JP7812832B2 - Imaging System - Google Patents

Description

The technology disclosed herein relates to an imaging device, an information processing device, an imaging system, and an observation method.

In recent years, the demand for infertility treatment has increased. Fertilized egg incubators are used to culture fertilized eggs that have undergone in vitro fertilization. Fertilized eggs (embryos) cultured in the incubator are then either transferred or frozen. An embryo is a fertilized egg that is in a dividing state.

Previously, to observe fertilized eggs during cultivation, it was necessary to remove the culture dish (also called a tray) containing the fertilized eggs from the incubator and then observe them under a microscope. Removing the culture dish from the incubator caused stress to the fertilized eggs due to temperature changes, which was a problem.

In response to this, Japanese Patent Application Laid-Open No. 2018-093795 proposes an incubator that allows for the 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 unit that holds multiple culture dishes in a culture environment, and an imaging unit that corresponds to the culture dishes held in the culture unit. As described in Japanese Patent Application Laid-Open No. 2018-093795, an incubator that allows for the observation of fertilized eggs while culturing them in the culture dish without removing the culture dish from the culture unit is called a time-lapse incubator.

Furthermore, the imaging unit described in JP 2018-093795 A is an optical camera with a lens, and focus adjustment is performed by moving the lens along the optical axis. Human eggs are approximately spherical, with a diameter of approximately 100 to 150 μm. It is not known where in the egg the pronucleus, which provides clues for determining egg fertilization, is located. For this reason, the imaging unit described in JP 2018-093795 A captures multiple images with different focus positions.

However, time-lapse incubators such as those described in JP 2018-093795 A are expensive because they are all-in-one devices with an imaging unit built into the culture unit. This type of time-lapse incubator presents a challenge as it is difficult to introduce into small-scale clinics. Furthermore, the incubator described in JP 2018-093795 A uses an optical camera as the imaging unit, which presents a challenge in that it is difficult to adjust the focus.

The technology disclosed herein aims to provide an imaging device, information processing device, imaging system, and observation method that can be used in an incubator for fertilized eggs, are inexpensive, and do not require focus adjustment.

In order to achieve the above-mentioned objective, the imaging device disclosed herein is an imaging device that includes a light source and an imaging sensor, and generates image data including interference fringe images by capturing images of fertilized eggs seeded in a culture container, and is capable of being inserted into and removed from a culture chamber provided in an incubator for fertilized eggs.

It is preferable to have a height adjustment mechanism that allows the height to be adjusted.

It is preferable that the device is provided with a support pillar to support the light source, and the height adjustment mechanism allows the length of the support pillar to be changed.

It is preferable that the height is less than 10 cm.

It is preferable that the incubator has multiple culture chambers and that it is possible to enter and exit each of the culture chambers.

It is preferable to have a communication unit that transmits image data wirelessly.

The information processing device disclosed herein receives image data transmitted from the imaging device and performs reconstruction processing based on the received image data, thereby enabling the generation of a reconstructed image at any focal position.

It is preferable that the information processing device receives image data transmitted periodically from the imaging device housed in the culture chamber, performs reconstruction processing each time image data is received, and displays the reconstructed image generated by the reconstruction processing on the display.

It is preferable that the light source has multiple light-emitting points, and the imaging device generates multiple image data by performing multiple imaging operations while illuminating the light-emitting points in sequence.

It is preferable to generate high-resolution image data based on multiple image data and perform reconstruction processing based on the generated high-resolution image data.

The imaging system disclosed herein comprises an incubator equipped with an imaging device having a light source and an imaging sensor that generates image data including an interference fringe image by capturing an image of a fertilized egg seeded in a culture vessel, and an information processing device that generates a reconstructed image at any focal position by performing reconstruction processing based on the image data.

It is preferable that the information processing device performs reconstruction processing each time the imaging device generates image data, and displays the reconstructed image generated by the reconstruction processing on a display.

The incubator has a culture chamber that houses the culture vessel and a lid that keeps the culture chamber airtight, and it is preferable that the light source be provided on the lid.

It is preferable that the imaging sensor be located at the bottom of the culture chamber in which the culture vessel is placed.

