Biological culture device, torrent bioreactor and regulation and control method thereof

Abstract

The invention relates to a biological culture device, a torrent bioreactor and a regulation and control method of the torrent bioreactor, which can realize synergistic coupling of basic oxygen supply and enhanced mixing and dynamically meet the requirements of each stage of cell culture so as to improve the cell culture performance of the torrent bioreactor. The biological culture device comprises a culture container used for containing a culture solution; and one or more spoilers, the spoilers are arranged in the culture container, and the spoilers are provided with filling cavities used for containing fluid; when the filling cavity is used for being filled with fluid, the turbulent flow piece expands so as to inwards protrude out of the inner wall of the culture container to form a turbulent flow structure; and when the filling cavity is used for discharging the fluid, the turbulent flow piece shrinks to be attached to the inner wall of the culture container so as to remove the turbulent flow structure.

Description

Technical Field

[0001] This application relates to the field of bioreactor technology, and in particular to a biological culture device, a turbulent flow bioreactor, and a method for controlling the same. Background Technology

[0002] The turbulent flow bioreactor employs a non-bubbling interface oxygen transfer mechanism, which typically generates a turbulent flow field through the periodic oscillation of the tank. This causes the culture medium to repeatedly flush the culture bag, carrying away gas and creating nanoscale soluble microbubbles. The bubbles are continuously mixed, ensuring that each cell receives sufficient oxygen and nutrients to maintain normal cell growth and metabolism.

[0003] Although this type of turbulent bioreactor is widely used for the culture of sensitive cells such as animal cells and stem cells due to its low shear force and mild mixing, it relies solely on the top air inlet for basic oxygen supply. In the later stages of biological culture (when cell density is high), the oxygen mass transfer rate becomes a limiting factor, which cannot meet the oxygen demand of rapid cell growth, leading to inhibition of cell proliferation and a decrease in product yield.

[0004] Furthermore, the flow field inside existing turbulent bioreactors is usually determined by fixed geometry (such as an inverted cone) and fixed oscillation parameters. The mixing intensity cannot be dynamically adjusted according to the metabolic state of the cells. This can easily lead to energy waste due to overmixing at low cell densities and generate unnecessary shear forces that can damage the cells. Alternatively, at high cell densities, insufficient mixing can result in uneven distribution of nutrients and dissolved oxygen, forming local "dead zones" that severely affect cell proliferation efficiency and product yield. Summary of the Invention

[0005] Addressing the issues that existing turbulent flow bioreactors cannot meet the oxygen demand of rapidly growing cells with basic oxygen supply and / or cannot balance the shear force and material distribution requirements in the early and late stages of cell culture, this application provides a biological culture device, a turbulent flow bioreactor, and its control method. This device can achieve synergistic coupling of basic oxygen supply and enhanced mixing, dynamically meeting the needs of each stage of cell culture, thereby improving the cell culture performance of the turbulent flow bioreactor.

[0006] According to one aspect of this application, one embodiment provides a biological culture apparatus, comprising: a culture container for holding a culture medium; and one or more flow disruptors disposed within the culture container, the flow disruptors having a filling cavity for containing fluid; when the filling cavity is used to fill fluid, the flow disruptors expand to bulge inwardly out of the inner wall of the culture container to form a flow disruptor structure; when the filling cavity is used to discharge fluid, the flow disruptors contract to conform to the inner wall of the culture container to remove the flow disruptor structure.

[0007] According to one embodiment of this application, the spoiler is an airbag.

[0008] According to one embodiment of this application, the airbag includes a flexible limiting outer layer fixed to the culture container and / or an elastically inflatable inner layer disposed within the flexible limiting outer layer to define the filling cavity.

[0009] According to one embodiment of this application, when the airbag is inflated, the airbag has a streamlined wing-shaped protrusion structure; wherein the thickness of the front end of the airbag is greater than the thickness of the back end of the airbag.

