Measurement device and culture system

Abstract

To be able to continuously measure the fluorescence intensity of a target product in a series of steps while measuring the turbidity of a culture solution, and to do so stably and accurately. [Solution] A measuring device 1 is provided which includes at least one light irradiation unit 10 which irradiates excitation light EL towards the interface between the culture solution W and the inner surface of a culture vessel 2 which contains a culture solution W in which a target product is expressed, a first imaging unit (dual-purpose imaging unit 12) which captures an image of scattered light reflected from the interface from the excitation light and obtains it as a scattered light image, a second imaging unit (dual-purpose imaging unit 12) which captures an image of fluorescence emitted by the expressed target product due to irradiation with excitation light and obtains it as a fluorescence image, a fluorescent filter 13 which transmits light in a wavelength range including the wavelength of the fluorescence and restricts the transmission of light in at least the wavelength range of the excitation light, and a measuring unit 91 which measures the turbidity of the culture solution and the fluorescence intensity of the target product based on the scattered light image and the fluorescent image.

Description

[Technical field]

[0001] The present invention relates to a measuring device and a culture system. [Background technology]

[0002] For example, in order to perform structural and functional analysis of a target substance (target product substance) such as a protein, it is necessary to mass-produce the target substance. In this regard, a method has been used in which a target substance is expressed by using a microorganism such as Escherichia coli as a host. For example, in a protein expression system using E. coli, a technique is known that uses an expression vector whose expression is induced depending on temperature. The expression vector used in this technique contains, for example, a target gene that encodes a target substance (target protein) and a specific promoter whose expression is induced when the culture temperature of E. coli becomes a low temperature condition (e.g., 15°C).

[0003] In this case, E. coli containing the expression vector is introduced into the culture solution contained in the culture vessel. Next, the culture vessel is shaken while maintaining a predetermined culture temperature (e.g., 37°C) to culture the E. coli. The turbidity of the culture solution tends to increase as the culture of E. coli progresses. Therefore, when a certain turbidity is reached, it can be determined (estimated) that a certain amount of E. coli has been cultured. Therefore, after the certain turbidity is reached, the culture vessel is cooled and maintained at a low temperature (e.g., about 15°C).

[0004] This allows the specific promoter to be expressed under low temperature conditions. On the other hand, the expression of proteins contained in E. coli itself can be suppressed. This makes it possible to express the target substance (target protein) efficiently and with high purity. This allows the fluorescence intensity of the target substance (target protein) to be measured by fluorescent observation using a fluorescent microscope or the like, making it possible to confirm whether a certain amount of the target substance (target protein) has been obtained.

[0005] As a prerequisite for expressing such a target substance, it is necessary to culture a certain amount of E. coli in a culture medium. Regarding this type of culture, a method for continuously measuring the proliferation of a culture sample such as E. coli in a non-contact manner is known (for example, see Patent Document 1). This method has a light irradiating unit that irradiates infrared light toward the culture vessel during shaking, and a light receiving unit that receives the light that has passed through the culture vessel. In particular, this method utilizes centrifugal force caused by shaking the culture vessel to spread the culture fluid thinly and to a thickness with a certain degree of fluctuation on the inner surface of the culture vessel, thereby enabling the light to pass through. This allows the infrared light irradiated from the light irradiating unit to pass through both the culture vessel and the culture fluid (the culture fluid spread on the inner wall surface of the culture vessel) and then reach the light receiving unit.

[0006] Furthermore, the calculation unit of the device body stores model data of optical density to calculate the change in optical density (OD) due to the proliferation of the culture sample by comparing the difference between the amount of irradiated light and the amount of transmitted light. This makes it possible to calculate the optical density and measure the proliferation state of the culture sample by comparing and calculating the change in the amount of light actually measured (the difference between the change in the amount of irradiated light and the amount of transmitted light) with the model data. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] Patent No. 5774352 Summary of the Invention [Problem to be solved by the invention]

[0008] By using the above-mentioned conventional method, it is possible to measure the turbidity of the culture solution. However, when measuring the fluorescence intensity of the target substance expressed thereafter, it is necessary to take the culture solution as a sample from the culture vessel and measure it using a separate fluorescence microscope, for example. Therefore, since it is necessary to measure the turbidity of the culture solution and the fluorescence intensity of the target substance using separate devices, the work becomes complicated and there is room for improvement.

[0009] Furthermore, the conventional method described above employs a so-called light transmission type in which the infrared light irradiated from the light irradiating unit is transmitted through the culture solution. In this case, it is difficult to transmit the infrared light appropriately because it is easily affected by the film thickness of the culture solution spread on the inner surface of the culture vessel and the concentration of the culture solution. Therefore, there is room for improvement in terms of stably and accurately measuring the turbidity of the culture solution.

[0010] The present invention has been made in consideration of the above circumstances, and its object is to provide a measuring device and a culture system equipped with the measuring device, which are capable of continuously measuring the turbidity of a culture solution while measuring the fluorescence intensity of a target product in a single flow, and which are capable of performing these measurements stably and accurately. [Means for solving the problem]

[0011] (1) The measuring device of the present invention is characterized in that it comprises at least one light irradiation unit that is arranged outside a culture vessel containing a culture solution that expresses a target product having at least the function of emitting fluorescence, and irradiates excitation light toward an interface between the inner surface of the culture vessel and the culture solution; a first imaging unit that is arranged outside the culture vessel and captures an image of scattered light reflected from the interface of the excitation light to obtain a scattered light image; a second imaging unit that is arranged outside the culture vessel and captures an image of fluorescence emitted by the expressed target product due to irradiation with the excitation light to obtain a fluorescence image; a fluorescence filter that is arranged between the second imaging unit and the culture vessel and transmits light in a wavelength range that includes the wavelength of the fluorescence and restricts the transmission of light in at least the wavelength range of the excitation light; and a measuring unit that measures the turbidity of the culture solution and the fluorescence intensity of the target product based on the scattered light image and the fluorescence image.

[0012] According to the measuring device of the present invention, excitation light can be irradiated from the outside of the culture vessel containing the culture solution by the light irradiating unit. At this time, the light irradiating unit irradiates the excitation light toward the interface between the inner surface of the culture vessel and the culture solution. Therefore, a part of the irradiated excitation light becomes scattered light by being reflected at the interface. As a result, an image of the scattered light reflected at the interface can be captured and acquired as a scattered light image by using the first imaging unit arranged outside the culture vessel. Therefore, the turbidity of the culture solution can be measured based on the scattered light image by the measuring unit. As a result, the culture state of the culture solution containing the target production substance can be grasped based on the turbidity. Therefore, after confirming that the culture has been performed appropriately, it is possible to express the target product using various expression systems, etc. Furthermore, if it is found that the culture is insufficient, it is also possible to provide feedback such as continuing the culture.

[0013] When the target substance is expressed as described above, the target substance emits fluorescence due to irradiation with excitation light. Specifically, the target substance absorbs the light energy of the excitation light and transitions to an excited state, and then transitions to a ground state while emitting fluorescence. This allows the second imaging unit disposed outside the culture vessel to capture an image of the fluorescence emitted by the target substance and obtain it as a fluorescence image. In particular, since a fluorescent filter is disposed between the second imaging unit and the culture vessel, it is possible to block at least the light in the wavelength range of the excitation light reflected by the culture vessel, and prevent the excitation light from reaching the second imaging unit. Therefore, it is possible to remove noise caused by the excitation light from the acquired fluorescent image, and it is possible to acquire a highly accurate fluorescent image. Therefore, it is possible to measure the fluorescent intensity of the target produced substance based on the fluorescent image by the measuring unit, and it is possible to know whether a certain amount of the target produced substance has been obtained.

[0014] As a result, the turbidity of the culture solution can be measured at the required timing, and the fluorescence intensity of the target product can be measured continuously in a series of steps. In particular, unlike the conventional light transmission type, the turbidity of the culture solution can be measured based on the scattered light reflected at the interface between the inner surface of the culture vessel and the culture solution, so it is less susceptible to the influence of, for example, the concentration of the culture solution or bubbles on the surface of the culture solution. Therefore, even if the culture solution is highly turbid and difficult to transmit light, the turbidity of the culture solution can be measured stably and accurately, making it easy to accurately grasp the culture state of the culture solution containing the target product (protein, etc.). Furthermore, since the fluorescence intensity of the target substance can be measured without removing the culture solution from the culture vessel, contamination of the culture solution can be prevented, and the fluorescence intensity can be measured with high accuracy.

[0015] (2) The culture solution contains host cells transformed with an expression vector that expresses the target product, and the light irradiation unit may irradiate the excitation light toward the interface between the inner surface of the culture vessel and the culture solution containing the host cells.

[0016] In this case, since host cells such as E. coli transformed with an expression vector (an expression vector containing a target gene encoding a target product) are contained in the culture solution, it is easy to efficiently culture E. coli in the culture vessel and to easily produce a certain amount of the target product. Furthermore, if an expression method is adopted in which the target product is efficiently expressed while suppressing the expression of proteins possessed by E. coli itself, it is easy to obtain a highly pure expressed target product.

[0017] (3) Only one light irradiation unit may be provided, and a single dual-purpose imaging unit that serves both the first imaging unit and the second imaging unit may be provided outside the culture vessel, and the fluorescent filter may be disposed between the dual-purpose imaging unit and the culture vessel so that the image captured by the dual-purpose imaging unit simultaneously includes two images, the scattered light image and the fluorescent image.

