Multi-stage feeding mixed strengthening device for semi-continuous fermentation of hyaluronic acid
By designing a device with multi-stage precision feeding and enhanced mixing, the problems of uneven gas distribution and high viscosity during hyaluronic acid fermentation were solved, achieving uniform gas distribution and improved dissolved oxygen rate. This ensured the stability of the fermentation process and the uniformity of product molecular weight, while reducing energy consumption.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Utility models(China)
- Current Assignee / Owner
- SHANDONG FOCUSFREDA BIOTECH CO LTD
- Filing Date
- 2025-06-06
- Publication Date
- 2026-06-05
AI Technical Summary
During the microbial fermentation of hyaluronic acid, uneven gas distribution and high viscosity of the fermentation broth lead to bubble aggregation and insufficient dissolved oxygen, affecting the stability of the fermentation broth and the uniformity of product molecular weight. Furthermore, high viscosity results in low mass and heat transfer efficiency, difficulty in stirring and mixing, and increased energy consumption.
The device adopts a multi-stage precision feeding and enhanced mixing design, including a ring-shaped mixing feeding device and gas-liquid mixing nozzles with different tilt angles. Combined with a pH detector and a level gauge, it achieves uniform mixing of gas and liquid. Semi-continuous fermentation is carried out using a buffer tank, and different types of stirring blades are used to improve dissolved oxygen rate and fermentation stability.
This method achieves uniform gas distribution during hyaluronic acid fermentation, increases dissolved oxygen rate, ensures the stability of the fermentation process and the uniformity of product molecular weight, reduces energy consumption, and improves mass and heat transfer efficiency.
Smart Images
Figure CN224325343U_ABST
Abstract
Description
Technical Field
[0001] This utility model belongs to the field of hyaluronic acid fermentation technology, specifically relating to a multi-stage feeding and mixing enhancement device for semi-continuous fermentation of hyaluronic acid. Background Technology
[0002] Hyaluronic acid (HA), also known as hyaluronic acid, is a linear polysaccharide composed of alternating D-glucuronic acid and N-acetylglucosamine. Due to the presence of a large number of hydrophilic groups, it has a super water absorption capacity and can form viscoelastic solutions or gels. It is widely found in human skin, synovial fluid, and other tissues, and plays an important physiological role in moisturizing and lubrication.
[0003] In terms of preparation technology, early methods mainly relied on animal tissue extraction, using raw materials such as rooster combs and bovine vitreous humor. However, this method suffered from limitations in raw materials, high costs, and the risk of viral contamination. Currently, microbial fermentation has become the mainstream method, utilizing Streptococcus or genetically engineered strains to synthesize hyaluronic acid using sugars as substrates. By optimizing fermentation conditions and purification techniques, it not only achieves high yields and low costs but also allows for precise control of molecular weight. However, uneven gas distribution and high viscosity of the fermentation broth are key issues that urgently need to be addressed during the microbial fermentation of hyaluronic acid. High molecular weight HA in the fermentation broth forms a network structure, leading to bubble aggregation and gas "short-circuiting." Insufficient dissolved oxygen can easily cause metabolic abnormalities and uneven product molecular weight. Furthermore, CO2 accumulation can affect pH stability. At the same time, high viscosity results in low mass and heat transfer efficiency in the fermentation broth and makes stirring and mixing difficult, which increases energy consumption and easily damages the HA structure due to shear stress, leading to low downstream separation efficiency.
