Bioreactor, bioreactor system, and method for operating bioreactor

Abstract

To provide a bioreactor that enables cultivation according to cell growth phases within a compact design.SOLUTION: A bioreactor according to the present disclosure comprises: an outer cylinder which is centered on an axis line extending in a vertical direction; an inner cylinder which is provided inside the outer cylinder and centered on the axis line; a rotary cylinder which is disposed between the outer cylinder and the inner cylinder, defines a first pool between the inner cylinder and the rotary cylinder, defines a second pool between the outer cylinder and the rotary cylinder, and is rotatable about the axis line; a drive unit for rotationally driving the rotary cylinder around the axis line; a first supply port through which liquid may be supplied to the first pool; and a second supply port through which liquid may be supplied to the second pool.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present disclosure relates to bioreactors, bioreactor systems, and methods of operating bioreactors. [Background technology]

[0002] For example, Patent Document 1 discloses a bioreactor for culturing cells. This bioreactor has a double-cylinder structure with a rotating cylinder and an outer cylinder. A pool for containing a culture solution is partitioned and formed between the rotating cylinder and the outer cylinder. When the rotating cylinder rotates, Taylor vortices are formed in the culture solution contained in the pool. The Taylor vortices stir the culture solution, promoting cell culture. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Japanese Patent Application Publication No. 8-308560 Summary of the Invention [Problem to be solved by the invention]

[0004] Meanwhile, the environmental conditions suitable for the cells to be cultured change depending on the growth phase of the cells. In particular, it is preferable to change the components of the medium that serves as the cell growth environment according to the growth phase. However, when the bioreactor described in Patent Document 1 is used, it is necessary to install a plurality of different bioreactors according to the growth stage of the cells, which increases the installation space.

[0005] The present disclosure has been made to solve the above-mentioned problems, and aims to provide a bioreactor, a bioreactor system, and a method for operating a bioreactor that are capable of culturing cells according to their growth phase with a compact configuration. [Means for solving the problem]

[0006] In order to solve the above problems, the bioreactor of the present disclosure comprises an outer cylinder centered on an axis extending in a vertical direction, an inner cylinder centered on the axis inside the outer cylinder, a rotating cylinder disposed between the outer cylinder and the inner cylinder, defining a first pool between the outer cylinder and the inner cylinder and defining a second pool between the outer cylinder and the inner cylinder, and capable of rotating about the axis, a drive unit that drives the rotating cylinder to rotate about the axis, a first supply port capable of supplying liquid to the first pool, and a second supply port capable of supplying liquid to the second pool.

[0007] The bioreactor system according to the present disclosure comprises the above-mentioned bioreactor and a control device for controlling the bioreactor, wherein the bioreactor comprises a first culture medium supply unit capable of supplying a first culture medium as the liquid to the first pool via the first supply port, and a second culture medium supply unit capable of supplying the second culture medium, which has components different from the first culture medium as the liquid, to the second pool via the second supply port, and the control device has a culture medium supply control unit that executes a culture medium supply step of controlling the first culture medium supply unit to supply the first culture medium to the first pool, and controlling the second culture medium supply unit to supply the second culture medium to the second pool.

[0008] The method for operating a bioreactor according to the present disclosure is a method for operating a bioreactor comprising: an outer cylinder centered on an axis extending in a vertical direction; an inner cylinder centered on the axis inside the outer cylinder; a rotating cylinder disposed between the outer cylinder and the inner cylinder, defining a first pool between the outer cylinder and the inner cylinder and defining a second pool between the outer cylinder and the inner cylinder, and capable of rotating about the axis; and a drive unit that drives the rotating cylinder to rotate about the axis, the method including a culture medium supplying step of supplying a first culture medium to the first pool and supplying a second culture medium having components different from those of the first culture medium to the second pool. Effect of the Invention

[0009] According to the present disclosure, it is possible to carry out cell culture according to the growth phase with a compact configuration. [Brief description of the drawings]

[0010] [Figure 1] FIG. 1 is a schematic vertical cross-sectional view illustrating an overall configuration of a bioreactor system according to a first embodiment of the present disclosure. [Diagram 2] FIG. 2 is a cross-sectional view taken along line II-II of FIG. [Diagram 3] FIG. 2 is a functional block diagram of a control device of the bioreactor system according to the first embodiment of the present disclosure. [Figure 4] 1 is a flowchart showing a processing flow of a control device of a bioreactor system according to the first embodiment of the present disclosure. [Diagram 5] 1 is a flowchart illustrating the procedure of a culture process according to a first embodiment of the present disclosure. [Figure 6] 11 is a flowchart illustrating a procedure of a moving process according to the first embodiment of the present disclosure. [Figure 7] FIG. 11 is a schematic vertical cross-sectional view illustrating the overall configuration of a bioreactor system according to a second embodiment of the present disclosure. [Figure 8] FIG. 8 is a cross-sectional view taken along line VIII-VIII of FIG. 7. [Figure 9] FIG. 11 is a horizontal cross-sectional view of the rotating cylinder of the bioreactor system according to the second embodiment of the present disclosure, showing the state in which the rotating cylinder is driven in forward rotation. [Figure 10] FIG. 13 is a horizontal cross-sectional view of the rotating cylinder of the bioreactor system according to the second embodiment of the present disclosure, showing the state in which the rotating cylinder is driven in reverse rotation. [Figure 11] 13 is a flowchart illustrating a procedure of a moving process according to a second embodiment of the present disclosure. [Figure 12] FIG. 13 is a horizontal cross-sectional view of a rotating cylinder of a bioreactor system according to a modified example of the second embodiment of the present disclosure, illustrating a state in which the rotating cylinder is driven in forward rotation. [Figure 13]FIG. 13 is a horizontal cross-sectional view of a rotating cylinder of a bioreactor system according to a modified example of the second embodiment of the present disclosure, showing a state in which the rotating cylinder is driven in reverse rotation. [Figure 14] FIG. 11 is a schematic vertical cross-sectional view illustrating the overall configuration of a bioreactor system according to a third embodiment of the present disclosure. [Figure 15] FIG. 13 is a functional block diagram of a control device of a bioreactor system according to a third embodiment of the present disclosure. [Figure 16] 13 is a flowchart showing the processing flow of a control device of a bioreactor system according to a third embodiment of the present disclosure. [Figure 17] FIG. 11 is a schematic vertical cross-sectional view illustrating the overall configuration of a bioreactor system according to a fourth embodiment of the present disclosure. [Figure 18] FIG. 13 is an enlarged view of a main part illustrating the configuration of a seal part of a bioreactor system according to a fifth embodiment of the present disclosure. [Figure 19] FIG. 13 is an enlarged view of a main part illustrating the configuration of a seal portion of a bioreactor system according to a first modified example of the fifth embodiment of the present disclosure. [Figure 20] FIG. 13 is an enlarged view of a main part illustrating the configuration of a seal portion of a bioreactor system according to a second modified example of the fifth embodiment of the present disclosure. [Figure 21] FIG. 13 is an enlarged view of a main portion illustrating the configuration of a low thermal conductivity member of a bioreactor system according to a sixth embodiment of the present disclosure. [Figure 22] FIG. 2 is a hardware configuration diagram of a control device of a bioreactor system according to the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] First Embodiment <Bioreactor System> Hereinafter, a first embodiment of the present disclosure will be described in detail with reference to FIGS. The bioreactor system 1 shown in Fig. 1 is a system for performing two-stage cell culture, i.e., cell proliferation and antibody production. The bioreactor system 1 produces an antibody as a final product. The bioreactor system 1 includes a bioreactor 10 and a control device 200.

[0012] <Bioreactor> As shown in FIG. 1, the bioreactor 10 includes a casing 20, an inner cylinder 30, a rotating section 40, a driving section 50, a first culture medium supplying section 60, a second culture medium supplying section 70, a cell supplying section 80, a first temperature control section 91, a second temperature control section 92, an oxygen supplying section 100, a removal section 110, and a moving mechanism 150.

[0013] <Casing> The casing 20 constitutes the outer shell of the bioreactor 10. The casing 20 has a structure centered on an axis O extending in the vertical direction. The casing 20 has a lower base 21, an outer cylinder 22, and a lid 23. The lower base 21 is a plate-like member that extends horizontally and is placed on the floor surface. The lower base 21 has a circular shape with the axis O as the center in a plan view, for example.

[0014] <Outer cylinder> The outer cylinder 22 is a cylindrical member centered on the axis O. The outer peripheral surface and inner peripheral surface of the outer cylinder 22 form a cylindrical surface extending in the vertical direction centered on the axis O. The outer diameter and inner diameter of the outer cylinder 22 are constant in the vertical direction. The outer cylinder 22 is provided so as to extend upward from the outer peripheral edge of the lower bottom 21. In other words, the lower opening of the outer cylinder 22 is configured to be closed by the lower bottom 21.

[0015] The lid part 23 closes the upper opening of the outer cylinder 22. The lid part 23 has a bottomed cylindrical shape with the upper part closed. The lower end of the lid part 23 is connected to the upper end of the outer cylinder 22 around the entire circumference. This defines an enclosed space within the casing 20, ensuring a sterile state. The lid portion 23 has a through-hole 23a that passes through the lid portion 23 in the up-down direction. The through-hole 23a extends along the axis O in the up-down direction.

[0016] <Inner cylinder> The inner cylinder 30 is a cylindrical member centered on the axis O, and is provided inside the outer cylinder 22. The outer peripheral surface of the inner cylinder 30 forms a cylindrical surface extending in the vertical direction centered on the axis O. The outer diameter of the inner cylinder 30 is set to be smaller than the inner diameter of the outer cylinder 22, and is constant in the vertical direction. The lower end of the inner cylinder 30 forms a circular flat surface extending in the horizontal direction. The lower end of the inner cylinder 30 is fixed integrally to the lower bottom 21 over its entire surface. The upper end of the inner cylinder 30 forms a circular flat surface extending in the horizontal direction. The height of the upper end of the inner cylinder 30 is set to a height that can be accommodated in the space within the casing 20.

[0017] <Rotating part> The rotating part 40 has a shaft part 41 , an upper base part 42 , and a rotating cylinder 43 . The shaft portion 41 is a shaft-shaped member extending along the axis O, and is installed so as to vertically pass through a through hole of the cover portion 23. The shaft portion 41 is rotatable around the axis O via, for example, a bearing (not shown) installed in the through hole. The upper bottom portion 42 is connected to the lower end of the shaft portion 41 inside the casing 20. The upper bottom portion 42 is a disk-shaped member centered on an axis O extending horizontally. The upper bottom portion 42 is disposed above the upper end of the inner cylinder 30 with a gap therebetween. The center of the upper surface of the upper bottom portion 42 is fixed to the lower end of the shaft portion 41. The outer diameter of the upper bottom portion 42 is smaller than the inner diameter of the outer cylinder 22 and larger than the outer diameter of the inner cylinder 30.