[0018] In this case, a single combined imaging section serving as both the first imaging section and the second imaging section can be used, which can simplify the configuration and reduce component costs. Furthermore, since the fluorescent filters are arranged so that the captured image of the combined imaging section simultaneously includes two images, the scattered light image and the fluorescent image, a single combined imaging section can be used to appropriately acquire both the scattered light image and the fluorescent image. Furthermore, since a single image captured by the dual-purpose imaging unit can contain both a scattered light image and a fluorescent image, it is possible to grasp, for example, the relationship (correlation) between turbidity and fluorescent intensity.

[0019] (4) The dual-purpose imaging unit may be positioned so that the optical center of the excitation light irradiated to the interface is located at the center of the captured image, and the fluorescence filter may be positioned so as to block reflected light from the optical center from entering the captured image of the dual-purpose imaging unit.

[0020] In this case, since the optical center of the excitation light is located at the center of the captured image, the scattered light image and the fluorescent image can be included evenly and in a well-balanced manner in one captured image captured by the dual-purpose image capture unit. Moreover, the reflected light itself from the optical center can be blocked from directly entering the captured image by using a fluorescent filter. Therefore, it is possible to prevent strong light from entering the captured image, and to prevent problems such as whiteout from occurring in the scattered light image and the fluorescent image. This makes it possible to obtain scattered light images and fluorescent images in which changes in color information such as RGB (red, green, blue), changes in brightness such as gradations, changes in luminance, etc. are clearly shown, and measurements of turbidity and fluorescence intensity can be performed with high accuracy.

[0021] (5) The measurement unit may use areas of the scattered light image and the fluorescent image contained in the captured image of the dual-purpose imaging unit that are located at the same distance from the optical center as a data acquisition area, extract partial images of the scattered light image and partial images of the fluorescent image within the data acquisition area, and measure the turbidity of the culture solution and the fluorescence intensity of the target product.

[0022] In this case, partial images within the data acquisition region located at the same distance from the optical center are extracted to acquire a scattered light image and a fluorescent image, so that both images can be acquired under conditions of equivalent light intensity. Therefore, turbidity and fluorescent intensity can be measured based on the scattered light image and the fluorescent image acquired under equivalent conditions.

[0023] (6) The light irradiation unit may be positioned to irradiate the excitation light at an acute incident angle relative to the inner surface of the culture vessel, and the dual-purpose imaging unit may be positioned such that an imaging axis is non-coaxial with respect to an optical axis of the excitation light reflected at a reflection angle corresponding to the incident angle.

[0024] In this case, it is possible to prevent excitation light reflected at the interface from directly entering the image acquired by the dual-purpose image acquisition section, making it possible to acquire clear and distinct scattered light images and fluorescent images.

[0025] (7) The imaging device may further include a storage unit that stores the scattered light image captured by the first imaging unit and the fluorescent light image captured by the second imaging unit in association with each other.

[0026] In this case, the scattered light image and the fluorescent image can be stored in association with each other in the memory unit, so that information such as the correlation between the turbidity state and the expression state of the target substance can be grasped. Therefore, by accumulating this information, it is possible to estimate, for example, the degree of turbidity at which the target substance will be expressed. As a result, the operations from cultivation to expression of the target substance can be carried out efficiently.

[0027] (8) The apparatus may further include an excitation filter disposed between the light irradiation unit and the culture vessel, the excitation filter allowing the transmission of light in a wavelength range different from the wavelength range allowed to be transmitted by the fluorescence filter.

[0028] In this case, since the excitation filter is provided, the culture vessel can be appropriately irradiated with excitation light in a wavelength range suitable for emission of fluorescence. In particular, since the wavelength range of the excitation filter and the wavelength range of the fluorescence filter can be made different, it is possible to prevent the excitation spectrum and the fluorescence spectrum from overlapping, and to suppress a decrease in the contrast of the fluorescence image.

[0029] (9) The culture vessel may further include a focusing lens disposed between the light irradiation unit and the culture vessel, for focusing the excitation light onto the interface between the inner surface of the culture vessel and the culture solution.

[0030] In this case, the excitation light irradiated from the light irradiating section can be condensed onto the interface using a condensing lens, making it possible to obtain even clearer scattered light images and fluorescent light images.

[0031] (10) A holding member that holds the light irradiation unit, a first case that houses the holding member inside, and a second case that is combined with the first case and holds the dual-purpose imaging unit and the fluorescent filter, wherein the first case and the second case each have a set surface that is in close contact with an outer surface of the culture vessel, and the light irradiation unit may be held by the holding member so that it can irradiate the excitation light toward the culture vessel set so as to contact the set surface.

[0032] In this case, since the light irradiation unit, the dual-purpose image capture unit, the fluorescent filter, etc. are incorporated into one unit formed by combining the first case and the second case, the device can be made compact and the handling can be improved. In particular, the culture vessel, the light irradiation unit, and the dual-purpose image capture unit can be set to have an appropriate relative positional relationship by a simple method of simply setting the culture vessel so that the outer surface of the culture vessel contacts the set surface of the first case and the set surface of the second case. Therefore, without performing special position adjustment, etc., the excitation light can be accurately irradiated toward the interface between the inner surface of the culture vessel and the culture solution, and a scattered light image and a fluorescent image can be obtained by using the dual-purpose image capture unit.

[0033] (11) The holding member may be held displaceably relative to the first case.

[0034] In this case, by displacing the holding member with respect to the first case, it is possible to easily fine-tune the irradiation angle of the light irradiating unit with respect to the culture vessel.

[0035] (12) The second case may be provided with a first retaining hole that removably holds the dual-purpose imaging unit, and a second retaining hole that is formed between the first retaining hole and the set surface and that removably holds the fluorescent filter.

[0036] In this case, the first and second holding holes can be used to easily attach, detach, or replace the dual-purpose image capture unit and the fluorescent filter to the second case. In particular, the optimal dual-purpose image capture unit, fluorescent filter, etc. can be selected and used depending on the type of target production substance and culture solution, culture conditions, application, etc.

[0037] (13) The light irradiation unit may irradiate the excitation light toward the interface between the culture solution in which a protein is expressed as the target production substance and an inner surface of the culture vessel, the second imaging unit may capture an image of fluorescence emitted by the expressed protein due to irradiation with the excitation light and obtain the image as the fluorescence image, and the measurement unit may measure the turbidity of the culture solution and the fluorescence intensity of the protein based on the scattered light image and the fluorescence image.

[0038] In this case, the turbidity of the culture medium can be measured at the required timing, and further, the fluorescence intensity of the protein can be measured continuously in a series of steps.

[0039] (14) The culture system of the present invention comprises a shaking device having the measuring device, a shaking table having a mounting surface on which the culture vessel is placed, and a shaking mechanism for shaking the shaking table in a plane parallel to the mounting surface, and a control unit for controlling the measuring device and the shaking mechanism, wherein the control unit controls the shaking mechanism so that the culture vessel moves between a culture position spaced from the measuring device and a measurement position where measurement is performed by the measuring device, and controls the shaking mechanism so as to shake the shaking table at the culture position, and further, the control unit feedback-controls the shaking mechanism to change the shaking conditions of the shaking table based on the turbidity of the culture solution and the fluorescence intensity of the target product measured by the measurement unit.

[0040] According to the culture system of the present invention, during the process of culturing the culture solution while shaking the culture vessel using a shaking device at the culture position, or after the culture is completed, the culture vessel can be moved to a measurement position and the turbidity of the culture solution and the fluorescence intensity of the target product can be measured using a measuring device. In particular, when the control unit determines that, for example, the culture or the expression of the target substance is insufficient based on the measured turbidity of the culture medium and the fluorescence intensity of the target substance, it feedback controls the shaking mechanism to change the shaking conditions of the shaking table. This makes it possible to resume shaking of the culture vessel with a different shaking pattern, thereby promoting the culture or expression, etc. Therefore, a certain amount of the expressed target substance can be obtained reliably and efficiently. Effect of the Invention

[0041] According to the present invention, it is possible to continuously measure the fluorescence intensity of the target product while measuring the turbidity of the culture medium in a single flow, and the turbidity and fluorescence intensity measurements can be performed stably and accurately. [Brief description of the drawings]

[0042] [Figure 1] 1 is a vertical sectional view showing a first embodiment of a measuring device according to the present invention. [Diagram 2] FIG. 2 is a perspective view of a culture system equipped with the measurement device shown in FIG. [Diagram 3] 2 is a side view of the measuring device shown in FIG. 1 as viewed from the left and right direction. [Figure 4] FIG. 2 is a front perspective view of the measuring device shown in FIG. [Diagram 5] 2 is a perspective view of the measuring device shown in FIG. 1, seen obliquely from below and in front. [Figure 6] FIG. 2 is a front view of the measuring device shown in FIG. 1. [Figure 7] 2 is a perspective view of an upper case constituting the storage case shown in FIG. 1, as viewed from below. [Figure 8]2 is a perspective view of a lower case constituting the storage case shown in FIG. 1, as viewed from above. [Figure 9] 9 is a perspective view showing a state in which the fluorescence filter unit is removed from the state shown in FIG. 8. FIG. [Figure 10] FIG. 2 is a perspective view of the protein measurement shown in FIG. 1, showing the state through the upper case. [Figure 11] 11 is a perspective view showing the relationship between a holding member and an excitation light filter shown in FIG. 10. [Figure 12] 12 is a rear perspective view of the holding member shown in FIG. 11. FIG. [Figure 13] FIG. 2 is an exploded perspective view of the fluorescence filter unit shown in FIG. [Figure 14] 14 is a rear perspective view of the pressing plate shown in FIG. 13. FIG. [Figure 15] 4 is an example of an image (scattered light image, fluorescent image) captured by a dual-purpose image capturing section. [Figure 16] FIG. 4 is a vertical sectional view of a measurement device showing a modified example of the first embodiment. [Figure 17] FIG. 4 is a vertical cross-sectional view showing a second embodiment of a measuring device according to the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0043] (First embodiment) A first embodiment of a measuring device according to the present invention will be described below with reference to the drawings. As shown in Figures 1 and 2, the measuring device 1 is an apparatus capable of simultaneously measuring the turbidity of a culture solution W in which a target substance (hereinafter simply referred to as the target substance) is expressed, and measuring the fluorescence intensity of the target substance. The target product refers to a substance produced by a microorganism through a process such as fermentation or metabolism, and includes, for example, proteins, organic compounds produced by fermentation of lactic acid bacteria, peptides, etc. In this embodiment, a protein is assumed as the target product. Therefore, the measurement device 1 is assumed to be a protein measurement device capable of simultaneously measuring the turbidity of a culture solution W in which a protein is expressed and measuring the fluorescence intensity of the protein.