It is preferable that the light source has multiple light-emitting points, and the imaging device generates multiple image data by performing multiple imaging operations while illuminating the light-emitting points in sequence.

It is preferable that the information processing device generates high-resolution image data based on multiple image data and performs reconstruction processing based on the generated high-resolution image data.

The observation method disclosed herein is a method for observing fertilized eggs by capturing images of fertilized eggs seeded in a culture vessel to generate image data including an interference fringe image, and then performing reconstruction processing based on the generated image data to generate a reconstructed image at an arbitrary focal position, wherein the diameter of the fertilized eggs is greater than or equal to 100 μm and less than 200 μm.

The fertilized eggs are suspended in culture medium dropped into the culture vessel, and it is preferable that the height of the culture medium is at least 1 mm but less than 20 mm.

The technology disclosed herein makes it possible to provide an imaging device and information processing device that can be used in an incubator for fertilized eggs, is inexpensive, and does not require focus adjustment.

FIG. 1 is a perspective view illustrating an example of an imaging device. FIG. 2 is a side view of the imaging device on which the culture vessel is placed. FIG. 2 is a diagram illustrating an example of the configuration of an image sensor. 10A and 10B are diagrams showing how an interference fringe image is generated when illumination light is incident on a fertilized egg. FIG. 1 is a schematic diagram illustrating an example of the configuration of a time-lapse imaging system. FIG. 2 is a block diagram showing an example of the internal configuration of an imaging device and an information processing device. FIG. 2 is a block diagram illustrating an example of a functional configuration of the information processing device. FIG. 10 is a diagram illustrating an example of a reconstruction position. 10 is a flowchart illustrating an example of the overall operation of the time-lapse imaging system. FIG. 10 is a side view of an imaging device according to a modified example. 10A and 10B are diagrams illustrating height adjustment of an imaging device according to a modified example. 10A and 10B are schematic diagrams showing the configuration of a light emitting surface of a light source according to a modified example. FIG. 10 is a schematic diagram showing the configuration of a time lapse imaging system according to a modified example. FIG. 10 is a schematic diagram showing the configuration of an incubator according to a modified example. FIG. 1 is a diagram illustrating the diameter of a fertilized egg and the height of a culture medium.

An example of an embodiment of the technology disclosed herein is described with reference to the accompanying drawings.

Figure 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, which captures an image of an object being observed 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, etc.

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 a base 14. The base 14 is flat, with a stage 15 provided approximately in the center. The stage 15 is provided with a concave mounting portion 15A on which a culture vessel 20 for culturing fertilized eggs is placed. The support 13 supports the light source 11 so that the light source 11 faces the imaging surface 12A of the image sensor 12.

Hereinafter, the direction in which the light source 11 and the imaging surface 12A face each other will be referred to as the Z direction. The Z direction is also the direction of irradiation of the illumination light 16. The direction perpendicular to the Z direction will be referred to as the X direction. The direction perpendicular to the Z direction and the X direction will be referred to as the Y direction. The imaging surface 12A is perpendicular 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. The culture vessel 20 is placed on the imaging surface 12A of the imaging sensor 12. The culture vessel 20 is a shallow cylindrical container, also called a culture dish. The culture vessel 20 is used with a lid (not shown). The culture vessel 20 is transparent and allows the illumination light 16 to pass through. The diameter of the culture vessel 20 is approximately 30 to 60 mm. The thickness of the culture vessel 20 is approximately 10 to 20 mm.

The culture vessel 20 is seeded with fertilized eggs 21 that have been subjected to in vitro fertilization treatment. IVF treatments include intracytoplasmic sperm injection (ICS) performed under a microscope, and standard in vitro fertilization, in which eggs and sperm are combined in a designated vessel. The method of fertilization of the fertilized eggs 21 to be cultured is not important. The fertilized eggs 21 are, for example, human fertilized eggs. The fertilized eggs 21 are approximately spherical, with a diameter of approximately 100 to 200 μm.

