Patent Description:
There is a known imaging apparatus that images a sample by using transmitted light in order to analyze a sample such as biological molecules (<CIT>). In this imaging apparatus, the sample which is a subject, a lens, a light source, and the like are arranged in a housing, whereby the sample is imaged. Further, a plane light source, in which a light guide using a reflective diffusion plate and a transmission diffusion plate is formed, is used.

<CIT> discloses a sample imaging apparatus using a transmission light source capable of suppressing the influence of ambient light. In the housing there is provided a lens unit movable in a direction to and from the sample. A subject observation monitor displays a state on the stage imaged by a compact camera provided in the upper portion of the housing. Therefore, it is possible to check the position of the subject placed on the stage or the height of the stage and to adjust the position of the subject or the height of the stage so that the arrangement of the subject is suitable for imaging.

A sample imaging apparatus, which images a sample such as biological molecules usually, performs imaging by arranging not only a sample as a subject but also a lens, a light source, and the like in a housing forming a closed space. Moreover, in order to appropriately perform analysis and the like, samples such as biological molecules have to be imaged on a certain environmental condition.

However, in a case where the heat generation of the light source used for imaging is large, the temperature in the housing may rise and the state of the sample may change. In addition, in a case where the type of light to be emitted to the sample is changed and imaging is performed a plurality of times, it takes a long time to complete the imaging. In such a case, the effect of the temperature change in the housing due to the heat generation of the light source is serious.

According to the present invention, there is provided a sample imaging apparatus comprising the features of claim <NUM>.

According to the invention the housing includes a sample loading door that is capable of being opened and closed, and a filter turret that has a plurality of filters for limiting a wavelength used for imaging by being inserted between the sample and the lens. Driving of the filter turret is stopped in a case where the sample loading door is opened. This feature is for the safety since the user is likely to touch the filter turret.

According to the present invention, it is possible to provide a sample imaging apparatus which suppresses heat generation of a light source so as to reduce the environmental change in the housing due to the heat generation of the light source.

As illustrated in <FIG>, a sample imaging apparatus <NUM> is an apparatus that images a sample <NUM> (refer to <FIG>) such as biological molecules in a housing <NUM> forming a closed space. The housing <NUM> has a substantially rectangular parallelepiped shape, and has a touch panel <NUM> on the upper front side. The touch panel <NUM> is an operation unit and a display unit of the sample imaging apparatus <NUM>. The touch panel <NUM> displays an operable menu for selecting an imaging menu and/or an image obtained by imaging the sample <NUM>. Further, a sample loading door <NUM>, which is capable of being opened and closed in order to load a sample <NUM> as a subject, is provided on the lower part of the front surface of the housing <NUM>. In addition, on the side surface of the housing <NUM>, there is a filter replacement window <NUM> for replacing a filter or the like used for imaging.

The housing <NUM> forms a closed space inside by closing the sample loading door <NUM> and the filter replacement window <NUM>. The closed space is a space that forms a substantially constant imaging environment without being affected by the outside. Therefore, it is possible to provide a ventilating opening in the housing <NUM> for cooling or the like of a built-in device. It can be said that the housing <NUM> forms a closed space inside in a case where the inner space forms an imaging environment which is substantially not affected by the outside even in a case where air or the like enters and exits through the ventilating opening.

As illustrated in <FIG>, the sample imaging apparatus <NUM> comprises an imaging unit <NUM> that images the sample <NUM>, a first epi-illumination light source <NUM>, a second epi-illumination light source <NUM>, and a plane light source <NUM>, in the housing <NUM>. The first epi-illumination light source <NUM>, the second epi-illumination light source <NUM>, and the plane light source <NUM> are arranged in this order from the imaging unit <NUM> present on the uppermost part in the housing <NUM>, along an imaging optical axis L1 of the imaging unit <NUM>.

