Preparation system and method of gelatin embolization microspheres

Abstract

The invention provides a preparation system and method of gelatin embolization microspheres, and belongs to the technical field of microsphere preparation. Firstly, a preparation system of the gelatin embolism microspheres is provided, the preparation system comprises a feeding device, a micro-fluidic device, a cross-linking curing device and a cleaning device, and a continuous passage for preparing the gelatin embolism microspheres is formed among the feeding device, the micro-fluidic device, the cross-linking curing device and the cleaning device; secondly, an adaptive preparation method of the gelatin embolism microspheres is provided, and the preparation method comprises the steps of material preparation, material feeding, microfluidic reaction, low-temperature cross-linking curing, isopropanol cleaning, water cleaning and freeze drying. Finally, the gelatin embolism microspheres which are stable and uniform in performance and large in scale are obtained, and then large-scale, batch, controllable and standardized preparation of the gelatin embolism microspheres is achieved.

Description

Technical Field

[0001] The present invention relates to a preparation system and method for gelatin embolization microspheres, and particularly to a system and method for large-scale production of degradable gelatin embolization microspheres by using microfluidic technology, which meet the production and standardization requirements of microspheres and belong to the technical field of microsphere preparation. Background Art

[0002] Tumorous cancers have become the primary problem endangering global public health. In China, about 4 million new cancer patients are added every year, and 600,000 - 700,000 patients undergo tumor interventional treatment, with a growth rate of 10% - 20%. With the development of minimally invasive technology, transcatheter arterial embolization as a new embolization technology is emerging. Embolization microspheres are injected into blood vessels through a catheter, reach the affected position, cut off the nutrient supply of tumor cells, cause the tumor cells to atrophy due to lack of nutrients, and thus "starve" the tumor.

[0003] Microspheres generally refer to spherical particles with a particle size in the range of 50 nm - 2 mm, and most are solid particles or spheres. There are many carrier materials for preparing microspheres, which are mainly divided into natural polymer microspheres (such as starch microspheres, albumin microspheres, gelatin microspheres, chitosan microspheres, etc.) and synthetic polymer microspheres (such as polylactic acid microspheres, polyvinyl alcohol microspheres), etc.

[0004] Currently, due to the limitations of the particularity of microsphere production processes and existing equipment conditions, etc., it is difficult to realize the continuous, batch and industrial production of microsphere production processes. Moreover, there are many manual operation procedures in the microsphere preparation process, which easily lead to non-uniform product performance and increase the risk of product contamination. In addition, the existing methods for preparing microspheres generally adopt the stirring emulsification method, but the microsphere products prepared by the stirring emulsification method have non-uniform particle sizes and a large particle size range, and need to be screened after preparation to obtain microsphere products that meet the requirements, resulting in a low yield of microsphere products.

[0005] Based on microfluidic technology, embolization microspheres with uniform particle sizes can be prepared. Fluids are manipulated at the microscale to form droplets with uniform sizes. For example, in the prior art CN107418872A, a focusing type and T-type droplet microfluidic chip is used to prepare bioink microspheres. Among them, although single pipelines or single chips can prepare microspheres with uniform particle sizes, there are difficulties in process scale-up, that is, currently, it is still impossible to carry out microfluidic production processes to prepare a large number of microspheres. At the same time, there is a lack of stable, efficient and high-throughput equipment for preparing microspheres. CN112569878A discloses "an apparatus for preparing polyvinyl alcohol embolization microspheres with uniform particle sizes and its production process", in which multiple microfluidic devices are connected in parallel and finally collected in a container, with complex operations, a large number of required equipment and high cost investment; CN108704578A discloses "an apparatus for continuously producing microspheres and its application", in which an emulsification module is used and the uniformity of microspheres cannot be effectively achieved.

[0006] Therefore, a system and method for producing gelatin embolization microspheres that can ensure the uniformity, scale, and stability of microspheres are required. Summary of the Invention

[0007] The present invention aims to solve the problems in the prior art that the preparation process of gelatin embolization microspheres cannot be scaled up, and there is a lack of a stable, efficient, and high-throughput production line for preparing microspheres. Therefore, a preparation system and method for gelatin embolization microspheres are proposed.