The fertilized egg 21 is suspended in culture solution 22 that has been dropped into the culture vessel 20. The culture solution 22 is covered with oil 23 that has been filled into the culture vessel 20. The oil 23 prevents evaporation and changes in pH of the culture solution 22. The fertilized egg 21 in a dividing state is also referred to as an embryo. In this disclosure, the fertilized egg 21 includes an embryo.

The base 14 is a flat member having sides parallel to the X and Y directions. The length of the base 14 in the X direction is Xi, and the length in the Y direction is Yi. 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.

Figure 2 is a side view of the imaging device 10 on which the culture vessel 20 is placed. As shown in Figure 2, the length from the bottom surface of the base 14 to the top end of the light source 11 is designated Zi. In this embodiment, length Zi is the maximum length of the imaging device 10 in the Z direction. Hereinafter, length Zi will also be referred to as the height of the imaging device 10. In other words, the size of the imaging device 10 is determined by 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 vessel 20. Specifically, the illumination light 16 enters the culture vessel 20 and is diffracted by the fertilized egg 21, generating an interference fringe image that reflects the shape and internal structure of the fertilized egg 21. The interference fringe image is also called a hologram image. The imaging sensor 12 captures the interference fringe image generated by the fertilized egg 21.

Figure 3 shows an example of the configuration of the image sensor 12. The image sensor 12 has a plurality of pixels 12B arranged on the imaging surface 12A. The pixels 12B are photoelectric conversion elements that convert incident light photoelectrically and output pixel signals corresponding to the amount of 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 perpendicular to the Z direction. The Y direction is perpendicular to the X and Z directions. The pixels 12B are arranged at a first arrangement pitch Δx in the X direction and at a second arrangement pitch Δy in the Y direction.

The image 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.

Figure 4 shows how an interference fringe image is generated when illumination light 16 is incident on a fertilized egg 21. Part of the illumination light 16 incident on the culture vessel 20 is diffracted by the fertilized egg 21. That is, the illumination light 16 is split into diffracted light 30, which is diffracted by the fertilized egg 21, and transmitted light 31, which is not diffracted by the fertilized egg 21 and passes through the culture vessel 20. The transmitted light 31 is a spherical wave or a plane wave. The diffracted light 30 and transmitted light 31 pass through the bottom surface of the culture vessel 20 and are incident on the imaging surface 12A of the image 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 areas 36 and dark areas 38. In Figure 4, the bright areas 36 and dark areas 38 of the interference fringe image 33 are each illustrated as being circular, but the shape of the interference fringe image 33 changes depending on the shape and internal structure of the fertilized egg 21. The imaging sensor 12 captures a light image including the interference fringe image 33 formed on the imaging surface 12A and outputs image data including the interference fringe image 33.

Figure 5 shows an example of the configuration of a time-lapse imaging system. As shown in Figure 5, 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 eggs 21 are cultured in the incubator 40 for a predetermined period of time (e.g., 7 days).

The incubator 40 does not have a single culture chamber like a typical incubator for culturing cells other than fertilized eggs, but has multiple culture chambers 41. This is because each culture chamber 41 houses an imaging device 10, allowing for individual management of fertilized eggs 21 to prevent them from being mistaken for someone else's fertilized eggs 21. The culture chambers 41 are also referred to as culture chambers. Note that while the incubator 40 shown in Figure 5 has two culture chambers 41, the number of culture chambers 41 is not limited to this and can be changed as appropriate.

Each culture chamber 41 is provided with an openable/closable lid 42. The incubator 40 is provided with a switch 43 for opening and closing the lid 42 for each culture chamber 41. When the user operates the switch 43, the lid 42 is opened and closed by a drive mechanism (not shown). The lid 42 may also be configured to be opened and closed manually. When the lid 42 is closed, the culture chamber 41 is kept airtight.

A mixed gas of carbon dioxide (CO ₂ ) gas, nitrogen (N ₂ ) gas, and outside air (air) is supplied from an external gas cylinder (not shown) to the culture chamber 41 via a HEPA filter (High Efficiency Particulate Air Filter). Heaters (not shown) are provided on the sides and bottom of the culture chamber 41. The culture chamber 41 maintains a constant culture environment by controlling the concentration, temperature, and humidity of the mixed gas to be constant.

