A flow control apparatus, a perfusion culture apparatus, and a method of using the same

Abstract

The present application belongs to the technical field of biopharmaceutical equipment, and particularly relates to a flow control device for cell perfusion culture, a perfusion culture device and a use method thereof. In the flow control device for cell perfusion culture, the combination of a control system and an automatic pressure regulating valve is used to realize self-adaptive regulation and control of air pressure, and is combined with the way of limiting flow through a plurality of capillary bodies with different lengths and / or inner diameters, so that continuous and accurate regulation of gas flow is realized at low cost, thereby meeting the dynamic flow requirements in different stages of the cell culture process.

Description

Technical Field

[0001] This invention belongs to the field of biopharmaceutical equipment technology, and specifically relates to a flow control device and a perfusion culture device for cell perfusion culture, as well as the method of using them. Background Technology

[0002] Currently, the mainstream ATF controllers on the market are represented by Shibipure products. Their flow control principle utilizes a combination of six different pore sizes of flow-limiting micro-orifices to achieve 32 different gas flow outputs, thereby matching the gas inlet rate and vacuum suction rate of the perfusion balloon. For details on the matching method of the flow-limiting micro-orifices and the gas flow output range, please refer to [link / reference needed]. Figure 1 .

[0003] However, this technology has many inherent drawbacks: 1. Limitations of flow rate adjustment: The flow rate can only be changed in a stepwise manner through a combination of micropores with a fixed aperture. It is impossible to make smooth and seamless flow rate adjustments according to process requirements, and it is difficult to accurately match the dynamic flow rate requirements at different stages of cell culture.

[0004] 2. High processing and control complexity: Micro-hole modules require ultra-high precision processing and need to be matched with a complex valve control system, resulting in high equipment production costs and high maintenance difficulty.

[0005] 3. Insufficient adaptability: The fixed pore size combination mode is difficult to flexibly adapt to diverse cell culture processes, and has poor adaptability to special process requirements.

[0006] Therefore, developing a low-cost, precise, and flexible perfusion culture device has become a pressing technical problem in the biopharmaceutical field. Summary of the Invention

[0007] This invention provides a flow control device for cell perfusion culture, which solves the technical problem in the prior art that the gas flow rate of perfusion culture equipment cannot be smoothly and seamlessly adjusted according to process requirements, and it is difficult to accurately match the dynamic flow requirements at different stages of cell culture.

[0008] This invention is achieved through the following technical solution: A flow control device for cell perfusion culture includes an automatic pressure regulating valve, a capillary assembly, and a control system; The capillary assembly includes multiple capillary bodies with different lengths and / or inner diameters, and the outlet end of the capillary body is provided with an on / off valve. The outlet of the automatic pressure regulating valve is connected to the inlet of the capillary body; Both the automatic pressure regulating valve and the on / off valve are connected to the control system signal.

[0009] To better realize the present invention, further optimizations are made to the above structure, and the flow control device for cell perfusion culture also includes a vacuum pump; The air inlet of the vacuum pump is connected to the air inlet of the capillary body, and the vacuum pump is signal-connected to the control system.

[0010] To better realize the present invention, the above structure is further optimized, and the inner diameter of the plurality of capillary bodies is 0.2-4 mm respectively.

[0011] To better realize the present invention, the above structure is further optimized, and the lengths of the multiple capillary bodies are 20-100cm respectively.

[0012] To better realize the present invention, the above structure is further optimized, and the pressure regulating range of the automatic pressure regulating valve is 0-0.5MPa.

[0013] To better realize the present invention, further optimizations are made to the above structure, and the flow control device for cell perfusion culture also includes a flow sensor; The flow sensor is located at the outlet end of the capillary assembly and is signal-connected to the control system.

[0014] In addition, the present invention also provides a perfusion culture device, including a perfusion culture unit and the above-mentioned flow control device for cell perfusion culture; The outlet end of the capillary assembly in the flow control device for cell perfusion culture is connected to the perfusion culture unit.