[0044] The culture solution W in which the target substance is expressed is contained in the culture vessel 2. The culture vessel 2 is shaken under predetermined culture conditions by a culture device including a shaking table (not shown). As a result, the culture of the culture solution W progresses in the culture vessel 2, and the turbidity increases with the progress of the culture. The measurement device 1 of this embodiment measures the turbidity of the culture solution W to grasp the progress of the culture (culture state), and also measures the fluorescence intensity of the target substance to grasp that a certain amount of the target substance has been obtained.

[0045] Furthermore, as shown in FIG. 2, the culture system 150 of this embodiment includes the measurement device 1, a shaking device 151, and a control unit 15 that controls the measurement device 1 and the shaking device 151 in an overall manner. The shaking device 151 includes a shaking table 152 having a mounting surface 152a on which the culture vessel 2 is placed, and a shaking mechanism 153 for shaking the shaking table 152 in a plane parallel to the mounting surface 152a. The culture vessel 2 is held by a holding member (not shown) in a state in which it is placed directly on the mounting surface 152a or indirectly via a support member (not shown).

[0046] The shaking mechanism 153 is capable of arbitrarily moving the shaking table 152 two-dimensionally in a plane parallel to the mounting surface 152a, and is capable of shaking the shaking table 152 in various shaking patterns. For example, the shaking mechanism 153 is capable of shaking the shaking table 152 in a shaking pattern that moves the shaking table 152 linearly, a shaking pattern that moves the shaking table 152 in a circular or elliptical motion, a shaking pattern that repeats a semicircular motion back and forth, a shaking pattern that draws a figure eight, and the like.

[0047] The control unit 15 controls the shaking mechanism 153 so that the culture container 2 moves between a culture position P1 spaced away from the measuring device 1 and a measurement position P2 where measurement is performed by the measuring device 1, and also controls the shaking table 152 to shake in a predetermined shaking pattern at the culture position P1.

[0048] In this embodiment, a glass Erlenmeyer flask is used as the culture vessel 2. Therefore, the culture vessel 2 has a flat bottom 3 and a conical side wall 4. The connection portion between the bottom 3 and the side wall 4 is an annular curved surface portion 5 that extends continuously around the entire circumference of the bottom 3. However, the culture vessel 2 is not limited to an Erlenmeyer flask, and various flasks such as an eggplant-shaped flask, a round-bottom flask, a shake flask, etc. may be used as the culture vessel 2. Furthermore, a test tube, a petri dish, etc., or a cylindrical vessel such as a beaker may be used as the culture vessel 2.

[0049] Furthermore, in this embodiment, an example will be described in which Escherichia coli is used as a host cell, an expression vector whose expression is induced depending on temperature is used, and the target substance is expressed by the technique of the Escherichia coli cold shock expression system. Therefore, the culture solution W contains E. coli transformed with an expression vector (an expression vector containing a target gene that encodes a target substance).

[0050] Furthermore, the expression vector contains a specific promoter including the E. coli cold shock gene, the expression of which is induced when the culture temperature of E. coli is low (e.g., 15°C). Specifically, the lactose operon (lac I, Lac operator) is contained as a specific promoter. The lactose operon controls the expression of the promoter of the E. coli cold shock gene. It is possible to express the promoter of the E. coli cold shock gene by deregulating the lactose operon with a reagent (expression inducer) such as IPTG (Isopropyl-β-D-thiogalactopyranoside). However, a specific promoter such as the lactose operon is not essential and does not have to be included in the expression vector.

[0051] As shown in Figure 1, the measuring device 1 is provided with a light irradiation unit 10 arranged outside the culture vessel 2 and irradiating excitation light EL toward the culture vessel 2, an excitation filter 11 arranged between the light irradiation unit 10 and the culture vessel 2, a dual-purpose imaging unit 12 arranged outside the culture vessel 2 and acquiring a scattered light image 16 (see Figure 15) and a fluorescent image 17 (see Figure 15), respectively, a fluorescent filter 13 arranged between the dual-purpose imaging unit 12 and the culture vessel 2, and a storage case 14 for accommodating each of these components inside.

[0052] (Storage case) First, the storage case 14 will be described. 3 to 6, the storage case 14 includes an upper case (first case according to the present invention) 20 and a lower case (second case according to the present invention) 40 that is combined integrally with the upper case 20, and is made of, for example, synthetic resin. The light irradiation section 10 and the excitation filter 11 are housed in the upper case 20 while being held by a holding member 30. The combined image capturing section 12 and the fluorescence filter 13 are housed and held in the lower case 40.

[0053] The upper case 20 and the lower case 40 are combined together in a vertically stacked state. In this embodiment, as shown in Fig. 1, two directions perpendicular to each other in a horizontal plane (a plane parallel to the mounting surface 152a of the shaking table 152 shown in Fig. 2) are defined as a front-rear direction L1 and a left-right direction L2. In the front-rear direction L1, the direction toward the culture vessel 2 is defined as a forward direction FW, and the opposite direction is defined as a backward direction BK.

[0054] 3 to 6, the upper case 20 is formed in a rectangular shape with a length (width) in the front-rear direction L1 and the left-right direction L2 being longer than the length (height) in the up-down direction. An upper set surface (set surface according to the present invention) 21 with which the outer surface of the culture vessel 2 comes into close contact is formed on a front surface 20a of the upper case 20. The upper set surface 21 is formed in the center in the left-right direction L2 on the front surface 20a of the upper case 20, and is formed so as to be three-dimensionally recessed toward the rear BK in accordance with the shape of the conical side wall portion 4. This allows the outer surface of the side wall portion 4 of the culture vessel 2 to be in close contact with the upper set surface 21.

[0055] 1 and 7, an upper storage chamber 22 that opens downward is formed inside the upper case 20. Furthermore, a step portion 23 that is recessed upward and formed along the opening of the upper storage chamber 22 is formed on the lower surface 20b of the upper case 20. The step portion 23 is formed in a C-shape so as to be located in the left-right direction L2 and rearward BK with respect to the opening of the upper storage chamber 22 when the upper case 20 is viewed from below.

[0056] 1 to 6, the lower case 40 is formed in a rectangular shape with a length (width) in the front-rear direction L1 and the left-right direction L2 being longer than its length (height) in the up-down direction. In the illustrated example, the lower case 40 is formed so that its length in the up-down direction is shorter than that of the upper case 20, and its length in the left-right direction L2 is equal to that of the upper case 20. Furthermore, the lower case 40 is formed so that its length in the front-rear direction L1 is shorter than that of the upper case 20. The lower case 40 is assembled so that its rear surface 40c is flush with the rear surface 20c of the upper case 20. As a result, the front surface 40a of the lower case 40 is shifted rearward toward the BK side relative to the front surface 20a of the upper case 20.

[0057] 8 and 9, a protrusion 41 that bulges upward is formed on the upper surface 40b of the lower case 40. The protrusion 41 is disposed so as to face the step portion 23 of the upper case 20 in the up-down direction, and is formed in a C-shape in plan view corresponding to the step portion 23. 1, when the upper case 20 and the lower case 40 are assembled, the lower surface 20b of the upper case 20 and the upper surface 40b of the lower case 40 can be brought into contact with each other with the protruding portion 41 contacting the stepped portion 23 from below. In particular, since the protruding portion 41 can be fitted into the inside of the stepped portion 23, the upper case 20 and the lower case 40 can be assembled together integrally with high precision.

[0058] As shown in Figures 1, 8 and 9, the lower case 40 is provided with a first retaining hole 42 that removably holds the dual-purpose imaging section 12, and a second retaining hole 43 that removably holds the fluorescent filter unit 60 including the fluorescent filter 13.

[0059] The second retaining hole 43 is formed to open upward in the lower case 40, and is formed in a rectangular shape that is longer in the left-right direction L2 than in the front-rear direction L1 when viewed from above. Furthermore, the second retaining hole 43 is disposed inside the protruding portion 41 when viewed from above. A measurement hole 44 penetrating the lower case 40 in the front-rear direction L1 is formed in a portion of the lower case 40 that is located forward FW from the second retaining hole 43. The measurement hole 44 is disposed in the center of the front surface 40a of the lower case 40 in the left-right direction L2, and is formed in a rectangular shape when viewed from the front FW and is formed to open upward. As a result, the interior of the second retaining hole 43 is widely open toward the front FW through the measurement hole 44.