The imaging device 10 is sized so that it can be inserted and removed from the culture chamber 41. As shown in Figure 5, one imaging device 10 is inserted into one culture chamber 41. In other words, the lid 42 can be closed while the imaging device 10 with the culture container 20 placed on it is inserted into the culture chamber 41. This allows the fertilized egg 21 to be imaged by the imaging device 10 while culturing the fertilized egg 21 in the culture chamber 41, without having to remove the culture container 20 from the culture chamber 41.

For example, the culture chamber 41 is a space with a substantially rectangular parallelepiped shape. The length of the culture chamber 41 in the X direction is designated Xc, the length in the Y direction is designated Yc, and the length in the Z direction is designated Zc. Hereinafter, the length Zc is also referred to as the height of the culture chamber 41. Since the height of the culture vessel 20 used to culture the fertilized eggs 21 is typically about 10 to 20 mm, the height Zc of the culture chamber 41 is lower than the height of a culture chamber of a typical incubator used to culture cells other than fertilized eggs, and is, for example, less than 10 cm. For this reason, it is preferable that the height Zi of the imaging device 10 satisfy the relationship Zi<Zc and also satisfy the relationship Zi<10 cm.

Furthermore, the lengths Xi and Yi of the imaging device 10 satisfy the relationships Xi<Xc and Yi<Yc. Furthermore, the lengths Xi and Yi of the imaging device 10 are each approximately 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 the mouse 53 constitute an input device 54 through which the user inputs information. The input device 54 also includes a touch panel, etc.

The information processing device 50 wirelessly communicates with the imaging devices 10 housed in each of the culture chambers 41 to exchange data. The imaging devices 10 periodically capture images (e.g., every 5 to 15 minutes). The information processing device 50 periodically receives image data including an interference fringe image 33 (see Figure 4) from the imaging devices 10, performs reconstruction processing based on the received image data, and displays the reconstructed image generated by the reconstruction processing. The reconstructed image is also called a tomographic image.

Figure 6 shows an example of the internal configuration of the imaging device 10 and the information processing device 50. As shown in Figure 6, in addition to the light source 11 and the imaging sensor 12, 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, which are interconnected via a bus line 65.

The processor 60 is, for example, an FPGA (Field Programmable Gate Array) and controls the operation of each component within the imaging device 10. The storage device 61 is, for example, a RAM (Random Access Memory) or flash memory. The storage device 61 stores image data generated by the imaging device 10 and various other data.

The communication unit 62 is a communication circuit that performs wireless communication with the information processing device 50. The processor 60 transmits image data to the information processing device 50 via the 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 charge control circuit. The power supply unit 63 supplies power from the battery 64 to the processor 60, etc. The power supply unit 63 also controls the charging of the battery 64 using power supplied from an external source. The power supply unit 63 may be configured to be able to charge the battery 64 wirelessly.

The information processing device 50 includes a processor 55, a storage device 56, and a communication unit 57, which are interconnected via a bus line 58. The aforementioned display 51 and input device 54 are also connected to the bus line 58.

The processor 55 is composed of, for example, a CPU (Central Processing Unit) and realizes various functions by reading out the operating program 56A and various data stored in the memory device 56 and executing the processing.

The storage device 56 includes, for example, RAM, ROM (Read Only Memory), or a storage device. RAM is, for example, volatile memory used as a work area, etc. ROM is, for example, non-volatile memory such as flash memory that stores the operating program 56A and various data. The storage device is, for example, an HDD (Hard Disk Drive) or SSD (Solid State Drive). The storage stores the OS (Operating System), application programs, image data, various data, etc.

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 unit 57. The processor 55 also transmits control signals to the imaging device 10 via the communication unit 57 to control imaging.

The display 51 displays various screens. The information processing device 50 accepts input of operation instructions from the input device 54 through the various screens.

Figure 7 shows an example of the functional configuration of the information processing device 50. The functions of the information processing device 50 are realized by the processor 55 executing processing based on the operating program 56A. As shown in Figure 7, the processor 55 is configured with an imaging control unit 70, an image data acquisition unit 71, a reconstruction processing unit 72, and a display control unit 73.