[0008] In order to achieve the above technical objectives, the following technical solutions are proposed: The first objective of this technical solution is to provide: a preparation system for gelatin embolization microspheres, including a feeding device, a microfluidic device, a cross-linking and curing device, and a cleaning device; The feeding device includes a dispersed-phase delivery pipe and a continuous-phase delivery pipe. One end of the dispersed-phase delivery pipe is connected to a dispersed-phase storage tank, and the other end is connected to the dispersed-phase inlet on the microfluidic device. An injection pump is provided on the dispersed-phase delivery pipe; one end of the continuous-phase delivery pipe is connected to a continuous-phase storage tank, and the other end is connected to the continuous-phase inlet on the microfluidic device. A constant-pressure pump is provided on the continuous-phase delivery pipe; The microfluidic device includes a bracket and a microfluidic chip assembly provided on the bracket. The bracket is arranged on a lifting mechanism I; The cross-linking and curing device includes a cross-linking and curing tank, which is arranged directly below the microfluidic chip assembly; the cross-linking and curing tank is connected to an ice bath cooling system; The cleaning device is arranged behind the working station of the cross-linking and curing device. The microsphere outlet on the cross-linking and curing tank is connected to the cleaning device, and the cleaning device is connected to a drying device; A continuous path for preparing gelatin embolization microspheres is formed among the feeding device, the microfluidic device, the cross-linking and curing device, the cleaning device, and the drying device.

[0009] Preferably, the microfluidic chip assembly includes at least two groups of microfluidic chips. The microfluidic chips are respectively connected to the feeding device, are distributed in a constant-temperature system, and are arranged side by side or in a circular distribution. Among them, the microfluidic chip is a flow-focusing type microfluidic chip, such as: a CNC-machined PMMA chip.

[0010] Preferably, the inner diameter of the dispersed-phase channel in the microfluidic chip is 200 ± 20 to 500 ± 50 μm, and the inner diameter of the continuous-phase channel is 300 ± 20 to 1000 ± 100 μm.

[0011] Preferably, the bottom of the bracket is provided with a stirring mechanism I, which extends into the cross-linking curing tank to ensure that the droplets discharged from the microfluidic chip assembly can be effectively cross-linked and cured, and improve the efficiency and quality of cross-linking and curing. In which, a filter element I (such as a filter bucket, 316L material) for filtering the cross-linking liquid is provided in the cross-linking curing tank.

[0012] Preferably, the cleaning device includes a cleaning tank, a stirring mechanism II is provided directly above the cleaning tank, the stirring mechanism II is arranged on the lifting mechanism II, the stirring mechanism II extends into the cleaning tank, a filter element II (such as: filter bucket, 316L material) is provided in the cleaning tank; the cleaning tank is connected to an isopropyl alcohol storage tank through an isopropyl alcohol delivery pipe, the cleaning tank is connected to a water storage tank through a water delivery pipe, a switch valve is provided at the bottom of the cleaning tank, and the switch valve can be connected to the waste liquid treatment system through the waste liquid delivery pipe; both the isopropyl alcohol delivery pipe and the water delivery pipe are provided with metering pumps.

[0013] Preferably, the preparation system further comprises a central controller, which is respectively connected to the injection pump, the constant pressure pump, the metering pump, the lifting mechanism I, the lifting mechanism II, the stirring mechanism I, the stirring mechanism II, the ice bath cooling system and the constant temperature system through electrical signals.