[0018] <Rotating cylinder> The rotating cylinder 43 is a cylindrical member centered on the axis O, and is disposed between the outer cylinder 22 and the inner cylinder 30 inside the casing 20. The outer peripheral surface and inner peripheral surface of the rotating cylinder 43 form a cylindrical surface extending in the vertical direction centered on the axis O. The outer diameter of the rotating cylinder 43 is set to be smaller than the inner diameter of the outer cylinder 22. The inner diameter of the rotating cylinder 43 is set to be larger than the outer diameter of the inner cylinder 30. The outer diameter and inner diameter of the rotating cylinder 43 are constant in the vertical direction.

[0019] The upper end of the rotating cylinder 43 is integrally connected over the entire circumferential area to the outer circumferential edge of the upper bottom portion 42. In other words, the upper opening of the inner cylinder 30 is closed by the upper bottom portion 42. The lower edge 43a of the rotating cylinder 43 faces the upper surface of the lower bottom 21 with a small clearance therebetween. The size of this clearance is small compared to the overall size of the bioreactor 10. The vertical size of the clearance is set to, for example, 1 / 1000 to 1 / 100 of the vertical length of the casing 20. The size of the clearance is set to, for example, 1 mm to 10 mm.

[0020] The rotating cylinder 43 is rotatable around the axis O together with the shaft portion 41 and the upper bottom portion 42. A clearance is formed between the lower end of the inner cylinder 30 and the lower bottom plate, allowing the rotating cylinder 43 to rotate smoothly without interfering with the lower bottom portion 21. The lower end of the rotating cylinder 43 may be in slidable contact with the upper surface of the upper bottom portion 42.

[0021] <First Pool, Second Pool> By this rotating cylinder 43, two spaces, a first pool P1 and a second pool P2, are formed independently of each other within the casing 20. The first pool P1 and the second pool P2 are each capable of containing a liquid. The contained liquid is a culture solution containing a medium and cells. The first pool P1 is defined by the outer circumferential surface of the inner cylinder 30 and the inner circumferential surface of the rotating cylinder 43. The first pool P1 is an annular space centered on the axis O and extending vertically. The second pool P2 is defined by the outer peripheral surface of the rotating cylinder 43 and the inner peripheral surface of the outer cylinder 22. The second pool P2 is an annular space that is one size larger than the first pool P1 and that extends vertically. The first pool P1 and the second pool P2 are slightly in communication with each other via the above-mentioned clearance. Because the clearance is slight, almost no movement of the culture medium occurs between the first pool P1 and the second pool P2.

[0022] <Drive unit> The driving unit 50 drives the rotating unit 40 to rotate around the axis O. The driving unit 50 is provided outside the casing 20. The driving unit 50 is, for example, an electric motor, and an output shaft is connected to an upper end of the shaft portion 41 of the rotating unit 40. When the output shaft of the driving unit 50 rotates at a predetermined rotation speed, the rotating unit 40 is driven to rotate at the same rotation speed.

[0023] The driving unit 50 may be provided inside the casing 20. In this case, for example, the driving unit 50 may be installed at the upper end of the inner cylinder 30, and the rotating unit 40 may be rotationally driven by the driving unit 50.

[0024] <First medium supply section> The first culture medium supply unit 60 supplies a first culture medium to the first pool P1. The first culture medium supply unit 60 includes a first supply pipe 61, a first supply line 62, a first supply valve 63, and a first culture medium storage unit 64. The first supply pipe 61 is a pipe inserted from the outside of the casing 20 and has a first supply port 61a that opens toward the first pool P1. The first supply pipe 61 of this embodiment penetrates the inner cylinder 30, and is provided so that the first supply port 61a opens to the lower part of the first pool P1.

[0025] The first supply line 62 is a pipe extending outside the casing 20, and is connected to the end of the first supply pipe 61 opposite to the first supply port 61a. The first supply valve 63 is provided on the first supply line 62 and is configured to be able to open and close the flow path of the first supply line 62 .

[0026] The first culture medium storage section 64 stores a first culture medium. The first culture medium is adjusted to have ingredients suitable for cell growth. The first culture medium storage section 64 is connected to the end of the first supply line 62 opposite to the first culture medium supply pipe. The first culture medium supply section 60 is configured such that, by changing the first supply valve 63 from a closed state to an open state, the first culture medium in the first culture medium storage section 64 is supplied into the first pool P1 via the first supply line 62 and the first supply pipe 61 through the first supply port 61a.

[0027] <Second medium supply unit> The second culture medium supply unit 70 supplies the second culture medium to the second pool P2. The second culture medium supply unit 70 includes a second supply pipe 71, a second supply line 72, a second supply valve 73, and a second culture medium storage unit 74. The second supply pipe 71 is a pipe inserted from the outside of the casing 20 and has a second supply port 71a that opens toward the second pool P2. The second supply pipe 71 of this embodiment is provided above the second pool P2 such that the second supply port 71a opens downward.

[0028] The second supply line 72 is a pipe extending outside the casing 20, and is connected to the end of the second supply pipe 71 opposite to the second supply port 71a. The second supply valve 73 is provided on the second supply line 72 and is configured to be able to open and close the flow path of the second supply line 72 .

[0029] The second culture medium storage section 74 stores a second culture medium. The second culture medium is adjusted to have components suitable for the cells to produce antibodies while suppressing cell proliferation. The second culture medium storage section 74 is connected to the end of the second supply line 72 on the opposite side to the second culture medium supply pipe. The second culture medium supply section 70 is configured such that, by changing the second supply valve 73 from a closed state to an open state, the second culture medium in the second culture medium storage section 74 is supplied into the second pool P2 via the second supply line 72 and the second supply pipe 71 through the second supply port 71a.

[0030] <Cell supply section> The cell supply unit 80 supplies cells to the first pool P1. The cell supply unit 80 includes a cell supply pipe 81, a cell supply line 82, a cell supply valve 83, and a cell storage unit 84. The cell supply pipe 81 is a pipe inserted from the outside of the casing 20 and has a cell supply port 81a that opens toward the cell pool. The cell supply pipe 81 of this embodiment penetrates the inner cylinder 30, and is provided so that the cell supply port 81a opens to the lower part of the first pool P1.

[0031] The cell supply line 82 is a pipe extending outside the casing 20, and is connected to the end of the cell supply pipe 81 opposite to the cell supply port 81a. The cell supply valve 83 is provided on the cell supply line 82 and is configured to be able to open and close the flow path of the cell supply line 82 .

[0032] The cell storage section 84 stores cells to be cultured. The cell storage section 84 is connected to the end of the cell supply line 82 on the opposite side to the cell supply pipe 81. The cell supply section 80 is configured such that, by changing the cell supply valve 83 from a closed state to an open state, cells in the cell storage section 84 are supplied via the cell supply line 82 and the cell supply pipe 81 into the cell pool through the cell supply port 81a.

[0033] <First temperature control section> The first temperature adjustment unit 91 adjusts the temperature of the first pool P1. The first temperature adjustment unit 91 sets the temperature of the first pool P1 to a predetermined temperature by increasing or decreasing the temperature of the first pool P1. The first temperature adjustment unit 91 is provided inside the inner cylinder 30. That is, the first temperature adjustment unit 91 is provided inside the inner cylinder 30 in the circumferential direction and the up-down direction, and the temperature of the first pool P1 can be adjusted via the outer circumferential surface of the inner cylinder 30.

[0034] <Second temperature control section> The second temperature adjustment unit 92 adjusts the temperature of the second pool P2. The second temperature adjustment unit 92 sets the temperature of the second pool P2 to a predetermined temperature by increasing or decreasing the temperature of the second pool P2. The second temperature adjustment unit 92 is provided so as to surround the outer periphery of the outer cylinder 22. The second temperature adjustment unit 92 is annular and provided so as to extend in the circumferential direction and the up-down direction of the outer cylinder 22. That is, the second temperature adjustment unit 92 is capable of adjusting the temperature of the first pool P1 via the inner circumferential surface of the outer cylinder 22.

[0035] As the first temperature adjustment unit 91 and the second temperature adjustment unit 92, various temperature adjustment mechanisms such as a heater, a cooler, a Peltier element, etc. can be used.

[0036] <Oxygen supply unit> The oxygen supply unit 100 supplies oxygen to the first pool P1 and the second pool P2. As shown in Figs. 1 and 2, the oxygen supply unit 100 of this embodiment is disposed on the upper surface of the lower bottom portion 21. A plurality of oxygen supply units 100 are provided at intervals in the circumferential direction. Each oxygen supply unit 100 extends in the radial direction of the axis O, and is provided so as to straddle the first pool P1 and the second pool P2 across the rotating cylinder 43 in a plan view. Each oxygen supply unit 100 is a sparger capable of releasing oxygen. The oxygen concentration of the culture solution in the first pool P1 and the second pool P2 is adjusted by releasing oxygen from the sparger.

[0037] <Removal section> The take-out unit 110 has a role of taking out the liquid in the second pool P2 to the outside. The take-out unit 110 has a discharge line 111, a discharge valve 112, a take-out pump 113, a cell acquisition unit 120, and an antibody acquisition unit . The discharge line 111 is a pipe provided outside the casing 20, and one end of the discharge line 111 is connected to the second pool P2. The discharge valve 112 is provided in the discharge line 111 and can be opened and closed. The extraction pump 113 is provided in the discharge line 111 and is capable of pumping the fluid from one end of the discharge line 111 to the other end.

[0038] The cell acquisition unit 120 is a filter capable of extracting cells from the culture solution. The cell acquisition unit 120 is provided on the discharge line 111, upstream of the discharge valve 112 and the extraction pump 113. The antibody acquisition unit 130 is a filter capable of extracting antibodies produced by cells from the culture solution. The antibody acquisition unit 130 is provided on the discharge line 111, upstream of the discharge valve 112 and the extraction pump 113, and downstream of the cell acquisition unit 120.

[0039] With the above-described configuration, the removal section 110 is capable of discharging the culture medium in the second pool P2 to the outside by closing the discharge valve 112 and operating the discharge pump 113.