[0060] The first retaining hole 42 is formed in a portion of the lower case 40 that is located rearward BK from the second retaining hole 43, and is formed to penetrate the lower case 40 in the front-rear direction L1. The first retaining hole 42 is formed to be located in the center of the lower case 40 in the left-right direction L2. As a result, the inside of the second retaining hole 43 opens toward the rear BK through the first retaining hole 42.

[0061] 1 and 5, an auxiliary accommodating chamber 45 that opens downward is formed in a portion of the lower case 40 that is located rearward BK from the second retaining hole 43. The auxiliary accommodating chamber 45 is formed in a rectangular shape that is longer in the left-right direction L2 than in the front-rear direction L1 when viewed from below. The interior of the auxiliary accommodating chamber 45 communicates with the second retaining hole 43 through the first retaining hole 42.

[0062] 4 to 6, 8 and 9, a lower set surface (set surface according to the present invention) 46 that comes into close contact with the outer surface of the culture vessel 2 is formed on the front surface 40a of the lower case 40. As a result, the second holding hole 43 is disposed between the first holding hole 42 and the lower set surface 46.

[0063] The lower set surface 46 has a first lower set surface 46a formed so as to be three-dimensionally recessed toward the rear BK in correspondence with the shape of the conical side wall portion 4 of the culture vessel 2, and a second lower set surface 46b formed so as to be three-dimensionally recessed toward the rear BK in correspondence with the shape of the curved surface portion 5 of the culture vessel 2. The lower set surfaces 46 (the first lower set surface 46a and the second lower set surface 46b) are arranged in the left-right direction L2 with the measurement hole 44 therebetween. This allows the side wall portion 4 and the outer surface of the curved portion 5 of the culture vessel 2 to be in intimate contact with the lower set surface 46 .

[0064] Since the storage case 14 (upper case 20 and lower case 40) is constructed as described above, it is possible to set the culture vessel 2 with the outer surface of the culture vessel 2 in close contact with the upper set surface 21 and the lower set surface 46, as shown in Figures 1 and 2. The position of the culture vessel 2 when the culture vessel 2 is in close contact with the upper set surface 21 and the lower set surface 46 is referred to as a measurement position P2.

[0065] (Light irradiation part) 1, the light irradiating unit 10 irradiates excitation light EL toward the interface between the inner surface of the culture vessel 2 and the culture solution W. For example, an LED light source can be used as the light irradiating unit 10. However, the light irradiating unit 10 is not limited to an LED light source, and other light sources may be used as long as they can irradiate light including the wavelength range of the excitation light EL.

[0066] The light irradiation unit 10 is disposed so as to irradiate the excitation light EL obliquely downward and at an acute incident angle θ1 with respect to the inner surface of the conical side wall portion 4 of the culture vessel 2. Specifically, the light irradiation unit 10 is accommodated in the upper accommodation chamber 22 of the upper case 20 while being held by a holding member 30. In particular, the light irradiating unit 10 is held by the holding member 30 so as to be able to irradiate excitation light EL toward the culture vessel 2 set at the measurement position P2 so as to be in contact with the upper set surface 21 and the lower set surface 46. The excitation light EL irradiated from the light irradiating unit 10 is irradiated to the culture vessel 2 through the measurement hole 44 of the lower case 40.

[0067] (Excitation filter) As shown in FIG. 1, the excitation filter 11 is held by a holding member 30 so as to be located between the light irradiation unit 10 and the culture vessel 2. The excitation filter 11 allows the transmission of light in a specific wavelength range used as the excitation light EL from the light irradiated by the light irradiating unit 10. As the excitation filter 11, for example, a known optical filter (bandpass filter) having a dielectric multilayer film and capable of wavelength separation can be suitably adopted. In particular, the excitation filter 11 allows the transmission of light in a wavelength range different from the wavelength range that the fluorescence filter 13 allows to pass.

[0068] In the illustrated example, the excitation filter 11 is a framed filter having an excitation filter body 11a having a dielectric multilayer film or the like and a ring-shaped frame portion 11b surrounding the entire circumference of the excitation filter body 11a. The excitation filter body 11a is formed to have a diameter at least larger than that of the light irradiation unit 10. The excitation filter 11 is held by a holding member 30 in a replaceable manner.

[0069] (holding member) As shown in FIGS. 1, 7 and 10, the holding member 30 holds the light irradiation unit 10 and the excitation filter 11 in a state in which the holding member 30 is disposed in the upper storage chamber 22 of the upper case 20. The holding member 30 is made of, for example, synthetic resin and formed in a block shape. The holding member 30 is disposed in the upper storage chamber 22 such that the front wall surface 30a faces diagonally downward in the forward direction FW, with the side wall surface 30b facing in the left-right direction L2 being in contact with the inner wall surface of the upper storage chamber 22.

[0070] In particular, the holding member 30 is held in the upper case 20 by using fixing screws 31, and is held so as to be displaceable relative to the upper case 20. As shown in Figures 11 and 12, a side wall surface 30b of the holding member 30 is formed with screw holes 32 through which two fixing screws 31 are respectively inserted. Furthermore, a rear wall surface 30c of the holding member 30 is formed with a nut storage hole 33 in which a nut (not shown) is stored. This makes it possible to hold the retaining member 30 within the upper storage chamber 22 by inserting the fixing screw 31 into the screw hole 32 from the outside of the upper case 20 in the left-right direction L2 and screwing it into the nut, as shown in Figures 7 and 10.

[0071] 3, screw insertion holes 34 are formed in the side surface of the upper case 20, penetrating the upper case 20 in the left-right direction L2. The screw insertion holes 34 are formed large enough to allow the two fixing screws 31 to be inserted therethrough while being displaceable in the up-down direction and the front-rear direction L1. The fixing screw 31 is screwed into the screw hole 32 via a blind cover 35 arranged on the side of the upper case 20 so as to cover the screw insertion hole 34. This makes it possible to change the attitude of the holding member 30 by displacing the holding member 30 relatively to the upper case 20 by loosening the fastening of the fixing screw 31. Specifically, it is possible to change the angle of the optical axis OA of the excitation light EL irradiated by the light irradiation unit 10 by finely adjusting the angle at which the front wall surface 30a of the holding member 30 faces diagonally downward and forward.

[0072] 1, 7, and 10 to 12, a filter holding hole 36 that removably holds the excitation filter 11 is formed in the upper wall surface 30d of the holding member 30. The filter holding hole 36 is formed in a size that allows the entire excitation filter 11, including the frame portion 11b, to be removably inserted from above. The excitation filter 11 is held inside the filter holding hole 36 by being fitted into the filter holding hole 36.

[0073] Furthermore, a filter hole 37 is formed in the front wall surface 30a of the holding member 30, penetrating the front wall surface 30a in the thickness direction and communicating with the inside of the filter holding hole 36. The filter hole 37 is formed in a circular shape in a plan view with a diameter smaller than that of the frame portion 11b. As a result, the excitation filter 11 held in the filter holding hole 36 has the excitation filter body 11a exposed to the outside through the filter hole 37.

[0074] Furthermore, a light source holding hole 38 is formed in the rear wall surface 30c of the holding member 30, penetrating the rear wall surface 30c in the thickness direction and communicating with the inside of the filter holding hole 36. The light source holding hole 38 is formed in a circular shape in a plan view, with a diameter larger than that of the excitation filter main body 11a and smaller than that of the case of the light irradiation unit 10. 1 and 10, the light irradiating unit 10 is held by the holding member 30 by fitting a tip portion into the light source holding hole 38. This makes it possible to arrange the light irradiating unit 10 and the excitation filter 11 on the optical axis OA of the light irradiating unit 10 by using the holding member 30. Therefore, the excitation light EL emitted from the light irradiating unit 10 and transmitted through the excitation filter 11 can be irradiated toward the culture container 2.

[0075] The light irradiation unit 10 is combined with a heat dissipation member 39 including a plurality of heat dissipation fins. The heat dissipation member 39 is housed in the upper housing chamber 22 together with the light irradiation unit 10. This allows the heat generated by the light irradiation unit 10 to be dissipated into the upper housing chamber 22 via the heat dissipation member 39. The heat in the upper housing chamber 22 is dissipated to the outside through the measurement hole 44 of the lower case 40.

[0076] (Combined imaging unit) As shown in Figure 1, the dual-purpose imaging unit 12 has the function of capturing an image of scattered light that is generated when excitation light EL irradiated from the light irradiation unit 10 is reflected at the interface between the inner surface of the culture vessel 2 and the culture solution W, and acquiring it as a scattered light image 16 (see Figure 15), and the function of capturing an image of the fluorescence emitted by the expressed target substance due to irradiation with excitation light EL, and acquiring it as a fluorescence image 17 (see Figure 15). Therefore, the dual-purpose imaging section 12 serves both as a first imaging section for acquiring a scattered light image 16 and as a second imaging section for acquiring a fluorescent image 17, and is capable of acquiring both the scattered light image 16 and the fluorescent image 17.

[0077] The dual-purpose imaging section 12 includes, for example, a soft (flexible) or hard tubular imaging guide 50 and an imaging unit 51 provided at the tip of the imaging guide 50. At least an objective lens (not shown) and an imaging element (not shown) that captures an image through the objective lens are included inside the imaging unit 51. As the imaging element, for example, a CMOS sensor or a CCD sensor can be adopted.

[0078] The dual-purpose imaging section 12 is held in the lower case 40 by being inserted into a first holding hole 42 formed in the lower case 40. The dual-purpose imaging section 12 is held in the first holding hole 42 with the imaging unit 51 facing the second holding hole 43. The base end of the imaging guide 50 is pulled out to the outside of the lower case 40. Inside the imaging guide 50, a wiring cable (power line, signal line) (not shown) is arranged which is electrically connected to the imaging element, and outputs the two captured images (scattered light image 16 and fluorescent image 17) to the control unit 15 which controls the measuring device 1.

