Preparation system and method for gelatin embolization microspheres

Abstract

A preparation system and method for gelatin embolization microspheres. The preparation system comprises a feed device, a microfluidic device, a cross-linking curing device, and a cleaning device. The feed device, the microfluidic device, the cross-linking curing device, and the cleaning device form a continuous pathway for the preparation of gelatin embolization microspheres. The preparation method comprises: formulation, feeding, microfluidic reaction, low-temperature cross-linking curing, isopropanol washing, water washing, and freeze drying. By means of said method, uniform and large-scale gelatin embolization microspheres with stable performance are obtained, thereby achieving large-scale, batch, controlled, and standardized preparation of gelatin embolization microspheres.

Description

A preparation system and method for gelatin embolic microspheres

[0001] This application claims priority to the Chinese patent application filed with the China Patent Office on December 28, 2023, with application number 2023118308355 and invention name “A system and method for preparing gelatin embolic microspheres”, the entire contents of which are incorporated by reference into this application. Technical Field

[0002] The present invention relates to a system and method for preparing gelatin embolic microspheres, and specifically to a system and method for large-scale production of degradable gelatin embolic microspheres using microfluidic technology, which meets the requirements of microsphere production and standardization and belongs to the technical field of microsphere preparation. Background Art

[0003] Cancer has become a leading global public health threat. Approximately 4 million new cancer patients are diagnosed in my country each year, with 600,000 to 700,000 undergoing interventional cancer treatment, a figure that is increasing at a rate of 10-20%. With the development of minimally invasive techniques, transcatheter arterial embolization (TEE) is emerging as a new embolization technique. Embolic microspheres are injected into the blood vessels via a catheter, reaching the affected area and cutting off the nutrient supply to tumor cells, causing them to shrink and ultimately "starve" the tumor to death.

[0004] Microspheres generally refer to spherical particles with a diameter of 50nm-2mm, most of which are solid particles or spheres. There are many carrier materials for preparing microspheres, 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 and polyvinyl alcohol microspheres).

[0005] Currently, due to the specific nature of microsphere production processes and the limitations of existing equipment, continuous, mass-produced, and industrialized microsphere production is difficult to achieve. Furthermore, the microsphere preparation process involves numerous manual procedures, which can easily lead to inconsistent product performance and increase the risk of product contamination. Furthermore, existing methods for preparing microspheres generally utilize a stirring and emulsification method. However, the microspheres produced using this method have an uneven particle size range and require post-production screening to obtain the desired microspheres, resulting in a low yield.

[0006] Embolic microspheres with uniform particle size can be prepared using microfluidic technology, manipulating fluids at the microscale to form uniformly sized droplets. For example, prior art CN107418872A uses focused and T-shaped droplet microfluidic chips to prepare bio-ink microspheres. While a single pipeline or single chip can produce microspheres with uniform particle size, scaling up the process is difficult. Currently, microfluidic production processes for large quantities of microspheres are still not feasible. Furthermore, there is a lack of stable, efficient, and high-throughput equipment for microsphere production. CN112569878A discloses "Apparatus and production process for preparing polyvinyl alcohol embolic microspheres with uniform particle size." This involves connecting multiple microfluidic devices in parallel and ultimately collecting them into a single container. This is complex, requires a large amount of equipment, and is costly. CN108704578A discloses "Apparatus and application for continuous microsphere production." However, the use of an emulsification module prevents effective microsphere uniformity.

[0007] Therefore, a system and method are needed to ensure the uniformity of the microspheres and to produce gelatin embolic microspheres on a large scale and stably. Summary of the Invention

[0008] The present invention aims to solve the problems in the prior art that the preparation process of gelatin embolic microspheres cannot be scaled up for production, as well as the lack of a stable, efficient, and high-throughput production line for preparing microspheres, and proposes a preparation system and method for gelatin embolic microspheres.