[0040] <Movement mechanism> The movement mechanism 150 is a mechanism capable of moving the liquid in the first pool P1 to the second pool P2. The movement mechanism 150 in this embodiment has a movement line 151 and a movement valve 152. The transfer line 151 is a pipe disposed outside the casing 20, and one end of the transfer line 151 is connected to the first pool P1. The other end of the transfer line 151 is connected to the second pool P2. In this embodiment, the other end of the transfer line 151 is connected to the upstream side of the cell acquisition unit 120 in the discharge line 111. As a result, the transfer line 151 is connected to the second pool P2 via the discharge line 111. Note that the other end of the transfer line 151 may be configured to be directly connected to the second pool P2.

[0041] The transfer valve 152 is provided on the discharge line 111 and can be opened and closed. When the liquid level in the second pool P2 is lower than the liquid level in the first pool P1, the transfer valve 152 is opened from a closed state, and the liquid in the first pool P1 moves to the second pool P2 due to the head difference.

[0042] <Control device> Next, the control device 200 of this embodiment will be described with reference to Fig. 3. As shown in Fig. 3, the control device 200 has a culture medium supply control unit 201, a temperature setting unit 202, a cell supply control unit 203, a culture execution unit 204, a movement execution unit 205, a discharge execution unit 206, a valve control unit 211, an oxygen supply control unit 212, a rotation control unit 213, and a pump control unit 214.

[0043] The medium supply control unit 201 controls the first medium supply unit and the second medium supply unit 70 via the valve control unit 211 to supply the first medium to the first pool P1 and the second medium to the second pool P2. The temperature setting unit 202 controls the first temperature adjustment unit 91 and the second temperature adjustment unit 92 so that the first pool P1 and the second pool P2 become the target temperatures, respectively. The cell supply control unit 203 controls the cell supply unit 80 via the valve control unit 211 to supply the first culture medium to the first pool P1.

[0044] The culture execution unit 204 controls the drive unit 50 via the rotation control unit 213 to rotate the rotation unit 40. The culture execution unit 204 controls the oxygen supply unit 100 via the oxygen supply control unit 212 to supply oxygen into the first pool P1 and the second pool P2. The movement execution unit 205 controls the movement mechanism 150 via the valve control unit 211 to move the culture medium from the first pool P1 to the second pool P2. The discharge execution unit 206 controls the take-out unit 110 via the valve control unit 211 and the pump control unit 214 to take out the culture medium from the second pool P2.

[0045] The valve control unit 211 controls the opening and closing operations of the first supply valve 63, the second supply valve 73, the cell supply valve 83, the movement valve 152, and the discharge valve 112 in response to instructions from the culture medium supply control unit 201, the cell supply control unit 203, the movement execution unit 205, and the discharge execution unit 206.

[0046] The oxygen supply control unit 212 controls the oxygen supply unit 100 in response to a command from the culture execution unit 204 . The rotation control unit 213 controls the drive unit 50 in response to a signal from the culture execution unit 204 to drive the rotation unit 40 to rotate. The pump control unit 214 controls the extraction pump 113 in response to a command from the discharge execution unit 206 .

[0047] <How to operate a bioreactor> Next, the processing procedure of the control device 200 (the method of operating the bioreactor 10) will be described with reference to the flowchart shown in Fig. 4. The control device 200 sequentially performs a medium supplying step S1, a temperature setting step S2, a cell supplying step S3, a culturing step S4, a moving step S5, a culturing step S6, and a discharging step S7.

[0048] <Culture medium supply process> First, the culture medium supply control unit 201 outputs a signal to the valve control unit 211, which causes the valve control unit 211 to change the first supply valve 63 and the second supply valve 73 from a closed state to an open state. As a result, the first culture medium in the first culture medium storage unit 64 is supplied to the first pool P1 via the first supply port 61a of the first supply pipe 61. Also, the second culture medium in the second culture medium storage unit 74 is supplied to the second pool P2 via the second supply port 71a of the second supply pipe 71 (culture medium supply step S1). When the first pool P1 and the second pool P2 are supplied with appropriate amounts of the first medium and the second medium, the valve control unit 211 changes the first supply valve 63 and the second supply valve 73 from the open state to the closed state, thereby stopping the supply of the first medium and the second medium. In addition, in order to smoothly carry out the transfer process described below, the first culture medium supply unit 60 and the second culture medium supply unit 70 may be controlled so that the liquid level of the first culture medium is higher than the liquid level of the second culture medium.

[0049] <Temperature setting process> Next, the temperature setting unit 202 controls the first temperature adjustment unit 91 and the second temperature adjustment unit 92 to adjust the first medium in the first pool P1 and the second medium in the second pool P2 to a predetermined temperature (temperature setting step S2). Here, the temperature of the first medium is set to a temperature suitable for cell proliferation. That is, the first pool P1 is set to a temperature of, for example, 36 to 38°C, and preferably to a temperature around 37°C. The temperature of the second medium is set to a temperature that suppresses cell proliferation and is suitable for the cells to produce antibodies. That is, the second pool P2 is set to a temperature lower than that of the first pool P1, for example, 30 to 33°C, and preferably to a temperature of 31 to 32°C.

[0050] <Cell supply process> Thereafter, the cell supply control unit 203 outputs a signal to the valve control unit 211, which then changes the cell supply valve 83 from a closed state to an open state. As a result, the cells in the cell storage unit 84 are supplied to the first pool P1 via the cell supply port 81a of the cell supply pipe 81 (cell supply step S3). When an appropriate amount of cells has been supplied to the first pool P1, the valve control unit 211 changes the cell supply valve 83 from an open state to a closed state. As a result, the supply of cells is stopped.

[0051] <Culture process> Next, the culture execution unit 204 cultures the cells in the first pool P1 (culture step S4). The culture step S4 is performed according to the procedure of the flowchart shown in FIG. That is, first, the culture execution unit 204 outputs a signal to the oxygen supply control unit 212, which then operates the oxygen supply unit 100. This starts the supply of oxygen to the first pool P1 and the second pool P2 (step S41).

[0052] Next, the culture execution unit 204 sends a signal to the rotation control unit 213, whereby the rotation control unit 213 controls the drive unit 50 to rotate the rotation unit 40 (step S42). Here, the rotation speed of the rotation unit 40 is set to a value suitable for forming Taylor vortices in the first pool P1 and the second pool P2. The rotation control unit 213 drives the rotation cylinder 43 in a forward rotation so that the Taylor number in the first pool P1 and the second pool P2 is, for example, 20,000 to 30,000, taking into consideration the radial dimensions of the first pool P1 and the second pool P2. As a result, turbulence is unlikely to occur in the first pool P1 and the second pool P2, and the first pool P1 and the second pool P2 are stirred by a stable vortex, promoting cell proliferation in the first pool P1.

[0053] Next, the culture execution unit 204 determines whether the culture is completed or not (step S43). For example, when the cell concentration in the first pool P1 measured by the cell counter does not exceed a predetermined value, the culture execution unit 204 determines that the culture is not completed and continues the forward rotation drive of the rotating cylinder 43 (step S43: No). For example, when the cell concentration does not exceed a predetermined value, the culture execution unit 204 determines that the culture is not completed (step S43: Yes). The culture executing unit 204 may determine that the culture is completed when a predetermined time has elapsed after the rotation cylinder 43 has been driven to rotate.

[0054] After the cultivation is completed, the cultivation execution unit 204 outputs a signal to the oxygen supply control unit 212, which causes the oxygen supply control unit 212 to stop the supply of oxygen by the oxygen supply unit 100 (step S45). Thereafter, the culture execution unit 204 outputs a signal to the rotation control unit 213, and the rotation control unit 213 stops the rotation of the rotating cylinder 43 (step S46). In this way, the culture step S4 is completed, and the first medium becomes filled with proliferated cells.

[0055] <Moving process> 4, after the culture step S4, the transfer execution unit 205 transfers the culture medium from the first pool P1 to the second pool P2 (transfer step S5). As a result, the cells grown in the first pool P1 are supplied to the second medium of the second pool P2. 6, in the transfer step S5, the transfer execution unit 205 outputs a signal to the valve control unit 211, which causes the valve control unit 211 to open the transfer valve 152 (S51). As a result, if the liquid level in the first pool P1 is higher than the liquid level in the second pool P2, the culture solution in the first pool P1 transfers to the second pool P2 via the transfer line 151 due to the head difference.

[0056] When the liquid level in the first pool P1 is not higher than the liquid level in the second pool P2, the movement execution unit 205 may control the valve control unit 211 to temporarily open the discharge valve 112 and control the pump control unit 214 to temporarily operate the extraction pump 113 prior to opening the movement valve 152. This allows the liquid in the second pool P2 to be discharged to the outside, making the liquid level in the first pool P1 higher than the liquid level in the second pool P2. Alternatively, a pump may be provided in the transfer line 151, and the culture solution may be transferred from the first pool P1 to the second pool P2 by driving the pump.

[0057] Next, the movement execution unit 205 determines whether the movement of the culture medium is complete (step S52). For example, if a predetermined time has not elapsed after the movement valve is opened, the movement execution unit 205 determines that the movement is not complete (step S52: No). On the other hand, if a predetermined time has elapsed after the movement valve is opened, the movement execution unit 205 determines that the movement is complete (step S52: Yes). The movement execution unit 205 may determine that the movement of the culture medium is completed when the liquid levels in the first pool P1 and the second pool P2 become equal. Alternatively, the movement execution unit 205 may detect the cell concentrations in the first pool P1 and the second pool P2 and determine that the movement of the culture medium is completed based on the detected cell concentrations.

[0058] After the movement of the culture solution is completed, the movement execution unit 205 outputs a signal to the valve control unit 211, and the valve control unit 211 changes the movement valve 152 from the open state to the closed state (step S53). This completes the movement step S5.

[0059] <Re-cultivation process after the transfer process> After the transfer step S5 is completed, as shown in Fig. 4, a culture step S6 similar to the culture step S4 is performed. This stirs the culture solution in the second pool P2, promoting antibody production by the cells in the second pool P2. In the culture step S6 after the transfer step S5, the culture is determined to be complete when the detected cell concentration in the second pool P2 begins to decrease, assuming that antibody production has ended (Fig. 5: step S43). Alternatively, the culture may be determined to be complete when a predetermined time has elapsed.

[0060] <Discharge process> After the completion of the second culture step S6 following the moving step S5, the culture medium in the second pool P2 is discharged by the discharge execution unit 206 (discharge step S7). That is, the discharge execution unit 206 controls the valve control unit 211 to change the discharge valve 112 from a closed state to an open state, and controls the pump control unit 214 to operate the extraction pump 113. As a result, the culture medium in the second pool P2 is discharged from the second pool P2 via the discharge line 111 together with the cells and the antibodies. In the process of flowing through the discharge line 111, the cells in the culture medium are extracted by the cell acquisition unit 120, and the antibodies in the culture medium are extracted by the antibody acquisition unit 130. The extracted cells can be reused by supplying them to the first pool P1 again. The extracted antibodies are used for various purposes as products of this system. This completes the method for operating the bioreactor 10.