[0015] Meanwhile, the present invention also provides a method for using a perfusion culture device, the method being implemented using the aforementioned perfusion culture device, comprising the following steps: According to the cell culture process requirements, the control system will automatically calculate the required gas pressure value based on the preset target flow parameters. The control system sends a pressure adjustment command to the automatic pressure regulating valve, which adjusts the gas supply pressure to the required gas pressure value through closed-loop feedback control. At the same time, the control system controls the opening and closing of the on-off valves on multiple capillary bodies, so that the automatic pressure regulating valve is connected to the perfusion culture unit through one or more capillary bodies. The actual flow rate of gas entering the perfusion culture unit is monitored in real time by a flow sensor, and the information of the actual flow rate is fed back to the control system. If there is a deviation between the actual flow rate and the preset target flow rate, the control system will adjust the gas pressure output by the automatic pressure regulating valve or adjust the opening and closing status of the opening and closing valves on multiple capillary bodies until the actual flow rate matches the preset target flow rate.

[0016] Compared with the prior art, the present invention has the following advantages: The flow control device for cell perfusion culture provided by this invention achieves adaptive gas pressure regulation through a combination of a control system and an automatic pressure regulating valve, and combines this with a flow-limiting method using multiple capillary bodies of different lengths and / or inner diameters to achieve continuous and precise adjustment of gas flow at low cost, thereby meeting the dynamic flow requirements at different stages of cell culture.

[0017] In addition, the flow control device for cell perfusion culture can achieve seamless and continuous flow regulation through continuous control of air pressure and precise adjustment of the length and / or inner diameter of the capillary body. It can accurately match the dynamic flow requirements of different stages of cell culture and significantly improve process adaptability. The flow control device for cell perfusion culture does not require high-precision microporous modules and complex valve control systems. The processing and acquisition cost of the capillary body is much lower than that of the microporous components, which greatly reduces the production and maintenance costs of the flow control device for cell perfusion culture. The flow control device for cell perfusion culture combines an automatic pressure regulating valve with a closed-loop feedback control system, along with precise flow limiting based on the length and / or inner diameter of the capillary body. This enables high-precision flow control, with a control accuracy superior to existing stepped flow control devices. The control system of this flow control equipment for cell perfusion culture can preset a variety of process flow parameters. Operators only need to select the corresponding parameter mode according to the culture requirements to achieve automatic flow adjustment, which reduces the difficulty of operation and human error. Attached Figure Description

[0018] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0019] Figure 1 This is a table showing the matching method of the flow-limiting micro-orifice and the gas flow output range in existing ATF controllers.

[0020] Figure 2 This is a flow characteristic curve of pipeline A at different lengths in this invention.

[0021] Figure 3 This is a flow characteristic curve of pipeline B at different lengths in this invention. Detailed Implementation

[0022] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be described in detail below. Obviously, the described embodiments are merely some embodiments of this invention, and not all embodiments. Based on the embodiments of this invention, all other implementation methods obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0023] In the description of this invention, it should be noted that, unless otherwise stated, "a plurality of" means two or more; the terms "upper," "lower," "left," "right," "inner," "outer," "front end," "rear end," "head," "tail," etc., indicate the orientation or positional relationship based on the orientation or positional relationship shown in the accompanying drawings, and are only for the convenience of describing the invention 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 the invention. Furthermore, the terms "first," "second," "third," etc., are used for descriptive purposes only and should not be construed as indicating or implying relative importance.

[0024] In the description of this invention, it should also be noted that, unless otherwise explicitly specified and limited, the terms "installation," "connection," and "joining" should be interpreted broadly. For example, they can refer to a fixed connection, a detachable connection, or an integral connection; 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. Those skilled in the art can understand the specific meaning of the above terms in this invention according to the specific circumstances.