[0079] (fluorescence filter) As shown in FIG. 1, the fluorescent filter 13 is held by the lower case 40 so as to be located between the combined image capturing section 12 and the culture vessel 2. The fluorescence filter 13 transmits light in a wavelength range including the wavelength of the fluorescence emitted by the target substance, and restricts the transmission of light in at least the wavelength range of the excitation light EL. As the fluorescence filter 13, for example, a known optical filter (bandpass filter) having a dielectric multilayer film and capable of wavelength separation can be suitably used. In the illustrated example, the fluorescence filter 13 is a framed filter having a fluorescence filter body 13a having a dielectric multilayer film or the like, and a ring-shaped frame portion 13b surrounding the entire periphery of the fluorescence filter body 13a.

[0080] (Fluorescence filter unit) As shown in FIGS. 8, 13, and 14, the fluorescent filter 13 is removably fitted into the second holding hole 43 of the lower case 40 as a fluorescent filter unit 60. The fluorescent filter unit 60 includes a fluorescent filter 13, a filter case 70, and a pressing plate 80. The filter case 70 is made of, for example, synthetic resin, and formed into a block shape. The filter case 70 has a constant thickness in the front-rear direction L1, and is formed into a rectangular block shape that is longer in the left-right direction L2 than in the up-down direction.

[0081] A first recess 71 and a second recess 72 recessed toward the rear BK are formed in the front wall surface 70a of the filter case 70. The first recess 71 and the second recess 72 are formed in a circular shape when viewed from the front FW, and are arranged to line up in the left-right direction L2. In this case, the first recess 71 and the second recess 72 are arranged to line up evenly in the left-right direction L2 with respect to the center of the filter case 70 in the left-right direction L2.

[0082] The diameter of the first recess 71 is slightly larger than the diameter of the frame portion 13b of the fluorescent filter 13. The diameter of the second recess 72 is the same as the diameter of the first recess 71. The depth of the first recess 71 is equal to the thickness of the fluorescent filter 13. In contrast, the depth of the second recess 72 is formed to be deeper than the first recess 71. This makes it possible to fit the fluorescent filter 13 into the first recess 71 from the front FW.

[0083] Furthermore, the filter case 70 is formed with a first through hole 73 and a second through hole 74 that penetrate the filter case 70 in the front-rear direction L1. The first through-hole 73 is formed in a circular shape when viewed from the front FW, and is formed coaxially with the first recess 71. The diameter of the first through-hole 73 is formed smaller than the diameter of the first recess 71. As a result, an annular first step wall 75 facing the front FW is formed at the connection between the first recess 71 and the first through-hole 73. Therefore, when the fluorescent filter 13 is fitted into the first recess 71, the fluorescent filter 13 can be positioned by bringing the frame portion 13b into contact with the first step wall 75.

[0084] Similarly, the second through hole 74 is formed in a circular shape when viewed from the front FW, and is formed coaxially with the second recess 72. The diameter of the second through hole 74 is formed smaller than the diameter of the second recess 72. As a result, an annular second step wall 76 facing the front FW is formed at the connection portion between the second recess 72 and the second through hole 74.

[0085] The second recess 72 is used to incorporate an auxiliary optical filter for transmitting or blocking light in a specific wavelength range as necessary when acquiring the scattered light image 16. Therefore, the second recess 72 and the second through-hole 74 are not essential and may not be provided.

[0086] The pressing plate 80 is assembled to the filter case 70 from the front FW in order to press the fluorescent filter 13 fitted in the first recess 71. Therefore, the pressing plate 80 prevents the fluorescent filter 13 from falling off from the first recess 71. The pressing plate 80 has a constant thickness in the front-rear direction L1, and is formed to have an outer size equivalent to that of the filter case 70. The pressing plate 80 is formed with a first imaging hole 81 and a second imaging hole 82 that penetrate the pressing plate 80 in the front-rear direction L1.

[0087] The first imaging hole 81 is formed in a circular shape when viewed from the front FW, and is formed coaxially with the first recess 71 and the first through-hole 73. The diameter of the first imaging hole 81 is formed to be smaller than the diameter of the first recess 71. This prevents the fluorescent filter 13 from falling off from the first recess 71. Similarly, the second imaging hole 82 is formed in a circular shape when viewed from the front FW, and is formed coaxially with the second recess 72 and the second through-hole 74. The diameter of the second imaging hole 82 is smaller than the diameter of the second recess 72, and is formed to be the same diameter as the first imaging hole 81.

[0088] Furthermore, the pressing plate 80 is formed with a fitting protrusion 83 that protrudes toward the rear BK and extends continuously along the periphery of the second imaging hole 82. The fitting protrusion 83 is adapted to be able to fit into the inside of the second recess 72. By fitting the fitting protrusion 83 into the second recess 72, the pressing plate 80 can be combined integrally with the filter case 70 without being misaligned.

[0089] 1 and 8, the entire fluorescent filter unit 60 configured as described above can be fitted into the second holding hole 43 formed in the lower case 40. In this way, the fluorescent filter 13 is disposed between the combined image capturing section 12 and the culture vessel 2. 1, the dual-purpose imaging unit 12 held in the first holding hole 42 is disposed so that the imaging axis IA is aligned along the front-rear direction L1 and so that the imaging axis IA intersects with the interface irradiated with the excitation light EL. Therefore, the dual-purpose imaging unit 12 is disposed so that the imaging axis IA is non-coaxial with the optical axis OA of the excitation light EL reflected at a reflection angle θ2 corresponding to the incidence angle θ1.

[0090] 6, the dual-purpose imaging section 12 is disposed so that the imaging axis IA passes through, in the front-rear direction L1, a central portion in the left-right direction L2 between a first imaging hole 81 and a second imaging hole 82 formed in a pressing plate 80 that constitutes the fluorescence filter unit 60. As a result, when the fluorescence filter unit 60 is viewed from the front FW, the imaging units 51 of the dual-purpose imaging section 12 are disposed so as to fit inside the first imaging hole 81 and the second imaging hole 82, respectively.

[0091] 15, the dual-purpose imaging section 12 is capable of acquiring a fluorescent image 17 through the fluorescent filter 13 and the first imaging hole 81, and is also capable of acquiring a scattered light image 16 through the second imaging hole 82. Therefore, it is possible to acquire both the scattered light image 16 and the fluorescent image 17 using one dual-purpose imaging section 12. Furthermore, the fluorescent image 17 and the scattered light image 16 can be included in one captured image 18 captured by the dual-purpose imaging section 12. As shown in FIG. 1, the dual-purpose imaging section 12 is positioned so that the imaging axis IA intersects with the interface where the excitation light EL is irradiated. Therefore, the optical center LO of the excitation light EL irradiated to the interface can be positioned at the center of the captured image 18 as shown in FIG. 15.

[0092] In particular, the fluorescence filter 13 is disposed so that the center of the fluorescence filter body 13a is shifted in the left-right direction L2 with respect to the imaging axis IA, as shown in Fig. 6. In addition, the fluorescence filter 13 is disposed so that the frame portion 13b is located on the imaging axis IA. This causes part of the frame portion 13b to be intentionally reflected in the captured image 18, as shown in Fig. 15. In this way, the fluorescence filter 13 uses the frame portion 13b to block strong reflected light from the optical center LO from entering the captured image 18.

[0093] (Control unit) 1, the control unit 15, which comprehensively controls the measurement device 1 and the shaking device 151, is connected to the light irradiating unit 10 and the dual-purpose image capturing unit 12 and controls their operations. For example, the control unit 15 controls the irradiation timing, irradiation time, etc. of the light irradiating unit 10, and also controls the image capturing timing, etc. of the dual-purpose image capturing unit 12. Furthermore, the control unit 15 includes at least a memory unit (a storage unit according to the present invention) 90 that stores the scattered light image 16 and the fluorescent image 17 captured by the dual-purpose imaging unit 12, and a measurement unit 91 that measures the turbidity of the culture solution W and the fluorescent intensity of the target substance based on the scattered light image 16 and the fluorescent image 17.

[0094] In this embodiment, one captured image 18 includes the scattered light image 16 and the fluorescent light image 17, and therefore the memory unit 90 stores the scattered light image 16 and the fluorescent light image 17 in association with each other. As shown in Figure 15, the measurement unit 91 sets the area of ​​the scattered light image 16 and the fluorescent image 17 contained in the captured image 18 that is located at the same distance from the optical center LO as the data acquisition area R, extracts a partial image of the scattered light image 16 and a partial image of the fluorescent image 17 within the data acquisition area R, and measures the turbidity of the culture solution W and the fluorescence intensity of the target substance from each of these partial images.

[0095] Furthermore, the control unit 15 feedback-controls the shaking mechanism 153 so as to change the shaking conditions of the shaking table 152 based on the turbidity of the culture solution W and the fluorescence intensity of the target substance measured by the measurement unit 91 .

[0096] (Functions of the measuring device and the culture system) Next, a case will be described in which the turbidity of the culture solution W and the fluorescence intensity of the expressed target substance are measured using the measurement device 1 and the culture system 150 configured as described above. The description will also cover the culture of E. coli and the expression of the target substance.