[0061] <Action and effect> According to the bioreactor 10, bioreactor system 1, and operating method of the bioreactor 10 described above, cell culture can be performed in each of the first pool P1 and the second pool P2, which are independent of each other. Therefore, it is possible to culture cells in different growth phases, such as cell proliferation and antibody production, in one device. Therefore, it is not necessary to use multiple devices, and the entire system can be made compact.

[0062] In addition, since the first pool P1 and the second pool P2 can be supplied with media containing different components, it is possible to supply media containing components suitable for cell proliferation and antibody production, respectively, thereby enabling efficient cell culture in each growth phase.

[0063] Here, in order to stir the culture solution in each of the first pool P1 and the second pool P2, it is possible to rotate, for example, each of the inner cylinder 30 and the outer cylinder 22. However, in this case, the need to rotate two cylinders complicates the device configuration. In addition, more power is required to rotate the outer cylinder 22 than to rotate the rotating cylinder 43. In this embodiment, the first pool P1 and the second pool P2 can be stirred by rotating only the rotating cylinder 43, so the device configuration is not complicated and can be made efficient. In addition, in this embodiment, since there is no need to rotate the inner cylinder 30, the first culture medium supply pipe and the cell supply pipe 81 can be installed so as to penetrate the inner cylinder 30. Therefore, the space inside the inner cylinder 30 can be effectively utilized, and the installation space of the entire device can be reduced.

[0064] Furthermore, the first pool P1 and the second pool P2 are temperature-controlled by the first temperature controller 91 and the second temperature controller 92, which can set temperatures independently, so that the first pool P1 and the second pool P2 can be set to temperatures suitable for the respective cultures. This allows cell culture in different growth phases to be performed more efficiently.

[0065] Moreover, antibody production can be carried out by transferring the cells grown in the first pool P1 to the second pool P2. In other words, a series of processes from cell growth to antibody production can be completed in one device, so that antibody production can be carried out efficiently.

[0066] Furthermore, in this embodiment, since the oxygen supply unit 100 is disposed across the first pool P1 and the second pool P2, oxygen can be efficiently supplied to both the first pool P1 and the second pool P2. This allows an environment suitable for cells to be set.

[0067] Second Embodiment Next, a second embodiment of the present disclosure will be described with reference to Figures 7 to 13. In Figures 7 to 13, components similar to those in the first embodiment are given the same reference numerals and detailed description thereof will be omitted. The bioreactor system 1 of the second embodiment differs from the first embodiment in the configurations of the drive unit 50, the oxygen supply unit 100, and the movement mechanism 150.

[0068] <Drive unit> The drive unit 50 is capable of driving the rotation unit 40 to rotate in both the forward and reverse directions. That is, the drive unit 50 drives the rotation cylinder 43 to rotate forward and reverse. In addition, in the culture steps S4 and S6, the culture execution unit 204 controls the drive unit 50 via the rotation control unit 213 to rotate the rotation cylinder 43 forward. <Oxygen supply unit> 7 and 8, the oxygen supply unit 100 of the second embodiment has a first oxygen supply unit 101 and a second oxygen supply unit 102. The first oxygen supply unit 101 and the second oxygen supply unit 102 are spargers capable of supplying oxygen into liquid. The first oxygen supply unit 101 is disposed in a region between the inner cylinder 30 and the rotating cylinder 43 on the upper surface of the lower bottom portion 21 of the casing 20. That is, the first oxygen supply unit 101 is disposed so as to face only the first pool P1 out of the first pool P1 and the second pool P2.

[0069] The second oxygen supply unit 102 is disposed in a region between the outer cylinder 22 and the rotating cylinder 43 on the upper surface of the lower bottom portion 21 of the casing 20. That is, the second oxygen supply unit 102 is disposed so as to face only the second pool P2 out of the first pool P1 and the second pool P2.

[0070] The first oxygen supply unit 101 and the second oxygen supply unit 102 are independent of each other, and each releases a set supply amount of oxygen. That is, in the culture steps S4 and S6, the oxygen supply control unit 212 controls the first oxygen supply unit 101 and the second oxygen supply unit 102 so that the oxygen supply amount is suitable for the first pool P1 and the second pool P2, which are the oxygen supply destinations.

[0071] As a result, the first oxygen supply unit 101 supplies an amount of oxygen suitable for cell proliferation, for example, so that cell proliferation in the first pool P1 is promoted. Further, the second oxygen supply unit 102 supplies an amount of oxygen suitable for antibody production, for example, so as to suppress proliferation of cells in the second pool P2 and promote antibody production by the cells.

[0072] <Movement mechanism> The movement mechanism 150 of the second embodiment is provided on the rotating cylinder 43. As shown in Figures 7, 9 and 10, a plurality of openings 43b penetrating the rotating cylinder 43 in the radial direction are provided at the lower part of the rotating cylinder 43 at intervals in the circumferential direction.

[0073] Furthermore, the moving mechanism 150 has a sliding door 160 as an opening / closing part capable of opening and closing the opening 43b. The sliding door 160 is in the form of a plate extending in the circumferential direction and the vertical direction, and is sized to be able to close the opening 43b. The sliding door 160 is provided along the outer circumferential surface of the rotating cylinder 43. The sliding door 160 is provided so as to be movable between a closing position where the opening 43b is closed from the outer circumferential side, and an opening position where the opening 43b is opened. The opening position is a position closer to the front side in the rotation direction of the rotating cylinder 43 than the closing position. The sliding door 160 is provided so as to be able to slide in the circumferential direction along the outer circumferential surface of the rotating cylinder 43 between the closing position and the opening position.

[0074] The movement mechanism 150 has a stopper 161. The stopper 161 is provided so as to protrude from the edge of the opening 43b of the rotating cylinder 43 on the rear side in the forward rotation direction toward the outer periphery. The sliding door 160 in the closed position abuts against the stopper 161 from the front side in the forward rotation direction. The stopper 161 restricts the movement of the sliding door 160 from the closed position toward the rear side in the forward rotation direction.

[0075] Next, the moving step S5 of this embodiment will be described with reference to FIG. First, the movement execution unit 205 determines whether or not a predetermined time has elapsed after the completion of the initial culture step S4, that is, after the rotation of the rotating cylinder 43 has stopped (step S54). If the predetermined time has not elapsed, the movement execution unit 205 waits until the predetermined time has elapsed (step S53: No). If the predetermined time has elapsed, the movement execution unit 205 proceeds to the next step (step S53: Yes). In this way, by waiting after the rotation of the rotating cylinder 43 has stopped, the cells grown in the culture solution in the first pool P1 settle to the bottom of the first pool P1. This results in a higher cell concentration in the bottom of the first pool P1 (the vertical position of the opening / closing part) than in the top.

[0076] Next, the movement execution unit 205 drives the drive unit 50 to rotate in the reverse direction via the rotation control unit 213. Accordingly, the rotating cylinder 43 rotates in the reverse direction opposite to that in the culture step S4 (step S55). Here, during forward rotation of the rotating cylinder 43, flow resistance of the liquids in the first pool P1 and the second pool P2 is applied to the sliding door 160, and an external force is applied to the sliding door 160 toward the rear side in the forward rotation direction. This causes the sliding door 160 to remain in contact with the stopper 161 at the closed position. Therefore, during forward rotation of the rotating cylinder 43, the sliding door 160 closes the opening 43b, and the liquids in the first pool P1 and the second pool P2 do not mix through the opening 43b.

[0077] On the other hand, when the rotating cylinder 43 is rotated in the reverse direction in the moving step S5, an external force toward the rear side in the reverse rotation direction (front side in the forward rotation direction) is applied to the sliding door 160 due to the flow resistance of the liquid in the first pool P1 and the second pool P2. As a result, the sliding door 160 moves toward the rear side in the reverse rotation direction relative to the rotating cylinder 43. That is, the sliding door 160 slides from the closed position to the open position. As a result, the first pool P1 and the second pool P2 are in radial communication via the sliding door 160 of the rotating cylinder 43.

[0078] Here, the movement execution unit 205 controls the rotation control unit 213 to rotate the rotating cylinder 43 in the reverse direction at a lower rotation speed than during the culture steps S4 and S6. As a result, Taylor vortices are not formed in the first pool P1 and the second pool P2, and active mixing is not performed. On the other hand, as the rotating cylinder 43 comes into contact with the culture solution in the first pool P1 at a low rotation speed, the culture solution in the first pool P1 rotates together with the rotating cylinder 43 due to viscosity. As a result, a gentle centrifugal force is applied to the culture solution in the first pool P1. Due to this centrifugal force, the culture solution with a high cell concentration in the first pool P1 moves to the second pool P2 through the opening 43b.

[0079] Next, the movement execution unit 205 judges whether the movement of the culture medium from the first pool P1 to the second pool P2 is completed or not (step S56). If it is judged that the movement is not completed (step 56: No), the movement execution unit 205 continues the reverse rotation of the rotating cylinder 43. If it is judged that the movement is completed (step 56: Yes), the movement execution unit 205 controls the rotation control unit 213 to stop the reverse rotation of the rotating cylinder 43 (step S57). With the above, the movement step S5 is completed.

[0080] The determination of whether the movement by the movement execution unit 205 is complete may be made, for example, by determining whether a predetermined time has elapsed since the start of reverse rotation of the rotating cylinder 43. Alternatively, the cell concentrations of the liquids in the first pool P1 and the second pool P2 may be measured, and the movement may be determined to be complete when the cell concentration in the first pool P1 falls below a predetermined amount and the cell concentration in the second pool P2 exceeds the predetermined amount. Alternatively, the cell concentration in either the first pool P1 or the second pool P2 may be used as the determination criterion.

[0081] <Action and effect> In the bioreactor system 1 of the second embodiment configured as above, oxygen can be supplied separately to each of the first pool P1 and the second pool P2. Therefore, when cells in different growth phases exist in the first pool P1 and the second pool P2, an appropriate amount of oxygen can be supplied to each of the cells, and the culture can be promoted. In particular, in this embodiment, the first pool P1 is supplied with an amount of oxygen suitable for cell culture, and the second pool P2 is supplied with an amount of oxygen suitable for antibody production, thereby making it possible to efficiently carry out the two processes of cell culture and antibody production.

