Preparation device of gamma-polyglutamic acid-chitosan composite hydrogel

Abstract

The invention discloses a preparation device of gamma-polyglutamic acid-chitosan composite hydrogel, and particularly relates to the technical field of biochemical engineering, the preparation device comprises: (a) a dual-channel temperature control dissolving module: a gamma-polyglutamic acid alkaline dissolving cavity and a chitosan acid pre-dissolving cavity which are arranged in parallel are respectively provided with an independent temperature control system and a viscosity sensor; the invention discloses a mechanical arm linkage system. The gamma-polyglutamic acid alkaline dissolving cavity and the chitosan acid pre-dissolving cavity which are arranged in parallel are matched with the independent temperature control system, so that the dissolving temperature requirements of the two raw materials can be accurately met, and the problem of chitosan molecular chain breakage or insufficient gamma-polyglutamic acid dissolution caused by temperature fluctuation in a traditional process is solved. The viscosity sensor is combined with the mechanical arm linkage system, so that the stirring speed can be adjusted in real time according to the viscosity of the solution, the problem of non-uniform local concentration caused by the fixed stirring speed is effectively solved, and a good foundation is laid for the consistency of subsequent cross-linking reaction.

Description

Technical Field

[0001] The invention relates to the technical field of biochemical engineering, and in particular to a device for preparing a gamma-polyglutamic acid-chitosan composite hydrogel. Background Art

[0002] Both γ-polyglutamic acid and chitosan are natural polymer materials with excellent biocompatibility, degradability, and bioactivity. Their composite hydrogels have broad application prospects in biomedicine, tissue engineering, wound dressings, and other fields. Currently, the preparation of γ-polyglutamic acid-chitosan composite hydrogels mainly relies on traditional step-by-step processes, covering raw material dissolution, solution mixing, chemical / physical crosslinking, drying and molding, and functional modification. However, existing technologies have significant limitations in terms of automation, product uniformity, performance control accuracy, and preparation efficiency, making it difficult to meet the needs of large-scale production of high-performance composite hydrogels.

[0003] In existing technologies, the dissolution of γ-polyglutamic acid and chitosan often involves single-chamber batch processing, or dual-chamber processes that lack precise temperature control and viscosity feedback mechanisms. For example, the dissolution of γ-polyglutamic acid under alkaline conditions requires specific temperature assistance, while chitosan is susceptible to molecular chain breakage due to temperature fluctuations under acidic conditions. In traditional processes, the dual-chamber temperature is often set manually and cannot be adjusted in a coordinated manner, often resulting in insufficient dissolution or excessive degradation. Furthermore, the stirring rate is often fixed and cannot be adjusted in real time based on the solution viscosity, which can easily lead to localized concentration unevenness and affect the consistency of subsequent cross-linking reactions. Summary of the Invention

[0004] The purpose of the present invention is to provide a device for preparing γ-polyglutamic acid-chitosan composite hydrogel to solve the above-mentioned shortcomings in the technology.