[0009] In order to achieve the above technical objectives, the following technical solutions are proposed:

[0010] The first purpose of the present technical solution is to provide: a preparation system of gelatin embolic microspheres, comprising a feeding device, a microfluidic device, a cross-linking and curing device, and a cleaning device;

[0011] The feeding device includes a dispersed phase delivery tube and a continuous phase delivery tube, one end of the dispersed phase delivery tube is connected to a dispersed phase storage tank, and the other end is connected to the dispersed phase inlet on the microfluidic device, and a syringe pump is provided on the dispersed phase delivery tube; one end of the continuous phase delivery tube is connected to the continuous phase storage tank, and the other end is connected to the continuous phase inlet on the microfluidic device, and a constant pressure pump is provided on the continuous phase delivery tube;

[0012] The microfluidic device includes a bracket and a microfluidic chip assembly arranged on the bracket, and the bracket is arranged on the lifting mechanism I;

[0013] The cross-linking and curing device includes a cross-linking and curing tank, which is located directly below the microfluidic chip component; the cross-linking and curing tank is connected to an ice bath cooling system;

[0014] The cleaning device is arranged at the rear side 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 the drying device;

[0015] A continuous passage for preparing gelatin embolic microspheres is formed among the feeding device, the microfluidic device, the cross-linking and curing device, the cleaning device and the drying device.

[0016] Preferably, the microfluidic chip assembly includes at least two groups of microfluidic chips, each of which is connected to a feed device. The microfluidic chips are distributed within the constant temperature system, and the microfluidic chips are arranged side by side or in a circular pattern. The microfluidic chips are flow-focusing microfluidic chips, such as CNC-machined PMMA chips.

[0017] 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.

[0018] Preferably, the bottom of the bracket is provided with a stirring mechanism I, which extends into the crosslinking and curing tank to ensure that the droplets discharged from the microfluidic chip assembly can be effectively crosslinked and cured, thereby improving the efficiency and quality of crosslinking and curing. A filter element I (e.g., a filter funnel made of 316L material) is provided in the crosslinking and curing tank for filtering the crosslinking liquid.

[0019] 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, and a filter element II (such as: filter bucket, 316L material) is provided in the cleaning tank; the cleaning tank is connected to the isopropyl alcohol storage tank through an isopropyl alcohol delivery pipe, and the cleaning tank is connected to the 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.

[0020] Preferably, the preparation system further comprises a central controller, which is respectively connected to the injection pump, constant pressure pump, metering pump, lifting mechanism I, lifting mechanism II, stirring mechanism I, stirring mechanism II, ice bath cooling system and constant temperature system through electrical signals.

[0021] The second purpose of this technical solution is to provide: a method for preparing gelatin embolic microspheres, comprising the following steps:

[0022] S1: Ingredients

[0023] Dissolve gelatin in water, heat and stir in a 60°C water bath for 2 hours to prepare a gelatin-water solution with a mass fraction of 7-20% to obtain a dispersed phase, which is set aside;

[0024] 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, which is set aside;

[0025] 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, which is set aside;

[0026] S2: Feed

[0027] The microfluidic chip is controlled to descend by the lifting mechanism until the distance between the microfluidic chip and the liquid surface in the cross-linking curing tank is 1 to 5 cm;

[0028] The dispersed phase feed rate was controlled at 150 to 500 μL / min, and the dispersed phase was injected into the microfluidic chip assembly;

[0029] The continuous phase pressure is controlled to be 350 to 5000 m / s and the continuous phase is injected into the microfluidic chip assembly;

[0030] S3: Microfluidic reactions

[0031] The ambient temperature of the microfluidic chip assembly is controlled to be 40-50°C. After shear force, the dispersed phase contacts the continuous phase to form droplets (water-in-oil type). The droplets are controlled to enter the crosslinking liquid in the crosslinking curing tank.

[0032] S4: Cross-linking and curing

[0033] The crosslinking liquid temperature in the crosslinking curing tank is controlled to be 0-5° C., the stirring mechanism is stirred at 100-500 rpm, and the crosslinking curing is carried out for 15-24 hours to form a preliminary product of gelatin embolic microspheres;

[0034] S5: Cleaning and drying

[0035] The gelatin embolic microspheres are placed in a cleaning device for cleaning; then, freeze-dried and sterilized by irradiation to obtain the gelatin embolic microspheres;

[0036] Among them, the cleaning procedures include:

[0037] Isopropyl alcohol cleaning: liquid volume: 1-8L, stirring speed: 300-500r / min, stirring time: 1-20min, cleaning times: 2-8 times; water cleaning: liquid volume: 1-8L, stirring speed: 300-500r / min, stirring time: 2-40min, cleaning times: 3-10 times; after each cleaning, open the switch valve to control the flow of cleaning waste liquid into the waste liquid collection tank;

[0038] The freeze-drying process includes:

[0039] Pre-freeze at -20~-40℃, sublimation dry at -30~-40℃, and desorption dry at 0~10℃.

[0040] In this technical solution, positional relationships such as "one end", "the other end", "above", "directly below", "back side of the workstation", "bottom", and "inside" are defined according to the actual usage conditions. They are conventional terms in this technical field and are also conventional terms used by technical personnel in this field in actual use.