[0010] According to one embodiment of this application, a plurality of the disturbance elements are arranged in a spirally staggered manner on the inner wall of the culture container.

[0011] According to one embodiment of this application, each of the disturbance elements extends spirally from bottom to top on the inner wall of the culture container in the direction of the flow.

[0012] According to one embodiment of this application, the inner cavity of the culture container has a cylindrical portion and a frustum-shaped portion that tapers downward from the cylindrical portion; the turbulence-disrupting element is located on the conical surface of the frustum-shaped portion.

[0013] According to one embodiment of this application, the culture container includes a rigid tank, and the baffle is disposed on the inner surface of the rigid tank.

[0014] According to one embodiment of this application, the culture container further includes a flexible bag disposed within and adapted to the rigid tank, such that the baffle is located between the rigid tank and the flexible bag.

[0015] According to one embodiment of this application, the culture container includes a flexible bag body, and the flow-disrupting element is disposed on the bag wall of the flexible bag body.

[0016] According to another aspect of this application, one embodiment of this application further provides a turbulent bioreactor, comprising: any of the above-described biological culture devices; and an eccentric drive device, driven and connected to the biological culture device, so that the biological culture device performs eccentric oscillating motion under the drive of the eccentric drive device.

[0017] According to one embodiment of this application, the turbulent flow bioreactor further includes a sensing and control system, which includes a basic oxygen supply module connected to the culture vessel of the bioreactor and used to provide a basic oxygen supply to the culture medium, a turbulence drive module connected to the turbulence element of the bioreactor and used to drive the turbulence element to fill and drain, a dissolved oxygen sensor disposed in the culture vessel and used to monitor the dissolved oxygen concentration in the culture medium in real time, and a central controller communicatively connected to the basic oxygen supply module, the turbulence drive module, and the dissolved oxygen sensor.

[0018] According to one embodiment of this application, the central controller is configured to: when the dissolved oxygen concentration monitored by the dissolved oxygen sensor is higher than a preset dissolved oxygen threshold, control the basic oxygen supply module to work independently to maintain the basic dissolved oxygen level and keep the turbulence component in a contracted state; when the dissolved oxygen concentration monitored by the dissolved oxygen sensor is lower than the preset dissolved oxygen threshold, control the basic oxygen supply module to increase the oxygen supply and control the turbulence drive module to drive at least one turbulence component in an expanded state.

[0019] According to one embodiment of this application, the central controller is communicatively connected to the eccentric drive device and is used to control the turbulence drive module to drive multiple turbulence components to sequentially charge and discharge based on the real-time oscillation phase signal of the eccentric drive device.

[0020] According to another aspect of this application, one embodiment of this application further provides a method for regulating a turbulent bioreactor, comprising the steps of: maintaining a basic dissolved oxygen level in the culture medium through a basic oxygen supply module; acquiring parameters reflecting the metabolic state of cells in real time, including dissolved oxygen concentration and / or viable cell density; determining the oxygen consumption state of cells in the culture medium based on the acquired parameters; and activating a collaborative regulation strategy when the oxygen consumption of cells in the culture medium exceeds a preset oxygen consumption threshold, the collaborative regulation strategy comprising: instructing the basic oxygen supply module to provide oxygen supply intensity; and / or instructing at least one flow-inducing element to expand to enhance liquid mixing and oxygen dispersion.

[0021] In summary, the turbulent flow bioreactor of this application utilizes a non-bubbling interface oxygen transfer mechanism. It generates a turbulent flow through mechanical oscillation, causing the culture medium to repeatedly flush the inner surface of the culture vessel to rapidly dissolve oxygen. Simultaneously, the culture medium carries away gas, creating nanoscale soluble microbubbles, which are continuously mixed. This ensures that each cell in the low-density cell culture stage receives sufficient oxygen and nutrients to maintain normal cell growth and metabolism. In the high-density cell culture stage, the turbulence-inducing element expands to form a turbulence structure on the inner wall of the culture vessel. This creates a significant turbulence effect as the culture medium flows through this structure, enhancing mixing. This improves both liquid mixing and nutrient distribution uniformity, as well as oxygen dispersion and dissolved oxygen efficiency.

