device 56 and executing the processes.
  • a CPU Central Processing Unit
  • the storage device 56 includes, for example, RAM, ROM (Read Only Memory), or a storage device.
  • RAM is, for example, a volatile memory used as a work area or the like.
  • the ROM is a nonvolatile memory such as a flash memory that holds the operating program 56A and various data, for example.
  • the storage device is, for example, a HDD (Hard Disk Drive) or an SSD (Solid State Drive).
  • the storage stores an OS (Operating System), application programs, image data, various data, and the like.
  • the communication unit 57 is a communication circuit that performs wireless communication with the communication unit 62 of the imaging device 10 .
  • the processor 55 receives image data transmitted from the imaging device 10 via the communication section 57 .
  • the processor 55 also transmits a control signal for controlling imaging to the imaging device 10 via the communication unit 57 .
  • the display 51 displays various screens.
  • the information processing apparatus 50 receives input of operation instructions from the input device 54 through various screens.
  • FIG. 7 shows an example of the functional configuration of the information processing device 50.
  • the functions of information processing device 50 are realized by processor 55 executing processing based on operation program 56A.
  • the processor 55 includes an imaging control section 70 , an image data acquisition section 71 , a reconstruction processing section 72 , and a display control section 73 .
  • the imaging control unit 70 controls the operation of the imaging device 10 . Specifically, the imaging control unit 70 controls the operation of generating the illumination light 16 by the light source 11 and the imaging operation of the imaging sensor 12 by transmitting control signals to the imaging device 10 .
  • the operation of generating the illumination light 16 by the light source 11 and the imaging operation of the imaging sensor 12 are collectively referred to as the imaging operation of the imaging device 10 .
  • the imaging control unit 70 causes the imaging device 10 to start imaging operation based on the operation signal input from the input device 54 .
  • the image data acquisition unit 71 acquires generated image data transmitted from the imaging device 10 after the imaging device 10 has captured an image of the fertilized egg 21 in the culture container 20 .
  • the image data acquisition unit 71 supplies the acquired image data to the reconstruction processing unit 72 .
  • the reconstruction processing unit 72 generates a reconstructed image by performing calculations based on the image data. For example, as shown in FIG. 8, the reconstruction processing unit 72 changes the reconstruction position P by a constant value in the Z direction, and generates a reconstructed image each time the reconstruction position P is changed.
  • the reconstruction position P is a position represented by a distance d from the imaging surface 12A of the imaging sensor 12 toward the light source 11 (so-called depth position).
  • the reconstruction position P will also be referred to as the focal position.
  • the reconstruction processing unit 72 performs reconstruction processing based on, for example, the Fresnel transform equations represented by the following equations (1) to (3).
  • I(x, y) represents image data.
  • x represents the coordinate in the X direction of the pixel 12B (see FIG. 3) of the image sensor 12;
  • y represents the coordinate of the pixel 12B in the Y direction.
  • ⁇ x is the aforementioned first array pitch
  • ⁇ y is the aforementioned second array pitch (see FIG. 3).
  • ⁇ is the wavelength of the illumination light 16 .
  • ⁇ (m,n) is a complex amplitude image obtained by Fresnel transforming the interference fringe image included in the image data.
  • Nx represents the number of pixels in the X direction of the image data.
  • Ny represents the number of pixels in the Y direction of the image data.
  • a 0 (m,n) is an intensity distribution image representing intensity components of the complex amplitude image ⁇ (m,n).
  • ⁇ 0 (m,n) is a phase distribution image representing the phase component of the complex amplitude image ⁇ (m,n).
  • the reconstruction processing unit 72 obtains a complex amplitude image ⁇ (m,n) based on equation (1), and applies the obtained complex amplitude image ⁇ (m,n) to equation (2) or equation (3). By doing so, an intensity distribution image A 0 (m, n) or a phase distribution image ⁇ 0 (m, n) is obtained.
  • the reconstruction processing unit 72 obtains one of the intensity distribution image A 0 (m, n) and the phase distribution image ⁇ 0 (m, n) and outputs it as a reconstructed image.
  • the reconstruction processing unit 72 outputs the phase distribution image ⁇ 0 (m, n) as a reconstructed image.
  • the phase distribution image ⁇ 0 (m,n) is an image representing the refractive index distribution of the object to be observed. Since the fertilized egg 21, which is the object to be observed in this embodiment, is translucent, most of the illumination light 16 is transmitted or diffracted without being absorbed by the fertilized egg 21, so the intensity distribution is hardly any image appears in Therefore, in this embodiment, it is preferable to use the phase distribution image ⁇ 0 (m, n) as the reconstructed image.
  • the reconstruction processing unit 72 is not limited to the method using the Fresnel transform formula, and may perform the reconstruction processing using the Fourier iterative phase retrieval method or the like.