[0005] In order to achieve the above object, the present invention provides the following technical solution: a device for preparing γ-polyglutamic acid-chitosan composite hydrogel, comprising: (a) Dual-channel temperature-controlled dissolution module: The γ-polyglutamic acid alkaline dissolution chamber and chitosan acidic pre-dissolution chamber are set in parallel, each equipped with an independent temperature control system and viscosity sensor; A robotic arm linkage system is used to adjust the stirring rate between 200 and 500 revolutions per minute and the temperature in real time based on feedback from the viscosity sensor, wherein the temperature of the γ-polyglutamic acid dissolution chamber is controlled between 40 and 60 degrees Celsius and the temperature of the chitosan pre-dissolution chamber is controlled at room temperature; (b) Microfluidic gradient cross-linking module: A multi-stage microchannel mixer, the inlet of which is connected to the dual-cavity output end of the dual-channel temperature-controlled dissolution module, wherein the multi-stage microchannel mixer adopts a laminar flow channel design to ensure that the Reynolds number is less than 10; a dynamic shear reactor connected to the outlet of the multi-stage microchannel mixer, having a built-in coaxial rotor and a rheometer, and configured to automatically adjust the shear rate between 0.1 and 100 radians per second based on the storage modulus feedback monitored by the rheometer; (c) Trimodal drying-imprinting module: A three-stage drying chamber with integrated vacuum drying, freeze drying, and hot air drying functions. The freeze drying temperature can reach -40 degrees Celsius, while the hot air drying temperature is controlled at 25 degrees Celsius. The drying chamber is equipped with a moisture content sensor. An air pressure-driven microporous template imprinting unit is connected to the drying chamber, wherein the pore size of the microporous template is adjustable within the range of 85 to 142 microns and the imprinting pressure is between 0.1 and 0.5 MPa; (d) Rotary drum functionalization module: a rotating drum having circumferential partitions for fixing the gel film; The enzymatic hydrolysis tank, the termination tank and the drug loading tank are sequentially arranged on the circumferential path of the rotating drum so that the gel membrane fixed on the rotating drum can pass through in sequence; An electrode pair is provided in the drug loading tank for applying an electric field-assisted electrodialysis of 10 to 100 volts per centimeter; (e) A central controller: configured to receive signals from the viscosity sensor, rheometer, and moisture content sensor, and to control and adjust the robotic arm linkage system, the micropump supplying liquid to the microfluidic gradient cross-linking module, the drying mode of the three-stage drying chamber, the operating parameters of the air pressure-driven microporous template imprinting unit, and the rotation speed of the drum between 0.1 and 5 revolutions per minute.

[0006] Preferably, the surface of the coaxial rotor of the dynamic shear reactor is provided with a bionic micro-groove structure, wherein the depth of the micro-groove is between 50 and 200 microns and the width is between 100 and 300 microns, which is used to induce directional arrangement of molecules to improve cross-linking uniformity.

[0007] Preferably, the air pressure driven microporous template imprinting unit is driven by a shape memory alloy, and the pore size of the microporous template is dynamically adjusted within the range of 85 to 142 microns by applying current, with an adjustment accuracy of ±2 microns.

[0008] Preferably, an ultrasonic oscillator is further provided in the drug loading tank of the rotary drum functionalization module, and the oscillation frequency is between 20 and 100 kHz, which is used to destroy the hydration layer on the surface of the gel to improve the drug penetration efficiency.

[0009] Preferably, the central controller has a built-in artificial intelligence optimization algorithm for automatically generating a combination of preparation parameters according to the performance requirements of the target gel, including porosity, drug loading rate, and compression modulus, and adjusting the linkage process of the device in real time.

[0010] Preferably, the method for preparing the above-mentioned γ-polyglutamic acid-chitosan composite hydrogel in a linked manner comprises the following steps: Dissolution stage: γ-polyglutamic acid solution is dissolved in the alkaline dissolution chamber, and chitosan solution is dissolved synchronously in the acidic pre-dissolution chamber. The robotic arm linkage system adjusts the stirring rate and temperature parameters in each dissolution chamber in real time based on the feedback from the viscosity sensor; Cross-linking stage: The dissolved γ-polyglutamic acid solution and chitosan solution are mixed in laminar flow in the multi-stage microchannel mixer and then injected into the dynamic shear reactor. The rheometer monitors the storage modulus and loss modulus in real time and adjusts the shear rate of the dynamic shear reactor accordingly until the gel point is reached. Drying stage: the formed gel enters the three-stage drying chamber for staged dehydration. When the moisture content sensor detects that the moisture content of the gel is lower than 10%, the air pressure-driven microporous template imprinting unit is triggered to perform imprinting on the dried gel. Functionalization stage: The embossed gel film is fixed on the drum, which drives the gel film at a set speed to pass through the enzymatic hydrolysis tank for enzymatic hydrolysis, the termination tank for enzymatic hydrolysis, and the drug loading tank for electric field assisted electrodialysis drug loading. In the above technical solution, the technical effects and advantages provided by the present invention are: 1. The parallel arrangement of the alkaline dissolution chamber for γ-polyglutamic acid and the acidic pre-dissolution chamber for chitosan, coupled with an independent temperature control system, precisely meets the required dissolution temperatures for both raw materials, avoiding the temperature fluctuations that can cause chitosan molecular chain breakage or inadequate dissolution of γ-polyglutamic acid in traditional processes. The combination of a viscosity sensor and a robotic arm linkage system allows for real-time adjustment of the stirring rate based on solution viscosity, effectively addressing the issue of localized concentration unevenness caused by a fixed stirring rate and laying a solid foundation for consistent cross-linking reactions.