[0022] In other words, the biological culture device of this application functionally couples oxygen supply and mixing, achieving a seamless switch from basic maintenance to enhanced supply. It can balance low energy consumption and low shear force in the low-density cell culture stage, so as to avoid unnecessary shear force without wasting energy, and it can also balance high dissolved oxygen and uniform nutrient distribution in the high-density cell culture stage, so as to improve dissolved oxygen efficiency while avoiding the formation of local dead zones and improving cell culture performance. Thus, the cells are always in the optimal physical microenvironment throughout the entire culture process, directly contributing to higher cell density, longer viability maintenance time, and higher yield of target products. Attached Figure Description

[0023] Figure 1 This is a schematic diagram of the structure of a turbulent bioreactor according to an embodiment of this application;

[0024] Figure 2 A schematic diagram of the state of the biological culture device in the turbulent bioreactor according to the above embodiments of this application when the turbulence element contracts is shown.

[0025] Figure 3 A schematic diagram of the state of the biological culture apparatus according to the above embodiments of this application when the turbulence element expands is shown;

[0026] Figure 4 An explosion schematic diagram of a biological culture apparatus according to the above embodiments of this application is shown;

[0027] Figure 5 It shows Figure 2 A cross-sectional schematic diagram of the biological culture apparatus shown;

[0028] Figure 6 It shows Figure 3 A cross-sectional schematic diagram of the biological culture apparatus shown;

[0029] Figure 7 A modified example of a biological culture apparatus according to the above embodiments of this application is shown;

[0030] Figure 8 A block diagram of a sensing and control system in a turbulent bioreactor according to the above embodiments of this application is shown;

[0031] Figure 9 This is a schematic flowchart of a method for regulating a turbulent bioreactor according to an embodiment of this application.

[0032] Figure label:

[0033] 1. Biological culture device; 10. Culture container; 101. Cylindrical part; 102. Frustum part; 11. Rigid tank; 12. Flexible bag; 20. Flow-disrupting component; 200. Filling cavity; 201. Flow-facing end; 202. Flow-reversing end; 21. Flexible limiting outer layer; 22. Elastic air-filled inner layer; 3. Sensing and control system; 31. Basic oxygen supply module; 32. Flow-disrupting drive module; 33. Dissolved oxygen sensor; 34. Central controller. Detailed Implementation

[0034] To make the above-mentioned objectives, features, and advantages of this application more apparent and understandable, the specific embodiments of this application are described in detail below with reference to the accompanying drawings. Many specific details are set forth in the following description to provide a thorough understanding of this application. However, this application can be implemented in many other ways different from those described herein, and those skilled in the art can make similar modifications without departing from the spirit of this application. Therefore, this application is not limited to the specific embodiments disclosed below.

[0035] In the description of this application, it should be understood that the terms "center", "longitudinal", "lateral", "length", "width", "thickness", "upper", "lower", "front", "rear", "left", "right", "vertical", "horizontal", "top", "bottom", "inner", "outer", "clockwise", "counterclockwise", "axial", "radial", "circumferential", etc., indicating the orientation or positional relationship based on the orientation or positional relationship shown in the accompanying drawings, are only for the convenience of describing this application and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation, and therefore should not be construed as a limitation of this application.

[0036] Furthermore, the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include at least one of that feature. In the description of this application, "multiple" means at least two, such as two, three, etc., unless otherwise explicitly specified.