[0014] The second purpose of the technical solution is to provide: a method for preparing gelatin embolic microspheres, comprising the following steps: S1: Ingredients Dissolve gelatin in water, heat and stir for 2 hours in a 60°C water bath to prepare a gelatin-water solution with a mass fraction of 7-20% to obtain a dispersed phase for later use; Add polyglycerol ricinoleate to soybean oil, stir and dissolve, and prepare a polyglycerol ricinoleate-oil solution with a mass fraction of 2-5% to obtain a continuous phase for later use; Add the glutaraldehyde aqueous solution to the soybean oil, stir and dissolve, and prepare a glutaraldehyde-oil solution with a mass fraction of 0.1-4% to obtain a cross-linking solution for later use; S2: Feed The microfluidic chip is controlled to descend by a lifting mechanism until the distance between the microfluidic chip and the liquid surface in the cross-linking curing tank is 1 to 5 cm; Controlling the dispersed phase feeding speed to 150-500 μL / min, injecting the dispersed phase into the microfluidic chip assembly; The continuous phase pressure is controlled to be 350-5000 mbr, and the continuous phase is injected into the microfluidic chip assembly; S3: Microfluidic reactions The ambient temperature of the microfluidic chip assembly is controlled to be 40-50°C, and after shearing force, the dispersed phase contacts the continuous phase to form droplets (water-in-oil type); the droplets are controlled to enter the cross-linking liquid in the cross-linking curing tank; S4: Cross-linking and curing Control the temperature of the crosslinking liquid in the crosslinking and curing tank to 0 - 5°C, and stir with the stirring mechanism at 100 - 500 rpm for 15 - 24 h to form the initial product of gelatin embolization microspheres; S5: Cleaning and drying Place the initial product of gelatin embolization microspheres in a cleaning device for cleaning; then, perform freeze-drying and irradiation sterilization to obtain gelatin embolization microspheres; Among them, the cleaning procedure includes: Clean with isopropanol, liquid inlet volume: 1 - 8 L, stirring speed: 300 - 500 r / min, stirring time: 1 - 20 min, number of cleaning times: 2 - 8 times; clean with water, liquid inlet volume: 1 - 8 L, stirring speed: 300 - 500 r / min, stirring time: 2 - 40 min, number of cleaning times: 3 - 10 times; after each cleaning, open the switch valve to control the cleaning waste liquid to flow into the waste liquid collection tank; The freeze-drying procedure includes: Pre-freeze at -20 to -40°C, sublimation dry at -30 to -40°C, and desorption dry at 0 to 10°C.

[0015] In this technical solution, the positional relationships such as "one end", "the other end", "above", "directly below", "behind the work station", "bottom", "inside", etc. are defined according to the actual use situation, which are common terms in this technical field and also common terms for those skilled in the art during actual use.

[0016] Adopting this technical solution brings the following beneficial technical effects: First, in the present invention, through the settings of the feeding device, microfluidic device, crosslinking and curing device, and cleaning device, a continuous path for the preparation of gelatin embolization microspheres is ensured among the feeding device, microfluidic device, crosslinking and curing device, and cleaning device, thereby realizing the large-scale, batch, controllable, and standardized preparation of gelatin embolization microspheres. Currently, the prior art mostly adopts the method of parallel connection of individual chips, which makes the process complex and costly and cannot achieve the purpose of effective integration; while the present invention uses a single integrated chip for amplification and ensures that the morphology and uniformity of the prepared microspheres are better, reducing the number of devices and the required personnel, thereby enabling the production output of microspheres to reach the industrial level; Second, in the present invention, the crosslinking and curing tank is connected with an ice bath cooling system to ensure the crosslinking and curing efficiency and quality of the microspheres, thereby ensuring the stable performance of the subsequent products to meet the actual requirements. Moreover, the microfluidic chips are distributed in a constant temperature system to ensure the stability of droplet formation and, at the same time, ensure the formation of uniform microspheres in the future; III. In the present invention, the preparation method includes batching, feeding, microfluidics, crosslinking and curing, cleaning, and drying. Among them, by controlling various conditions, it is ensured that uniform and stable-performance gelatin embolization microspheres can be formed. At the same time, large-scale, batch, controllable, and standardized production is achieved; IV. In the present invention, regarding the cleaning process, the cleaning process is simple to operate and thorough, and it can ensure that the residue limit of the microspheres after cleaning complies with the regulations. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 is the process flow chart of the present invention; Figure 2 is the logical connection block diagram of the preparation system in the present invention; Figure 3 is the equipment structure diagram (front view) in the present invention; Figure 4 is the equipment structure diagram (right view) in the present invention; Figure 5 is Figure 3 the cross-sectional view in the A-A direction; Figure 6 the schematic diagram of the working principle of the microfluidic chip in the present invention; Figure 7 is the flow chart related to the cleaning process in the present invention; Figure 8 is the schematic diagram of the cleaning device structure (front view) in the present invention; Figure 9 is the schematic diagram of the cleaning device structure (right view) in the present invention; Figure 10 is the partial circuit diagram (I) related to the present invention; Figure 11 is the partial circuit diagram (II) related to the present invention; Figure 12 is the product diagram of the gelatin embolization microspheres related to the present invention; In the figure, 1 is the dispersed phase delivery pipe, 2 is the continuous phase delivery pipe, 3 is the dispersed phase storage tank, 4 is the injection pump, 5 is the continuous phase storage tank, 6 is the constant pressure pump, 10 is the bracket, 11 is the microfluidic chip, 12 is the lifting mechanism I, 13 is the crosslinking and curing tank, 14 is the ice bath cooling system, 15 is the cleaning tank, 16 is the stirring mechanism I, 17 is the filter element I, 18 is the central controller, 19 is the stirring mechanism II, 20 is the lifting mechanism II, 21 is the isopropanol delivery pipe, 22 is the isopropanol storage tank, 23 is the water delivery pipe, 24 is the water storage tank, 25 is the switching valve, 26 is the metering pump, 27 is the filter element II, 28 is the constant temperature system, 29 is the waste liquid collection tank, 30 is the drying device, and 31 is the waste liquid delivery pipe. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0018] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of them. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts belong to the scope of protection of the present invention.