[0025] In an embodiment of this application, as shown in the figure, the flow control device for cell perfusion culture includes an automatic pressure regulating valve, a capillary assembly, and a control system; wherein, The capillary assembly includes multiple capillary bodies of different lengths and / or inner diameters, with an on / off valve at the outlet end of each capillary body. In this embodiment, various capillary bodies with different inner diameters are selected, such as 0.2mm, 0.5mm, 0.8mm, 1.6mm, 2.0mm, 2.5mm, and 4.0mm, etc., without being limited to a specific inner diameter, and can be combined according to flow requirements. It typically meets the flow requirements (from 0.5L / min to 40L / min) of ATF2, 4, 6, and 10 series perfusion filters, requiring only 2-4 types of capillary bodies. The length of the capillary body equipped with each inner diameter can range from 10cm to 500cm, typically 20cm to 100cm, with an accuracy of ±1cm. Combined with a supply air pressure of approximately 3-15psi, it can fully meet any air volume adjustment within a flow range of 80L / min. The automatic pressure regulating valve is a high-precision pneumatic pressure regulating valve with closed-loop feedback control. The pressure regulation range is 0-0.5MPa, and the control accuracy can reach ±0.1%FS. The air outlet of the automatic pressure regulating valve is connected to the air inlet of multiple capillary tube bodies. The control system uses a PLC controller as the core control unit, which has a human-machine interface and can realize flow parameter preset, real-time monitoring and automatic adjustment. The aforementioned automatic pressure regulating valve and opening and closing valve are all connected to the control system signal.

[0026] In some embodiments, the flow control device for cell perfusion culture further includes a vacuum pump; The air inlet of the vacuum pump is connected to the air inlet of the capillary body, and the vacuum pump is connected to the control system. During the vacuum phase, the vacuum pump can be started by the control system to draw gas from the perfusion culture unit, so that air is formed inside to meet the needs of cell culture.

[0027] In some embodiments, the flow control device for cell perfusion culture further includes a flow sensor; The flow sensor is installed at the outlet of the capillary assembly and is connected to the control system signal. It can monitor the gas flow at the outlet of the capillary assembly in real time and feed the gas flow information back to the control system to realize closed-loop control of the airflow.

[0028] To better illustrate the effect of the flow control device for cell perfusion culture, this invention uses a flow-limiting gas path assembly composed of four types of capillary tubes (A / B / C / D types) with different inner diameters.

[0029]

[0030] The table above shows the range of linear gas flow rates that a typical capillary tube assembly (4 length or diameter combinations) can provide under a certain supply pressure. Increasing the supply pressure can further increase the gas flow rate.

[0031] The above data are also suitable for flow control during the vacuum phase. A key capability of this invention is its ability to achieve equivalent gas flow control within a positive pressure range of 15 psi and a vacuum range of -14.5 psi (i.e., the pressure required for positive pressure intake does not exceed one atmosphere; therefore, the flow capacity obtained from the positive pressure path can be directly transferred to the vacuum level control of the vacuum pump. That is, if a C-type pipeline achieves an intake flow rate of 5 L / min at a positive pressure of 5 psi, then similarly, during the vacuum phase pumping process, controlling the vacuum pump to -5 psi will also allow the C-type pipeline to achieve an exhaust flow rate close to 5 L / min).

[0032] In this embodiment, the control system can collect the actual flow data at the outlet of the capillary assembly in real time through a flow sensor and compare it with the preset flow parameters.

[0033] When flow rate needs to be adjusted, the control system first calculates the required air pressure range and multiple capillary body length combinations based on the flow rate demand. Then, it sends a pressure adjustment command to the automatic pressure regulating valve and simultaneously adjusts the access length of the capillary body. Through the synergistic effect of air pressure and capillary length, smooth and precise flow rate regulation is achieved.

[0034] To better illustrate how capillary bodies of different lengths and inner diameters can alter flow rates, the following comparison uses specific data: See Figure 2 The figure illustrates the gas flow characteristics provided by three different lengths of type A capillary bodies with the same inner diameter under varying pressures. As can be seen, at the same pressure (e.g., 4 psi), changing the length allows for flow rate control from 50 to 600 ml / min; while at the same length (e.g., 100 cm), changing the pressure allows for flow rate control from 50 ml / min to 500 ml / min. Simple combinations of length and pressure enable completely smooth gas flow rate control over a very wide range (e.g., 0.1 L / min to 40 L / min). See Figure 3 Two different lengths of the same inner diameter B-type capillary body were used to demonstrate the airflow characteristics provided under different pressures. Their flow capacity exhibits a perfect linear relationship with the supply pressure and length. By adjusting the length and supply pressure under only a few extremely limited parameter conditions, the gas flow rate output by the B-type capillary body can be smoothly adjusted from 100 ml / min to 1000 ml / min.