[0004] CN210683772U discloses a fermenter for hyaluronic acid production. The fermenter has a tank body and a tank cover. The bottom of the tank is fixed to a connecting plate by a support arm, and an annular gas distribution plate and a lower bearing are installed on it. A central shaft passes through the connecting plate, with a propeller-type agitator at the lower end and a motor connected to the upper end. Stirring blades are distributed on the shaft, and alkaline solution can be introduced into the top of the central shaft. The annular gas distribution plate ensures uniform gas distribution, and the propeller-type agitator can circulate the material below the gas distribution plate in a timely manner, resulting in good stirring and mixing effect and effectively improving the fermentation yield of hyaluronic acid. However, it does not solve the problem of the impact of the overall increase in viscosity of the fermentation liquid on stirring. Moreover, the gas enters from the bottom, and with the increase in viscosity, problems such as bubble aggregation are prone to occur, leading to insufficient dissolved oxygen and ultimately resulting in uneven molecular weight of the product. Utility Model Content
[0005] The purpose of this invention is to overcome the defects of the existing technology and provide a multi-stage feeding and mixing enhancement device for semi-continuous fermentation of hyaluronic acid. Through multi-stage precise feeding, enhanced mixing and optimized gas distribution, the device achieves a reasonable supply of nutrients during the fermentation of hyaluronic acid, uniform gas distribution during fermentation, improves the dissolved oxygen rate in the fermentation liquid, and ensures the stability of the fermentation process.
[0006] The multi-stage feeding and mixing enhancement device for semi-continuous fermentation of hyaluronic acid described in this utility model includes a fermenter, a storage device, and a buffer tank. The fermenter has inlets at the top, middle, and bottom. The top inlet is connected to the storage device, which has a branch line connected to the bottom inlet. The middle inlet is connected to an alkali tank. The bottom inlet is connected to an oxygen pipeline, which has a branch line connected to the middle inlet. The bottom of the fermenter is connected to the buffer tank via a pump, and the buffer tank has a return pipeline to the middle of the fermenter. The fermenter contains an annular mixing feeder and a stirrer, with the annular mixing feeder connected to the middle and bottom inlets.
[0007] Preferably, the fermenter is equipped with a pH detector, a level gauge and a pressure relief valve on the top.
[0008] Preferably, both the fermenter and the buffer tank are equipped with sewage discharge pipes at the bottom.
[0009] Preferably, the annular mixing feeder consists of an annular tube and a gas-liquid mixing nozzle, wherein the annular tube consists of an outer tube and an inner tube.
[0010] Preferably, the gas-liquid mixing nozzle is provided with a gas channel and a liquid channel. The gas channel is connected to the outer pipe, and the liquid channel is connected to the inner pipe. Further, inside the gas-liquid mixing nozzle, the gas channel is located at the center of the gas-liquid mixing nozzle, and the liquid channel surrounds the outside of the gas channel, forming an annular gap. Under the pressure of the gas, the liquid flows through the liquid channel to the outlet of the gas-liquid mixing nozzle. The gas is ejected at high speed from the central channel and collidees with the liquid flowing out of the annular gap at the outlet of the gas-liquid mixing nozzle, causing the liquid to break into small droplets. After being fully mixed with the gas, the liquid is sprayed into the fermenter. An atomizing plate is provided at the outlet of the gas-liquid mixing nozzle to further refine the droplet size and improve the uniformity of gas-liquid mixing and mass transfer efficiency.
[0011] Preferably, the gas-liquid mixing nozzles are evenly distributed on the annular pipe, with the included angle between adjacent gas-liquid mixing nozzles being 30°. Furthermore, some gas-liquid mixing nozzles are tilted upward at 30° to promote gas-liquid mixing in the upper part of the fermenter, while others are sprayed horizontally to form a transverse gas-liquid flow in the middle. The gas-liquid mixing nozzles with the two tilting angles are arranged in a cross pattern.
[0012] Preferably, the annular mixing and feeding device is fixed inside the fermenter by multiple support brackets.
[0013] Preferably, the agitator consists of an agitator shaft and agitator blades, and the agitator blades are, from top to bottom, anchor blades, ribbon blades and turbine blades. Furthermore, the bottom turbine blades are on the same horizontal plane as the feed inlet at the bottom of the fermentation tank.