[0037] In this application, unless otherwise expressly specified and limited, the terms "installation," "connection," "joining," and "fixing," etc., should be interpreted broadly. For example, they can refer to a fixed connection, a detachable connection, or an integral part; they can refer to a mechanical connection or an electrical connection; they can refer to a direct connection or an indirect connection through an intermediate medium; they can refer to the internal communication of two components or the interaction between two components, unless otherwise expressly limited. Those skilled in the art can understand the specific meaning of the above terms in this application according to the specific circumstances.

[0038] In this application, unless otherwise expressly specified and limited, "above" or "below" the second feature can mean that the first feature is in direct contact with the second feature, or that the first feature is in indirect contact with the second feature through an intermediate medium. Furthermore, "above," "on top of," and "over" the second feature can mean that the first feature is directly above or diagonally above the second feature, or simply that the first feature is at a higher horizontal level than the second feature. "Below," "below," and "under" the second feature can mean that the first feature is directly below or diagonally below the second feature, or simply that the first feature is at a lower horizontal level than the second feature.

[0039] It should be noted that when an element is referred to as being "fixed to" or "set on" another element, it can be directly on the other element or there may be an intervening element. When an element is considered to be "connected to" another element, it can be directly connected to the other element or there may be an intervening element. The terms "vertical," "horizontal," "upper," "lower," "left," "right," and similar expressions used herein are for illustrative purposes only and do not represent the only possible implementation.

[0040] Studies have found that the oxygen and nutrient requirements vary at different stages of biological culture. For example, low-density cell culture requires less oxygen and nutrients, while high-density cell culture requires more. However, existing turbulent flow bioreactors have the following problems: First, relying solely on the top air inlet for basic oxygen supply cannot meet the oxygen demand of rapidly growing cells during high-density cell culture, leading to inhibited cell proliferation and reduced product yield. Second, the mixing intensity of the flow field inside the reactor cannot be dynamically adjusted according to the metabolic state of the cells. This can easily lead to energy waste due to over-mixing at low cell densities and the generation of unnecessary shear forces that damage cells, or uneven distribution of nutrients and dissolved oxygen due to insufficient mixing at high cell densities, forming local "dead zones" that severely affect cell proliferation efficiency and product yield.

[0041] Furthermore, in the high-density cell culture stage, existing turbulent bioreactors, by simply increasing the top oxygen flow rate, cannot effectively dissolve and rapidly disperse oxygen, resulting in a slow response and low efficiency, and cannot meet the needs of high-density cell culture.

[0042] Based on this, this application provides a biological culture device, a turbulent flow bioreactor and its control method, which can achieve synergistic coupling of basic oxygen supply and enhanced mixing, dynamically meet the needs of each stage of cell culture, so as to improve the cell culture performance of the bioreactor.

[0043] Specifically, refer to the accompanying drawings in the specification of this application. Figures 1 to 7 According to one embodiment of this application, a turbulent flow bioreactor is provided, which may include a biological culture device 1 for containing cells and mixing dissolved oxygen, and an eccentric drive device 2 connected to the biological culture device 1, such that the biological culture device 1 performs eccentric oscillating motion under the drive of the eccentric drive device 2. It is understood that the biological culture device 1 may also include, but is not limited to, components such as pipes, connectors, flow clamps, or filters, and can control microbial environmental parameters such as temperature and pH online; these will not be elaborated further in this application.

[0044] More specifically, such as Figures 2 to 7 As shown, the biological culture apparatus 1 may include a culture container 10 for holding culture medium and one or more flow-dispersing elements 20. The flow-dispersing elements 20 are disposed within the culture container 10 and have a filling cavity 200 for containing fluid. When the filling cavity 200 is filled with fluid, the flow-dispersing element 20 expands to protrude inward from the inner wall of the culture container 10, forming a flow-dispersing structure. When the filling cavity 200 is discharged with fluid, the flow-dispersing element 20 contracts to conform to the inner wall of the culture container 10, thus removing the flow-dispersing structure.