[0041] The beneficial technical effects brought about by adopting this technical solution are:

[0042] 1. In the present invention, by setting up a feeding device, a microfluidic device, a cross-linking and curing device, and a cleaning device, a continuous path for preparing gelatin embolic microspheres is formed between the feeding device, the microfluidic device, the cross-linking and curing device, and the cleaning device, thereby realizing the large-scale, batch, controllable, and standardized preparation of gelatin embolic microspheres. At present, the existing technology mostly adopts a single chip in parallel, which makes the process complicated and costly, and cannot achieve the purpose of effective integration; the present invention uses a single integrated chip for amplification, and ensures that the prepared microspheres have good morphology and uniformity, reducing the number of equipment and the required personnel, thereby making the microsphere production output reach industrial level;

[0043] Second, in the present invention, the crosslinking and curing tank is connected to an ice bath cooling system to ensure the efficiency and quality of the crosslinking and curing of the microspheres, thereby ensuring the stable performance of subsequent products to meet actual needs. In addition, the microfluidic chip is distributed within the constant temperature system to ensure the stability of droplet formation and the subsequent formation of uniform microspheres.

[0044] 3. In the present invention, the preparation method includes batching, feeding, microfluidics, cross-linking and curing, cleaning and drying. By controlling each condition, it is ensured that uniform and stable gelatin embolic microspheres can be formed. At the same time, large-scale, batch, controllable and standardized production can be achieved.

[0045] 4. In the present invention, the cleaning process is simple to operate and cleans thoroughly, which can ensure that the limit of the residual amount of microspheres after cleaning meets the regulations. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are merely embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the provided drawings without paying any creative work.

[0047] FIG1 is a process flow chart of the present invention;

[0048] FIG2 is a logical connection block diagram of the preparation system of the present invention;

[0049] FIG3 is a structural diagram of the device in the present invention (front view);

[0050] FIG4 is a structural diagram of the device of the present invention (right side view);

[0051] FIG5 is a cross-sectional view taken along the AA direction in FIG3 ;

[0052] FIG6 is a schematic diagram of the working principle of the microfluidic chip of the present invention;

[0053] FIG7 is a flow chart of the cleaning process of the present invention;

[0054] FIG8 is a schematic structural diagram of the cleaning device of the present invention (front view);

[0055] FIG9 is a schematic structural diagram of the cleaning device of the present invention (right side view);

[0056] FIG10 is a partial circuit diagram (1) of the present invention;

[0057] FIG11 is a partial circuit diagram (II) of the present invention;

[0058] FIG12 is a diagram of the gelatin embolic microsphere product according to the present invention;

[0059] In the figure, 1. dispersed phase delivery pipe, 2. continuous phase delivery pipe, 3. dispersed phase storage tank, 4. injection pump, 5. continuous phase storage tank, 6. constant pressure pump, 10. bracket, 11. microfluidic chip, 12. lifting mechanism I, 13. cross-linking curing tank, 14. ice bath cooling system, 15. cleaning tank, 16. stirring mechanism I, 17. filter element I, 18. central controller, 19. stirring mechanism II, 20. lifting mechanism II, 21. isopropyl alcohol delivery pipe, 22. isopropyl alcohol storage tank, 23. water delivery pipe, 24. water storage tank, 25. switch valve, 26. metering pump, 27. filter element II, 28. constant temperature system, 29. waste liquid collection tank, 30. drying device, 31. waste liquid delivery pipe. DETAILED DESCRIPTION

[0060] Example 1

[0061] This embodiment provides: a preparation system for gelatin embolic microspheres, as shown in FIG2 , comprising a feeding device, a microfluidic device, a cross-linking and curing device, and a cleaning device; wherein,

[0062] Feeding device: including dispersed phase delivery tube 1 and continuous phase delivery tube 2. One end of dispersed phase delivery tube 1 is connected to dispersed phase storage tank 3, and the other end is connected to the dispersed phase inlet of the microfluidic device. Dispersed phase delivery tube 1 is provided with a syringe pump 4; one end of continuous phase delivery tube 2 is connected to continuous phase storage tank 5, and the other end is connected to the continuous phase inlet of the microfluidic device. Continuous phase delivery tube 2 is provided with a constant pressure pump 6;

[0063] Microfluidic device: includes a bracket 10 and a microfluidic chip 11 component arranged on the bracket 10, and the bracket 10 is arranged on a lifting mechanism I 12;

[0064] Cross-linking and curing device: including a cross-linking and curing tank 13, which is located directly below the microfluidic chip 11 component; the cross-linking and curing tank 13 is connected to an ice bath cooling system 14;

[0065] Cleaning device: located at the rear side of the cross-linking and curing device. The microsphere outlet on the cross-linking and curing tank 13 is connected to the cleaning device, which is connected to the drying device 30.