[0014] Specifically, the multi-stage feeding and mixing enhancement device for semi-continuous fermentation of hyaluronic acid has the following working process: Check the sealing of the fermenter, storage device, and buffer tank; open the drain pipe to remove debris from the tank, ensuring cleanliness and sterility; install a pH detector and level gauge on the top of the fermenter; calibrate equipment parameters; set the pressure threshold of the pressure relief valve to ensure safe production; introduce hyaluronic acid production bacteria, carbon source, nitrogen source, and other nutrients required for fermentation from the storage device into the fermenter through the top feed inlet; monitor the fermentation liquid volume to the set height using the level gauge; start the stirrer to begin fermentation; open the oxygen pipeline; gas enters through the bottom and middle feed inlets; the bottom gas is ejected at high speed through the outer pipe of the annular mixing feed device and the center of the gas-liquid mixing nozzle; no feeding is added to the bottom during this stage; a control valve is installed on the branch connected to the storage device, and this control valve remains closed during fermentation; during fermentation, the pH detector monitors the acidity and alkalinity in real time; when the pH value is lower than the set range, the alkali tank automatically enters the annular mixing feed from the middle feed inlet. The gas-liquid mixture flows out through the annular gap of the gas-liquid mixing nozzle, colliding with the central gas at the outlet and breaking it into fine droplets, achieving efficient gas-liquid mixing. At a specific fermentation stage, a portion of the fermentation broth is discharged through a buffer tank. The discharge rate is controlled by a level gauge to ensure subsequent fermentation stability. After partial discharge, nutrients from the storage device are transported via a branch line to the bottom inlet of the fermenter. The timing and ratio of nutrient (such as carbon and nitrogen sources), alkali, and oxygen replenishment can be controlled according to different fermentation stages. Nutrients sequentially enter the inner tube of the annular mixing feed device, mixing with the gas before being sprayed into the tank to continue hyaluronic acid fermentation. Throughout the process, a pH detector and level gauge monitor and control the process in real time, while a pressure relief valve ensures safety. During the discharge of the fermentation broth, a return pipeline is installed in the buffer tank to prevent excessive discharge due to level gauge malfunction, allowing for broth recirculation. After fermentation, the fermentation broth is transported to the next device via the buffer tank. Residual fermentation broth at the bottom is discharged through a drain pipeline, and the tank is cleaned in preparation for the next batch.
[0015] Compared with the prior art, the beneficial effects of this utility model are as follows: The multi-stage feeding and mixing enhancement device for semi-continuous fermentation of hyaluronic acid described in this utility model achieves precise feeding in stages through the feed inlets at the top, middle, and bottom of the fermentation tank. The dual-channel gas-liquid mixing nozzle of the annular mixing feed device improves oxygen transfer efficiency through gas and liquid mixing and atomization. The nozzles with different tilt angles are arranged in a cross pattern to achieve no dead corners in the fermentation tank, avoiding uneven gas distribution. At the same time, in conjunction with a pH detector and a liquid level gauge, the stable fermentation process is achieved. Secondly, the use of a buffer tank to achieve semi-continuous fermentation during the fermentation process ensures the viscosity of the fermentation liquid and avoids the phenomenon of excessively high viscosity of the fermentation liquid caused by over-fermentation. Finally, the combination of different types of stirring blades, in conjunction with the gas-liquid mixing nozzle, enhances mass transfer and reduces energy consumption, increases the dissolved oxygen rate in the fermentation liquid, and ensures the stability of the fermentation process. Attached Figure Description
[0016] Figure 1 This is a schematic diagram of the multi-stage feeding and mixing enhancement device for semi-continuous fermentation of hyaluronic acid in this utility model;
[0017] Figure 2 This is a schematic diagram of the gas-liquid mixing nozzle connection in the annular mixing feed device of this utility model.
[0018] In the diagram: 1. Fermentation tank; 2. Storage device; 3. Buffer tank; 4. Alkali tank; 5. Oxygen pipeline; 6. Sewage pipeline; 7. Agitator; 701. Agitator shaft; 702. Agitator blade; 8. Annular mixing and feeding device; 801. Gas-liquid mixing nozzle; 802. Inner pipe; 803. Outer pipe; 804. Liquid channel; 805. Gas channel; 806. Support bracket; 9. Level gauge; 10. pH detector; 11. Pressure relief valve; 12. Transfer pump. Detailed Implementation
[0019] The specific technical solution of this utility model will be further described below with reference to the accompanying drawings.