A tray <NUM>, on which the sample <NUM> is placed in the housing <NUM>, is alternatively disposed at either of two positions, that is, a first position <NUM> or a second position <NUM>. The first position <NUM> is between the first epi-illumination light source <NUM> and the second epi-illumination light source <NUM>. The second position <NUM> is between the second epi-illumination light source <NUM> and the plane light source <NUM>. In <FIG>, the tray <NUM> is disposed at the first position <NUM>. The tray <NUM> is made of, for example, glass and is transparent. The term "transparent" of the tray <NUM> means that the illumination light emitted by the plane light source <NUM> is transmitted to such an extent that the imaging unit <NUM> is able to image the sample <NUM> using the tray <NUM>. Further, the term "transparent" includes guiding the illumination light by diffusing, scattering, or diffracting the illumination light emitted by the plane light source <NUM> toward the imaging unit <NUM>.

In a case where the tray <NUM> on which the sample <NUM> is placed is disposed at the first position <NUM>, the first epi-illumination light source <NUM> irradiates the sample <NUM> with the illumination light from the side of the imaging unit <NUM>. The illumination light emitted by the first epi-illumination light source <NUM> is, for example, excitation light that causes fluorescent light from the sample <NUM> or the fluorescent reagent added to the sample <NUM> by exciting the sample <NUM> or the fluorescent reagent added to the sample <NUM>. The first epi-illumination light source <NUM> is able to emit excitation light that excites, for example, a Cy2 dye (cyanine dye), a Cy3 dye (indocarbocyanine dye), a Cy5 dye (indodicarbocyanine dye) or the like. The Cy2 dye emits fluorescent light having a wavelength of about <NUM> by irradiating the dye with excitation light having a wavelength of about <NUM>. The Cy3 dye emits fluorescent light having a wavelength of about <NUM> by irradiating the dye with excitation light having a wavelength of about <NUM>. The Cy5 dye emits fluorescent light having a wavelength of about <NUM> by irradiating the dye with excitation light having a wavelength of about <NUM>. Besides, the first epi-illumination light source <NUM> is able to emit ultraviolet light and infrared light.

In a case where the tray <NUM> on which the sample <NUM> is placed is disposed at the second position <NUM>, the second epi-illumination light source <NUM> irradiates the sample <NUM> with the illumination light from the side of the imaging unit <NUM>. Further, the illumination light emitted by the second epi-illumination light source <NUM> is, for example, excitation light that causes fluorescent light from the sample <NUM> or the fluorescent reagent added to the sample <NUM> by exciting the sample <NUM> or the fluorescent reagent added to the sample <NUM>. The illumination light (excitation light), which is capable of being emitted by the second epi-illumination light source <NUM>, is the same as that of the first epi-illumination light source <NUM>. That is, the first epi-illumination light source <NUM> and the second epi-illumination light source <NUM> each are an excitation light source which irradiates excitation light, which is for emitting fluorescent light, to the sample <NUM> placed on the tray <NUM> from the side of the lens <NUM> (refer to <FIG>) included in the imaging unit <NUM>.

The plane light source <NUM> emits illumination light to the sample <NUM> through the tray <NUM> disposed at the first position <NUM> or the second position <NUM> in the housing <NUM>. In the sample imaging apparatus <NUM>, the plane light source <NUM> is used as a so-called transmission light source. Further, the illumination light emitted by the plane light source <NUM> has a substantially uniform amount of light over substantially the entire portion (flat surface) of the tray <NUM> on which the sample <NUM> is placed. The plane light source <NUM> is able to emit red light, green light, blue light, or light (for example, white light) obtained by mixing two or more of them.

In addition to the above-mentioned description, a black insert (hereinafter referred to as a light blocking plate) <NUM> is capable of being freely inserted and removed between the tray <NUM> at the second position <NUM> and the plane light source <NUM>.

As illustrated in <FIG>, the imaging unit <NUM> includes an imaging element <NUM>, a shutter <NUM>, a lens <NUM>, a filter turret <NUM>, and an imaging control unit <NUM>. The imaging element <NUM> is, for example, a charge coupled device (CCD) sensor. The shutter <NUM> is a so-called mechanical shutter.

The imaging element <NUM> and the lens <NUM> are disposed in the housing <NUM> so as to face the plane light source <NUM> with the tray <NUM> interposed therebetween. The imaging element <NUM>, the lens <NUM>, and the filter turret <NUM> are used for imaging the sample <NUM>.