  • the display control unit 73 causes the display 51 to display the reconstructed image generated by the reconstruction processing unit 72 .
  • the display 51 may display a reconstructed image at one focus position, or may display reconstructed images at a plurality of focus positions. Also, the focus position of the reconstructed image displayed on the display 51 may be set or selected by the user operating the input device 54 .
  • the fertilized egg 21 has a thickness of about 100 to 200 ⁇ m and floats in the culture solution 22, it is difficult to adjust the focal position for the pronucleus inside the fertilized egg 21 in conventional microscopic observation. For this reason, in the conventional technique described in Japanese Patent Application Laid-Open No. 2018-093795, a plurality of images with different focal positions are captured. On the other hand, in the lens-free imaging of the present disclosure, it is possible to generate a reconstructed image at an arbitrary focal position based on image data obtained by one imaging.
  • the user places the culture container 20 on the stage 15 of the imaging device 10, and then inserts the imaging device 10 into the culture chamber 41 of the incubator 40 (step S10).
  • the imaging device 10 may be inserted into at least one culture chamber 41 among the plurality of culture chambers 41 .
  • the user closes the lid 42 of the culture chamber 41 and causes the incubator 40 to start culturing (step S11).
  • the imaging device 10 images the fertilized egg 21 in the incubation container 20 under the control of the information processing device 50 (step S12).
  • the imaging device 10 wirelessly transmits the image data generated by performing the imaging operation to the information processing device 50 (step S13).
  • the information processing device 50 receives the image data transmitted from the imaging device 10 (step S14).
  • the reconstruction processing unit 72 of the information processing device 50 generates at least one reconstructed image by performing reconstruction processing based on the image data (step S15).
  • the display control unit 73 causes the display 51 to display the reconstructed image generated by the reconstruction processing unit 72 (step S16).
  • the information processing device 50 determines whether or not the culture by the incubator 40 has ended (step S17). Cultivation is performed, for example, for a maximum of 7 days from the start of culturing. The information processing device 50 determines whether or not culturing has ended, for example, based on the elapsed time from the start of culturing. When the information processing device 50 determines that the culture has not ended (step S17: NO), it determines whether or not a certain period of time (for example, 10 minutes) has passed since the previous imaging (step S18). .
  • a certain period of time for example, 10 minutes
  • step S18 When the information processing device 50 determines that a certain period of time has passed since the previous imaging (step S18: YES), the process returns to step S12.
  • the processes of steps S12 to S18 are repeatedly executed until the determination in step S17 is affirmative.
  • step S17 after the information processing device 50 determines that the culture by the incubator 40 is finished (step S17: YES), the user takes out the imaging device 10 from the culture room 41 of the incubator 40 (step S19).
  • the imaging device 10 according to the technology of the present disclosure can be put in and taken out of the culture room 41 of the incubator 40 for fertilized eggs.
  • the fertilized egg incubator 40 is inexpensive because it does not include an optical camera or the like.
  • the imaging device 10 according to the technology of the present disclosure captures an interference fringe image by lens-free imaging, there is no need to perform focus adjustment during imaging.
  • FIG. 10 shows an imaging device 10A according to a modification.
  • the imaging device 10A differs from the imaging device 10 according to the above embodiment in that the height Zi can be changed.
  • the height Zi of the imaging device 10A can be changed by changing the length of the support 13.
  • FIG. 10 shows an imaging device 10A according to a modification.
  • the imaging device 10A differs from the imaging device 10 according to the above embodiment in that the height Zi can be changed.
  • the height Zi of the imaging device 10A can be changed by changing the length of the support 13.
  • the post 13 of the imaging device 10A is separated into an upper portion 13A and a lower portion 13B.
  • a light source 11 is connected to the upper portion 13A.
  • the lower portion 13B is connected to the base 14.
  • the upper portion 13A and the lower portion 13B are slidably fitted to each other.
  • the upper portion 13A and the lower portion 13B are examples of the "height adjustment mechanism" according to the technology of the present disclosure.
  • the height Zi of the imaging device 10A can be changed by sliding the upper portion 13A with respect to the lower portion 13B.
  • the column 13 is provided with fixing screws 17 for fixing to the upper portion 13A and the lower portion 13B.
  • the user adjusts the position of the upper portion 13A with respect to the lower portion 13B and operates the fixing screw 17 with the height Zi of the imaging device 10A set to a desired value, thereby fixing the upper portion 13A with respect to the lower portion 13B.
  • the upper portion 13A may be configured to slide relative to the lower portion 13B by a drive mechanism (not shown). In this case, it is preferable to configure the upper portion 13A to move by operating a switch (not shown).
  • the height adjustment mechanism that enables adjustment of the height Zi of the imaging device 10A is not limited to the configuration described above, and can be changed as appropriate.