[0011] 2. The multi-stage microchannel mixer utilizes a laminar flow design, achieving gentle, uniform mixing of the two solutions. This overcomes the localized crosslinking variations caused by turbulence in traditional stirring-type mixing. The dynamic shear reactor's built-in rheometer monitors the storage modulus in real time, automatically adjusting the shear rate to ensure precise and controllable crosslinking. The biomimetic microgrooves on the coaxial rotor surface induce directional molecular alignment, further enhancing the crosslinking uniformity of the composite hydrogel and improving the mechanical stability of the gel.

[0012] 3. A three-stage drying chamber integrating vacuum, freezing, and hot air allows for phased dehydration based on gel properties, avoiding the drawbacks of a single drying mode while improving drying efficiency. A moisture sensor is linked to the air pressure-driven microporous template imprinting unit, triggering imprinting when the moisture content is <10%, ensuring optimal imprinting. Furthermore, the shape memory alloy-driven imprinting unit enables dynamic adjustment of pore size, significantly improving molding precision and flexibility compared to traditional manual template replacement, meeting varying porosity requirements. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments. Obviously, the drawings described below are only some embodiments described in the present invention. For ordinary technicians in this field, other drawings can also be obtained based on these drawings.

[0014] Figure 1 It is a schematic diagram of the overall framework structure of the present invention; Figure 2 This is a schematic diagram of the dissolution stage process of the present invention; Figure 3 This is a schematic flow chart of the cross-linking stage of the present invention; Figure 4 This is a schematic diagram of the drying stage process of the present invention; Figure 5 Schematic diagram of the functionalization stage of the present invention. DETAILED DESCRIPTION

[0015] In order to enable those skilled in the art to better understand the technical solution of the present invention, the present invention will be further described in detail below with reference to the accompanying drawings.

[0016] The present invention provides Figures 1 to 5 The device for preparing a γ-polyglutamic acid-chitosan composite hydrogel shown includes: Dual-channel temperature-controlled dissolution module: This module is mainly used to achieve the separate dissolution of γ-polyglutamic acid and chitosan, preparing for the subsequent mixing and cross-linking.

[0017] The module contains a parallel arrangement of an alkaline dissolution chamber for γ-polyglutamic acid and an acidic pre-dissolution chamber for chitosan. γ-polyglutamic acid dissolves more readily in alkaline environments, while chitosan pre-dissolves better in acidic conditions. This arrangement aligns with the solubility characteristics of both substances.

[0018] Each dissolution chamber is equipped with an independent temperature control system and viscosity sensor. These independent temperature control systems precisely control the temperature according to the dissolution requirements of the two substances. The γ-polyglutamic acid dissolution chamber is kept at a temperature between 40 and 60 degrees Celsius, which promotes its dissolution in an alkaline environment. The chitosan pre-dissolution chamber is kept at room temperature to prevent adverse effects of temperature on the pre-dissolution of chitosan in an acidic environment.

[0019] Viscosity sensors monitor changes in viscosity of the solutions in the two dissolution chambers in real time and transmit signals to the robotic linkage system. The robotic linkage system, receiving feedback from the viscosity sensors, adjusts the stirring rate between 200 and 500 revolutions per minute and the temperature in real time. When the solution viscosity is high, the robotic linkage system increases the stirring rate and adjusts the temperature appropriately to accelerate dissolution. When the viscosity drops to an appropriate range, the stirring rate is reduced to prevent excessive stirring from affecting the solution's properties.

[0020] Microfluidic gradient cross-linking module: The function of this module is to mix the dissolved γ-polyglutamic acid solution and chitosan solution and form a gel precursor through a cross-linking reaction.

[0021] The module consists of a multi-stage microchannel mixer and a dynamic shear reactor. The inlet of the multi-stage microchannel mixer is connected to the dual-chamber output of the dual-channel temperature-controlled dissolution module. It utilizes a laminar flow channel design to ensure a Reynolds number of less than 10. Under laminar flow, the two solutions can be mixed smoothly, avoiding uneven mixing caused by turbulence and facilitating a uniform cross-linking reaction.