[0035] Based on the above-mentioned flow control device for cell perfusion culture, the present invention also provides a perfusion culture device, which includes a perfusion culture unit and the above-mentioned flow control device for cell perfusion culture. The outlet of the capillary assembly in the flow control device used for cell perfusion culture is connected to the perfusion culture unit.

[0036] The control system can collect the actual flow data at the outlet of the capillary assembly in real time through a flow sensor and compare it with the preset flow parameters. When the flow needs to be adjusted, the control system first calculates the required combination of air pressure range and capillary length based on the flow requirements, then sends a pressure adjustment command to the automatic pressure regulating valve, and simultaneously adjusts the capillary connection length. Through the synergistic effect of air pressure and capillary length, smooth and precise flow regulation is achieved to meet the needs of cell culture.

[0037] Meanwhile, the present invention also provides a method for using the perfusion culture device, the method being implemented using the aforementioned perfusion culture device, including the following steps: According to the cell culture process requirements, the control system will automatically calculate the required gas pressure value based on the preset target flow parameters. The control system sends a pressure adjustment command to the automatic pressure regulating valve, which adjusts the gas supply pressure to the required gas pressure value through closed-loop feedback control. At the same time, the control system controls the opening and closing of the on-off valves on multiple capillary bodies, so that the automatic pressure regulating valve is connected to the perfusion culture unit through one or more capillary bodies. The actual flow rate of gas entering the perfusion culture unit is monitored in real time by a flow sensor, and the information of the actual flow rate is fed back to the control system. If there is a deviation between the actual flow rate and the preset target flow rate, the control system will adjust the gas pressure output by the automatic pressure regulating valve or adjust the opening and closing status of the opening and closing valves on multiple capillary bodies until the actual flow rate matches the preset target flow rate.

[0038] The performance of this device was verified through CHO cell perfusion culture experiments: 1. Experimental conditions: A 10L bioreactor was used to culture CHO cells that produce monoclonal antibodies, and the perfusion culture period was 14 days.

[0039] 2. Experimental results: This equipment can achieve continuous flow rate adjustment from 0.1 to 5 L / min, with a flow control accuracy of ±2%; compared with traditional ATF equipment, cell density is increased by 15%, product recovery rate is increased by 10%, and equipment cost is reduced by 40%.

[0040] Experiment 1: Small-scale laboratory CHO cell perfusion culture: 1. Experimental objective: To verify the flow control performance and cultivation effect of this equipment in a small-scale laboratory cultivation scenario.

[0041] 2. Equipment Configuration: A 1L glass bioreactor is used, equipped with the flow control device of this invention. The automatic pressure regulating valve is a small pneumatic pressure regulating valve of model AT-100. The capillary assembly consists of capillary bodies with inner diameters of 0.5mm (A gas path) and 0.8mm (B gas path), and lengths of 30cm and 60cm respectively. The control system uses a small PLC controller (model S7-1200), integrating a pressure sensor with an accuracy of ±0.5% for P / E cycle control, and a gas flow meter with an accuracy of ±0.5% for verification.

[0042] 3. Culture Process: CHO cells producing recombinant human interferon were cultured at a seeding density of 2 × 10^6 cells / mL, at a culture temperature of 37℃, a pH of 7.2, and a dissolved oxygen concentration of 50% air saturation. The perfusion culture period was 10 days. The perfusion flow rate was set at 0.1 L / min for the first 3 days, adjusted to 0.3 L / min for days 4-7, and increased to 0.5 L / min for days 8-10.

[0043] 4. Parameter Preset for Implementation: Flow parameters for different stages are set sequentially through the human-machine interface of the control system. Based on the built-in capillary length-flow characteristic database, the control system automatically calculates the corresponding pressure value and capillary length combination for each stage. The first 3 days correspond to a pressure of 10 psi, Pcycle air path A, and Ecycle air path A; days 4-7 correspond to a pressure of 15 psi, Pcycle air path A, Ecycle air path B, and a capillary length of 20 cm; days 8-10 correspond to a pressure of 20 psi, Pcycle air path A, and Ecycle air path B.

[0044] It is worth noting that Pcycle and Ecycle refer to the air intake cycle and air extraction cycle, respectively. In this invention, the performance verification is performed using self-developed equipment. The logic for controlling the perfusion filtration is divided into two actions: the air intake cycle (Pcycle) and the air extraction cycle (Ecycle), which drive the reciprocating tangential flow of the diaphragm at the bottom of the perfusion device to the hollow fiber membrane column.