  • the incubator 40 for fertilized eggs is sold by various manufacturers, and the height Zc of the culture chamber 41 is not standardized and varies. Since the imaging device 10A according to this modification can change the height Zi, it can be inserted into the incubation chambers 41 of the incubators 40 of various manufacturers.
  • the illumination light 16 from the light source 11 illuminates the entire imaging surface 12A.
  • the illumination light 16 is preferably radial light.
  • the imaging device 10 can be modified in various ways.
  • the stage 15 having the imaging sensor 12 is provided on the base 14 in the above embodiment, the stage 15 may be integrated with the base 14 .
  • the base 14 has a rectangular flat plate shape, but the base 14 may have a circular shape or the like.
  • the light source 11 is connected to the end of the support 13 in the above embodiment, the light source 11 may be embedded in the support 13 .
  • the light source 11 may be a laser light source in which a plurality of light emitting points (for example, 36 light emitting points) are arranged in a two-dimensional array.
  • a vertical cavity surface emitting laser (Vertical Cavity Surface Emitting Laser) can be used.
  • Image data including a high-resolution interference fringe image can be obtained by synthesizing a plurality of image data obtained by the imaging sensor 12 while sequentially emitting light from a plurality of light-emitting points. . By reconstructing this image data, a reconstructed image with high image quality can be obtained.
  • FIG. 12 shows the configuration of the light emitting surface 11A of the light source 11 having multiple light emitting points 11B.
  • the light emitting surface 11A is arranged at a position facing the imaging sensor 12 .
  • a plurality of light emitting points 11B are arranged in a two-dimensional array on the light emitting surface 11A.
  • the arrangement pitch of the light emitting points 11B is about 10 ⁇ m to 100 ⁇ m.
  • Each of the light emitting points 11B is selected in order to emit illumination light 16.
  • the light emission time interval of the plurality of light emission points 11B is several milliseconds.
  • the arrangement pitch of the light emitting points 11B only needs to be different from the arrangement pitch of the pixels 12B (the first arrangement pitch ⁇ x and the second arrangement pitch ⁇ y), and does not necessarily have to be smaller than the arrangement pitch of the pixels 12B. For example, even if the light emitting point 11B is located directly above the adjacent pixel 12B, the array pitch of the light emitting point 11B does not have to match the array pitch of the pixels 12B. In this case, since different positions on the pixels 12B are illuminated with the illumination light 16, when combining a plurality of image data, different pixels 12B that are directly below the respective light emitting points 11B and illuminated with the illumination light 16 can be selected. It is possible to generate image data including a super-resolution interference fringe image by regarding them as the same pixel and aligning them with an accuracy of one pixel or less.
  • the light-emitting points 11B are arranged in a 6 ⁇ 6 square, and 36 light-emitting points 11B are provided on the light-emitting surface 11A.
  • the imaging device 10 can be moved into and out of the culture room 41 of the incubator 40, but it is also possible to integrate the imaging device 10 and the incubator 40 together.
  • FIG. 13 shows a time-lapse imaging system 2A configured by an incubator 40A integrally incorporating an imaging device and an information processing device 50.
  • FIG. FIG. 14 shows an incubator 40A in which an imaging device is integrally incorporated. Note that the time-lapse imaging system 2A is an example of an "imaging system" according to the technology of the present disclosure.
  • An incubator 40A according to this modified example is provided with a plurality of culture chambers 41, like the incubator 40 according to the above embodiment (see FIG. 5).
  • Each culture chamber 41 is provided with an openable lid 42 .
  • the lid 42 is provided with the light source 11 .
  • the light source 11 is embedded in the inner surface of the lid 42 and emits illumination light 16 toward the inside of the culture chamber 41 .
  • the light source 11 may have a plurality of light emitting points 11B shown in FIG.
  • the imaging sensor 12 is provided on the bottom 41A of the culture chamber 41. Specifically, the imaging sensor 12 is embedded in the bottom portion 41A of the incubation chamber 41 and the imaging surface 12A is exposed inside the incubation chamber 41 . Note that the bottom portion 41A is part of a housing that constitutes the incubator 40A.
  • the light source 11 is arranged at a position facing the imaging sensor 12 with the lid 42 closed.
  • a culture vessel 20 is placed on the bottom portion 41A of the culture chamber 41 .
  • Illumination light 16 emitted from the light source 11 enters the imaging sensor 12 via the culture container 20 .
  • the imaging sensor 12 captures an interference fringe image generated by the fertilized egg 21 .
  • the imaging sensor 12 operates in the same manner as in the above embodiment.
  • the light source 11 and the imaging sensor 12 constitute an imaging device.
  • the incubator 40A according to this modified example is provided with the processor 60, the storage device 61, and the communication unit 62 included in the imaging device 10 shown in FIG.