[0082] Moreover, according to the transfer mechanism 150 of this embodiment, the culture solution can be transferred from the first pool P1 to the second pool P2 simply by the reverse rotation of the rotating cylinder 43. Therefore, the culture solution can be transferred smoothly and appropriately. Furthermore, the control targets are only the drive unit 50 and the rotary cylinder 43, eliminating the need for the moving valve 152 in the first embodiment. This reduces the number of parts, improving maintainability.

[0083] <Modification of the second embodiment> As a modification of the second embodiment, the moving mechanism 150 may have a configuration shown in, for example, FIGS. The movement mechanism 150 of the modified example has an opening / closing door 170 and a hinge 171 instead of the sliding door 160 and the stopper 161 of the second embodiment. The hinge 171 is provided on the inner circumferential surface of the rotating cylinder 43 at the edge on the front side in the positive rotation direction of the opening 43b so as to extend in the vertical direction.

[0084] The opening / closing door 170 is provided inside the rotating cylinder 43 by a hinge 171 so as to be rotatable about a rotation axis extending in the vertical direction. The opening / closing door 170 rotates between a closed position and an open position. As shown in FIG. 12, the closed position is a position where the door is disposed so as to follow the shape of the cylindrical surface and closes the opening 43b. As shown in FIG. 13, the open position is a position where the door rotates from the closed position toward the inside of the rotating cylinder 43 and opens the opening 43b.

[0085] During forward rotation of the rotating cylinder 43, flow resistance of the first pool P1 is applied to the door 170, so that an external force toward the rear side in the forward rotation direction, i.e., toward the front side in the reverse rotation direction, is applied to the door 170. As a result, the door 170 is held in the closed position, and the opening 43b is closed. On the other hand, when the rotating cylinder 43 is rotated in the reverse direction, the flow resistance of the first pool P1 applies an external force from the closed position to the open position to the opening door 170. This opens the opening 43b, and the first pool P1 and the second pool P2 are in communication with each other. Therefore, similarly to the second embodiment, the culture medium can be transferred from the first pool P1 to the second pool P2.

[0086] <Third embodiment> Next, a bioreactor system 1 according to a third embodiment will be described with reference to Figures 14 to 16. In Figures 14 to 16, components similar to those in the second embodiment are given the same reference numerals and detailed description thereof will be omitted. In the third embodiment, the discharge section 110 further includes a circulation line 140 and a circulation valve 141 . <Circulation Line> One end of the circulation line 140 is connected to a portion of the discharge line 111 between the removal pump 113 and the discharge valve 112. The other end of the circulation line 140 is connected to the inside of the second pool P2. The other end of the circulation line 140 is provided so as to face the culture solution in the second pool P2 from above.

[0087] <Circulation valve> The circulation valve 141 is provided on the circulation line 140. The circulation valve 141 switches the circulation line 140 between a flowing state and a non-flowing state by opening and closing.

[0088] <Control device> As shown in FIG. 15, the control device 200 of the third embodiment includes a circulation execution unit 207 and a determination unit 208 in addition to the configuration of the control device 200 of the first embodiment shown in FIG. The circulation execution unit 207 controls the opening and closing of the circulation valve 141 via a valve control unit 211 , and also controls the extraction pump 113 via a pump control unit 214 . The determination unit 208 determines whether or not to perform continuous operation.

[0089] Next, the processing procedure of the control device 200 of the third embodiment (the method of operating the bioreactor 10) will be described with reference to the flowchart shown in FIG. First, similarly to the first embodiment, a medium supplying step S11, a temperature setting step S12, a cell supplying step S13, a culture step S14, and a transfer step S15 are sequentially performed. In the configuration of the bioreactor system 1 of the third embodiment shown in Fig. 14, the transfer step S15 is performed in the same manner as in the second embodiment, but may be performed in the same manner as in the first embodiment.

[0090] After the transfer step S15, the cell supply step S16 is performed again in the same manner as described above. Here, by performing the transfer step S15, most of the cells in the first pool P1 have been transferred to the second pool P2. Therefore, the first pool P1 is in a state of having a reduced number of cells. By performing the cell supply step S16, cells are present in both the first pool P1 and the second pool P2. If the number of cells in the first pool P1 is ensured after the transfer step S15, the cell supply step S16 may be omitted.

[0091] Next, the culture execution unit 204 executes the culture step S17 again in the same manner as described above. As a result, Taylor vortices are formed in the first pool P1 and the second pool P2 by the rotation of the rotating cylinder 43. In this embodiment, since cells exist in both the first pool P1 and the second pool P2, cell culture proceeds in both the first pool P1 and the second pool P2. That is, cell proliferation proceeds in the first pool P1, and antibody production proceeds in the second pool P2.

[0092] After the incubation step S17 following the transfer step S15, the determination unit 208 determines whether or not to continue operation (determination step S18).

[0093] The determination of whether or not to perform continuous operation is based on, for example, whether or not a required amount of antibody production has been reached. That is, when the discharge step S20 is executed in the next step, if it is not expected that the target amount of antibody production will be reached by obtaining the antibody in the discharge step S20, the determination unit 208 determines to perform continuous operation. On the other hand, if it is expected that the target amount of antibody production will be reached, the determination unit 208 determines not to perform continuous operation. Note that the determination unit 208 may determine whether or not to perform continuous operation based on the number of times it has been determined that continuous operation should be performed.

[0094] When the determination unit 208 determines that continuous operation is to be performed (determination step S18: Yes), the circulation execution unit 207 performs the circulation step S19. That is, the circulation execution unit 207 opens the circulation valve 141 via the valve control unit 211, and drives the extraction pump 113 via the pump control unit 214. In this state, the discharge valve 112 is closed. As a result, the culture solution in the second pool P2 is taken out via the discharge line 111, and the cells and antibodies are extracted by the cell acquisition unit 120 and the antibody acquisition unit 130. Then, the medium remaining after the cells and antibodies have been extracted from the culture solution is returned to the second pool P2 via the circulation line 140.

[0095] After the circulation step S19, the above-mentioned transfer step S15, cell supply step S16, culture step S17, and determination step S18 are performed again. Here, too, the cell supply step S16 may be omitted.

[0096] When the determination unit 208 determines that continuous operation is not to be performed (determination step S18: No), the discharge step S20 is performed similarly to the first embodiment. This results in the final extraction of cells and antibodies, and the processing by the control device 200 is completed.

[0097] As described above, according to this embodiment, cell culture can be performed simultaneously in each of the first pool P1 and the second pool P2. That is, by partitioning the first pool P1 and the second pool P2, cell culture in different growth phases, such as cell proliferation and antibody production, can be performed simultaneously. Therefore, in addition to improving the efficiency of cell culture, different cell cultures can be performed using only one bioreactor 10, making the entire cell culture facility more compact.

[0098] In addition, by performing continuous operation, cell proliferation in different growth phases, such as cell proliferation and antibody production, can be performed simultaneously and continuously, thereby increasing the number of antibodies produced. Furthermore, in the circulation process, the medium is returned to the second pool P2, thereby making it possible to reuse resources required for cell culture.

[0099] In the case of continuous operation as in this embodiment, the first medium and the second medium may be appropriately supplied to the first pool P1 and the second pool P2 during operation. Alternatively, only the nutrients in the first medium and the second medium may be appropriately supplied. This allows the cells to maintain the nutrients necessary for the cells, and allows continuous operation without slowing down the culture speed.

[0100] <Fourth embodiment> Next, a bioreactor system 1 according to a fourth embodiment will be described with reference to Fig. 17. In Fig. 17, components similar to those in the third embodiment are given the same reference numerals, and detailed description thereof will be omitted. In the third embodiment, a part of the discharge line 111 passes through the inside of the inner cylinder 30. That is, the discharge line 111 is disposed penetrating the lower bottom portion 21 from bottom to top, thereby reaching the inside of the inner cylinder 30. Then, the discharge line 111 extends to the top of the inner cylinder 30, turns back downward, and then penetrates the lower bottom portion 21 from top to bottom to reach the outside of the inner cylinder 30.

[0101] The cell acquisition unit 120 and the antibody acquisition unit 130 on the discharge line 111 are provided inside the inner cylinder 30. Note that only one of the cell acquisition unit 120 and the antibody acquisition unit 130 may be provided inside the inner cylinder 30. That is, it is sufficient that at least one of the cell acquisition unit 120 and the antibody acquisition unit 130 is provided inside the inner cylinder 30. In addition, although the take-out pump 113 and the discharge valve 112 are provided outside the inner cylinder 30, they may be configured to be provided inside the inner cylinder 30. Furthermore, a part of the circulation line 140 and the circulation valve 141 may be provided inside the inner cylinder 30.

[0102] This allows for effective use of the space inside the inner cylinder 30. In other embodiments, the configuration provided outside the casing 20 is provided inside the inner cylinder 30, thereby making the entire device more compact. Furthermore, by consolidating and arranging various configurations inside the inner cylinder 30, maintainability can be improved.

[0103] <Fifth embodiment> Next, a bioreactor system 1 according to a fifth embodiment will be described with reference to Fig. 18. In Fig. 18, components similar to those in the other embodiments are given the same reference numerals, and detailed description thereof will be omitted.

[0104] <Sealing section> In the fifth embodiment, a seal portion 180 is provided that seals between the lower end edge portion 43a of the rotating cylinder 43 and the upper surface of the lower bottom portion 21 in the circumferential direction. The seal portion 180 has a rotating seal piece 181 and a stationary seal piece 182 .

[0105] The rotating seal piece 181 is provided over the entire circumference of each of the inner and outer circumferential surfaces of the rotating cylinder 43. The rotating seal piece 181 protrudes from the inner and outer circumferential surfaces of the rotating cylinder 43 and then extends downward.

[0106] A pair of stationary seal pieces 182 are provided on the upper surface of the lower bottom portion 21. The stationary seal pieces 182 are provided so as to correspond to the pair of rotating seal pieces 181 on the upper surface of the lower bottom portion 21. The stationary seal pieces 182 protrude upward from the lower bottom portion 21 and are provided so as to fit between the rotating cylinder 43 and the rotating seal pieces 181 over the entire circumference. A labyrinth mechanism is formed on the radial inside and outside of the clearance by such rotating seal pieces 181 and stationary seal pieces 182.

[0107] In this embodiment, the provision of the sealing portion 180 makes it possible to suppress the movement of cells and culture medium through the clearance between the rotating cylinder 43 and the lower bottom portion 21. This allows the first pool P1 and the second pool P2 to be appropriately partitioned, so that cell culture can be reliably performed in each pool according to the growth phase.

[0108] <First Modification of Fifth Embodiment> As a first modification of the fifth embodiment, the seal portion 180 may have a configuration as shown in Fig. 19. The seal portion 180 of the first modification is composed of an annular groove 183 formed in the rotating cylinder 43 and fins 184, 186 provided on the lower bottom portion 21.