[0022] The dynamic shear reactor is connected to the outlet of the multi-stage microchannel mixer and houses a coaxial rotor and rheometer. The rheometer monitors the storage modulus of the mixture in real time, and the dynamic shear reactor automatically adjusts the shear rate between 0.1 and 100 radians per second based on this feedback. By properly adjusting the shear rate, the progress and extent of the cross-linking reaction can be controlled, allowing the mixture to form a gel precursor with specific properties.

[0023] In addition, the dynamic shear reactor's coaxial rotor features a biomimetic microgroove structure with a depth ranging from 50 to 200 microns and a width ranging from 100 to 300 microns. This structure can induce directional molecular alignment, further enhancing cross-linking uniformity and thus improving gel properties.

[0024] Trimodal Drying-Imprinting Module: This module is used to dry the gel and give it a specific microporous structure by imprinting.

[0025] The module includes a three-stage drying chamber integrating vacuum drying, freeze drying, and hot air drying. Freeze drying can reach temperatures as low as -40°C, while hot air drying is controlled at 25°C. The drying chamber is equipped with a moisture sensor. These three drying methods can be optimally selected and combined based on the gel's characteristics and drying requirements, achieving efficient and uniform dehydration. The moisture sensor monitors the gel's moisture content in real time, providing a basis for controlling the drying process.

[0026] The pneumatically driven microporous template imprinting unit is connected to the drying chamber. The microporous template pore size is adjustable between 85 and 142 microns, and the imprinting pressure is between 0.1 and 0.5 MPa. When the moisture sensor detects that the gel moisture content is below 10%, the imprinting unit is triggered to imprint the dried gel. By adjusting the template pore size and imprinting pressure, gels with different microporous structures can be obtained to meet different application requirements.

[0027] Furthermore, the pneumatically driven microporous template imprinting unit utilizes a shape memory alloy drive. By applying an electric current, the pore size of the microporous template is dynamically adjusted within a range of 85 to 142 microns, with an adjustment accuracy of ±2 microns. This drive method enables precise adjustment of the pore size, ensuring a consistent microporous structure.

[0028] (IV) Rotary drum functional module This module mainly performs functionalization on the embossed gel film to give it specific functions.

[0029] The module includes a rotating drum, an enzymatic hydrolysis tank, a termination tank, and a drug loading tank. The circumferential partitions of the drum are used to fix the gel film. The enzymatic hydrolysis tank, the termination tank, and the drug loading tank are sequentially arranged on the circumferential path of the drum, so that the gel film fixed on the drum can pass through these tanks in sequence.

[0030] When the gel membrane passes through the enzymatic hydrolysis tank, it will undergo enzymatic hydrolysis treatment to change the chemical structure and properties of the gel; then it enters the termination tank to terminate the enzymatic hydrolysis reaction to avoid excessive enzymatic hydrolysis; finally, it enters the drug loading tank for drug loading treatment.

[0031] Electrode pairs are placed within the drug-loading tank to apply an electric field of 10 to 100 volts per centimeter to assist electrodialysis, thereby increasing the drug loading and uniformity within the gel membrane. Furthermore, an ultrasonic oscillator, operating at a frequency between 20 and 100 kilohertz, is also located within the tank to disrupt the hydration layer on the gel surface, further enhancing drug penetration efficiency.

[0032] (5) Central Controller The central controller is the core control part of the entire device. It is used to receive signals from the viscosity sensor, rheometer and moisture content sensor, and to control and adjust the robotic arm linkage system, the micropump that supplies liquid to the microfluidic gradient cross-linking module, the drying mode of the three-stage drying chamber, the operating parameters of the air pressure-driven microporous template imprinting unit, and the rotation speed of the drum between 0.1 and 5 revolutions per minute.

[0033] The central controller incorporates a built-in artificial intelligence optimization algorithm that automatically generates a combination of preparation parameters based on target gel performance requirements, including porosity, drug loading, and compression modulus, and adjusts the device's interlocking processes in real time. This AI optimization algorithm enables the device to more intelligently adapt to varying preparation requirements, improving production efficiency and maintaining consistent product quality.