The lens <NUM> is a lens in which longitudinal chromatic aberration in a wavelength range of chemiluminescent light (chemiluminescence) emitted by the sample <NUM> or a chemiluminescent reagent added to the sample <NUM> is corrected. More specifically, the lens <NUM> is a so-called achromatic lens, and as illustrated in <FIG>, the longitudinal chromatic aberration of the lens <NUM> has a bell-shaped residual error. However, the general achromatic lens (comparative example) is adjusted such that the focus shift becomes zero at the F line and the C line. In contrast, the lens <NUM> used in the sample imaging apparatus <NUM> is characterized in that the focus shift becomes substantially infinitesimal and minimal in the wavelength range of the chemiluminescent light of the sample <NUM> or the like. Further, in the range of visible light, the focus shift of the lens <NUM> is greater as the wavelength is longer. Furthermore, an amount of focus shift ΔCL in the wavelength range of the chemiluminescent light is less than an amount of focus shift ΔFL in the wavelength range of the fluorescent light. In the present specification, the "wavelength range of the chemiluminescent light" is an emission band of the sample <NUM> or the chemiluminescent reagent (such as luminol) usually added to the sample <NUM>, and refers to, for example, a wavelength range of about <NUM> to about <NUM>. In addition, in the present specification, the "wavelength range of the fluorescent light" refers to a wavelength range of the fluorescent light emitted by the sample <NUM> or a fluorescent reagent (such as Cy3 dye) generally added to the sample <NUM>, for example, a wavelength of about <NUM> to about <NUM>.

As illustrated in <FIG>, the filter turret <NUM> comprises a plurality of optical filters <NUM> to <NUM> disposed between the lens <NUM> and the sample <NUM>. Then, by rotating the filter turret <NUM>, any one of these optical filters <NUM> to <NUM> is capable of being selected and appropriately inserted on the imaging optical axis L1. The optical filters <NUM> to <NUM> include a plurality of optical filters for limiting the wavelength used for imaging. The sample imaging apparatus <NUM> automatically rotates the filter turret <NUM> in accordance with the imaging menu. Thereby, the sample imaging apparatus <NUM> automatically selects an optical filter appropriate for imaging among the optical filters <NUM> to <NUM> appropriate for imaging.

The optical filter <NUM> is a so-called "pass-through" and transmits light with substantially the entire wavelength range. For convenience of description, the optical filter <NUM> is defined to include a case where the optical filter is not actually provided. The optical filter <NUM> is, for example, an infrared (IR) long pass filter, and the optical filter <NUM> is, for example, an IR short pass filter. The optical filter <NUM> is, for example, a band pass filter for Cy5 dye, the optical filter <NUM> is, for example, a band pass filter for Cy3 dye and ultraviolet light, and the optical filter <NUM> is a band pass filter for Cy2 dye. The optical filter <NUM> and the optical filter <NUM> are custom filters optionally set by the user. Each of the optical filters <NUM> to <NUM> other than the optical filter <NUM> which is a pass-through is a filter unit <NUM> which is detachable from the filter turret <NUM>, and all of them are replaceable. Since each filter unit <NUM> has an identifier <NUM> attached thereto, the sample imaging apparatus <NUM> is able to use the identifier <NUM> to identify what kind of optical filter is attached to which position on the filter turret <NUM>.

In the filter turret <NUM>, the optical filters <NUM> to <NUM> other than the optical filter <NUM> and the optical filter <NUM> which are custom filters are arranged from the vicinity of the optical filter <NUM> which is a pass-through, in the order of longer wavelengths (or in the order of shorter wavelengths). The reason for this is that the arrangement has to match with the imaging sequence for shortening the imaging time period.

The imaging control unit <NUM> controls each unit of the imaging unit <NUM>. For example, the imaging control unit <NUM> adjusts the focal length of the lens <NUM> in accordance with the imaging menu. The imaging control unit <NUM> also performs the operation of the imaging element <NUM>, the opening and closing of the shutter <NUM>, the rotation of the filter turret <NUM> (selection of the optical filter), and the like in accordance with the imaging menu.