[0109] The annular groove 183 is recessed upward from the lower end edge 43a of the rotating cylinder 43 and extends annularly around the entire circumference. A plurality of annular grooves 183 (two in this embodiment) are formed at intervals in the radial direction. A plurality of fins 184, 186 (two in this embodiment) are provided to correspond to the annular groove 183. The lower end of each of the fins 184, 186 is fixed to the upper surface of the lower bottom portion 21, and extends upward into each of the annular grooves 183.

[0110] This allows a labyrinth mechanism to be formed in the clearance. Compared to the fourth embodiment, there are no protruding parts from the inner and outer surfaces of the rotating cylinder 43, so the generation of turbulent flows in the first pool P1 and the second pool P2 is suppressed. Therefore, appropriate Taylor vortices can be formed in the first pool P1 and the second pool P2.

[0111] <Second Modification of Fifth Embodiment> As a second modification of the fifth embodiment, the seal portion 180 may have a configuration as shown in Fig. 20. The seal portion 180 of the second modification is composed of a notch 185 formed in the rotating cylinder 43 and fins 184, 186 provided on the lower bottom portion 21.

[0112] A pair of cutouts 185 are provided in the lower part of the rotating cylinder 43 so as to be recessed from the outer circumferential surface and the inner circumferential surface of the rotating cylinder 43 and open downward. As a result, the lower end of the rotating cylinder 43 is formed to have a smaller radial thickness than the upper part.

[0113] As in the first modification, the fins 184, 186 are annular and protrude from the upper surface of the lower bottom portion 21 and extend over the entire circumferential direction. The fins 184, 186 are provided to be accommodated in the pair of notches 185 so as to correspond to the pair of notches 185. The inner peripheral surface of the rotating cylinder 43 and the inner peripheral surface of the radially inner fin 184, 186 of the pair of fins 184, 186 are located flush with each other on the same cylindrical surface. The outer peripheral surface of the rotating cylinder 43 and the outer peripheral surface of the radially outer fin 184, 186 of the pair of fins 184, 186 are located flush with each other on the same cylindrical surface.

[0114] This makes it possible to form a labyrinth mechanism, as in the first modified example, and since no protrusions are formed into the first pool P1 and the second pool P2, appropriate Taylor vortices can be formed in the first pool P1 and the second pool P2.

[0115] Sixth Embodiment Next, a bioreactor system 1 according to a sixth embodiment will be described with reference to Fig. 21. In Fig. 21, components similar to those in the other embodiments are given the same reference numerals, and detailed description thereof will be omitted.

[0116] <Low thermal conductivity materials> In the sixth embodiment, a low thermal conductivity member 190 is provided on the surface of the rotating cylinder 43. The low thermal conductivity member 190 is provided along the inner circumferential surface and outer circumferential surface of the rotating cylinder 43. The low thermal conductivity member 190 is provided over at least the entire area of ​​the inner circumferential surface and outer circumferential surface of the rotating cylinder 43 that come into contact with the culture solution. The low thermal conductivity member 190 may be provided on at least one of the inner circumferential surface and outer circumferential surface of the rotating cylinder 43.

[0117] The low thermal conductivity member 190 is made of a material having a lower thermal conductivity than the material constituting the rotating cylinder 43. For example, when the low thermal conductivity member 190 is made of a steel material such as stainless steel, the low thermal conductivity member 190 may be made of ceramic applied by thermal spraying or rubber attached separately.

[0118] The presence of the low thermal conductivity member 190 can suppress the transfer of heat between the first pool P1 and the second pool P2. Therefore, the first temperature adjustment unit 91 and the second top temperature unit can more appropriately control the temperatures of the first pool P1 and the second pool P2 independently. This allows more appropriate cell culture in the first pool P1 and the second pool P2 according to the growth phase.

[0119] In order to suppress the heat transfer between the first pool P1 and the second pool P2, for example, the material constituting the rotating cylinder 43 itself may be made of a material having a lower thermal conductivity than the outer cylinder 22. This makes it possible to appropriately adjust the temperature inside the second pool P2 from the outside of the outer cylinder 22 by the second temperature adjustment unit 92, while suppressing the heat transfer between the first pool P1 and the second pool P2, and to independently set the temperature in each pool.

[0120] <Other embodiments> Although the embodiment of the present invention has been described above, the present invention is not limited to this, and can be modified as appropriate without departing from the technical concept of the invention.

[0121] For example, the method of operating the bioreactor 10 in the embodiment has been described as being configured to be performed by the control device 200, but all or part of each step may be performed by an operator. For example, the medium supplying step, the cell supplying step, the moving step, the circulating step, and the discharging step may be performed manually by an operator. Furthermore, the temperature setting unit 202 may receive an input from an operator and control the first temperature adjustment unit and the second temperature adjustment unit in accordance with the input. Furthermore, the rotation control unit 213 may receive an input from an operator and rotate the rotating cylinder 43 via the drive unit 50 in accordance with the input. Similarly, the oxygen supply unit 100 may receive an input from an operator and control the oxygen supply unit 100 in accordance with the input.

[0122] In the embodiment, cells grown in the first pool P1 were moved to the second pool P2 and used, but simultaneous culture may also be performed by supplying cells in different growth phases to the first pool P1 and the second pool P2 from the outside.

[0123] <Hardware configuration> The above-mentioned process steps of the control device 200 are stored in a computer-readable recording medium in the form of a program, and the above-mentioned process is performed by the computer reading and executing the program. A specific example of a computer is shown below.

[0124] As shown in FIG. 22, the computer includes a CPU 301, a main memory 302, a storage 303, and an interface 304. For example, the above-mentioned arithmetic device is implemented in a computer. The operations of the above-mentioned processing units are stored in the storage 303 in the form of a program. The CPU 301 reads the program from the storage 303, loads it in the main memory 302, and executes the above-mentioned processing in accordance with the program. The CPU 301 also secures a storage area in the main memory 302 in accordance with the program.

[0125] Examples of the storage 303 include a hard disk drive (HDD), a solid state drive (SSD), a magnetic disk, a magneto-optical disk, a compact disc read only memory (CD-ROM), a digital versatile disc read only memory (DVD-ROM), and a semiconductor memory. The storage 303 may be an internal medium directly connected to a bus of the computer, or an external medium connected to the computer via an interface 304 or a communication line. In addition, when the program is distributed to a computer via a communication line, the computer that receives the program may load the program in the main memory 302 and execute the above-mentioned process. The storage 303 is a non-transitory tangible storage medium.

[0126] The program may also realize some of the functions described above. Furthermore, the program may be a file that can realize the functions described above in combination with a program already recorded in the computer, that is, a so-called differential file (differential program).

[0127] In addition to or instead of the above configuration, a custom LSI (Large Scale Integrated Circuit) such as a PLD (Programmable Logic Device), an ASIC (Application Specific Integrated Circuit), a GPU (Graphics Processing Unit), or a processing device similar thereto may be provided. Examples of PLDs include PAL (Programmable Array Logic), GAL (Generic Array Logic), CPLD (Complex Programmable Logic Device), and FPGA (Field Programmable Gate Array). In this case, some or all of the functions realized by the processor may be realized by the integrated circuit.

[0128] <Additional Notes> The description in each embodiment can be understood, for example, as follows.

[0129] (1) A bioreactor 10 according to a first embodiment includes an outer cylinder 22 centered on an axis O extending in a vertical direction, an inner cylinder 30 provided inside the outer cylinder 22 and centered on the axis O, a rotating cylinder 43 disposed between the outer cylinder 22 and the inner cylinder 30, defining a first pool P1 between the outer cylinder 22 and the inner cylinder 30 and defining a second pool P2 between the outer cylinder 22 and the inner cylinder 30, and configured to rotate around the axis O, a drive unit 50 that drives the rotating cylinder 43 to rotate around the axis O, a first supply port 61a capable of supplying liquid to the first pool P1, and a second supply port 71a capable of supplying liquid to the second pool P2, Equipped with.

[0130] This allows different media to be supplied to the first pool P1 and the second pool P2. In addition, by rotating the rotating cylinder 43, Taylor vortices can be formed in both the first pool P1 and the second pool P2. This allows cells in different growth phases to be cultured simultaneously in a compact configuration.

[0131] (2) The bioreactor 10 of the second embodiment is the bioreactor 10 of (1) provided with a first culture medium supply unit 60 capable of supplying a first culture medium as the liquid to the first pool P1 via the first supply port 61a, and a second culture medium supply unit 70 capable of supplying a second culture medium having different components from the first culture medium as the liquid to the second pool P2 via the second supply port 71a.

[0132] This makes it possible to create growth environments for cells corresponding to different growth phases in each of the first pool P1 and the second pool P2.

[0133] (3) The bioreactor 10 of the third aspect is the bioreactor 10 of (1) or (2) provided with a first temperature control unit 91 capable of adjusting the temperature of the first pool P1 and a second temperature control unit 92 capable of adjusting the temperature of the second pool P2 independently of the first temperature control unit 91.

[0134] This allows the first pool P1 and the second pool P2 to be set to appropriate temperatures according to the growth phase of the cells.

[0135] (4) A bioreactor (10) according to a fourth aspect is the bioreactor (10) of (3) including a low thermal conductivity member (190) provided on the surface of the rotating cylinder (43) and having a thermal conductivity lower than that of the rotating cylinder (43).

[0136] This makes it possible to suppress heat transfer between the first pool P1 and the second pool P2.

[0137] (5) A bioreactor 10 according to a fifth aspect is the bioreactor 10 according to (3) or (4), in which the rotating cylinder 43 is made of a material having a lower thermal conductivity than the outer cylinder 22.

[0138] This makes it possible to suppress heat transfer between the first pool P1 and the second pool P2.

[0139] (6) The bioreactor 10 according to a sixth aspect is any one of the bioreactors 10 of (1) to (5) including an oxygen supply unit 100 capable of supplying oxygen to the first pool P1 and the second pool P2.

[0140] This makes it possible to supply oxygen necessary for cell culture to the first pool P1 and the second pool P2.

[0141] (7) A sixth aspect of the bioreactor 10 is the bioreactor 10 of (6), wherein the oxygen supply section 100 includes a first oxygen supply section 101 capable of supplying oxygen to the first pool P1, and a second oxygen supply section 102 capable of supplying oxygen to the second pool P2 independently of the first oxygen supply section 101.

[0142] This makes it possible to set appropriate oxygen supply amounts in accordance with the growth phases of the cells in the first pool P1 and the second pool P2.