[0045] Thus, as Figure 2 and Figure 5 As shown, during the low-density cell culture stage, the fluid in the filling cavity 200 only needs to be discharged, causing the turbulence-disrupting component 20 to contract and adhere to the inner wall of the culture container 10. At this time, the turbulence-disrupting structure in the culture container 10 is automatically removed, without changing the original flow field structure in the culture container 10. This allows the mixing intensity in the culture container 10 to meet the dissolved oxygen requirements of low-density cell culture with only basic oxygen supply, while avoiding excessive mixing and wasting energy, and preventing unnecessary shear force from damaging the cells.

[0046] Similarly, such as Figure 3 and Figure 6As shown, during the high-density cell culture stage, fluid is simply introduced into the filling cavity 200, causing the turbulence-inducing element 20 to expand and protrude inward from the inner wall of the culture container 10. At this time, a turbulence structure is formed inside the culture container 10, which can change the flow field structure inside the culture container 10 and enhance the mixing intensity inside the culture container 10. This improves the dissolved oxygen efficiency and nutrient mixing under basic oxygen supply, achieving a synergistic effect between basic oxygen supply and enhanced mixing, which is beneficial to improving the cell culture performance of the turbulent bioreactor.

[0047] It is worth noting that the turbulent bioreactor of this application utilizes a non-bubbling interface oxygen transfer mechanism. It generates a turbulent flow through mechanical oscillation, causing the culture medium to repeatedly flush the inner surface of the culture container 10 to rapidly dissolve oxygen. Simultaneously, the culture medium carries away gas, creating nanoscale soluble microbubbles, which continuously mix. This ensures that each cell in the low-density cell culture stage receives sufficient oxygen and nutrients to maintain normal cell growth and metabolism. In the high-density cell culture stage, the turbulence-inducing element 20 expands to form a turbulence structure on the inner wall of the culture container 10. This creates a significant turbulence effect as the culture medium flows through this structure, enhancing mixing. This improves both liquid mixing and nutrient distribution uniformity, as well as oxygen dispersion and dissolved oxygen efficiency.

[0048] In other words, the biological culture device 1 of this application functionally couples oxygen supply and mixing, achieving a seamless switch from basic maintenance to enhanced supply. It can balance low energy consumption and low shear force in the low-density cell culture stage, so as to avoid unnecessary shear force without wasting energy, and it can also balance high dissolved oxygen and uniform nutrient distribution in the high-density cell culture stage, so as to improve dissolved oxygen efficiency while avoiding the formation of local dead zones and improving cell culture performance. Thus, the cells are always in the optimal physical microenvironment throughout the entire culture process, directly contributing to higher cell density, longer viability maintenance time, and higher yield of target products.

[0049] For example, such as Figures 4 to 6 As shown, the agitator 20 can be, but is not limited to, implemented as an airbag, so that the agitator 20 expands and contracts by inflation or deflation, allowing the agitator structure to be dynamically formed and removed, achieving a seamless switch from basic maintenance to enhanced supply. It is understood that the airbag mentioned in this application can be filled not only with gas, but also with liquids such as water or solutions, or even other flowable materials such as creams or flowable particles, as long as the airbag can expand and contract; this application will not elaborate further on this.

[0050] Optionally, such as Figure 5 and Figure 6As shown, the airbag includes a flexible limiting outer layer 21 fixed to the culture container 10 and an elastic inflatable inner layer 22 disposed within the flexible limiting outer layer 21 to define the filling cavity 200. The flexible limiting outer layer 21 restricts the shape of the elastic inflatable inner layer 22 after inflation, thus defining the specific shape of the turbulence structure. The elastic inner layer 22 automatically releases air, causing the turbulence member 20 to automatically contract and remove the turbulence structure. It is understood that the flexible limiting outer layer 21 mentioned in this application may be, but is not limited to, made of fiber or plastic; the elastic inflatable inner layer 22 mentioned in this application may be, but is not limited to, made of rubber or plastic.