[0034] (1) Dissolution stage During the dissolution phase, the γ-polyglutamic acid solution dissolves in the alkaline dissolution chamber, while the chitosan solution dissolves simultaneously in the acidic pre-dissolution chamber. The robotic arm linkage system adjusts the stirring rate and temperature parameters in each dissolution chamber in real time based on feedback from the viscosity sensor.

[0035] The viscosity sensor monitors the viscosity of the solution in real time. When the viscosity is high, it means that the dissolution is not sufficient. The robotic arm linkage system will increase the stirring rate and adjust to the appropriate temperature to speed up the dissolution. When the viscosity drops to the appropriate range, it indicates that the dissolution is basically completed. The robotic arm linkage system will reduce the stirring rate to maintain the stability of the solution.

[0036] (2) Cross-linking stage The dissolved γ-polyglutamic acid solution and chitosan solution are mixed in a laminar flow in a multi-stage microchannel mixer and then injected into a dynamic shear reactor. Due to the laminar flow design of the multi-stage microchannel mixer, the two solutions can be evenly mixed.

[0037] The rheometer monitors the storage modulus and loss modulus of the mixture in real time. When the storage modulus gradually increases and exceeds the loss modulus, the mixture begins to form a gel structure. Based on this monitoring data, the dynamic shear reactor adjusts the shear rate until the gel point is reached, allowing the mixture to form a stable gel structure.

[0038] (3) Drying stage The formed gel enters a three-stage drying chamber for phased dehydration. Based on the gel's initial and target moisture contents, the chamber automatically selects the appropriate drying mode combination, such as vacuum drying to quickly remove some moisture, followed by freeze drying or hot air drying to further reduce the moisture content.

[0039] When the moisture sensor detects that the gel's moisture content is less than 10%, the air pressure is triggered to drive the microporous template imprinting unit to emboss the dried gel. This is because at this moisture content, the gel has the appropriate hardness and plasticity to ensure the imprinting effect.

[0040] (IV) Functionalization stage The embossed gel film is fixed on a rotating drum, which drives the gel film through the enzymatic hydrolysis tank, the termination tank and the drug loading tank in sequence at a set speed.

[0041] In the enzymatic hydrolysis tank, the gel membrane undergoes enzymatic hydrolysis, which can change the chemical structure of the gel, giving it better biocompatibility or other specific properties. After entering the termination tank, the enzymatic hydrolysis reaction is terminated to prevent excessive enzymatic hydrolysis from affecting the gel performance. Finally, in the drug loading tank, through the synergistic effect of electric field-assisted electrodialysis and ultrasonic oscillation, the drug is efficiently and evenly loaded onto the gel membrane, completing the functionalization of the gel.

[0042] The above description is merely illustrative of certain exemplary embodiments of the present invention. It goes without saying that those skilled in the art will be able to modify the described embodiments in various ways without departing from the spirit and scope of the present invention. Therefore, the above drawings and description are illustrative in nature and should not be construed as limiting the scope of protection of the claims.