The imaging control unit 70 controls the operation of the imaging device 10. Specifically, the imaging control unit 70 controls the generation of illumination light 16 by the light source 11 and the imaging operation of the imaging sensor 12 by sending control signals to the imaging device 10. Hereinafter, the generation of illumination light 16 by the light source 11 and the imaging operation of the imaging sensor 12 will be collectively referred to as the imaging operation of the imaging device 10. The imaging control unit 70 causes the imaging device 10 to start the imaging operation based on an operation signal input from the input device 54.

The image data acquisition unit 71 acquires the image data generated and transmitted from the imaging device 10 after the imaging device 10 captures 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 in the Z direction by a fixed amount, and generates a reconstructed image each time the reconstruction position P is changed. The reconstruction position P is a position (so-called depth position) represented by the distance d from the imaging surface 12A of the image sensor 12 in the direction of the light source 11. Hereinafter, the reconstruction position P is also referred to as the focal position.

The reconstruction processing unit 72 performs reconstruction processing, for example, based on the Fresnel transform equations expressed by the following equations (1) to (3).

Here, I(x, y) represents image data. x represents the coordinate in the X direction of pixel 12B of the image sensor 12 (see Figure 3). y represents the coordinate in the Y direction of pixel 12B. Δx is the first array pitch mentioned above, and Δy is the second array pitch mentioned above (see Figure 3). λ is the wavelength of the illumination light 16.

As shown in equation (1), Γ(m, n) is a complex amplitude image obtained by Fresnel transforming the interference fringe image contained in the image data. Here, m = 1, 2, 3, ... Nx-1, and n = 1, 2, 3, ... Ny-1. 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.

As shown in equation (2), A ₀ (m, n) is an intensity distribution image representing the intensity components of the complex amplitude image Γ(m, n). As shown in equation (3), φ ₀ (m, n) is a phase distribution image representing the phase components of the complex amplitude image Γ(m, n).

The reconstruction processing unit 72 obtains a complex amplitude image Γ(m,n) based on equation (1), and obtains an intensity distribution image A ₀ (m,n) or a phase distribution image φ ₀ (m,n) by applying the obtained complex amplitude image Γ(m,n) to equation (2) or equation (3). The reconstruction processing unit 72 obtains either the intensity distribution image A ₀ (m,n) or the phase distribution image φ ₀ (m,n) and outputs it as a reconstructed image.

In this embodiment, the reconstruction processing unit 72 outputs a phase distribution image φ ₀ (m, n) as a reconstructed image. The phase distribution image φ ₀ (m, n) is an image that represents 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 semi-transparent, most of the illumination light 16 is not absorbed by the fertilized egg 21 but is transmitted or diffracted, and therefore almost no image appears in the intensity distribution. For this reason, in this embodiment, it is preferable to use the phase distribution image φ ₀ (m, n) as the reconstructed image.

The reconstruction processing unit 72 is not limited to methods using the Fresnel transform formula, and may also perform reconstruction processing using methods such as Fourier iterative phase recovery.

The display control unit 73 displays the reconstructed image generated by the reconstruction processing unit 72 on the display 51. The display 51 may display a reconstructed image at one focal position, or may display reconstructed images at multiple focal positions. In addition, the user may be able to set or select the focal position of the reconstructed image displayed on the display 51 by operating the input device 54.

The fertilized egg 21 is approximately 100 to 200 μm thick and suspended in the culture solution 22. This makes it difficult to adjust the focal position on the pronucleus and other internal components of the fertilized egg 21 using conventional microscope observation. For this reason, the conventional technology described in JP 2018-093795 A captures multiple images with different focal positions. In contrast, the lens-free imaging disclosed herein makes it possible to generate a reconstructed image at any focal position based on image data obtained from a single capture.

Next, an example of the overall operation of the time-lapse imaging system 2 will be described using the flowchart shown in Figure 9. First, the user places the culture vessel 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). Note that it is sufficient to insert the imaging device 10 into at least one of the multiple culture chambers 41.