[0045] During the intake cycle (Pcycle), this invention can select one of the aforementioned gas paths, such as gas path A, and combine it with a reasonable supply pressure, such as 10 psi, to achieve the system's set push speed, such as 0.8 L / min. Similarly, during the extraction cycle (Ecycle), a reasonable gas path, such as gas path A, can be selected based on the vacuum pump's extraction capacity to achieve a basically equivalent extraction speed, such as 0.8 L / min.

[0046] As cell culture progresses, factors such as increased cell density and viscosity, and changes in the feed level in the cell culture tank necessitate increased pushing power to compensate for these material changes after a period of operation. The present invention compensates for these changes by either increasing the gas supply pressure or altering the gas path size. In this example, the strategy employed is to compensate for the increased airflow by increasing the pressure; vacuum pumping is compensated for by changing to a larger pipe (B).

[0047] 5. Pressure and capillary tube body adjustment: The control system sends a pressure adjustment command to the automatic pressure regulating valve, which adjusts the gas supply pressure precisely to the target value through closed-loop feedback control; at the same time, it switches the capillary tube body of the corresponding length.

[0048] 6. Flow Monitoring and Feedback: The flow sensor monitors the actual flow rate of the perfusion culture unit in real time, collecting data every 5 seconds and feeding it back to the control system. If the actual flow rate deviates from the preset flow rate by more than ±2%, the control system automatically fine-tunes the pressure of the pressure regulating valve or the length of the capillary body to ensure that the flow rate remains stable within the preset range.

[0049] 7. Experimental results: Throughout the culture process, the flow control accuracy remained stable within ±10%, the cell density reached a maximum of 2.5×10^7 cells / mL, the yield of recombinant human interferon increased by more than 3 times compared with traditional batch culture, the equipment operated stably, and no malfunctions occurred.

[0050] Experiment 2: Large-scale industrial production of monoclonal antibodies: Experimental objective: To verify the reliability and flow control capability of this equipment in large-scale industrial production scenarios.

[0051] Equipment configuration: A 5000L stainless steel bioreactor is used, equipped with the flow control device of this invention. The automatic pressure regulating valve is a high-flow pneumatic pressure regulating valve of model AT-5000, with a pressure adjustment range of 0-0.5MPa and a control accuracy of ±0.5%FS. Capillary assemblies are selected from four types with inner diameters of A (0.5mm), B (1mm), C (2.5mm), and D (4mm), and lengths ranging from 50cm to 100cm. Multiple capillary switching devices are equipped to achieve parallel control. For example, the E-type gas path is composed of one D-type and one A-type combination.

[0052] The control system employs a large-scale PLC controller (model S7-1500) with an integrated high-precision flow sensor achieving an accuracy of ±0.5%. Culture process: CHO-K1 cells producing monoclonal antibodies were cultured at a seeding density of 1.5 × 10^6 cells / mL, at a culture temperature of 36.5℃, pH 7.0, and dissolved oxygen concentration of 40% air saturation. The perfusion culture cycle was 18 days. The perfusion flow rate was set to 1 L / min for the first 5 days, adjusted to 3 L / min from days 6-12, and increased to 5 L / min from days 13-18.

[0053] Implementation process: Based on the requirements of large-scale production processes, flow parameters for different stages are set in the control system. The control system calculates the corresponding gas pressure value and capillary length combination based on factors such as reactor volume and fluid characteristics. The first 10 days correspond to a gas pressure of 17 psi, with Pcycle gas path type C and Ecycle gas path type E; days 10-18 correspond to a gas pressure of 20 psi, with Pcycle gas path type C and Ecycle gas path type D.

[0054] Pressure and capillary tube body adjustment: The automatic pressure regulating valve receives instructions from the control system and quickly adjusts the gas supply pressure to the target value. Multiple capillary tube switching devices operate synchronously, connecting capillary tube bodies of corresponding lengths to the gas circuit and achieving parallel control.