[0143] (8) The bioreactor 10 of the eighth aspect is a bioreactor 10 of (1) to (7) comprising a cell supply section 80 that supplies cells to the first pool P1, and a moving mechanism 150 that moves at least a portion of the liquid in the first pool P1 to the second pool P2.

[0144] As a result, for example, after cells have been grown in the first pool P1, when the cells progress to the next growth phase, the cells can be moved to the second pool P2 and cultured in a manner appropriate for that growth phase.

[0145] (9) A ninth aspect of the bioreactor 10 is the bioreactor 10 of (8), wherein the transfer mechanism 150 has a transfer pipe connecting the first pool P1 and the second pool P2, and a transfer valve 152 provided in the transfer pipe and capable of being opened and closed.

[0146] This allows the transfer of medium and cells from the first pool P1 to the second pool P2.

[0147] (10) The bioreactor 10 of the tenth aspect is the bioreactor 10 of (8), wherein the drive unit 50 is capable of driving the rotating cylinder 43 to rotate in both forward and reverse directions, the rotating cylinder 43 has an opening 43b that penetrates the rotating cylinder 43 radially, and the moving mechanism 150 has an opening / closing unit that closes the opening 43b when the rotating cylinder 43 rotates forward and opens the opening 43b when the rotating cylinder 43 rotates reversely.

[0148] This allows the medium and cells to be easily transferred from the first pool P1 to the second pool P2.

[0149] (11) The bioreactor 10 according to an eleventh aspect is the bioreactor 10 of (10), in which the moving mechanism 150 has a sliding door 160 that can slide between a blocking position that blocks the opening 43b and an opening position that is located forward of the blocking position in the forward rotation direction and opens the opening 43b.

[0150] This allows the medium and cells to be easily transferred from the first pool P1 to the second pool P2.

[0151] (12) The bioreactor 10 of the twelfth aspect is the bioreactor 10 of (10), in which the moving mechanism 150 has an opening / closing door 170 that is rotatable around a rotation axis extending vertically at the front side of the opening 43b in the positive rotation direction, and the opening / closing door 170 is rotatable between a closing position that closes the opening 43b and an opening position that moves away from the opening 43b to open the opening 43b.

[0152] This allows the medium and cells to be easily transferred from the first pool P1 to the second pool P2.

[0153] (13) The bioreactor 10 of the thirteenth aspect is any of the bioreactors 10 of (1) to (12), further comprising an extraction section 110 having a discharge line 111 capable of removing the liquid in the second pool P2 to the outside, a cell acquisition section 120 provided in the discharge line 111 for extracting the cells from the liquid, and an antibody acquisition section 130 provided in the discharge line 111 for extracting antibodies produced by the cells from the liquid.

[0154] This allows liquid to be removed from the second pool P2 and allows cells and antibodies to be extracted from the liquid.

[0155] (14) The bioreactor 10 of the fourteenth aspect is the bioreactor 10 of (13), in which the discharge line 111 passes through the inside of the inner cylinder 30, and at least one of the cell acquisition section 120 and the antibody acquisition section 130 is provided inside the inner cylinder 30.

[0156] This allows the internal space of the inner cylinder 30 to be effectively utilized, and the installation space for the cell acquisition section 120 and the antibody acquisition section 130 to be efficiently used.

[0157] (15) The bioreactor 10 of the fifteenth aspect is the bioreactor 10 of (13) or (14), in which the removal section 110 is connected to the discharge line 111 downstream of the cell acquisition section 120 and the antibody acquisition section 130 and has a circulation line 140 capable of returning the liquid to the second pool P2.

[0158] This allows the medium and cells to be reused, and since continuous culture can be performed, the efficiency of antibody production can be improved.

[0159] (16) The bioreactor 10 of the fourteenth aspect is any of the bioreactors 10 of (1) to (15), which has a lower bottom 21 that closes the outer cylinder 22 from below, and the lower edge 43a of the rotating cylinder 43 faces the lower end of the lower bottom 21 via a clearance.

[0160] This makes it possible to smoothly rotate the rotating cylinder 43 while preventing the liquids in the first pool P1 and the second pool P2 from accidentally mixing with each other.

[0161] (17) The bioreactor (10) according to a seventeenth aspect is the bioreactor (16) further comprising a seal part (180) for sealing between the lower end edge part (43a) of the rotating cylinder (43) and the upper surface of the lower bottom part (21).

[0162] This makes it possible to further prevent the liquids in the first pool P1 and the second pool P2 from mixing with each other.

[0163] (18) A bioreactor system 1 according to an eighteenth aspect includes a bioreactor 10 of (1) and a control device 200 for controlling the bioreactor 10. The bioreactor 10 includes a first culture medium supply unit 60 capable of supplying a first culture medium as the liquid to the first pool P1 via the first supply port 61a, and a second culture medium supply unit 70 capable of supplying the second culture medium, which has a different component from the first culture medium as the liquid, to the second pool P2 via the second supply port 71a. The control device 200 includes a culture medium supply control unit 201 for executing a culture medium supply step of controlling the first culture medium supply unit 60 to supply the first culture medium to the first pool P1 and controlling the second culture medium supply unit 70 to supply the second culture medium to the second pool P2.

[0164] This makes it possible to create a growth environment for cells in different growth phases in a compact configuration.

[0165] (19) A bioreactor system 1 according to a 19th aspect is the bioreactor system 1 of (18), wherein the bioreactor 10 has a cell supplying unit 80 which supplies cells to the culture medium of the first pool P1, and the control device 200 has a cell supply control unit 203 which executes a cell supplying step of supplying the cells to the first pool P1 by controlling the cell supplying unit 80 after the culture medium supplying step, and a culture execution unit 204 which executes a culture step of rotating the rotating cylinder 43 by controlling the drive unit 50 after the cell supplying step.

[0166] This allows cell proliferation in the first pool P1.

[0167] (20) A bioreactor system 1 according to a twentieth aspect is the bioreactor system 1 of (19), in which the bioreactor 10 has a moving mechanism 150 that moves at least a portion of the liquid in the first pool P1 to the second pool P2, the control device 200 has a moving execution unit 205 that executes a moving step of moving the liquid in the first pool P1 to the second pool P2 by controlling the moving mechanism 150 after the culture step, and the culture execution unit 204 executes the culture step again after the moving step.

[0168] By transferring the cells grown in the first pool P1 to the second pool P2, it is possible to sequentially culture the cells according to their growth phase in one device. For example, in the second phase, an environment suitable for the cells to produce antibodies can be created, allowing for efficient antibody production.

[0169] (21) A bioreactor system 1 according to a 21st aspect is a bioreactor system 1 (20) in which the movement mechanism 150 has a movement pipe connecting the first pool P1 and the second pool P2, and a movement valve 152 that is provided in the movement pipe and can be opened and closed, and the movement execution unit 205 moves the liquid in the first pool P1 to the second pool P2 by controlling the movement valve 152 as the movement process.

[0170] This facilitates the transfer of cells from the first pool P1 to the second pool P2.

[0171] (22) A bioreactor system 1 according to a 22nd aspect is the bioreactor system 1 of (20), wherein the drive unit 50 is capable of driving the rotating cylinder 43 in both forward and reverse rotation, the culture execution unit 204 drives the rotating cylinder 43 in the forward rotation by controlling the drive unit 50, the rotating cylinder 43 has an opening 43b that penetrates the rotating cylinder 43 in the radial direction, the movement mechanism 150 has an opening / closing unit that closes the opening 43b when the rotating cylinder 43 rotates in the forward direction and opens the opening 43b when the rotating cylinder 43 rotates in the reverse direction, and the movement execution unit 205 controls the drive unit 50 to drive the rotating cylinder 43 in the reverse rotation at a rotation speed smaller than the forward rotation drive as the movement process.

[0172] As a result, the cells and culture medium in the first pool P1 can be moved to the second pool P2 simply by rotating the rotating cylinder 43. That is, since the cells can be moved by controlling only the rotating cylinder 43, a simple configuration can be achieved.

[0173] (23) The bioreactor system 1 of the 23rd aspect is the bioreactor system 1 of any of (20) to (22), in which the bioreactor 10 is provided with a discharge line 111 capable of discharging the liquid in the second pool P2 to the outside, an extraction unit 110 having a cell acquisition unit 120 provided in the discharge line 111 for extracting the cells from the liquid, and an antibody acquisition unit 130 provided in the discharge line 111 for extracting antibodies produced by the cells from the liquid, and the control device 200 has a discharge execution unit 206 that performs a discharge process of extracting and discharging the liquid from the second pool P2 by controlling the removal unit 110 after the culture process following the movement process is completed.

[0174] This makes it possible to remove the liquid in the second pool P2 after antibody production to the outside, and to extract the cells and antibodies from the liquid.

[0175] (24) In a bioreactor system 1 according to a 24th aspect, the removal unit 110 has a circulation line 140 that is connected to the discharge line 111 downstream of the cell acquisition unit 120 and the antibody acquisition unit 130 and is capable of returning the liquid to the second pool P2, the cell supply control unit 203 executes the cell supply step again between the moving step and the culture step after the moving step, and the control device 200 determines whether or not to perform continuous operation between the culture step after the moving step and the discharge step. The discharge execution unit 206 further includes a determination unit 208 that performs the discharge step when the determination unit 208 determines that continuous operation is not to be performed, and the discharge execution unit 206 further includes a circulation execution unit 207 that performs a circulation step of returning the liquid removed from the second pool P2 to the second pool P2 via the circulation line 140 by controlling the removal unit 110 when the determination unit 208 determines that continuous operation is to be performed, and the transfer execution unit 205 performs the transfer step again after the circulation step (23).

[0176] This allows the medium to be reused. Furthermore, by repeating the circulation process, cell proliferation in the first pool P1 and antibody production in the second pool P2 can be carried out sequentially. In other words, continuous culture is possible, which improves the efficiency of antibody production.

[0177] (25) A bioreactor system 1 according to a 25th aspect includes the bioreactor 10 of (1) and a control device 200 for controlling the bioreactor 10. The bioreactor 10 includes a first temperature control unit 91 capable of controlling the temperature of the first pool P1, a second temperature control unit 92 capable of controlling the temperature of the second pool P2, and The bioreactor system 1 is provided with the control device 200 having a temperature setting unit 202 that controls the first temperature adjustment unit 91 and the second temperature adjustment unit 92 so that the first pool P1 and the second pool P2 have different temperatures.

[0178] This allows the first pool P1 and the second pool P2 to be set to appropriate temperatures separately.