Next, the user closes the lid 42 of the incubation chamber 41 and causes the incubator 40 to start incubation (step S11). When the incubator 40 starts incubation, the imaging device 10 captures an image of the fertilized egg 21 in the incubation container 20 under control of the information processing device 50 (step S12). The imaging device 10 wirelessly transmits image data generated by 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 performs reconstruction processing based on the image data to generate at least one reconstructed image (step S15). The display control unit 73 displays the reconstructed image generated by the reconstruction processing unit 72 on the display 51 (step S16).

Next, the information processing device 50 determines whether the culture in the incubator 40 has finished (step S17). The culture is carried out for, for example, up to 7 days from the start of the culture. The information processing device 50 determines whether the culture has finished based on, for example, the time elapsed since the start of the culture. If the information processing device 50 determines that the culture has not finished (step S17: NO), it determines whether a certain time (for example, 10 minutes) has passed since the previous image capture (step S18).

If the information processing device 50 determines that a certain amount of time has passed since the previous image capture (step S18: YES), it returns the process to step S12. The processes of steps S12 to S18 are repeatedly executed until the determination in step S17 is affirmative. After the information processing device 50 determines in step S17 that incubation in the incubator 40 has ended (step S17: YES), the user removes the imaging device 10 from the incubation chamber 41 of the incubator 40 (step S19).

As described above, the imaging device 10 according to the technology of the present disclosure can be taken in and out of the incubation chamber 41 of the incubator 40 for fertilized eggs. The incubator 40 for fertilized eggs is inexpensive because it does not have an optical camera or the like integrated into it. Furthermore, the imaging device 10 according to the technology of the present disclosure captures interference fringe images using lens-free imaging, so there is no need to adjust the focus when capturing images.

[Modification]
Next, a modified example of the imaging device 10 will be described. Fig. 10 shows an imaging device 10A according to the modified example. The imaging device 10A differs from the imaging device 10 according to the above embodiment in that the height Zi of the imaging device 10A is changeable. The height Zi of the imaging device 10A can be changed by changing the length of the support 13.

Specifically, the support 13 of the imaging device 10A according to this modified example is separated into an upper portion 13A and a lower portion 13B. The 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 together. The upper portion 13A and the lower portion 13B are an example of a "height adjustment mechanism" according to the technology of the present disclosure.

As shown in Figure 11, the height Zi of the imaging device 10A can be changed by sliding the upper part 13A relative to the lower part 13B. The support 13 is provided with a fixing screw 17 for fixing the upper part 13A to the lower part 13B. The user adjusts the position of the upper part 13A relative to the lower part 13B, and then operates the fixing screw 17 when the height Zi of the imaging device 10A is at the desired value, thereby fixing the upper part 13A to the lower part 13B.

The upper portion 13A may be configured to slide relative to the lower portion 13B using 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 modified as appropriate.

Incubators 40 for fertilized eggs are sold by a variety of manufacturers, and the height Zc of the incubation chamber 41 varies widely, with no unified standard. The imaging device 10A of this modified example allows the height Zi to be adjusted, so it can be inserted into the incubation chamber 41 of incubators 40 from a variety of manufacturers.

As shown in Figure 11, by lowering the height Zi of the imaging device 10A, when the light source 11 approaches the imaging sensor 12, it is preferable that the illumination light 16 from the light source 11 be radial light so that the entire imaging surface 12A is illuminated by the illumination light 16.

Furthermore, the imaging device 10 can be modified in various ways. In the above embodiment, a stage 15 having an imaging sensor 12 is provided on a base 14, but the stage 15 may be integrated with the base 14. Also, in the above embodiment, the base 14 is a rectangular flat plate, but the base 14 may be circular or other shapes.

Also, in the above embodiment, the light source 11 is connected to the end of the support 13, but the light source 11 may also be embedded in the support 13.

