A bullet-shaped polyvinyl alcohol embolism micro-particle, a preparation method and application thereof

Abstract

The application discloses a bullet-shaped polyvinyl alcohol embolism micro-particle and a preparation method thereof, and belongs to the field of non-spherical polymer micro-particle preparation. The embolism micro-particle is made of polyvinyl alcohol, and the overall shape is bullet-shaped, with a smooth joint between a hemispherical head and a cylindrical tail. The bullet-shaped polyvinyl alcohol embolism micro-particle is continuously prepared by using microfluidic technology, and the steps are as follows: (1) preparing modified polyvinyl alcohol macromolecules; (2) preparing a dispersed phase fluid, a continuous phase 1 fluid and a continuous phase 2 fluid; (3) preparing bullet-shaped non-spherical micro-particles by using a two-stage microfluidic device; and (4) storing the washed bullet-shaped polyvinyl alcohol embolism micro-particles in pure water. The bullet-shaped polyvinyl alcohol embolism micro-particle prepared by the application can effectively improve the flow characteristics and movement rate of the micro-particle in a channel, thereby improving the embolism effect of the micro-particle, and has important clinical application value for tumor embolism treatment.

Description

Technical Field

[0001] This invention belongs to the field of preparation of non-spherical polymer microparticles, specifically relating to a bullet-shaped polyvinyl alcohol embolization microparticle, its preparation method, and its application in embolization therapy. Background Technology

[0002] Currently, the number of people diagnosed with cancer worldwide is increasing, and cancer has become one of the major diseases threatening human health. With the advancement of science and technology, some treatment methods for cancer have been developed. Clinically, surgical resection, radiotherapy, chemotherapy, and embolization are commonly used to treat cancer. However, many cancers are diagnosed at an advanced stage, and most are no longer suitable for surgical resection. Moreover, radiotherapy and chemotherapy have significant systemic toxicity. Therefore, embolization is currently a more reliable cancer treatment strategy. It mainly involves injecting emboli to block the blood supply arteries of the tumor, thereby causing the tumor to "starve" due to lack of nutrient supply, achieving the goal of cancer treatment. This treatment method has the advantages of minimal trauma, simple and safe operation, rapid recovery, few complications, low cost, and good treatment effect.

[0003] Currently, commonly used suppositories include embolic microspheres, liquid suppositories, and coils, with microspheres being the most prevalent. However, research indicates that bullet-shaped embolic particles exhibit faster flow velocity and higher embolization efficiency during the embolization process. However, due to limitations in preparation methods, currently available embolic particles are only irregularly shaped particles and microspheres; bullet-shaped embolic microparticles with controllable shapes are still unavailable. Therefore, developing a method for controllably preparing bullet-shaped microparticles is of significant importance.

[0004] Microfluidic technology possesses the ability to manipulate microfluidics at the microscale, precisely controlling the size and morphology of microparticles. CN109482111A discloses a microfluidic method for preparing bullet-shaped microparticles. This invention uses a two-stage microfluidic device to prepare bullet-shaped droplets, then uses ultraviolet light to induce a polymerization reaction in the droplets to form bullet-shaped particles. However, the material proposed in this patent has poor biocompatibility and cannot be practically applied to embolization therapy. Polyvinyl alcohol (PVA) is a biocompatible and non-degradable material. Using microfluidic technology to prepare bullet-shaped PVA embolization microparticles has significant clinical implications for tumor embolization therapy. Summary of the Invention

[0005] This invention aims to address the shortcomings of existing research and practical application needs by providing bullet-shaped polyvinyl alcohol embolization microparticles, their preparation method, and applications. These bullet-shaped polyvinyl alcohol embolization microparticles are prepared using controllable microfluidic technology to improve the flow characteristics and movement rate of the microparticles within the channel, thereby enhancing the embolization effect. This has significant clinical application value for tumor embolization therapy.

[0006] The objective of this invention is achieved through the following technical solution: A bullet-shaped polyvinyl alcohol embolization microparticle, the microparticle having a polyvinyl alcohol matrix and an overall bullet-shaped shape, consisting of a hemispherical head and a cylindrical tail smoothly connected as one piece; wherein, the diameter of the cylindrical tail is 50~600 μm; the length ratio of the hemispherical head to the cylindrical tail is 1:1~5, and the length direction is along the axis of the cylinder.