As illustrated in <FIG>, the plane light source <NUM> is formed by using a light emitting unit <NUM> including one or more light emitting elements <NUM>, and a light guide plate <NUM> having a flat plate shape that propagates the light emitted by the light emitting elements <NUM> in a plane direction (in an XY in-plane direction in <FIG>). The light emitting element <NUM> is, for example, a light emitting diode (LED). The light guide plate <NUM> is connected to the light emitting unit <NUM> on the side surface. Therefore, the light emitted from the light emitting element <NUM> is incident into the light guide plate <NUM> from the side surface of the light guide plate <NUM>. A light amount adjustment pattern <NUM> is provided on the surface 83b of the light guide plate <NUM> such that the amount of light emitted from the light guide plate <NUM> increases as the distance from the light emitting element <NUM> increases. The light amount adjustment pattern <NUM> is formed of a plurality of reflectors that reflect light propagating in the light guide plate <NUM>, and the area of each reflector increases as the distance from the light emitting element <NUM> increases. On the other hand, for example, a diffusion film or a diffusion plate (not shown) is capable of being provided on the surface 83a facing the surface 83b (the surface facing the imaging unit <NUM> (lens <NUM>) side) as needed. In the present embodiment, the light amount adjustment pattern <NUM> is formed of a reflector, but the light amount adjustment pattern <NUM> may be formed of a light blocker having a plurality of light transmitting portions (openings and the like). It is preferable that the light amount adjustment pattern formed by the light blocker is provided on the surface 83a of the light guide plate <NUM>, and a reflective film or a reflector is provided on the surface 83b.

As compared with the plane light source constituted by using a reflection plate and a diffusion plate, the plane light source <NUM> configured as described above has a high light guiding efficiency. Therefore, it is possible to reduce the number of light emitting elements <NUM>. As a result, the heat generation of the plane light source <NUM> is suppressed. In addition, it is possible to reduce the environmental change in the housing <NUM> constituting the closed space.

In addition to the above, as illustrated in <FIG>, the sample imaging apparatus <NUM> comprises a control unit <NUM>, a door open/close detection unit <NUM>, a tray detection unit <NUM>, and a light blocking plate detection unit <NUM>.

The control unit <NUM> integrally controls each part of the sample imaging apparatus <NUM>. For example, the first epi-illumination light source <NUM>, the second epi-illumination light source <NUM>, and the plane light source <NUM> are turned on or off. Further, the control unit <NUM> controls each unit of the imaging unit <NUM> through the imaging control unit <NUM>, and performs imaging of the sample <NUM> in an appropriate imaging sequence in accordance with the imaging menu.

The door open/close detection unit <NUM> detects open/close states of the sample loading door <NUM> and the filter replacement window <NUM>. The tray detection unit <NUM> detects the tray <NUM>. The detection of the tray <NUM> is detection of whether or not the tray <NUM> is disposed in the housing <NUM> and detection of which of the first position <NUM> and the second position <NUM> the tray <NUM> is disposed. The light blocking plate detection unit <NUM> detects that the light blocking plate <NUM> is inserted. The detection of the light blocking plate <NUM> is detection as to whether or not the light blocking plate <NUM> is inserted on the imaging optical axis L1. The control unit <NUM> controls the operation of the sample imaging apparatus <NUM> by using the detection results of these detection units.

Hereinafter, an operation sequence of the sample imaging apparatus <NUM> configured as described above will be described. First, in a case of imaging the sample <NUM> by using a plurality of types of fluorescent light, the sample imaging apparatus <NUM> adjusts the focal length of the lens <NUM> for each imaging. That is, in a case of imaging one sample <NUM>, the imaging control unit <NUM> adjusts the focal length of the lens <NUM> a plurality of times, thereby performing imaging. Further, a state of focusing on a long wavelength side changed from a state of focusing on a short wavelength side is compared with the state of focusing on the short wavelength side changed from the state of focusing on the long wavelength side. In a case where an error of the focal length is smaller in the state of focusing on the long wavelength side changed from the state of focusing on the short wavelength side, imaging is performed sequentially from imaging using the light with a short wavelength. For example, as illustrated in <FIG>, the imaging using the fluorescent light of the Cy2 dye and the imaging using the fluorescent light of the Cy3 dye may be performed. In this case, imaging is performed by performing focusing for imaging using the fluorescent light of Cy2 dye that emits fluorescent light with a shorter wavelength, and then imaging is performed by performing focusing for imaging using the fluorescent light of Cy3 dye that emits fluorescent light with a relatively longer wavelength.