The light source 11 may also be a laser light source with multiple light-emitting points (e.g., 36 light-emitting points) arranged in a two-dimensional array. A vertical cavity surface-emitting laser (VCSL) can be used as this laser light source. By sequentially activating the multiple light-emitting points and combining multiple image data obtained by the imaging sensor 12, image data including a high-resolution interference fringe image (so-called super-resolution interference fringe image) can be obtained. By reconstructing this image data, a high-quality reconstructed image can be obtained.

Figure 12 shows the configuration of the light-emitting surface 11A of the light source 11, which has multiple light-emitting points 11B. The light-emitting surface 11A is positioned opposite the image sensor 12. Multiple 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 approximately 10 μm to 100 μm. Each of the light-emitting points 11B is selected in turn to emit illumination light 16. The light-emitting time interval between the multiple light-emitting 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 (first arrangement pitch Δx and second arrangement pitch Δy), and does not necessarily need to be smaller than the arrangement pitch of the pixels 12B. For example, even if a light-emitting point 11B is located directly above an adjacent pixel 12B, the arrangement pitch of the light-emitting points 11B does not need to match the arrangement pitch of the pixels 12B. In this case, since the illumination light 16 is illuminated at different positions on the pixels 12B, when combining multiple image data, different pixels 12B located directly below each light-emitting point 11B and illuminated by the illumination light 16 can be considered to be the same pixel and aligned with an accuracy of one pixel or less, thereby generating image data including super-resolution interference fringe images.

In Figure 12, the light-emitting points 11B are arranged in a 6x6 square, with 36 light-emitting points 11B provided on the light-emitting surface 11A, but the number and arrangement pattern of the light-emitting points 11B are not limited to the number and arrangement pattern shown in Figure 12. The more light-emitting points 11B there are, the higher the resolution of the interference fringe image can be, but the longer the calculation time for the synthesis process and reconstruction process. For this reason, it is preferable to optimize the number of light-emitting points 11B according to the required image quality and calculation time.

In addition, in the above embodiment, the imaging device 10 can be moved in and out of the culture chamber 41 of the incubator 40, but it is also possible to integrate the imaging device 10 and the incubator 40.

Figure 13 shows a time-lapse imaging system 2A composed of an incubator 40A integrated with an imaging device and an information processing device 50. Figure 14 shows an incubator 40A integrated with an imaging device. The time-lapse imaging system 2A is an example of an "imaging system" according to the technology of the present disclosure.

The incubator 40A according to this modified example is provided with multiple culture chambers 41, similar to the incubator 40 according to the above embodiment (see Figure 5). Each culture chamber 41 is provided with an openable/closable lid 42. In this modified example, the lid 42 is provided with a light source 11. Specifically, 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 multiple light-emitting points 11B as shown in Figure 12.

In this modified example, the image sensor 12 is provided on the bottom 41A of the culture chamber 41. Specifically, the image sensor 12 is embedded in the bottom 41A of the culture chamber 41, and the image sensor surface 12A is exposed inside the culture chamber 41. The bottom 41A is part of the housing that constitutes the incubator 40A.

With the lid 42 closed, the light source 11 is positioned opposite the image sensor 12. The culture vessel 20 is placed on the bottom 41A of the culture chamber 41. The illumination light 16 emitted from the light source 11 is incident on the image sensor 12 through the culture vessel 20. The image sensor 12 captures an interference fringe image generated by the fertilized egg 21. The image sensor 12 operates in the same manner as in the above embodiment. In this modified example, the light source 11 and the image sensor 12 constitute an imaging device.

The incubator 40A according to this modified example is provided with a processor 60, a storage device 61, and a communication unit 62 included in the imaging device 10 shown in FIG. 6. The incubator 40A communicates with the information processing device 50 via wired or wireless communication. The configuration and operation of the information processing device 50 are the same as those in the above embodiment. The information processing device 50 generates reconstruction data by performing reconstruction processing each time the imaging device generates image data.

The time-lapse imaging system 2A according to this modified example allows the fertilized eggs 21 to be observed while being cultured in the incubation chamber 41. It is also preferable to incorporate the information processing device 50 into the incubator 40A, thereby making the time-lapse imaging system 2A a single device.

Furthermore, in the above embodiment and the above variant example, the imaging device 10 is provided with one imaging sensor 12, but the number of imaging sensors 12 is not limited to one and may be two or more.