[0055] Flow monitoring and feedback: The flow sensor monitors the total flow rate of the perfusion culture unit in real time (its calculation logic is the cavity volume divided by the time required to reach the set pressure, which is the current gas flow rate in L / min, LPM). Data is collected every 30 seconds and fed back to the control system. If the actual flow rate deviates from the preset flow rate by more than ±10%, the control system automatically adjusts the pressure of the pressure regulating valve or the number and length of the parallel capillary tubes to ensure stable flow.

[0056] Experimental results: During large-scale production, the flow control accuracy remained stable within ±10%, the cell density reached a maximum of 14×10^7 cells / mL, the cell viability was consistently maintained at >85%, the monoclonal antibody yield was 12% higher than that of traditional ATF equipment, the equipment operated continuously for 18 days without failure, and the maintenance cost was 45% lower than that of traditional equipment.

[0057] Other implementation cases: RTF series hollow fiber products achieve high-density culture of HEK293 and MDCK cells through efficient cell retention. The maximum MDCK cell perfusion culture density before inoculation can reach 60 × 10⁶ cells / year. 6 The cell count / mL was [data missing]. Meanwhile, the viability of all three cell types remained above 90% throughout the culture period, indicating that the system can effectively maintain the stability of the cell growth microenvironment and ensure the continuous expression of recombinant proteins.

[0058] Our controller and hollow fiber system exhibit differentiated long-term culture capabilities tailored to the characteristics of different cell types: high-density stable culture periods for 293 cells and CHO cells can reach 30 days, while high-density culture periods for MDCK cells are 7 days. Throughout the culture process, the hollow fiber filter maintains stable performance with no significant fluctuations in filtration rate, demonstrating its excellent anti-fouling and anti-clogging capabilities, which meet the process requirements for long-term continuous perfusion.

[0059] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A flow control device for cell perfusion culture, characterized in that: Includes automatic pressure regulating valves, capillary assemblies, and control systems; The capillary assembly includes multiple capillary bodies with different lengths and / or inner diameters, and the outlet end of the capillary body is provided with an on / off valve. The outlet of the automatic pressure regulating valve is connected to the inlet of the capillary body; Both the automatic pressure regulating valve and the on / off valve are connected to the control system signal.

2. The flow control device for cell perfusion culture according to claim 1, characterized in that: It also includes vacuum pumps; The air inlet of the vacuum pump is connected to the air inlet of the capillary body, and the vacuum pump is signal-connected to the control system.

3. The flow control device for cell perfusion culture according to claim 1, characterized in that: The inner diameters of the multiple capillary bodies are 0.2-4 mm.

4. The flow control device for cell perfusion culture according to claim 1, characterized in that: The lengths of the multiple capillary bodies are 20-100cm respectively.

5. The flow control device for cell perfusion culture according to claim 1, characterized in that: The pressure regulating range of the automatic pressure regulating valve is 0-0.5MPa.

6. The flow control device for cell perfusion culture according to any one of claims 1 to 5, characterized in that: It also includes flow sensors; The flow sensor is located at the outlet end of the capillary assembly and is signal-connected to the control system.

7. A perfusion culture device, characterized in that: Includes a perfusion culture unit and a flow control device for cell perfusion culture as described in any one of claims 1 to 6; The outlet end of the capillary assembly in the flow control device for cell perfusion culture is connected to the perfusion culture unit.

8. A method of using a perfusion culture device, characterized in that: The method is implemented using the perfusion culture equipment described in claim 7, and includes the following steps: According to the cell culture process requirements, the control system will automatically calculate the required gas pressure value based on the preset target flow parameters. The control system sends a pressure adjustment command to the automatic pressure regulating valve, which adjusts the gas supply pressure to the required gas pressure value through closed-loop feedback control. At the same time, the control system controls the opening and closing of the on-off valves on multiple capillary bodies, so that the automatic pressure regulating valve is connected to the perfusion culture unit through one or more capillary bodies. The actual flow rate of gas entering the perfusion culture unit is monitored in real time by a flow sensor, and the information of the actual flow rate is fed back to the control system. If there is a deviation between the actual flow rate and the preset target flow rate, the control system will adjust the gas pressure output by the automatic pressure regulating valve or adjust the opening and closing status of the opening and closing valves on multiple capillary bodies until the actual flow rate matches the preset target flow rate.

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