[0020] like Figures 1-2As shown, the multi-stage feeding and mixing enhancement device for semi-continuous fermentation of hyaluronic acid includes a fermenter 1, a storage device 2, and a buffer tank 3. The storage device 2 is equipped with a pipeline connected to the top inlet of the fermenter 1. The middle inlet of the fermenter 1 is connected to an alkali tank 4. The bottom inlet of the fermenter 1 is connected to an oxygen pipeline 5. The oxygen pipeline 5 has a branch connected to the middle inlet of the fermenter 1. The storage device 2 has a branch connected to the bottom inlet of the fermenter 1. The bottom of the fermenter 1 is connected to the buffer tank 3 via a transfer pump 12. The buffer tank 3 is equipped with a pipeline for returning to the middle of the fermenter 1. The fermenter 1 is equipped with an annular mixing feeder 8 and a stirrer 7. The annular mixing feeder 8 is connected to the middle inlet and the bottom inlet of the fermenter 1.
[0021] The fermenter 1 is equipped with a pH detector 10, a level gauge 9 and a pressure relief valve 11 at the top; both the fermenter 1 and the buffer tank 3 are equipped with sewage discharge pipes 6 at the bottom.
[0022] The annular mixing feed device 8 consists of an annular pipe and a gas-liquid mixing nozzle 801, wherein the annular pipe consists of an outer pipe 803 and an inner pipe 802.
[0023] The gas-liquid mixing nozzle 801 is provided with a gas channel 805 and a liquid channel 804. The gas channel 805 is connected to the outer tube 803, and the liquid channel 804 is connected to the inner tube 802. The gas-liquid mixing nozzles 801 are evenly distributed on the annular tube, and the included angle between adjacent nozzles is 30°.
[0024] The annular mixing and feeding device 8 is fixed inside the fermenter 1 by a support bracket 806.
[0025] The agitator 7 consists of an agitator shaft 701 and agitator blades 702. The agitator blades 702 are, from top to bottom, anchor blades, ribbon blades, and turbine blades. The turbine blades are on the same horizontal plane as the bottom feed inlet of the fermenter 1.
[0026] The aforementioned multi-stage feeding and mixing enhancement device for semi-continuous fermentation of hyaluronic acid has the following working process: Check the sealing of fermenter 1, storage device 2, and buffer tank 3; open the drain pipe 6 to discharge impurities from the tank, ensuring cleanliness and sterility; install a pH detector 10 and a level gauge 9 on the top of fermenter 1; calibrate equipment parameters; set the pressure threshold of the pressure relief valve 11 to ensure safe production; and introduce hyaluronic acid production bacteria, carbon source, nitrogen source, and other nutrients required for fermentation from storage device 2 into fermenter 1 through the feed inlet at the top of fermenter 1. The level gauge 9... Monitor the fermentation broth volume to the set height; start the stirrer 7 to begin fermentation, open the oxygen pipeline 5, and gas enters through the bottom and middle feed inlets. The bottom gas is ejected at high speed through the outer pipe 803 of the annular mixing feed device 8 and the center of the gas-liquid mixing nozzle 801. During this stage, no material is added to the bottom. A control valve is installed on the branch connected to the storage device 2. This control valve is closed during fermentation. During fermentation, the pH detector 10 monitors the acidity and alkalinity in real time. When the pH value is lower than the set range, the alkali tank 4 automatically enters the annular mixing feed from the middle feed inlet. Feeding device 8: The gas flows out through the annular gap of gas-liquid mixing nozzle 801, and is counteracted by the central gas at the outlet, breaking it into fine droplets to achieve efficient gas-liquid mixing. When fermentation reaches a certain stage, part of the fermentation liquid is transferred to buffer tank 3 to prevent the viscosity of the fermentation liquid in fermenter 1 from being too high, which would lead to a decrease in dissolved oxygen and uneven molecular weight of the product. The discharge rate of fermentation liquid is controlled by level gauge 9 to ensure the stability of subsequent fermentation. After part of the fermentation liquid is discharged, the nutrients in storage device 2 are transported through a branch to the bottom feed inlet of fermenter 1 and enter the annular gap in sequence. The mixing and feeding device 8's inner tube 802 mixes with the gas and is then sprayed into the tank to continue hyaluronic acid fermentation. Throughout the process, the pH detector 10 and the level gauge 9 monitor and control the process in real time, while the pressure relief valve 11 ensures safety. During the discharge of the fermentation liquid, to prevent excessive discharge due to a malfunction of the level gauge 9, the buffer tank 3 is equipped with a return pipeline to allow for the return of the fermentation liquid. After fermentation, the fermentation liquid is transported to the subsequent device through the buffer tank 3, and the residual fermentation liquid at the bottom is discharged through the drain pipeline and the tank is cleaned in preparation for the next batch.