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 vessel 20. In the observation method for observing the fertilized egg 21 using the time-lapse imaging system according to the above embodiment or the above modification, as described above, the fertilized egg 21 is suspended in the culture solution 22. The fertilized egg 21 is a human ovum and is substantially spherical. The diameter D of the fertilized egg 21 is preferably equal to or greater than 100 μm and less than 200 μm.
Furthermore, the height H of the culture solution 22 is preferably 1 m or more and less than 20 mm in order to suspend the fertilized eggs 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 according to the above embodiment relates to a technology known as lens-free imaging, in which the imaging device 10 does not include an optical lens. The technology disclosed herein is applicable to digital holography in general (e.g., when using reference light).

The hardware configuration of the computer that constitutes the information processing device 50 can be modified in various ways. For example, the information processing device 50 can be configured with multiple computers separated as hardware in order to improve processing power and reliability.

In this way, the hardware configuration of the computer of the information processing device 50 can be changed as appropriate depending on the required performance, such as processing power, safety, and reliability. Furthermore, not only the hardware, but also application programs such as the operating program 56A can be duplicated or stored in a distributed manner across multiple storage devices in order to ensure safety and reliability.

In the above embodiment, the various processors listed below can be used as the hardware structure of the processing units that perform various processes, such as the imaging control unit 70, image data acquisition unit 71, reconstruction processing unit 72, and display control unit 73. As described above, the various processors include a CPU, which is a general-purpose processor that executes software (operating program 56A) and functions as various processing units, as well as dedicated electrical circuits, such as programmable logic devices (PLDs) that are processors whose circuit configuration can be changed after manufacture, such as FPGAs, and application-specific integrated circuits (ASICs), which are processors with a circuit configuration designed specifically to perform specific processes.

A single processing unit may be configured with one of these various processors, or may be configured with a combination of two or more processors of the same or different types (e.g., a combination of multiple FPGAs and/or a combination of a CPU and an FPGA). Also, multiple processing units may be configured with a single processor.

Examples of configuring multiple processing units with a single processor include, first, a form in which a single processor is configured with a combination of one or more CPUs and software, and this processor functions as multiple processing units, as typified by client and server computers. Second, a form in which a processor is used to realize the functions of an entire system including multiple processing units on a single IC (Integrated Circuit) chip, as typified by systems on chips (SoCs). In this way, various processing units are configured as a hardware structure using one or more of the various processors listed above.

Furthermore, the hardware structure of these various processors can be, more specifically, an electrical circuit that combines circuit elements such as semiconductor elements.

In addition, the above embodiments and variations can be combined as appropriate to the extent that no contradictions arise.

All publications, patent applications, and technical standards mentioned in this specification are incorporated by reference herein to the same extent as if each individual publication, patent application, and technical standard was specifically and individually indicated to be incorporated by reference.

Claims (4)

an incubator including an imaging device having a light source and an imaging sensor, which generates image data including an interference fringe image by imaging a fertilized egg seeded in a culture vessel , and a communication unit which wirelessly transmits the image data ;
an information processing device that receives the image data wirelessly transmitted from the incubator and performs reconstruction processing based on the received image data to generate a reconstructed image at an arbitrary focal position;
1. An imaging system comprising:
the incubator has a culture chamber that houses the culture vessel and a lid that makes the culture chamber airtight;
The light source is provided on the lid,
The imaging sensor is provided at the bottom of the culture chamber on which the culture vessel is placed.
Imaging system . The information processing device includes:
performing the reconstruction process each time the imaging device generates the image data;
displaying a reconstructed image generated by the reconstruction processing on a display;
The imaging system of claim 1 . the light source has a plurality of light-emitting points;
the imaging device performs imaging operations a plurality of times while sequentially causing the light emitting points to emit light, thereby generating a plurality of pieces of image data;
3. The imaging system according to claim 1 or claim 2 . The information processing device includes:
generating high-resolution image data based on the plurality of image data;
performing the reconstruction process based on the generated high-resolution image data;
The imaging system of claim 3 .