[0019] Embodiment 1 This embodiment provides a preparation system for gelatin embolization microspheres, as Figure 2 shown, which includes a feeding device, a microfluidic device, a cross-linking and curing device, and a cleaning device; wherein, Feeding device: It includes a dispersed phase delivery pipe 1 and a continuous phase delivery pipe 2. One end of the dispersed phase delivery pipe 1 is connected to a dispersed phase storage tank 3, and the other end is connected to the dispersed phase inlet on the microfluidic device. An injection pump 4 is provided on the dispersed phase delivery pipe 1; one end of the continuous phase delivery pipe 2 is connected to a continuous phase storage tank 5, and the other end is connected to the continuous phase inlet on the microfluidic device. A constant pressure pump 6 is provided on the continuous phase delivery pipe 2; Microfluidic device: It includes a bracket 10 and a microfluidic chip 11 assembly arranged on the bracket 10. The bracket 10 is arranged on a lifting mechanism I 12; Cross-linking and curing device: It includes a cross-linking and curing tank 13, and the cross-linking and curing tank 13 is arranged directly below the microfluidic chip 11 assembly; the cross-linking and curing tank 13 is connected to an ice bath cooling system 14; Cleaning device: It is arranged at the rear side of the working station of the cross-linking and curing device. The microsphere outlet on the cross-linking and curing tank 13 is connected to the cleaning device, and the cleaning device is connected to a drying device 30; A continuous path for the preparation of gelatin embolization microspheres is formed among the feeding device, the microfluidic device, the cross-linking and curing device, and the cleaning device. This entire system can achieve the large-scale, batch, controllable, and standardized preparation of gelatin embolization microspheres.

[0020] Embodiment 2 Based on Embodiment 1, this embodiment further defines the microfluidic chip 11 to further illustrate the present invention.

[0021] As Figure 6 shown, the microfluidic chip 11 assembly includes at least two groups of microfluidic chips 11. The microfluidic chips 11 are respectively connected to the feeding device. The microfluidic chips 11 are distributed in a constant temperature system 28, and the microfluidic chips 11 are arranged side by side or in a circular distribution. Among them, the microfluidic chip 11 is a flow focusing type microfluidic chip 11, such as: a CNC processed PMMA chip.

[0022] Among them, the inner diameter of the dispersed phase channel in the microfluidic chip 11 is 200 ± 20 to 500 ± 50 μm, and the inner diameter of the continuous phase channel is 300 ± 20 to 1000 ± 100 μm.

[0023] Currently, the prior art mostly adopts the method of parallel connection of single chips, which makes the process complex and costly, and fails to achieve the purpose of effective integration. Instead, the present invention uses a single integrated chip for amplification, ensures that the prepared microspheres have good morphology and uniformity, reduces the number of devices and the required personnel, and thus enables the production output of microspheres to reach the industrial level.

[0024] Example 3 On the basis of Examples 1-2, in order to improve the cross-linking curing efficiency and quality in this example, it is further defined that: A stirring mechanism I 16 is provided at the bottom of the bracket 10, and the stirring mechanism I 16 extends into the cross-linking curing tank 13 to ensure that the droplets discharged from the microfluidic chip 11 assembly can be effectively cross-linked and cured. In addition, a filter element I 17 (such as a filter funnel, made of 316L material) for filtering the cross-linking liquid is provided in the cross-linking curing tank 13, which facilitates the overall (batch) transfer and transmission of the gelatin embolization microsphere preliminaries formed by cross-linking curing, and thus improves the subsequent cleaning efficiency, etc.