[0066] A continuous passage for preparing gelatin embolic microspheres is formed between the feeding device, the microfluidic device, the cross-linking and curing device, and the cleaning device. The entire system can realize the large-scale, batch, controllable, and standardized preparation of gelatin embolic microspheres.

[0067] Example 2

[0068] Based on Example 1, this example further defines the microfluidic chip 11 to further illustrate the present invention.

[0069] As shown in FIG6 , the microfluidic chip 11 assembly includes at least two groups of microfluidic chips 11 , each connected to a feed device. The microfluidic chips 11 are distributed within the constant temperature system 28 , and the microfluidic chips 11 are arranged side by side or in a circular pattern. The microfluidic chips 11 are flow-focusing microfluidic chips 11 , such as CNC-machined PMMA chips.

[0070] 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.

[0071] Currently, existing technologies mostly use a single chip in parallel, which makes the process complex and costly, and fails to achieve the purpose of effective integration. The present invention, however, uses a single integrated chip for amplification, ensuring good morphology and uniformity of the prepared microspheres, reducing the number of equipment and required personnel, and thus enabling the microsphere production output to reach industrial levels.

[0072] Example 3

[0073] On the basis of Examples 1-2, this Example further defines the following in order to improve the efficiency and quality of cross-linking and curing:

[0074] 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 and curing tank 13 to ensure that the droplets discharged from the microfluidic chip 11 assembly can be effectively cross-linked and cured;

[0075] In addition, a filter element I17 (e.g., filter bucket, 316L material) for filtering the crosslinking liquid is provided in the crosslinking curing tank 13, which facilitates the overall (batch) transfer and transmission of the crosslinked and cured gelatin embolic microspheres, thereby improving the subsequent cleaning efficiency.

[0076] Example 4

[0077] Based on Examples 1-3, this example further defines the cleaning device to further illustrate the present invention.

[0078] The cleaning device includes a cleaning tank 15, a stirring mechanism II19 is provided directly above the cleaning tank 15, the stirring mechanism II19 is arranged on a lifting mechanism II20, the stirring mechanism II19 extends into the cleaning tank 15, and a filter element II27 (such as: a filter bucket, made of 316L material) is provided in the cleaning tank 15; the cleaning tank 15 is connected to an isopropyl alcohol storage tank 22 through an isopropyl alcohol delivery pipe 21, and the cleaning tank 15 is connected to a water storage tank 24 through a water delivery pipe 23. A switch valve 25 is provided at the bottom of the cleaning tank 15, and the switch valve 25 can be connected to the waste liquid treatment system through a waste liquid delivery pipe 31; both the isopropyl alcohol delivery pipe 21 and the water delivery pipe 23 are provided with a metering pump 26.

[0079] This limitation can effectively realize the multi-stage automated cleaning of gelatin embolic microspheres. There is no need to transfer the gelatin embolic microspheres when switching multiple cleaning processes, thus avoiding the contamination caused by the equipment and personnel operation. At the same time, the cleaning effect is good and the residue meets the requirements.

[0080] Example 5

[0081] Based on Examples 1-4, this example further defines the following in order to improve the automation of the preparation process of gelatin embolic microspheres:

[0082] The preparation system also includes a central controller 18, which is connected to the injection pump 4, the constant pressure pump 6, the metering pump 26, the lifting mechanism I 12, the lifting mechanism II 20, the stirring mechanism I 16, the stirring mechanism II 19, the ice bath cooling system 14 and the constant temperature system 28 through electrical signals;

[0083] Among them, some of the circuit diagrams involved are shown in Figures 10-11.

[0084] Example 6

[0085] Based on Examples 1-5, this embodiment further proposes an integrated preparation machine for gelatin embolic microspheres, as shown in Figures 3-5, specifically comprising: a box body and a feeding device, a microfluidic device, a cross-linking and curing device, and a cleaning device arranged in the box body;

[0086] The box body is arranged in a format that 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 located at the top of the box body, the control center compartment is located on one side of the preparation compartment, and the cleaning compartment is located on one side of the preparation compartment; the ice bath circulation compartment is located below the preparation compartment, and the storage compartment is located below the preparation compartment, and the storage compartment is located on one side of the ice bath circulation compartment. The above arrangement realizes functional zoning, which not only ensures the orderly and effective production of gelatin embolic microspheres, but also realizes the rational use of limited space. In addition, it can be used for laboratory operations, industrial production, etc.