A state of focusing on a long wavelength side changed from a state of focusing on a short wavelength side is compared with the state of focusing on the short wavelength side changed from the state of focusing on the long wavelength side. In a case where an error of the focal length is smaller in the state of focusing on the short wavelength side changed from the state of focusing on the long wavelength side, the sample imaging apparatus <NUM> performs imaging sequentially from imaging using the fluorescent light with a long wavelength.

As described above, by performing focusing for each imaging, it is possible to obtain an image with high image quality that is in focus in each imaging. Then, in a case of performing a plurality of imaging operations, by sequentially performing imaging from imaging using light of a relatively shorter wavelength (or longer wavelength), it is possible to obtain the image with high image quality that is in focus in each imaging operation even in a case where the plurality of imaging operations are sequentially performed. The reason for this is that it is possible to reduce backlash of a gear or the like for driving the lens <NUM>. It is the same for the housing where three types of imaging are sequentially performed.

In addition, in the above-mentioned embodiment, the sample imaging apparatus <NUM> adjusts the focal length of the lens <NUM> for each imaging in a case of imaging one sample <NUM> a plurality of times. However, as a matter of course, the sample imaging apparatus <NUM> adjusts the focal length of the lens <NUM> also in a case of imaging one sample <NUM> once.

In the above-mentioned embodiment, the sample imaging apparatus <NUM> uses the lens <NUM> capable of adjusting the focal length. However, the sample imaging apparatus <NUM> is able to image the sample <NUM> by using a single focus lens instead of the lens <NUM>. In such a case, in a case of imaging one sample <NUM>, the imaging control unit <NUM> performs imaging by focusing on the sample <NUM> through the single focus lens.

In a case of performing imaging using chemiluminescent light of the sample <NUM> or the like is performed, for example, as illustrated in <FIG>, the sample imaging apparatus <NUM> first performs imaging using the chemiluminescent light. The reason for this is that the chemiluminescent light becomes weak as time passes. Thereafter, imaging using the fluorescent light is performed. The reason for this is that it is possible to adjust the emission intensity of the fluorescent light by performing adjustment of the irradiation intensity of the excitation light or the like. The imaging using the fluorescent light is performed in the order of reducing the error of the focal length due to backlash as described above.

In a case where a plurality of imaging operations are performed, the images obtained through the respective imaging operations are capable of being sequentially displayed on the touch panel <NUM>. In a case where a part or all of the imaging operations is completed, the images obtained through the respective imaging operations may be arranged and displayed on the touch panel <NUM>. Further, in the case of performing the plurality of imaging operations, it is also possible to display, on the touch panel <NUM>, a composite image obtained by combining a part or all of the images obtained through the respective imaging operations.

In a case where the light blocking plate <NUM> is inserted between the tray <NUM> and the plane light source <NUM>, the control unit <NUM> is able to prevent the plane light source <NUM> from emitting light.

In a case where the light blocking plate <NUM> is removed from between the tray <NUM> and the plane light source <NUM>, the control unit <NUM> prevents the first epi-illumination light source <NUM> and the second epi-illumination light source <NUM> from emitting light. In a case where the light blocking plate <NUM> is inserted between the tray <NUM> and the plane light source <NUM>, it is possible to permit the first epi-illumination light source <NUM> and the second epi-illumination light source <NUM> to emit light. The reason for this is to appropriately perform imaging using the first epi-illumination light source <NUM> and the second epi-illumination light source <NUM>.

The control unit <NUM> is able to issue notification of a warning in a case of removing the light blocking plate <NUM> from between the tray <NUM> and the plane light source <NUM> and attempting to perform imaging of the sample <NUM> using the fluorescent light. The term "warning" is defined to include display of a message on the touch panel <NUM> and the like.