[0179] (26) A bioreactor system 1 according to a 26th aspect includes a bioreactor 10 of (1) and a control device 200 for controlling the bioreactor 10. The bioreactor 10 includes a first oxygen supply unit 101 capable of supplying oxygen to the first pool P1 and a second oxygen supply unit 102 capable of supplying oxygen to the second pool P2. The control device 200 has an oxygen supply control unit 212 for controlling the first oxygen supply unit 101 and the second oxygen supply unit 102 so that the amounts of oxygen supplied to the first pool P1 and the second pool P2 are different from each other.

[0180] This allows the oxygen concentrations in the first pool P1 and the second pool P2 to be set to appropriate values ​​separately.

[0181] (27) A method for operating a bioreactor 10 according to a 27th aspect is a method for operating a bioreactor 10 including an outer cylinder 22 centered on an axis O extending in the vertical direction, an inner cylinder 30 centered on the axis O inside the outer cylinder 22, a rotating cylinder 43 disposed between the outer cylinder 22 and the inner cylinder 30 to define a first pool P1 between the outer cylinder 22 and the inner cylinder 30 and to define a second pool P2 between the outer cylinder 22 and the inner cylinder 30 and to be rotatable about the axis O, and a drive unit 50 for driving the rotating cylinder 43 to rotate about the axis O, the method including a culture medium supplying step of supplying a first culture medium to the first pool P1 and supplying a second culture medium having components different from the first culture medium to the second pool P2.

[0182] This makes it possible to culture cells according to their growth phase with a compact configuration.

[0183] (28) A 28th aspect of the method for operating the bioreactor 10 is the method for operating the bioreactor 10 of (27), further including a cell supplying step of supplying the cells to the first pool P1 after the culture medium supplying step, and a culture step of rotating the rotating cylinder 43 via the driving unit 50 after the cell supplying step.

[0184] This allows the cells to grow in the first pool P1.

[0185] (29) A 29th aspect of the method for operating the bioreactor 10 is the method for operating the bioreactor 10 of (28), further comprising a transfer step of transferring the liquid in the first pool P1 to the second pool P2 after the culture step, and the culture step is executed again after the transfer step.

[0186] By transferring the cells grown in the first pool P1 to the second pool P2, it is possible to culture the cells according to their growth phase. For example, in the second phase, an environment suitable for the cells to produce antibodies can be created, allowing efficient antibody production.

[0187] (30) A 30th aspect of the method for operating the bioreactor 10 is the method for operating the bioreactor 10 of (29), further comprising a discharge step of removing the liquid from the second pool P2 and extracting the cells and the antibodies produced by the cells from the liquid after the culture step following the transfer step is completed.

[0188] This makes it possible to remove the liquid in the second pool P2 after antibody production to the outside, and to extract the cells and antibodies from the liquid.

[0189] (31) A method for operating a bioreactor 10 according to a 31st aspect includes a determination step for determining whether or not to perform continuous operation between the culture step and the discharge step after the transfer step, the discharge step being executed when it is determined in the determination step that continuous operation is not to be performed, and further includes a circulation step for removing liquid from the second pool P2, extracting the cells and the antibodies from the liquid, and returning the liquid to the second pool P2 when it is determined in the determination step that continuous operation is to be performed, and the method for operating a bioreactor 10 of (30) includes the transfer step being executed again after the circulation step.

[0190] This allows the medium to be reused. Furthermore, by repeating the circulation process, cell proliferation in the first pool P1 and antibody production in the second pool P2 can be carried out sequentially. In other words, continuous culture is possible, which improves the efficiency of antibody production. [Explanation of symbols]

[0191] 1. Bioreactor System 10 Bioreactor 20 Casing 21 Lower base 22 Outer Cylinder 23 Lid 23a Penetration 30 Inner Cylinder 40 Rotating section 41 Shaft 42 Upper base 43 Rotating Cylinder 43a Lower edge 43b opening 50 Drive unit 60 First medium supply unit 61 First supply pipe 61a First supply port 62 First Supply Line 63 First supply valve 64 First medium storage section 70 Second medium supply unit 71 Second supply pipe 71a Second supply port 72 Second Supply Line 73 Second supply valve 74 Second medium storage section 80 Cell supply section 81 Cell supply tube 81a Cell supply port 82 Cell supply line 83 Cell supply valve 84 Cell Containment Section 91 First temperature control section 92 Second temperature control section 100 Oxygen supply unit 101 First oxygen supply unit 102 Second oxygen supply section 110 Removal section 111 Discharge Line 112 Exhaust valve 113 Extraction Pump 120 Cell Acquisition Department 130 Antibody acquisition department 140 Circulation Line 141 Circulation valve 150 Moving mechanism 151 Moving Line 152 Moving valve 160 Sliding Door 161 Stopper 170 Opening and closing doors 171 Hinge 180 Seal part 181 Rotating seal piece 182 Fixed seal piece 183 Circular Groove 184 Finn 185 Notch 186 Finn 190 Low thermal conductivity materials 200 Control device 201 Culture medium supply control unit 202 Temperature setting section 203 Cell supply control unit 204 Cultivation Department 205 Mobile Execution Department 206 Discharge Execution Department 207 Circulation Executive Department 208 Judgment section 211 Valve control section 212 Oxygen supply control unit 213 Rotation control section 214 Pump control section 301 CPU 302 Main Memory 303 Storage 304 Interface O axis P1 First Pool P2 Second Pool

Claims

1. An outer cylinder having an axis extending in a vertical direction as a center; an inner cylinder disposed inside the outer cylinder and centered about the axis; a rotating cylinder disposed between the outer cylinder and the inner cylinder, defining a first pool between the inner cylinder and the rotating cylinder, and defining a second pool between the outer cylinder and the rotating cylinder, the rotating cylinder being rotatable about the axis; A drive unit that drives the rotating cylinder to rotate about the axis; a first supply port capable of supplying liquid to the first pool; a second supply port capable of supplying liquid to the second pool; A bioreactor comprising:

2. a first culture medium supply unit capable of supplying a first culture medium as the liquid to the first pool via the first supply port; a second culture medium supply unit capable of supplying a second culture medium having a different component from the first culture medium as the liquid to the second pool via the second supply port; The bioreactor of claim 1 .

3. A first temperature control unit capable of adjusting the temperature of the first pool; A second temperature control unit capable of controlling the temperature of the second pool independently of the first temperature control unit; The bioreactor of claim 1 .

4. The bioreactor according to claim 1 , further comprising an oxygen supply unit capable of supplying oxygen to the first pool and the second pool.

5. The oxygen supply unit is A first oxygen supply unit capable of supplying oxygen to the first pool; A second oxygen supply unit capable of supplying oxygen to the second pool independently of the first oxygen supply unit; 5. The bioreactor of claim 4 comprising:

6. A cell supplying unit that supplies cells to the first pool; a moving mechanism that moves at least a portion of the liquid in the first pool to the second pool; A bioreactor according to any one of claims 1 to 5, comprising:

7. The moving mechanism includes: A transfer pipe connecting the first pool and the second pool; A transfer valve provided in the transfer pipe and capable of being opened and closed; The bioreactor of claim 6, comprising:

8. The drive unit is capable of driving the rotating cylinder to rotate in forward and reverse directions, The rotating cylinder has an opening extending radially through the rotating cylinder, The bioreactor according to claim 6 , wherein the moving mechanism has an opening / closing part that closes the opening when the rotating cylinder rotates in the forward direction and opens the opening when the rotating cylinder rotates in the reverse direction.

9. The moving mechanism includes:

9. The bioreactor according to claim 8, further comprising a sliding door that is slidable between a closing position that closes the opening and an opening position that is located forward of the closing position in the forward rotation direction and opens the opening.

10. The moving mechanism includes: a door that is rotatable about a rotation axis that extends vertically at a front side of the opening in the forward rotation direction, 9. The bioreactor according to claim 8, wherein the door is rotatable between a closed position where the door closes the opening and an open position where the door moves away from the opening to open the opening.

11. 6. The bioreactor according to claim 1, further comprising an extraction section having a discharge line capable of removing the liquid in the second pool to the outside, a cell acquisition section provided in the discharge line for extracting cells from the liquid, and an antibody acquisition section provided in the discharge line for extracting antibodies produced by the cells from the liquid.

12. The discharge line passes through the interior of the inner cylinder, The bioreactor according to claim 11 , wherein at least one of the cell acquisition section and the antibody acquisition section is provided inside the inner cylinder.

13. The take-out section includes: The bioreactor according to claim 11 , further comprising a circulation line connected to the discharge line downstream of the cell capture section and the antibody capture section and capable of returning the liquid to the second pool.

14. A lower bottom portion is provided to close the outer cylinder from below, 6. The bioreactor according to claim 1, wherein a lower edge of the rotating cylinder faces an upper surface of the lower base with a clearance therebetween.

15. The bioreactor of claim 14, further comprising a seal portion for sealing between the lower edge of the rotating cylinder and the upper surface of the lower bottom portion.

16. A bioreactor according to claim 1; A control device for controlling the bioreactor; Equipped with The bioreactor comprises: a first culture medium supply unit capable of supplying a first culture medium as the liquid to the first pool via the first supply port; a second culture medium supply unit capable of supplying a second culture medium having a different component from the first culture medium as the liquid to the second pool via the second supply port; Equipped with The control device includes: A bioreactor system having a culture medium supply control unit that executes a culture medium supplying step of supplying the first culture medium to the first pool by controlling the first culture medium supply unit and supplying the second culture medium to the second pool by controlling the second culture medium supply unit.

17. An outer cylinder having an axis extending in a vertical direction as a center; an inner cylinder disposed inside the outer cylinder and centered about the axis; a rotating cylinder disposed between the outer cylinder and the inner cylinder, defining a first pool between the inner cylinder and the rotating cylinder, and defining a second pool between the outer cylinder and the rotating cylinder, the rotating cylinder being rotatable about the axis; A drive unit that drives the rotating cylinder to rotate about the axis; A method of operating a bioreactor comprising: A method for operating a bioreactor, comprising a medium supplying step of supplying a first medium to the first pool and supplying a second medium having components different from those of the first medium to the second pool.

18. a cell supplying step of supplying cells to the first pool after the medium supplying step; a culturing step of rotating the rotating cylinder via the driving unit after the cell supplying step; 20. The method of claim 17, further comprising:

19. The method further includes a transfer step of transferring the liquid in the first pool to the second pool after the incubation step, The method for operating a bioreactor according to claim 18, wherein the culturing step is carried out again after the transferring step.

20. The method for operating a bioreactor according to claim 19, further comprising a discharge step of removing the liquid from the second pool and extracting the cells and antibodies produced by the cells from the liquid after the culture step following the transfer step is completed.

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