Claims

1. A preparation device for γ-polyglutamic acid-chitosan composite hydrogel, characterized in that: include: (a) Dual-channel temperature-controlled dissolution module: The γ-polyglutamic acid alkaline dissolution chamber and chitosan acidic pre-dissolution chamber are set in parallel, each equipped with an independent temperature control system and viscosity sensor; A robotic arm linkage system is used to adjust the stirring rate between 200 and 500 revolutions per minute and the temperature in real time based on feedback from the viscosity sensor, wherein the temperature of the γ-polyglutamic acid dissolution chamber is controlled between 40 and 60 degrees Celsius and the temperature of the chitosan pre-dissolution chamber is controlled at room temperature; (b) Microfluidic gradient cross-linking module: A multi-stage microchannel mixer, the inlet of which is connected to the dual-cavity output end of the dual-channel temperature-controlled dissolution module, wherein the multi-stage microchannel mixer adopts a laminar flow channel design to ensure that the Reynolds number is less than 10; a dynamic shear reactor connected to the outlet of the multi-stage microchannel mixer, having a built-in coaxial rotor and a rheometer, and configured to automatically adjust the shear rate between 0.1 and 100 radians per second based on the storage modulus feedback monitored by the rheometer; (c) Trimodal drying-imprinting module: A three-stage drying chamber with integrated vacuum drying, freeze drying, and hot air drying functions. The freeze drying temperature can reach -40 degrees Celsius, while the hot air drying temperature is controlled at 25 degrees Celsius. The drying chamber is equipped with a moisture content sensor. An air pressure-driven microporous template imprinting unit is connected to the drying chamber, wherein the pore size of the microporous template is adjustable within the range of 85 to 142 microns and the imprinting pressure is between 0.1 and 0.5 MPa; (d) Rotary drum functionalization module: a rotating drum having circumferential partitions for fixing the gel film; The enzymatic hydrolysis tank, the termination tank and the drug loading tank are sequentially arranged on the circumferential path of the rotating drum so that the gel membrane fixed on the rotating drum can pass through in sequence; An electrode pair is provided in the drug loading tank for applying an electric field-assisted electrodialysis of 10 to 100 volts per centimeter; (e) A central controller: configured to receive signals from the viscosity sensor, rheometer, and moisture content sensor, and to control and adjust the robotic arm linkage system, the micropump supplying liquid to the microfluidic gradient cross-linking module, the drying mode of the three-stage drying chamber, the operating parameters of the air pressure-driven microporous template imprinting unit, and the rotation speed of the drum between 0.1 and 5 revolutions per minute.

2. The device for preparing a γ-polyglutamic acid-chitosan composite hydrogel according to claim 1, characterized in that: The coaxial rotor surface of the dynamic shear reactor is provided with a bionic micro-groove structure, wherein the depth of the micro-groove is between 50 and 200 microns and the width is between 100 and 300 microns, which is used to induce directional arrangement of molecules to improve cross-linking uniformity.

3. The device for preparing a γ-polyglutamic acid-chitosan composite hydrogel according to claim 1, characterized in that: The air pressure driven microporous template imprinting unit is driven by shape memory alloy, and the pore size of the microporous template is dynamically adjusted within the range of 85 to 142 microns by applying current, with an adjustment accuracy of ±2 microns.

4. The device for preparing a γ-polyglutamic acid-chitosan composite hydrogel according to claim 1, characterized in that: The drug loading tank of the rotary drum functionalization module is also provided with an ultrasonic oscillator with an oscillation frequency between 20 and 100 kHz, which is used to destroy the hydration layer on the surface of the gel to improve the drug penetration efficiency.

5. The device for preparing a γ-polyglutamic acid-chitosan composite hydrogel according to claim 1, characterized in that: The central controller has a built-in artificial intelligence optimization algorithm for automatically generating a combination of preparation parameters based on the performance requirements of the target gel, including porosity, drug loading rate, and compression modulus, and adjusting the linkage process of the device in real time.

6. A method for preparing a γ-polyglutamic acid-chitosan composite hydrogel according to any one of claims 1 to 5, characterized in that: The following steps are involved: Dissolution stage: γ-polyglutamic acid solution is dissolved in the alkaline dissolution chamber, and chitosan solution is dissolved synchronously in the acidic pre-dissolution chamber. The robotic arm linkage system adjusts the stirring rate and temperature parameters in each dissolution chamber in real time based on the feedback from the viscosity sensor; Cross-linking stage: The dissolved γ-polyglutamic acid solution and chitosan solution are mixed in laminar flow in the multi-stage microchannel mixer and then injected into the dynamic shear reactor. The rheometer monitors the storage modulus and loss modulus in real time and adjusts the shear rate of the dynamic shear reactor accordingly until the gel point is reached. Drying stage: the formed gel enters the three-stage drying chamber for staged dehydration. When the moisture content sensor detects that the moisture content of the gel is lower than 10%, the air pressure-driven microporous template imprinting unit is triggered to perform imprinting on the dried gel. Functionalization stage: The embossed gel film is fixed on the rotating drum, which drives the gel film at a set speed to pass through the enzymatic hydrolysis tank for enzymatic hydrolysis, the termination tank for terminating the enzymatic hydrolysis reaction, and the drug loading tank for electric field-assisted electrodialysis drug loading.

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