  • the incubator 40A communicates with the information processing device 50 by wire or wirelessly.
  • the configuration and operation of the information processing device 50 are the same as in the above embodiment.
  • the information processing device 50 generates reconstruction processing by performing reconstruction processing each time the imaging device generates image data.
  • the fertilized egg 21 can be observed while being cultured in the culture chamber 41. It is also preferable that the time-lapse imaging system 2A is integrated into one device by incorporating the information processing device 50 into the incubator 40A.
  • one imaging sensor 12 is provided in the imaging device 10, but the number of imaging sensors 12 is not limited to one, and may be two or more.
  • FIG. 15 is a diagram illustrating the diameter D of the fertilized egg 21 and the height H of the culture solution 22 in the culture container 20.
  • the fertilized egg 21 floats in the culture solution 22 as described above.
  • the fertilized egg 21 is a human egg and has a substantially spherical shape.
  • the diameter D of the fertilized egg 21 is preferably 100 ⁇ m or more and less than 200 ⁇ m.
  • the height H of the culture solution 22 is preferably 1 m or more and less than 20 mm in order to float the fertilized egg 21 .
  • the height H of the culture solution 22 is the length in the Z direction from the inner bottom surface 20A of the culture vessel 20 to the top of the culture solution 22.
  • the time-lapse imaging system 2 relates to a so-called lens-free imaging technique in which the imaging device 10 is not equipped with an optical lens.
  • the technology of the present disclosure is applicable to digital holography in general (for example, when using reference light).
  • the hardware configuration of the computer that constitutes the information processing device 50 can be configured with a plurality of computers separated as hardware for the purpose of improving processing capability and reliability.
  • the hardware configuration of the computer of the information processing device 50 can be appropriately changed according to required performance such as processing power, safety, and reliability.
  • application programs such as the operating program 56A can be duplicated or distributed and stored in multiple storage devices for the purpose of ensuring safety and reliability. .
  • the hardware structure of the processing unit (processing unit) that executes various processes such as the imaging control unit 70, the image data acquisition unit 71, the reconstruction processing unit 72, and the display control unit 73 is , various processors shown below can be used.
  • the various processors include, as described above, a CPU, which is a general-purpose processor that executes software (operation program 56A) and functions as various processing units, as well as FPGAs and the like whose circuit configuration can be changed after manufacture.
  • Programmable Logic Device which is a processor, ASIC (Application Specific Integrated Circuit), etc. Includes a dedicated electric circuit, which is a processor with a circuit configuration specially designed to execute specific processing. .
  • One processing unit may be configured with one of these various processors, or a combination of two or more processors of the same or different type (for example, a combination of a plurality of FPGAs and/or a CPU and combination with FPGA). Also, a plurality of processing units may be configured by one processor.
  • a single processor is configured by combining one or more CPUs and software.
  • a processor functions as multiple processing units.
  • SoC System On Chip
  • a processor that realizes the functions of the entire system including multiple processing units with a single IC (Integrated Circuit) chip. be.
  • the various processing units are configured using one or more of the above various processors as a hardware structure.

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Abstract

Dispositif d'imagerie équipé d'une source lumineuse et d'un capteur d'imagerie et générant des données d'image comprenant une image de frange d'interférence en imagerie d'un ovocyte fécondé ensemencé dans un récipient de culture. Le dispositif d'imagerie peut être introduit et retiré d'une chambre de culture prévue dans un incubateur pour des ovocytes fécondés.
PCT/JP2021/047726 2021-02-26 2021-12-22 Dispositif d'imagerie, dispositif de traitement d'informations, système d'imagerie et procédé d'observation WO2022181023A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023067971A1 (fr) * 2021-10-20 2023-04-27 富士フイルム株式会社 Dispositif d'imagerie et dispositif de traitement d'informations

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2018093795A (ja) * 2016-12-14 2018-06-21 憲隆 福永 胚培養装置およびその撮像装置
WO2018158947A1 (fr) * 2017-03-03 2018-09-07 株式会社島津製作所 Dispositif d'observation de cellules
WO2018235476A1 (fr) * 2017-06-22 2018-12-27 ソニー株式会社 Dispositif et procédé de traitement d'informations, et programme

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2018093795A (ja) * 2016-12-14 2018-06-21 憲隆 福永 胚培養装置およびその撮像装置
WO2018158947A1 (fr) * 2017-03-03 2018-09-07 株式会社島津製作所 Dispositif d'observation de cellules
WO2018235476A1 (fr) * 2017-06-22 2018-12-27 ソニー株式会社 Dispositif et procédé de traitement d'informations, et programme

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023067971A1 (fr) * 2021-10-20 2023-04-27 富士フイルム株式会社 Dispositif d'imagerie et dispositif de traitement d'informations

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