[0087] The feeding device includes a dispersed phase delivery tube 1 and a continuous phase delivery tube 2. Dispersed phase delivery tube 1 is connected to a dispersed phase storage tank 3 at one end and to the dispersed phase inlet of the microfluidic device at the other end. Dispersed phase delivery tube 1 is equipped with a syringe pump 4. Continuous phase delivery tube 2 is connected to a continuous phase storage tank 5 at one end and to the continuous phase inlet of the microfluidic device at the other end. Continuous phase delivery tube 2 is equipped with a constant pressure pump 6. Dispersed phase storage tank 3 and continuous phase storage tank 5 are arranged in the storage compartment.

[0088] The microfluidic device includes a bracket 10 and a microfluidic chip 11 mounted on the bracket 10. The bracket 10 is mounted on a lifting mechanism I 12. The bracket 10 and the microfluidic chip 11 are located in a preparation compartment, which is set at a constant temperature. The lifting mechanism I 12 is arranged longitudinally and extends toward the top of the box.

[0089] Cross-linking and curing device: including a cross-linking and curing tank 13, which is located directly below the microfluidic chip 11 component; the cross-linking and curing tank 13 is connected to an ice bath cooling system 14, which is distributed in the ice bath circulation compartment, and the cross-linking and curing tank 13 is located above the ice bath circulation compartment;

[0090] As shown in Figures 8-9, the cleaning device is located at the rear 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 the drying device 30. The cleaning device and the drying device 30 are distributed in the cleaning compartment, and the drying device 30 is located on one side of the cleaning device.

[0091] A continuous passage for preparing gelatin embolic microspheres is formed between the feeding device, the microfluidic device, the cross-linking and curing device, the cleaning device and the drying device 30 .

[0092] 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.

[0093] Example 7

[0094] This embodiment provides a method for preparing gelatin embolic microspheres, as shown in FIG1 , comprising the following steps:

[0095] S1: Ingredients

[0096] Dissolve gelatin in water, heat and stir in a 60°C water bath for 2 hours to prepare a gelatin-water solution with a mass fraction of 7-20% to obtain a dispersed phase, which is set aside;

[0097] 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, which is set aside;

[0098] 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, which is set aside;

[0099] S2: Feed

[0100] The microfluidic chip 11 is controlled to descend by the lifting mechanism until the distance between the microfluidic chip 11 and the liquid level in the cross-linking curing tank 13 is 1 to 5 cm;

[0101] Control the dispersed phase feeding rate to 150-500 μL / min and inject the dispersed phase into the microfluidic chip 11 component;

[0102] The continuous phase pressure is controlled to be 350-5000 m / s and the continuous phase is injected into the microfluidic chip 11 component;

[0103] S3: Microfluidic reactions

[0104] The ambient temperature of the microfluidic chip 11 assembly is controlled to be 40-50°C. After shear force, the dispersed phase contacts the continuous phase to form droplets (water-in-oil type). The droplets are controlled to enter the crosslinking liquid in the crosslinking curing tank 13.

[0105] S4: Cross-linking and curing

[0106] 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 carried out for 15-24 hours to form the initial gelatin embolic microspheres;

[0107] S5: Cleaning and drying

[0108] The gelatin embolic microspheres are placed in a cleaning device for cleaning; then, freeze-dried and sterilized by irradiation to obtain gelatin embolic microspheres (as shown in FIG12 );

[0109] As shown in FIG7 , the cleaning procedure includes:

[0110] Isopropyl alcohol cleaning: liquid input volume: 1-8L, stirring speed: 300-500r / min, stirring time: 1-20min, cleaning times: 2-8 times; water cleaning: liquid input volume: 1-8L, stirring speed: 300-500r / min, stirring time: 2-40min, cleaning times: 3-10 times; after each cleaning, open the switch valve 25 to control the flow of cleaning waste liquid into the waste liquid collection tank 29;

[0111] Among them, the freeze-drying process includes:

[0112] Pre-freeze at -20~-40℃, sublimation dry at -30~-40℃, and desorption dry at 0~10℃.