[0025] Example 4 On the basis of Examples 1-3, this example further defines the cleaning device to further illustrate the present invention.

[0026] The cleaning device includes a cleaning tank 15. A stirring mechanism II 19 is provided directly above the cleaning tank 15. The stirring mechanism II 19 is arranged on a lifting mechanism II 20 and extends into the cleaning tank 15. A filter element II 27 (such as a filter funnel, made of 316L material) is sleeved in the cleaning tank 15. The cleaning tank 15 is connected to an isopropanol storage tank 22 through an isopropanol delivery pipe 21, and the cleaning tank 15 is connected to a water storage tank 24 through a water delivery pipe 23. A switching valve 25 is provided at the bottom of the cleaning tank 15, and the switching valve 25 can be connected to a waste liquid treatment system through a waste liquid delivery pipe 31. Metering pumps 26 are provided on both the isopropanol delivery pipe 21 and the water delivery pipe 23.

[0027] This limitation can effectively achieve the multi-stage automatic cleaning of gelatin embolization microspheres. When switching multiple cleaning processes, it is not necessary to transfer the gelatin embolization microspheres, avoiding the pollution caused by the device and personnel operations. At the same time, the cleaning effect is good and the residue meets the requirements.

[0028] Example 5 On the basis of Examples 1-4, in order to improve the automation of the gelatin embolization microsphere preparation process in this example, it is further defined that: The preparation system further includes a central controller 18. The central controller 18 is respectively connected to an injection pump 4, a constant pressure pump 6, a metering pump 26, a lifting mechanism I 12, a lifting mechanism II 20, a stirring mechanism I 16, a stirring mechanism II 19, an ice bath cooling system 14, and a constant temperature system 28 through electrical signals; Among them, part of the circuit diagram involved is as Figures 10 - 11 shown.

[0029] Example 6 On the basis of Examples 1-5, this example also proposes an integrated preparation machine for gelatin embolization microspheres, as Figures 3 - 5 shown, specifically: a box body and a feeding device, a microfluidic device, a crosslinking and curing device, and a cleaning device arranged in the box body; The box body is set in component format. The box body includes a preparation compartment, a control center compartment, an ice bath circulation compartment, a storage compartment, and a cleaning compartment. The preparation compartment and the cleaning compartment are both arranged at the upper part of the box body. The control center compartment is arranged on one side of the preparation compartment, and the cleaning compartment is arranged on one side of the preparation compartment; the ice bath circulation compartment is arranged below the preparation compartment, and the storage compartment is arranged below the preparation compartment. The storage compartment is located on one side of the ice bath circulation compartment. The above layout realizes functional zoning, which not only ensures the orderly and effective production of gelatin embolization microspheres, but also realizes the rational use of limited space. In addition, it can be used for laboratory operations and can also be applied to industrial production, etc.; The feeding device includes a dispersed phase delivery pipe 1 and a continuous phase delivery pipe 2. One end of the dispersed phase delivery pipe 1 is connected to a dispersed phase storage tank 3, and the other end is connected to the dispersed phase inlet on the microfluidic device. An injection pump 4 is provided on the dispersed phase delivery pipe 1; one end of the continuous phase delivery pipe 2 is connected to a continuous phase storage tank 5, and the other end is connected to the continuous phase inlet on the microfluidic device. A constant pressure pump 6 is provided on the continuous phase delivery pipe 2. Among them, the dispersed phase storage tank 3 and the continuous phase storage tank 5 are arranged in the storage compartment; Microfluidic device: It includes a bracket 10 and a microfluidic chip 11 assembly arranged on the bracket 10. The bracket 10 is arranged on a lifting mechanism I 12. The bracket 10 and the microfluidic chip 11 assembly are distributed in the preparation compartment, and the preparation compartment is set at a constant temperature; the lifting mechanism I 12 is arranged longitudinally and extends towards the top of the box body; Crosslinking and curing device: It includes a crosslinking and curing tank 13, and the crosslinking and curing tank 13 is arranged directly below the microfluidic chip 11 assembly; the crosslinking and curing tank 13 is connected to an ice bath cooling system 14, and the ice bath cooling system 14 is distributed in the ice bath circulation compartment, and the crosslinking and curing tank 13 is located above the ice bath circulation compartment; As Figures 8 - 9 shown, the cleaning device: It is arranged at the rear side of the working station of the crosslinking and curing device. The microsphere outlet on the crosslinking and curing tank 13 is connected to the cleaning device, and the cleaning device is connected to a drying device 30; the cleaning device and the drying device 30 are distributed in the cleaning compartment, and the drying device 30 is arranged on one side of the cleaning device; A continuous path for the preparation of gelatin embolization microspheres is formed among the feeding device, the microfluidic device, the crosslinking and curing device, the cleaning device, and the drying device 30.