[0097] First, E. coli containing an expression vector is placed in the culture solution W contained in the culture vessel 2. Next, at the culture position P1 shown in FIG. 2, culture is performed using a shaking device 151. Specifically, while maintaining a predetermined culture temperature (e.g., 37°C), the shaking mechanism 153 shakes the shaking table 152 in a predetermined shaking pattern. This makes it possible to agitate and stimulate the culture solution W, thereby culturing the E. coli. The turbidity of the culture solution W tends to increase as the culture of E. coli progresses.

[0098] For example, when the culture is performed by the shaking device 151 until certain conditions (for example, the time for shaking the culture vessel 2, the number of shakings, etc.) are satisfied, the shaking of the shaking table 152 and the culture vessel 2 is temporarily stopped. Next, the culture vessel 2 is moved from the culture position P1 using the shaking mechanism 153 and set at the measurement position P2 shown in Figures 1 and 2. This allows the outer surface of the culture vessel 2 to be in close contact with the upper set surface 21 of the upper case 20 and the lower set surface 46 of the lower case 40, and the relative positional relationship between the culture vessel 2, the light irradiation unit 10, and the combined imaging unit 12 can be set to an appropriate positional relationship.

[0099] Next, light is irradiated from the light irradiating unit 10. This allows the excitation light EL to be irradiated toward the culture vessel 2 through the excitation filter 11, and also allows the excitation light EL to be irradiated toward the interface between the inner surface of the culture vessel 2 and the culture solution W. As a result, a portion of the excitation light EL is reflected at the interface and becomes scattered light.

[0100] Therefore, using the dual-purpose image capture unit 12, an image of the scattered light reflected at the interface can be captured and obtained as the scattered light image 16 shown in Fig. 15. At this time, a fluorescent image 17 is also captured by the dual-purpose image capture unit 12, but since the target substance has not yet been expressed at this stage, this differs from the fluorescent image 17 that should be obtained. The captured image 18 acquired by the dual-purpose image capturing section 12 is output to the control section 15 and stored in the memory section 90. Furthermore, the measurement section 91 measures the turbidity of the culture solution W based on the acquired scattered light image 16. Specifically, the measurement section 91 measures the turbidity based on the light intensity including the brightness and luminance of the scattered light image 16, or on changes in the color information of the RGB colors of the scattered light image 16, etc.

[0101] As a result, the culture state of E. coli can be grasped based on the measured turbidity, and it can be determined (estimated) whether or not a certain amount of E. coli has been cultured. Therefore, after confirming that E. coli has been cultured appropriately, it is possible to cause expression of the target substance by cold shock expression or the like.

[0102] On the other hand, when it is determined from the turbidity measurement results that the E. coli culture is insufficient, the control unit 15 performs feedback control to continue the E. coli culture. In this case, the control unit 15 uses the shaking mechanism 153 to move the culture vessel 2 from the measurement position P2 and set it at the culture position P1 shown in Fig. 2. Furthermore, the control unit 15 feedback controls the shaking mechanism 153 so as to change the shaking conditions of the shaking table 152. This allows the shaking mechanism 153 to resume shaking of the shaking table 152 and the culture vessel 2 under conditions different from the previous shaking conditions. In particular, since different shaking conditions are used, it is possible to promote culture while providing a different stimulus to the culture solution W.

[0103] After shaking is performed again, the turbidity of the culture solution W is measured again by the measuring device 1 at the measurement position P2. In this manner, the cultivation and the measurement of the turbidity are repeated until the E. coli is cultivated appropriately. Therefore, the cultivation can be performed efficiently. If it is determined that the E. coli is cultivated sufficiently as a result of these operations, a step of expressing the target substance by cold shock expression is performed.

[0104] In this case, the culture vessel 2 is maintained under a constant low temperature condition (about 15°C), and a reagent such as IPTG is added to the culture vessel 2. By adding this reagent, it is possible to release the control of the lactose operon contained in the expression vector, and to express a specific promoter whose expression is induced when the temperature condition becomes low. On the other hand, it is possible to suppress the expression of proteins contained in the E. coli itself. As a result, the target substance can be expressed efficiently and with high purity.

[0105] Next, after the target substance is expressed, the culture vessel 2 is set again at the measurement position P2 shown in Figures 1 and 2. Furthermore, excitation light EL is irradiated from the light irradiation unit 10 toward the interface between the inner surface of the culture vessel 2 and the culture solution W. This causes the expressed target substance to emit fluorescence due to the irradiation of the excitation light EL. Specifically, the target substance absorbs the light energy of the excitation light EL and transitions to an excited state, and then transitions to the ground state while emitting fluorescence.

[0106] Therefore, the dual-purpose image capture unit 12 can be used to capture an image of the fluorescence emitted by the target substance, and acquired as a fluorescence image 17 shown in Fig. 15. The fluorescence image 17 acquired by the dual-purpose image capture unit 12 is output to the control unit 15 and stored in the memory unit 90. Furthermore, the measurement unit 91 measures the fluorescence intensity of the target substance based on the acquired fluorescence image 17. Specifically, the measurement unit 91 measures the fluorescence intensity based on the light intensity including the brightness and luminance of the fluorescence image 17, or on changes in the color information of the RGB colors of the fluorescence image 17.

[0107] In particular, since the fluorescence filter 13 is disposed between the dual-purpose image capture unit 12 and the culture vessel 2, it is possible to block at least the light in the wavelength range of the excitation light EL reflected by the culture vessel 2, and to prevent the excitation light EL from reaching the dual-purpose image capture unit 12. This makes it possible to remove noise and the like caused by the excitation light EL from the acquired fluorescence image 17, and to acquire a highly accurate fluorescence image 17. Therefore, the measurement unit 91 can measure the fluorescence intensity of the target substance based on the fluorescence image 17, and it is possible to know whether or not a certain amount of the target substance has been obtained.

[0108] When capturing a fluorescent image 17 by the dual-purpose image capturing section 12, it is possible to capture a scattered light image 16 as well, as shown in Fig. 15, so that a single captured image 18 can include the scattered light image 16 and the fluorescent image 17. Therefore, the memory section 90 can store the scattered light image 16 and the fluorescent image 17 in association with each other.

[0109] Furthermore, if the measurement results of the fluorescence intensity indicate that the expression of the target substance is insufficient, the control unit 15 feedback controls the shaking mechanism 153 to resume shaking of the culture vessel 2 in order to further promote the expression. In this case, the control unit 15 uses the shaking mechanism 153 to move the culture vessel 2 from the measurement position P2 and set it at the culture position P1 shown in FIG. 2. Furthermore, the control unit 15 feedback controls the shaking mechanism 153 so as to change the shaking conditions of the shaking table 152. This makes it possible to resume shaking of the culture vessel 2 under conditions different from the previous shaking conditions. In particular, since the shaking conditions are different, it is possible to provide a different stimulus to the culture solution W. This makes it possible to promote the expression of the target substance.

[0110] After shaking again, the fluorescence intensity of the target substance is measured again by the measuring device 1 at the measurement position P2. In this manner, shaking of the culture solution W and measurement of the fluorescence intensity are repeated until the expressed target substance is appropriately obtained. Therefore, a constant amount of the target substance can be obtained efficiently.

[0111] As a result, the turbidity of the culture solution W can be measured at the required timing, and further, the fluorescence intensity of the target substance can be measured continuously in a series of steps. In particular, unlike the conventional light transmission type, the turbidity of the culture solution W can be measured based on scattered light reflected at the interface between the inner surface of the culture vessel 2 and the culture solution W, and is therefore less susceptible to influences such as the concentration of the culture solution W and bubbling on the liquid surface of the culture solution W. Therefore, the turbidity of the culture solution W can be measured stably and accurately, making it easy to accurately grasp the culture state of the culture solution W containing the target substance. Furthermore, since the fluorescence intensity of the target substance can be measured without removing the culture solution W from the culture container 2, contamination of the culture solution W can be prevented, and the fluorescence intensity can be measured with high accuracy.

[0112] Therefore, according to the measuring device 1 of this embodiment, it is possible to continuously measure the fluorescence intensity of the target substance while measuring the turbidity of the culture solution W in a single flow, and the turbidity measurements and fluorescence intensity measurements can be performed stably and accurately.

[0113] Furthermore, according to the measuring device 1 of this embodiment, the scattered light image 16 and the fluorescent image 17 are each captured using one combined image capturing section 12, so there is no need to use two image capturing sections. This makes it possible to simplify the configuration and reduce the cost of parts. Furthermore, since the scattered light image 16 and the fluorescent image 17 can be simultaneously included in one captured image 18 captured by the combined image capturing section 12, it is possible to grasp, for example, the relationship (correlation) between turbidity and fluorescent intensity.

[0114] Furthermore, as shown in Figure 15, since the optical center LO of the excitation light EL is located at the center of the captured image 18, the scattered light image 16 and the fluorescent image 17 can be included evenly and in a balanced manner in a single captured image 18 captured by the dual-purpose imaging unit 12. Moreover, frame 13b of fluorescence filter 13 can be used to block the reflected light (excitation light EL) itself from the optical center LO from directly penetrating into captured image 18. This makes it possible to prevent strong light from penetrating into captured image 18, and to prevent problems such as whiteout in scattered light image 16 and fluorescent image 17. This makes it possible to obtain scattered light image 16 and fluorescent image 17 in which, for example, changes in RGB color information, changes in brightness such as gradations, changes in luminance, etc., are clearly shown, allowing turbidity and fluorescent intensity measurements to be performed with high accuracy.