[0051] It is worth noting that in other examples of this application, the airbag may also lack an elastic inner layer and directly provide the filling cavity 200 through a flexible outer layer; in this case, the gas filled in the filling cavity 200 can be discharged by air extraction, and the turbulence structure can still be removed.

[0052] Optionally, such as Figure 3 and Figure 4 As shown, multiple flow-disrupting elements 20 are spirally staggered on the inner wall of the culture container 10, so that the multiple flow-disrupting elements 20 form a spiral staggered flow-disrupting structure when expanding, so as to form a spiral flow field within the culture container 10 and enhance mixing efficiency. It is understood that the multiple mentioned in this application can be three, two, four or more, and this application will not elaborate further.

[0053] Optionally, such as Figure 3 and Figure 4 As shown, each flow disruptor 20 extends spirally from bottom to top on the inner wall of the culture container 10 in the direction of flow to guide the culture medium to move up and down within the culture container 10, thereby improving the mixing efficiency. It is understood that the direction of flow referred to in this application is the opposite direction to the flow of the culture medium within the culture container 10.

[0054] Preferably, multiple flow disruptors 20 are controlled to sequentially fill and deflate based on the real-time oscillation phase signal of the eccentric drive device 2; for example, multiple airbags are controlled to sequentially fill and deflate based on the real-time oscillation phase signal of the eccentric drive device 2, which is beneficial to actively induce a three-dimensional spiral flow field in the culture container 10, and facilitates rapid enhancement of mixing efficiency.

[0055] More preferably, such as Figure 3 and Figure 6 As shown, when the airbag is inflated, it has a streamlined wing-shaped protrusion structure, wherein the thickness of the airbag's front end 201 is greater than the thickness of the airbag's back end 202, so as to reduce energy loss and avoid generating large shear forces while generating a huge turbulence effect.

[0056] It is worth noting that, such as Figures 1 to 6 As shown, the inner cavity of the culture container 10 mentioned in this application may have a cylindrical portion 101 and a frustum-shaped portion 102 extending downward from the cylindrical portion 101. The flow-disrupting element 20 is located on the conical surface of the frustum-shaped portion 102 to better achieve the flow-disrupting effect. It is understood that, compared with the existing cylindrical tank structure oscillating reactor, the turbulent bioreactor of this application uses an inverted truncated conical container, which has a larger specific surface area and better mass transfer effect.

[0057] Furthermore, the culture container 10 mentioned in this application can be a single rigid tank, a single flexible bag, or a composite container combining a rigid tank and a flexible bag.

[0058] For example, such as Figures 2 to 6 As shown, the culture container 10 may include a rigid tank 11, and the baffle 20 is disposed on the inner surface of the rigid tank 11 so as to form a baffle structure protruding from the inner surface of the rigid tank 11 when the baffle 20 expands.

[0059] Optionally, such as Figures 2 to 6 As shown, the culture container 10 may further include a flexible bag 12 disposed within and adapted to the rigid tank 11, such that the flow-dispersing member 20 is located between the rigid tank 11 and the flexible bag 12. Thus, when the filling cavity 200 is used to fill with fluid, the flow-dispersing member 20 expands to push the flexible bag 12 inward, forming an inwardly protruding flow-dispersing structure on the flexible bag 12. When the filling cavity 200 is used to discharge fluid, the flow-dispersing member 20 contracts to allow the flexible bag 12 to adhere to the inner wall of the rigid tank 11, thus removing the flow-dispersing structure. It is understood that the flexible bag 12 mentioned in this application may, but is not limited to, be implemented as a disposable culture bag for containing culture medium;

[0060] It is worth noting that, in one modified example of this application, such as Figure 7 As shown, the culture container 10 may include a flexible bag 12, and the flow-disrupting element 20 is disposed on the bag wall of the flexible bag 12 so as to form the desired flow-disrupting structure directly within the flexible bag 12.