[0030] In addition, universal wheels with brakes are provided under the box to facilitate the overall movement of the integrated preparation machine, thereby improving the practicality of the integrated preparation machine.

[0031] Example 7 This embodiment provides a method for preparing gelatin embolic microspheres. Figure 1 As shown, the following steps are included: S1: Ingredients Dissolve gelatin in water, heat and stir for 2 hours in a 60°C water bath to prepare a gelatin-water solution with a mass fraction of 7-20% to obtain a dispersed phase for later use; Add polyglycerol ricinoleate to soybean oil, stir and dissolve, and prepare a polyglycerol ricinoleate-oil solution with a mass fraction of 2-5% to obtain a continuous phase for later use; Add the glutaraldehyde aqueous solution to the soybean oil, stir and dissolve, and prepare a glutaraldehyde-oil solution with a mass fraction of 0.1-4% to obtain a cross-linking solution for later use; S2: Feed The microfluidic chip 11 is controlled to descend by the lifting mechanism until the distance between the microfluidic chip 11 and the liquid surface in the cross-linking curing tank 13 is 1 to 5 cm; Control the dispersed phase feeding speed to 150-500 μL / min, and inject the dispersed phase into the microfluidic chip 11 component; The continuous phase pressure is controlled to be 350-5000 mbr, and the continuous phase is injected into the microfluidic chip 11 component; S3: Microfluidic reactions The ambient temperature of the microfluidic chip 11 assembly is controlled to be 40-50°C, and after shearing force, the dispersed phase contacts the continuous phase to form droplets (water-in-oil type); the droplets are controlled to enter the cross-linking liquid in the cross-linking curing tank 13; S4: Cross-linking and curing The temperature of the crosslinking liquid in the crosslinking curing tank 13 is controlled to be 0-5° C., the stirring mechanism is stirred at 100-500 rpm, and the crosslinking curing is performed for 15-24 hours to form a preliminary product of gelatin embolic microspheres; S5: Cleaning and drying The gelatin embolic microspheres are placed in a cleaning device for cleaning; then, they are freeze-dried and sterilized by irradiation to obtain gelatin embolic microspheres (such as Figure 12 shown); Among them, Figure 7 As shown, the cleaning procedure includes: Isopropyl alcohol cleaning, liquid inlet volume: 1 - 8 L, stirring speed: 300 - 500 r / min, stirring time: 1 - 20 min, number of cleaning times: 2 - 8 times; water cleaning, liquid inlet volume: 1 - 8 L, stirring speed: 300 - 500 r / min, stirring time: 2 - 40 min, number of cleaning times: 3 - 10 times; after each cleaning, open the switching valve 25 to control the cleaning waste liquid to flow into the waste liquid collection tank 29; Among them, the freeze-drying procedure includes: Pre-freezing at -20 to -40 °C, sublimation drying at -30 to -40 °C, and desorption drying at 0 to 10 °C.

[0032] Example 8 In this example, PMMA is selected as the chip material, and the microfluidic chip 11 is processed by CNC and hot-pressed and formed. Among them, the inner diameter of the dispersed phase channel in the shear structure is 200 ± 20 μm, and the inner diameter of the continuous phase channel is 300 ± 20 μm.