[0115] Furthermore, since the measurement unit 91 extracts partial images within the data acquisition region R that are located the same distance from the optical center LO to acquire them as the scattered light image 16 and the fluorescent image 17, both images can be acquired under conditions of equivalent light intensity. Therefore, it is possible to perform measurements of turbidity and fluorescent intensity based on the scattered light image 16 and the fluorescent image 17 acquired under equivalent conditions. 1, the dual-purpose image capture unit 12 is disposed such that the image capture axis IA is non-coaxial with the optical axis OA of the excitation light EL reflected at a reflection angle θ2 corresponding to the incident angle θ1. This makes it possible to prevent the excitation light EL reflected at the interface from directly entering the captured image 18 shown in FIG. 15, so that a clear and distinct scattered light image 16 and fluorescent image 17 can be acquired.

[0116] Furthermore, since the scattered light image 16 and the fluorescent image 17 can be stored in association with each other in the memory unit 90, it is possible to grasp information such as the correlation between the turbidity state and the expression state of the target substance. Therefore, by accumulating this information, it is possible to estimate, for example, the degree of turbidity at which the target substance will be expressed. As a result, the operations from cultivation to expression of the target substance can be carried out efficiently.

[0117] Furthermore, since the excitation filter 11 is provided, excitation light EL in a wavelength range suitable for emission of fluorescence can be appropriately irradiated toward the culture vessel 2. In particular, since the wavelength range of the excitation filter 11 and the wavelength range of the fluorescence filter 13 can be made different, overlapping of the excitation spectrum and the fluorescence spectrum can be prevented, and a decrease in the contrast of the fluorescence image 17, etc. can be suppressed.

[0118] Furthermore, the light irradiation unit 10, excitation filter 11, dual-purpose imaging unit 12, fluorescence filter 13, etc. are incorporated into a single storage case 14 formed by combining the upper case 20 and the lower case 40, making it possible to make the device more compact and improving handleability. In particular, the culture vessel 2, the light irradiation unit 10, and the combined image capture unit 12 can be set to an appropriate relative positional relationship by a simple method of simply setting the culture vessel 2 so that the outer surface of the culture vessel 2 contacts the upper set surface 21 of the upper case 20 and the lower set surface 46 of the lower case 40. Therefore, without performing any special positional adjustment or the like, the excitation light EL can be accurately irradiated toward the interface between the inner surface of the culture vessel 2 and the culture solution W, and the scattered light image 16 and the fluorescent image 17 can be acquired by using the combined image capture unit 12.

[0119] Furthermore, by loosening the fixing screws 31, the holding member 30 can be displaced with respect to the upper case 20, so that the irradiation angle of the light irradiating unit 10 with respect to the culture vessel 2 can be finely adjusted with ease.

[0120] Furthermore, the first holding hole 42 and the second holding hole 43 can be used to easily attach, detach, or replace the dual-purpose imaging section 12 and the fluorescent filter 13 to the lower case 40. In particular, the optimal dual-purpose imaging section 12, fluorescent filter 13, etc. can be selected and used depending on the type of target substance and culture solution W, culture conditions, application, etc. Furthermore, since the fluorescent filter 13 can also be replaced using the filter holding hole 36, an optimal fluorescent filter 13 can be selected and used.

[0121] (Modification of the first embodiment) 16, for example, a condenser lens 100 that condenses the excitation light EL may be disposed between the light irradiation unit 10 and the culture vessel 2. In the illustrated example, the condenser lens 100 is provided on the holding member 30 so as to be disposed on the optical axis OA of the excitation light EL between the excitation filter 11 and the culture vessel 2. In this case, the focusing lens 100 can be used to focus the excitation light EL irradiated from the light irradiation unit 10 at the interface between the inner surface of the culture vessel 2 and the culture solution W, making it possible to obtain even clearer scattered light image 16 and fluorescent image 17.

[0122] Second embodiment Next, a second embodiment of the measuring device according to the present invention will be described with reference to the drawings. In the second embodiment, the same components as those in the first embodiment are denoted by the same reference numerals, and the description thereof will be omitted.

[0123] In the first embodiment, a single dual-purpose imaging unit 12 was used to acquire a scattered light image 16 and a fluorescent image 17, whereas in this embodiment, a first imaging unit is used to acquire a scattered light image 16, and a second imaging unit is used to acquire a fluorescent image 17.

[0124] 17, the measurement device 110 of this embodiment includes two storage cases. Specifically, the measurement device 110 includes a first storage case 120 and a second storage case 130 that are configured similarly to the storage case 14 of the first embodiment. Each of the first storage case 120 and the second storage case 130 includes a light irradiator 10 and an excitation filter 11 held by a holding member 30. Therefore, the measurement device 110 includes two light irradiators 10, and is capable of irradiating excitation light EL from each light irradiator 10 toward the interface between the inner surface of the culture container 2 and the culture solution W.

[0125] In place of the dual-purpose image capturing section 12, a first image capturing section 121 that captures a scattered light image 16 is held via a first holding hole 42 in the lower case 40 that constitutes the first storage case 120. The first image capturing section 121 captures the scattered light image 16 only through the second image capturing hole 82 of the pressing plate 80 that constitutes the fluorescent filter unit 60 held in the second holding hole 43 of the lower case 40.

[0126] In contrast, in the lower case 40 constituting the second storage case 130, a second imaging section 131 that acquires a fluorescent image 17 is held via the first holding hole 42, instead of the combined imaging section 12. The second imaging section 131 acquires the fluorescent image 17 only through the fluorescent filter 13 of the fluorescent filter unit 60 held in the second holding hole 43 of the lower case 40 and the first imaging hole 81.

[0127] Even with the measuring device 110 configured in this manner, it is possible to obtain a scattered light image 16 by utilizing the first imaging section 121, and to obtain a fluorescent image 17 by utilizing the second imaging section 131. Therefore, it is possible to achieve the same effects as those of the measuring device 1 of the first embodiment.

[0128] In the second embodiment, it is also possible to configure the system to include one light irradiation unit 10, a first imaging unit 121, and a second imaging unit 131, and to acquire a scattered light image 16 due to excitation light EL irradiated from a common light irradiation unit 10 by the first imaging unit 121, and to acquire a fluorescent image 17 due to the excitation light EL by the second imaging unit 131.

[0129] Although the embodiments of the present invention have been described above, these embodiments are presented as examples and are not intended to limit the scope of the invention. The embodiments can be implemented in various other forms, and various omissions, substitutions, and modifications can be made without departing from the gist of the invention. The embodiments and their modifications include, for example, those that can be easily imagined by a person skilled in the art, those that are substantially the same, those that are within the scope of the equivalents, and the like.

[0130] For example, in each of the above embodiments, if the fluorescence intensity of the target substance is confirmed based on the fluorescence image 17 and sufficient fluorescence intensity cannot be ascertained, the E. coli may not have been cultured sufficiently. In this case, the E. coli may be cultured again, and the same procedure may be repeated to obtain the scattered light image 16 and the fluorescence image 17. In particular, since the fluorescence intensity can be measured without removing the culture solution W from the culture vessel 2, it is also possible to perform feedback control such that such culture is repeated as necessary.

[0131] Furthermore, in the above embodiment, the expression vector does not need to contain a specific promoter such as the lactose operon. In this case, when the culture temperature of E. coli is lowered (about 15°C), the target substance can be expressed without adding any reagent. Furthermore, in the above embodiment, an example has been described in which an expression vector whose expression is induced depending on temperature is used to express a target substance by the method of E. coli cold shock expression system, but the present invention is not limited to this case. Any other expression vector can be used as long as it can express the target substance.

[0132] Furthermore, the target substance is not limited to a specific one as long as it has at least the function of emitting fluorescence and is a target of fluorescent staining. For example, a protein, which is a typical target of fluorescent staining, can be used as the target substance. Furthermore, as a target substance other than a protein, for example, a biomolecule, such as a nucleic acid, a cation, chitin, cellulose, or an AT region, which is a target of fluorescent staining, can be used.

[0133] Furthermore, in each of the above embodiments, an Erlenmeyer flask is used as the culture vessel 2, but as described above, other shapes of flasks, test tubes, petri dishes, beakers, etc. may be used as the culture vessel 2. When the culture vessel is changed, the relative positional relationship of the light irradiation unit 10 and the dual-purpose imaging unit 12 (first imaging unit, second imaging unit) with respect to the culture vessel may be appropriately changed in accordance with the shape of the culture vessel. For example, when a cylindrical beaker is used as the culture vessel, the light irradiation unit and the dual-purpose imaging unit may be arranged so as to be horizontal to the peripheral wall surface of the beaker. In this way, the relative positions of the light irradiation section and the dual-purpose imaging section (first imaging section, second imaging section) may be changed as appropriate depending on the type, shape, application, and the like of the culture vessel.