[0061] According to the above embodiments of this application, as Figure 1 and Figure 8As shown, the turbulent bioreactor may further include a sensing and control system 3, which includes a basic oxygen supply module 31 connected to the culture vessel 10 and used to provide basic oxygen supply to the culture medium, a turbulence drive module 32 connected to the turbulence element 20 and used to drive the turbulence element 20 to fill and drain, a dissolved oxygen sensor 33 disposed in the culture vessel 10 and used to monitor the dissolved oxygen concentration in the culture medium in real time, and a central controller 34 communicatively connected to the basic oxygen supply module 31, the turbulence drive module 32 and the dissolved oxygen sensor 33.

[0062] Preferably, the central controller 34 is configured to: when the dissolved oxygen concentration detected by the dissolved oxygen sensor 33 is higher than the preset dissolved oxygen threshold, control the basic oxygen supply module 31 to work independently to maintain the basic dissolved oxygen level and keep the turbulence member 20 in a contracted state; when the dissolved oxygen concentration detected by the dissolved oxygen sensor 33 is lower than the preset dissolved oxygen threshold, control the basic oxygen supply module 31 to increase the oxygen supply and control the turbulence drive module 32 to drive at least one turbulence member 20 in an expanded state to form a turbulence structure in the culture container 10, which facilitates enhanced gas-liquid mixing and mass transfer efficiency.

[0063] In this way, the turbulent bioreactor of this application integrates basic oxygen supply with dynamic turbulence, realizing closed-loop synergistic control of mixing intensity and dissolved oxygen efficiency. It can automatically and synchronously adjust the oxygen supply and mixing uniformity according to the actual needs of cells, and only activate the high-energy-consuming enhanced mixing mode when needed. This is conducive to achieving refined energy management and reducing the shear force on cells during low-demand periods.

[0064] More preferably, such as Figure 1 As shown, the central controller 34 can also be communicatively connected to the eccentric drive device 2 to control the turbulence drive module to drive multiple turbulence elements 20 to sequentially fill and drain based on the real-time oscillation phase signal of the eccentric drive device 2, so as to actively induce a three-dimensional spiral flow field in the culture container 10.

[0065] It is worth mentioning that, according to another aspect of this application, such as Figure 9 As shown, one embodiment of this application further provides a method for regulating a turbulent bioreactor, which may include the following steps:

[0066] S100: Maintains the basic dissolved oxygen level of the culture medium through the basic oxygen supply module;

[0067] S200: Real-time acquisition of parameters reflecting the metabolic state of cells, including dissolved oxygen concentration and / or viable cell density;

[0068] S300: Based on the acquired parameters, determine the oxygen consumption status of cells in the culture medium;

[0069] S400: When the oxygen consumption of cells in the culture medium exceeds the preset oxygen consumption threshold, a collaborative regulation strategy is activated. This collaborative regulation strategy includes: instructing the basic oxygen supply module to increase the oxygen supply intensity; and / or instructing at least one flow-inducing element to expand to enhance liquid mixing and oxygen dispersion.

[0070] Preferably, in step S400 of the control method of the turbulent bioreactor of this application: based on the oscillation phase of the eccentric drive device 2, multiple flow-turbing elements are sequentially controlled to make the culture medium form a three-dimensional spiral flow.

[0071] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0072] The above embodiments are merely illustrative of several implementation methods of this application, and their descriptions are quite specific and detailed. However, they should not be construed as limiting the scope of the patent application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these modifications and improvements all fall within the protection scope of this application.

Claims

1. A biological culture device, characterized in that, include: Culture containers are used to hold culture media; and One or more flow disruptors are disposed within the culture container and have a filling cavity for containing fluid; when the filling cavity is used to fill fluid, the flow disruptor expands to bulge inwardly out of the inner wall of the culture container to form a flow disruptor structure; when the filling cavity is used to discharge fluid, the flow disruptor contracts to conform to the inner wall of the culture container to remove the flow disruptor structure.