[0033] 1) Preparation of the dispersed phase: Dissolve gelatin in water, heat and stir in a water bath at 60 °C for 2 h to prepare a 15% gelatin-aqueous solution by mass fraction; 2) Preparation of the continuous phase: Add polyglycerol ricinoleate to soybean oil and dissolve it by magnetic stirring to prepare a 2% polyglycerol ricinoleate-oil solution by mass fraction; 3) Preparation of the cross-linking solution: Add an aqueous glutaraldehyde solution to soybean oil and dissolve it by magnetic stirring to prepare a glutaraldehyde solution with a mass fraction of 0.1 - 2%; 4) Connecting the equipment: The syringe pump 4 is connected to the dispersed phase solution, the constant pressure pump 6 is connected to the continuous phase solution, the cross-linking solution is added to the cross-linking and curing tank 13, and the microfluidic chip 11 is lowered to 1 - 5 cm above the cross-linking solution; turn on the constant temperature system 28; 5) Preparation of gelatin embolization microspheres: First, turn on the constant pressure pump 6 and set the flow rate of the dispersed phase to 150 μL / min; then turn on the syringe pump 4 and set the continuous phase pressure to 350 mbr; the dispersed phase at the flow focusing structure in the microfluidic chip 11 is sheared into droplets by the continuous phase, which belongs to the water-in-oil type and drops into the cross-linking and curing tank 13. The droplets are cured while being stirred. After stirring in an ice bath in the cross-linking and curing tank 13 for 15 - 24 h, they are respectively cleaned with isopropyl alcohol and water, freeze-dried, and then swollen to obtain gelatin embolization microspheres with uniform particle size.

[0034] Example 9 On the basis of Example 8, this example provides a method for cleaning gelatin embolization microspheres, and its steps include: 1) Place the initial product of gelatin microspheres to be cleaned in the cleaning tank 15, close the switching valve 25 below the cleaning tank 15, and lower the stirring mechanism II 19 (stirring paddle) to an appropriate height; 2) Set the cleaning program on the control panel: The first step: Isopropyl alcohol cleaning, liquid inlet volume: 5 L, stirring speed: 300 r / min, stirring time: 5 min, cleaning times: 3 times; The second step: Purified water for injection cleaning, liquid inlet volume: 5.5 L, stirring speed: 300 r / min, stirring time: 10 min, cleaning times: 5 times; After each cleaning, open the switching valve 25 and control the cleaning waste liquid to flow into the waste liquid collection tank 29; 3) Collect the microspheres.

[0035] The above are only the preferred embodiments of the present invention, and do not impose any form of limitation on the present invention. Any simple modification or equivalent change made to the above embodiments based on the technical essence of the present invention shall fall within the protection scope of the present invention.

Claims

1. A preparation system for gelatin embolization microspheres, characterized in that, It includes a feeding device, a microfluidic device, a crosslinking and curing device, and a cleaning device; The feeding device includes a dispersed-phase delivery pipe (1) and a continuous-phase delivery pipe (2). One end of the dispersed-phase delivery pipe (1) is connected to a dispersed-phase storage tank (3), and the other end is connected to the dispersed-phase inlet on the microfluidic device. An injection pump (4) is provided on the dispersed-phase delivery pipe (1); one end of the continuous-phase delivery pipe (2) is connected to a continuous-phase storage tank (5), and the other end is connected to the continuous-phase inlet on the microfluidic device. A constant-pressure pump (6) is provided on the continuous-phase delivery pipe (2); The microfluidic device includes a bracket (10) and a microfluidic chip (11) assembly arranged on the bracket (10). The bracket (10) is arranged on a lifting mechanism I (12); The crosslinking and curing device includes a crosslinking and curing tank (13), and the crosslinking and curing tank (13) is arranged directly below the microfluidic chip (11) assembly; the crosslinking and curing tank (13) is connected to an ice bath cooling system (14); The cleaning device is arranged at the rear side of the working station of the crosslinking and curing device. The microsphere outlet on the crosslinking and curing tank (13) is connected to the cleaning device, and the cleaning device is connected to a drying device (30); A continuous path for preparing gelatin embolization microspheres is formed among the feeding device, the microfluidic device, the crosslinking and curing device, the cleaning device, and the drying device (30).

2. The preparation system of the gelatin embolization microspheres according to claim 1, wherein, The microfluidic chip (11) assembly includes at least two groups of microfluidic chips (11), and the microfluidic chips (11) are respectively connected to the feeding device; the microfluidic chips (11) are distributed in a constant-temperature system (28), and the microfluidic chips (11) are arranged side by side or in a circular distribution.