[0134] The present invention further includes the following aspects. <1> At least one light irradiating unit is disposed outside a culture vessel that contains a culture solution for expressing a target product having at least a function of emitting fluorescence, and irradiates an excitation light toward an interface between an inner surface of the culture vessel and the culture solution; a first image capturing unit that is disposed outside the culture vessel and captures an image of scattered light resulting from the excitation light being reflected at the interface, and acquires the image as a scattered light image; a second image capturing unit that is disposed outside the culture vessel and captures an image of the fluorescence emitted by the expressed target substance due to irradiation with the excitation light, and acquires the image as a fluorescence image; a fluorescence filter disposed between the second imaging unit and the culture vessel, the fluorescence filter transmitting light in a wavelength range including the wavelength of the fluorescence and restricting transmission of light in at least the excitation light wavelength range; a measurement unit that measures the turbidity of the culture medium and the fluorescence intensity of the target substance based on the scattered light image and the fluorescent image. <2> <1> In the measuring device according to the present invention, The culture medium contains a host cell transformed with an expression vector that expresses the target product, The light irradiating unit irradiates the excitation light toward the interface between the inner surface of the culture vessel and the culture solution containing the host cells. <3> <1> or <2> In the measuring device according to the present invention, Only one light irradiation unit is provided, A single combined imaging unit serving as both the first imaging unit and the second imaging unit is provided outside the culture vessel, A measuring device, wherein the fluorescent filter is disposed between the dual-purpose imaging unit and the culture vessel so that the captured image of the dual-purpose imaging unit simultaneously includes two images, the scattered light image and the fluorescent image. <4> <3> In the measuring device according to the present invention, the dual-purpose image capture unit is disposed such that the optical center of the excitation light irradiated onto the interface is located at the center of the captured image; The measurement device, wherein the fluorescent filter is positioned to block reflected light from the optical center from entering the captured image of the dual-purpose imaging unit. <5> <4> In the measuring device according to the present invention, The measurement unit is a measuring device that sets, as a data acquisition area, an area of ​​the scattered light image and the fluorescent image contained in the captured image of the dual-purpose imaging unit that is located at the same distance from the optical center, extracts a partial image of the scattered light image and a partial image of the fluorescent image within the data acquisition area, and measures the turbidity of the culture solution and the fluorescence intensity of the target produced substance. <6> <3> from <5> In the measurement device according to any one of the above items, the light irradiation unit is disposed so as to irradiate the excitation light with an acute incident angle with respect to the inner surface of the culture vessel; The measurement device, wherein the dual-purpose imaging unit is disposed such that an imaging axis is non-coaxial with respect to an optical axis of the excitation light reflected at a reflection angle corresponding to the incidence angle. <7> <1> from <6> In the measurement device according to any one of the above items, a storage unit that stores the scattered light image captured by the first imaging unit and the fluorescent light image captured by the second imaging unit in association with each other. <8> <1> from <7> In the measurement device according to any one of the above items, A measuring device comprising an excitation filter disposed between the light irradiation unit and the culture vessel, the excitation filter allowing the transmission of light in a wavelength range different from the wavelength range allowed to be transmitted by the fluorescence filter. <9> <1> from <8> In the measurement device according to any one of the above items, A measuring device comprising a focusing lens disposed between the light irradiation unit and the culture vessel, the focusing lens focusing the excitation light onto the interface between the inner surface of the culture vessel and the culture solution. <10> <3> In the measuring device according to the present invention, A holding member for holding the light irradiation unit; A first case that accommodates the holding member therein; a second case that is combined with the first case and that holds the dual-purpose image capture unit and the fluorescent filter, The first case and the second case each have a set surface with which the outer surface of the culture vessel comes into close contact, The light irradiating unit is held by the holding member so as to be able to irradiate the excitation light toward the culture vessel set in contact with the set surface. <11> <10> In the measuring device according to the present invention, A measuring device, wherein the holding member is held displaceably relative to the first case. <12> <10> or <11> In the measuring device according to the present invention, The second case is provided with a first retaining hole that removably holds the dual-purpose imaging unit, and a second retaining hole that is formed between the first retaining hole and the set surface and that removably holds the fluorescent filter, a measuring device. <13> <1> from <12> In the measurement device according to any one of the above items, the light irradiation unit irradiates the excitation light toward the interface between the culture solution in which a protein is expressed as the target production substance and an inner surface of the culture vessel; the second imaging unit captures an image of fluorescence emitted by the expressed protein due to irradiation with the excitation light, and acquires the image as the fluorescence image; The measurement unit measures the turbidity of the culture medium and the fluorescence intensity of the protein based on the scattered light image and the fluorescent image. <14> <1> from <13> A measuring device according to any one of the above items, A shaking device having a shaking table having a mounting surface on which the culture vessel is mounted and a shaking mechanism for shaking the shaking table in a plane parallel to the mounting surface; A control unit that controls the measurement device and the shaking mechanism, the control unit controls the shaking mechanism so that the culture vessel moves between a culture position separated from the measurement device and a measurement position where measurement is performed by the measurement device, and controls the shaking mechanism so as to shake the shaking table at the culture position; The control unit further performs feedback control of the shaking mechanism so as to change the shaking conditions of the shaking table based on the turbidity of the culture solution and the fluorescence intensity of the target substance measured by the measurement unit. [Explanation of symbols]

[0135] R: Data acquisition area W…Culture solution θ1…Incidence angle θ2…reflection angle P1…Culture position P2…Measurement position EL…Excitation light OA: Optical axis of excitation light 1, 110...Measuring device 2…Culture container 10...Light irradiation unit 11…Excitation filter 12…Combined imaging section 13...Fluorescence filter 15...Control section 16…Scattered light image 17…Fluorescence image 18…Image 20…Upper case (first case) 21…Setting surface of upper case 30...Retaining member 40…Lower case (second case) 42...1st holding hole 43…Second holding hole 46…Lower case set surface 90...Memory section (storage section) 91...Measuring part 100...Condenser lens 121…First imaging unit 131…Second imaging unit 150…Culture system 151... Shaking device 152...Shaking table 152a...Shaking table mounting surface 153... Shaking mechanism

Claims

1. At least one light irradiating unit is disposed outside a culture vessel that contains a culture solution for expressing a target product having at least a function of emitting fluorescence, and irradiates an excitation light toward an interface between an inner surface of the culture vessel and the culture solution; a first image capturing unit that is disposed outside the culture vessel and captures an image of scattered light resulting from the excitation light being reflected at the interface and acquires the image as a scattered light image; a second image capturing unit that is disposed outside the culture vessel and captures an image of the fluorescence emitted by the expressed target substance due to irradiation with the excitation light, and acquires the image as a fluorescence image; a fluorescence filter disposed between the second imaging unit and the culture vessel, the fluorescence filter transmitting light in a wavelength range including a wavelength of the fluorescence and restricting transmission of light in at least a wavelength range of the excitation light; a measurement unit that measures the turbidity of the culture solution and the fluorescence intensity of the target substance based on the scattered light image and the fluorescent image, Only one light irradiation unit is provided, A dual-purpose imaging unit serving as both the first imaging unit and the second imaging unit is provided outside the culture vessel, A measuring device characterized in that the fluorescent filter is arranged between the dual-purpose imaging unit and the culture vessel so that the image captured by the dual-purpose imaging unit simultaneously includes two images, the scattered light image and the fluorescent image.

2. 2. The measuring device according to claim 1, The culture medium contains a host cell transformed with an expression vector that expresses the target product, The light irradiating unit irradiates the excitation light toward the interface between the inner surface of the culture vessel and the culture solution containing the host cells.

3. 2. The measuring device according to claim 1, the dual-purpose image capture unit is disposed such that the optical center of the excitation light irradiated onto the interface is located at the center of the captured image; The measurement device, wherein the fluorescent filter is positioned to block reflected light from the optical center from entering the captured image of the dual-purpose imaging unit.

4. 4. The measuring device according to claim 3, The measurement unit is a measuring device that sets, as a data acquisition area, an area of ​​the scattered light image and the fluorescent image contained in the captured image of the dual-purpose imaging unit that is located at the same distance from the optical center, extracts a partial image of the scattered light image and a partial image of the fluorescent image within the data acquisition area, and measures the turbidity of the culture solution and the fluorescence intensity of the target produced substance.

5. 2. The measuring device according to claim 1, the light irradiation unit is disposed so as to irradiate the excitation light with an acute incident angle with respect to the inner surface of the culture vessel; The measurement device, wherein the dual-purpose imaging unit is disposed such that an imaging axis is non-coaxial with respect to an optical axis of the excitation light reflected at a reflection angle corresponding to the incidence angle.

6. 2. The measuring device according to claim 1, A measuring device comprising an excitation filter disposed between the light irradiation unit and the culture vessel, the excitation filter allowing the transmission of light in a wavelength range different from the wavelength range allowed to be transmitted by the fluorescence filter.

7. 2. The measuring device according to claim 1, A measuring device comprising a focusing lens disposed between the light irradiation unit and the culture vessel, the focusing lens focusing the excitation light onto the interface between the inner surface of the culture vessel and the culture solution.

8. 2. The measuring device according to claim 1, A holding member for holding the light irradiation unit; a first case that accommodates the holding member therein; a second case that is combined with the first case and that holds the dual-purpose image capture unit and the fluorescent filter, The first case and the second case each have a set surface with which the outer surface of the culture vessel comes into close contact, The light irradiating unit is held by the holding member so as to be able to irradiate the excitation light toward the culture vessel set in contact with the set surface.

9. 9. The measuring device according to claim 8, A measuring device, wherein the holding member is held displaceably relative to the first case.

10. 9. The measuring device according to claim 8, A measuring device, wherein the second case is provided with a first retaining hole that removably holds the dual-purpose imaging unit, and a second retaining hole that is formed between the first retaining hole and the set surface and that removably holds the fluorescent filter.

11. A measuring device according to claim 1 ; A shaking device having a shaking table having a mounting surface on which the culture vessel is mounted and a shaking mechanism for shaking the shaking table in a plane parallel to the mounting surface; A control unit that controls the measurement device and the shaking mechanism, the control unit controls the shaking mechanism so that the culture vessel moves between a culture position separated from the measurement device and a measurement position where measurement is performed by the measurement device, and controls the shaking mechanism so as to shake the shaking table at the culture position; The culture system is further characterized in that the control unit feedback-controls the shaking mechanism so as to change the shaking conditions of the shaking table based on the turbidity of the culture solution and the fluorescence intensity of the target substance measured by the measurement unit.

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