[0113] Example 8

[0114] In this embodiment, PMMA is selected as the chip material, and the microfluidic chip 11 is processed by CNC, hot pressing and molding. In the shear structure, the inner diameter of the dispersed phase channel is 200±20 μm, and the inner diameter of the continuous phase channel is 300±20 μm.

[0115] 1) Dispersed phase preparation: Dissolve gelatin in water, heat and stir in a 60°C water bath for 2 h to prepare a 15% gelatin-water solution;

[0116] 2) Preparation of the continuous phase: Add polyglycerol ricinoleate to soybean oil and dissolve under magnetic stirring to prepare a polyglycerol ricinoleate-oil solution with a mass fraction of 2%;

[0117] 3) Preparation of crosslinking solution: Add glutaraldehyde aqueous solution to soybean oil and dissolve under magnetic stirring to prepare a glutaraldehyde solution with a mass fraction of 0.1-2%;

[0118] 4) Connecting equipment: Syringe pump 4 is connected to the dispersed phase solution, constant pressure pump 6 is connected to the continuous phase solution, crosslinking solution is added to crosslinking curing tank 13, and microfluidic chip 11 is lowered to 1 to 5 cm above the crosslinking solution; constant temperature system 28 is turned on;

[0119] 5) Preparation of Gelatin Embolic Microspheres: First, turn on the constant pressure pump 6 and set the dispersed phase flow rate to 150 μL / min; then turn on the syringe pump 4 and set the continuous phase pressure to 350 mbr; the dispersed phase in the flow-focusing structure of the microfluidic chip 11 is sheared into droplets by the continuous phase, which are of the oil-in-water type. These droplets are then dropped into the crosslinking and curing tank 13, where they are solidified while stirring. After stirring in an ice bath in the crosslinking and curing tank 13 for 15 to 24 hours, the droplets are washed with isopropyl alcohol and water, respectively, freeze-dried, and then swelled to obtain gelatin embolic microspheres with uniform particle size.

[0120] Example 9

[0121] Based on Example 8, this example provides a method for cleaning gelatin embolic microspheres, the steps of which include:

[0122] 1) Place the gelatin microspheres to be cleaned in the cleaning tank 15, close the on-off valve 25 below the cleaning tank 15, and lower the stirring mechanism II 19 (stirring paddle) to a suitable height;

[0123] 2) Set the cleaning program on the control panel:

[0124] Step 1: Isopropyl alcohol cleaning, liquid volume: 5L, stirring speed: 300r / min, stirring time: 5min, cleaning times: 3 times;

[0125] Step 2: Wash with injection water, liquid volume: 5.5L, stirring speed: 300r / min, stirring time: 10min, washing times: 5 times;

[0126] After each cleaning, the switch valve 25 is opened to control the cleaning waste liquid to flow into the waste liquid collection tank 29.

[0127] 3) Collect the microspheres.

[0128] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form. Any simple modification or equivalent change made to the above embodiment based on the technical essence of the present invention shall fall within the scope of protection 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 cross-linking 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 cross-linking and curing device includes a cross-linking and curing tank (13). 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); The cleaning device 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 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 (30).

2. The preparation system of the gelatin embolization microspheres according to claim 1, characterized in that, 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.

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). The stirring mechanism I (16) extends into the cross-linking and curing tank (13), and a filter element I (17) for filtering the cross-linking liquid is provided in the cross-linking and curing tank (13).

5. The preparation system of the gelatin embolization microspheres according to claim 4, wherein, 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). 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), 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); 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 connected to the injection pump (4), the constant pressure pump (6), the metering pump (26), the lifting mechanism I (12), the lifting mechanism II (20), the stirring mechanism I (16), the stirring mechanism II (19), the ice bath cooling system (14), and the constant temperature system (28) respectively through electrical signals.

7. A preparation method of gelatin embolization microspheres, characterized in that, It includes the following steps: S1: Ingredient preparation Prepare a gelatin-aqueous solution with a mass fraction of 7-20%, obtaining the dispersed phase for standby; Prepare a polyglycerol ricinoleate-oil solution with a mass fraction of 2-5%, obtaining the continuous phase for standby; Prepare a glutaraldehyde-oil solution with a mass fraction of 0.1-4%, obtaining the 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 environmental temperature of the microfluidic chip (11) assembly at 40-50 °C. Through shear force, the dispersed phase and the continuous phase come into contact to form droplets, and 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 for crosslinking and curing 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, wherein, In step S5, the cleaning procedure includes: cleaning 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; Cleaning 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.

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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