3. The preparation system of the gelatin embolization microspheres according to claim 1 or 2, characterized in that, The inner diameter of the dispersed-phase channel in the microfluidic chip (11) is 200 ± 20 to 500 ± 50 μm, and the inner diameter of the continuous-phase channel is 300 ± 20 to 1000 ± 100 μm.

4. The preparation system of the gelatin embolization microspheres according to claim 1, characterized in that, A stirring mechanism I (16) is provided at the bottom of the bracket (10), and the stirring mechanism I (16) extends into the crosslinking and curing tank (13). A filter element I (17) for filtering the crosslinking liquid is provided in the crosslinking and curing tank (13).

5. The preparation system of the gelatin embolization microspheres according to claim 4, characterized in that, The cleaning device includes a cleaning tank (15). A stirring mechanism II (19) is provided directly above the cleaning tank (15). The stirring mechanism II (19) is arranged on a lifting mechanism II (20), and the stirring mechanism II (19) extends into the cleaning tank (15). A filter element II (27) is sleeved in the cleaning tank (15); the cleaning tank (15) is connected to an isopropanol storage tank (22) through an isopropanol delivery pipe (21), the cleaning tank (15) is connected to a water storage tank (24) through a water delivery pipe (23), and a switching valve (25) is provided at the bottom of the cleaning tank (15). The switching valve (25) can be connected to a waste liquid treatment system through a waste liquid delivery pipe (31); A metering pump (26) is provided on both the isopropanol delivery pipe (21) and the water delivery pipe (23).

6. The preparation system of the gelatin embolization microspheres according to claim 5, characterized in that, The preparation system further includes a central controller (18), which is electrically connected to an injection pump (4), a constant pressure pump (6), a metering pump (26), a lifting mechanism I (12), a lifting mechanism II (20), a stirring mechanism I (16), a stirring mechanism II (19), an ice bath cooling system (14), and a constant temperature system (28) respectively through electrical signals.

7. A method for preparing gelatin embolization microspheres, characterized in that, The method includes the following steps: S1: Ingredients preparation Prepare a gelatin-aqueous solution with a mass fraction of 7-20% to obtain a dispersed phase for standby; Prepare a polyglycerol ricinoleate-oil solution with a mass fraction of 2-5% to obtain a continuous phase for standby; Prepare a glutaraldehyde-oil solution with a mass fraction of 0.1-4% to obtain a crosslinking solution for standby; S2: Feeding Through the lifting mechanism, control the microfluidic chip (11) to descend until the distance between the microfluidic chip (11) and the liquid level in the crosslinking and curing tank (13) is 1-5 cm; Control the feeding speed of the dispersed phase at 150-500 μL / min, and inject the dispersed phase into the microfluidic chip (11) assembly; Control the pressure of the continuous phase at 350-5000 mbr, and inject the continuous phase into the microfluidic chip (11) assembly; S3: Microfluidic reaction Control the ambient temperature of the microfluidic chip (11) assembly at 40-50 °C. After the dispersed phase and the continuous phase come into contact under shear force to form droplets, control the droplets to enter the crosslinking solution in the crosslinking and curing tank (13); S4: Crosslinking and curing Control the temperature of the crosslinking solution in the crosslinking and curing tank (13) at 0-5 °C, and the stirring mechanism stirs at 100-500 rpm for 15-24 h to form the initial product of gelatin embolization microspheres; S5: Cleaning and drying Place the initial product of gelatin embolization microspheres in a cleaning device for cleaning; then, perform freeze-drying and irradiation sterilization to obtain gelatin embolization microspheres.

8. The preparation method of the glue embolization microspheres according to claim 7, characterized in that, In step S5, the cleaning procedure includes: isopropanol cleaning, liquid inlet volume: 1-8 L, stirring speed: 300-500 r / min, stirring time: 1-20 min, number of cleaning times: 2-8 times; Water cleaning, liquid inlet volume: 1-8 L, stirring speed: 300-500 r / min, stirring time: 2-40 min, number of cleaning times: 3-10 times.

9. The preparation method of the gelatin embolization microspheres according to claim 7, characterized in that, In step S5, the freeze-drying procedure includes: pre-freezing at -20 to -40 °C, sublimation drying at -30 to -40 °C, and desorption drying at 0 to 10 °C.

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