The sample imaging apparatus <NUM> has a live view mode in which the plane light source <NUM> is turned off and a moving image of the sample <NUM> placed on the tray <NUM> is captured. The moving image in the live view mode is displayed on the touch panel <NUM>. Further, for example, in a case where the sample loading door <NUM> is opened, the control unit <NUM> executes the live view mode. In addition, in a case where the sample loading door <NUM> is opened and the tray <NUM> is set, the control unit <NUM> is able to execute the live view mode until the sample loading door <NUM> is closed.

The control unit <NUM> stops the drive (rotation operation or the like) of the filter turret <NUM>, in a case where the sample loading door <NUM> is opened. This is for safety since the user is likely to touch the filter turret <NUM>.

The control unit <NUM> is able to prevent the first epi-illumination light source <NUM> and the second epi-illumination light source <NUM>, which are excitation light sources, from emitting light in a case where the sample loading door <NUM> is opened. Similarly, the control unit <NUM> is able to prevent the plane light source <NUM> from emitting light in a case where the sample loading door <NUM> is opened. Each of these light sources has high brightness and is therefore safe.

In the above-mentioned embodiment, the hardware structure of the processing unit, which executes various kinds of processing of the imaging control unit <NUM>, the control unit <NUM>, and the like, is various processors as described below. The various processors include: a central processing unit (CPU) and a graphic processing unit (GPU) that are general purpose processors which execute software (programs) and function as various processing units; a programmable logic device (PLD) that is a processor capable of changing a circuit configuration after manufacture of a field programmable gate array (FPGA) or the like; and a dedicated electric circuit that is a processor having a circuit configuration specially designed to execute various processes.

One processing unit may be configured as one of these various types of processors, or may be configured as a combination of two or more processors of the same or different types (such as a plurality of FPGAs, a combination of a CPU and an FPGA, or a combination of a CPU and a GPU). Further, a plurality of processing units may be configured as one processor.

As an example in which a plurality of processing units are configured as one processor, there is a following configuration. First, one processor is configured as a combination of one or more CPUs and software as typified by computers such as clients and servers, and this processor functions as a plurality of processing units. Second, as typified by a system on chip (SoC) or the like, there is a configuration using a processor in which the function of the whole system including the plurality of processing units is implemented by one integrated circuit (IC) chip. In such a manner, the various processing units are configured using one or more of the above-mentioned various processors as a hardware structure.

Claim 1:
A sample imaging apparatus (<NUM>) comprising:
a housing (<NUM>) that forms a closed space;
a sample loading door (<NUM>) that is capable of being opened and closed;
a transparent tray (<NUM>) on which a sample is placed in the housing (<NUM>);
a plane light source (<NUM>) , which propagates light emitted by a light emitting element in a plane direction, so as to illuminate the sample with illumination light through the tray (<NUM>) in the housing (<NUM>);
a lens (<NUM>) that is disposed in the housing (<NUM>) so as to face the plane light source (<NUM>) with the tray (<NUM>) interposed between the lens (<NUM>) and the plane light source (<NUM>) and is used for imaging the sample;
an imaging control (<NUM>) unit that is adapted to adjust a focal length of the lens (<NUM>) and to perform imaging in a case of imaging the single sample; and
a control unit (<NUM>) configured to integrally control each part of the sample imaging apparatus (<NUM>),
wherein the control unit is configured to provide a live view mode, in which the plane light source (<NUM>) is turned off and a moving image of the sample placed on the tray (<NUM>) is captured,
wherein, in a case where the sample loading door (<NUM>) is opened and the tray (<NUM>) is set, the control unit (<NUM>) is configured to execute the live view mode until the sample loading door (<NUM>) is closed, wherein the plane light source (<NUM>) is formed by using a flat light guide plate (<NUM>),
wherein the housing (<NUM>) includes
a filter turret (<NUM>) that has a plurality of filters (<NUM>-<NUM>) for limiting a wavelength used for imaging by being inserted between the sample and the lens (<NUM>), and
wherein the control unit is configured to stop driving of the filter turret (<NUM>) in a case where the sample loading door (<NUM>) is opened.