2. The biological culture device according to claim 1, characterized in that, The aerodynamic component is an airbag; The airbag includes a flexible limiting outer layer fixed to the culture container and / or an elastically inflatable inner layer disposed within the flexible limiting outer layer to define the filling cavity.

3. The biological culture device according to claim 2, characterized in that, When the airbag is inflated, the airbag has a streamlined wing-shaped protrusion structure; wherein the thickness of the front end of the airbag is greater than the thickness of the back end of the airbag.

4. The biological culture apparatus according to any one of claims 1 to 3, characterized in that, Multiple of the aforementioned flow-disrupting elements are arranged in a spirally staggered manner on the inner wall of the culture container.

5. The biological culture device according to claim 4, characterized in that, Each of the aforementioned baffles extends spirally from bottom to top on the inner wall of the culture vessel in the direction of the incoming flow.

6. The biological culture apparatus according to any one of claims 1 to 3, characterized in that, The inner cavity of the culture container has a cylindrical portion and a frustum-shaped portion that tapers downward from the cylindrical portion; the flow-disrupting element is located on the conical surface of the frustum-shaped portion. The culture container includes a rigid tank, and the baffle is disposed on the inner surface of the rigid tank; The culture container also includes a flexible bag disposed within and adapted to the rigid tank, so that the flow-disrupting element is located between the rigid tank and the flexible bag; Alternatively, the culture container may include a flexible bag, and the flow disruptor may be disposed on the bag wall of the flexible bag.

7. A turbulent flow bioreactor, characterized in that, include: The biological culture apparatus as described in any one of claims 1 to 6; and An eccentric drive device is connected to the biological culture device to cause the biological culture device to perform eccentric oscillating motion under the drive of the eccentric drive device.

8. The turbulent flow bioreactor according to claim 7, characterized in that, The turbulent flow bioreactor also includes a sensing and control system, which includes a basic oxygen supply module connected to the culture container of the biological culture device and used to provide basic oxygen supply to the culture medium, a turbulence drive module connected to the turbulence element of the biological culture device and used to drive the turbulence element to fill and drain, a dissolved oxygen sensor disposed in the culture container and used to monitor the dissolved oxygen concentration in the culture medium in real time, and a central controller communicatively connected to the basic oxygen supply module, the turbulence drive module and the dissolved oxygen sensor. The central controller is configured to: when the dissolved oxygen concentration detected by the dissolved oxygen sensor is higher than a preset dissolved oxygen threshold, control the basic oxygen supply module to work independently to maintain the basic dissolved oxygen level and keep the turbulence component in a contracted state; when the dissolved oxygen concentration detected by the dissolved oxygen sensor is lower than the preset dissolved oxygen threshold, control the basic oxygen supply module to increase the oxygen supply and control the turbulence drive module to drive at least one turbulence component in an expanded state.

9. The turbulent flow bioreactor according to claim 8, characterized in that, The central controller is communicatively connected to the eccentric drive device and is used to control the turbulence drive module to drive multiple turbulence components to sequentially charge and discharge based on the real-time oscillation phase signal of the eccentric drive device.

10. A method for regulating a turbulent flow bioreactor, characterized in that, Including the following steps: The basic dissolved oxygen level of the culture medium is maintained by the basic oxygen supply module. Real-time acquisition of parameters reflecting cellular metabolic status, including dissolved oxygen concentration and / or viable cell density; Based on the acquired parameters, determine the oxygen consumption status of cells in the culture medium; as well as When the oxygen consumption of cells in the culture medium exceeds the preset oxygen consumption threshold, a collaborative regulation strategy is activated. This collaborative regulation strategy includes instructing the basic oxygen supply module to provide oxygen supply intensity. And / or, instruct at least one turbulence element to expand to enhance liquid mixing and oxygen dispersion.

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