Claims
1. A multi-stage fed-batch mixing and intensification device for semi-continuous fermentation of hyaluronic acid, comprising a fermenter (1), a storage device (2), and a buffer tank (3), characterized in that, The storage device (2) is provided with a pipeline connected to the top inlet of the fermenter (1), the middle inlet of the fermenter (1) is connected to the alkali tank (4), the bottom inlet of the fermenter (1) is connected to the oxygen pipeline (5), the oxygen pipeline (5) is provided with a branch connected to the middle inlet of the fermenter (1); the storage device (2) is provided with a branch connected to the bottom inlet of the fermenter (1); the bottom of the fermenter (1) is connected to the buffer tank (3) through the transfer pump (12), and the buffer tank (3) is provided with a pipeline for return flow to the middle of the fermenter (1); The fermenter (1) is equipped with an annular mixing feed device (8) and a stirrer (7) inside. The annular mixing feed device (8) is connected to the feed inlet in the middle and the feed inlet at the bottom of the fermenter (1).
2. The multi-stage fed-batch mixing and strengthening device for semi-continuous fermentation of hyaluronic acid according to claim 1, characterized in that, The fermenter (1) is equipped with a pH detector (10), a level gauge (9) and a pressure relief valve (11) on its top.
3. The multi-stage fed-batch mixing and strengthening device for semi-continuous fermentation of hyaluronic acid according to claim 1, characterized in that, Both the fermenter (1) and the buffer tank (3) are equipped with sewage pipes (6) at the bottom.
4. The multi-stage fed-batch mixing and strengthening device for semi-continuous fermentation of hyaluronic acid according to claim 1, characterized in that, The annular mixing feed device (8) consists of an annular tube and a gas-liquid mixing nozzle (801), and the annular tube consists of an outer tube (803) and an inner tube (802).
5. The multi-stage fed-batch mixing and strengthening device for semi-continuous fermentation of hyaluronic acid according to claim 4, characterized in that, The gas-liquid mixing nozzle (801) is provided with a gas channel (805) and a liquid channel (804). The gas channel (805) is connected to the outer tube (803), and the liquid channel (804) is connected to the inner tube (802). The included angle between adjacent gas-liquid mixing nozzles (801) is 30°.
6. The multi-stage fed-batch mixing and strengthening device for semi-continuous fermentation of hyaluronic acid according to claim 4, characterized in that, The annular mixing feed device (8) is fixed inside the fermenter (1) by multiple support brackets (806).
7. The multi-stage fed-batch mixing and strengthening device for semi-continuous fermentation of hyaluronic acid according to claim 1, characterized in that, The agitator (7) consists of an agitator shaft (701) and agitator blades (702). The agitator blades (702) are, from top to bottom, anchor blades, ribbon blades and turbine blades. The turbine blades are on the same horizontal plane as the bottom feed inlet of the fermenter (1).