[0007] The method for preparing the bullet-shaped polyvinyl alcohol embolic microparticles provided by the present invention includes the following steps: (1) Preparation of modified polyvinyl alcohol polymer Polyvinyl alcohol was dissolved in dimethyl sulfoxide (DMSO) solution under a nitrogen atmosphere at a mass fraction of 10%–20%. Then, ethyl 2-isocyanate methacrylate was added dropwise while stirring vigorously. The reaction temperature was 60°C and the reaction time was 4 hours. The resulting solution was then added dropwise to toluene, with the volume of toluene being 20–60 times the volume of DMSO, until no more precipitate formed. The reaction was then stopped. The precipitate was then dissolved in water, washed with a 10 kDa filtration membrane, and finally lyophilized to obtain the modified polyvinyl alcohol polymer. (2) Prepare the dispersed phase fluid, continuous phase 1 fluid, and continuous phase 2 fluid. Preparation of dispersed phase fluid: The modified polyvinyl alcohol polymer, water-soluble photoinitiator, and water-soluble surfactant obtained in step (1) are dissolved in water to obtain a dispersed phase fluid; in the dispersed phase fluid, the mass fraction of modified polyvinyl alcohol polymer is 1%~8%, the mass fraction of water-soluble photoinitiator is 0.5%~20%, and the mass fraction of water-soluble surfactant is 0%~20%; Preparation of continuous phase 1 fluid: Dissolve an oil-soluble surfactant in soybean oil to obtain continuous phase 1 fluid, wherein the mass fraction of the oil-soluble surfactant in continuous phase 1 fluid is 0.5%~20%; Preparation of continuous phase 2 fluid: Dissolve oil-soluble surfactant in soybean oil to obtain continuous phase 2 fluid, wherein the mass fraction of oil-soluble surfactant in continuous phase 2 fluid is 0%~20%; (3) Preparation of bullet-shaped non-spherical microparticles The dispersed phase fluid, continuous phase 1 fluid, and continuous phase 2 fluid obtained in step (2) are injected into the injection tube, transition tube, and collection tube of the microfluidic device respectively using an injection pump. At the conical opening of the injection tube, the continuous phase 1 fluid shears the dispersed phase fluid to form a monodisperse water-in-oil emulsion. The water-in-oil emulsion droplets flow with the continuous phase 1 through the transition tube into the downstream collection tube. Under the combined action of the spatial confinement of the collection tube wall and the shear force of the fluid in the collection tube, they are transformed into bullet-shaped water-in-oil emulsion droplet templates. Then, the bullet-shaped droplet templates in the collection tube are irradiated with ultraviolet light source. The modified polyvinyl alcohol polymer inside the bullet-shaped droplets is polymerized and cured to obtain bullet-shaped polyvinyl alcohol embolization microparticles. In this step, the flow rate of the dispersed phase fluid is controlled to be 50~600 μL / h, the flow rate of the continuous phase 1 fluid is 80~1200 μL / h, and the flow rate of the continuous phase 2 fluid is 100~2000 μL / h. (4) Washing The bullet-shaped polyvinyl alcohol embolization microparticles obtained in step (3) were washed with detergent to remove the continuous phase 1 and continuous phase 2 solutions from their surfaces. The washed bullet-shaped polyvinyl alcohol embolization microparticles were then stored in pure water.

[0008] In the above-mentioned method for preparing bullet-shaped polyvinyl alcohol embolization microparticles, the water-soluble photoinitiator mentioned in step (2) includes 2-hydroxy-2-methyl-1-phenyl-1-propanone (HMPP), photoinitiator 2959, etc.; the water-soluble surfactant includes Pluronic F-127, sodium dodecyl sulfonate (SDS), etc.; the oil-soluble surfactant includes polyricinoleic acid glycerol ester (PGPR), Span20, Span40, Span60, Span80, Tween85, etc.

[0009] In the above-mentioned method for preparing bullet-shaped polyvinyl alcohol embolization microparticles, the detergent in step (4) includes ethanol, isopropanol, etc.

[0010] In the above-mentioned method for preparing bullet-shaped polyvinyl alcohol embolization microparticles, the size and morphology of the bullet-shaped polyvinyl alcohol embolization microparticles can be precisely controlled by changing the inner diameter of the collection tube of the microfluidic device, as well as the composition and flow rate of the dispersed phase fluid, the continuous phase 1 fluid, and the continuous phase 2 fluid.

[0011] In the above method for preparing bullet-shaped polyvinyl alcohol embolization microparticles, step (2) uses a structure as shown in the figure. Figure 1The microfluidic device shown includes an injection tube, a first connecting tube, a transition tube, a second connecting tube, a collection tube, and an ultraviolet light source, and is used in conjunction with an injection pump. The injection tube is made of cylindrical glass capillary tube, the head of which is drawn into a conical shape using a needle puller and the conical tip is smoothed on sandpaper. The transition tube and the collection tube are both cylindrical glass capillary tubes. The first connecting tube and the second connecting tube are both square glass tubes with a square through hole in their center. The head of the injection tube is inserted into the tail of the transition tube and connected through the first connecting tube. The head of the transition tube is inserted into the second connecting tube from one end, and the tail of the collection tube is inserted into the second connecting tube from the other end. The transition tube and the collection tube are connected through the second connecting tube. The ultraviolet light source is located near the end of the collection tube. The injection tube, the first connecting tube, the transition tube, the second connecting tube, and the collection tube are coaxially arranged. The non-inlet ends of the first connecting tube and the second connecting tube are sealed with glue.

[0012] Compared with the prior art, the beneficial technical effects of the present invention are as follows: 1. This invention improves the morphology of current polyvinyl alcohol embolization microparticles. The polyvinyl alcohol embolization microparticles are bullet-shaped. Compared with microspheres, bullet-shaped polyvinyl alcohol embolization microparticles have a faster flow velocity in the channel, thus having greater kinetic energy. They can be embolized in blood vessels with greater kinetic energy. Moreover, their cylindrical cross-section fits the blood vessel wall better, and they are expected to become better embolic agents.

[0013] 2. This invention continuously prepares monodisperse water-in-oil emulsion droplets using a microfluidic device, which then deform in a downstream collection tube. Continuous ultraviolet light irradiation is used to polymerize the bullet-shaped droplet template to obtain bullet-shaped polyvinyl alcohol embolization microparticles, thus realizing the continuous preparation of bullet-shaped polyvinyl alcohol embolization microparticles.

[0014] 3. This invention combines microfluidics technology. First, uniformly sized oil-in-water emulsion droplets are formed at the conical opening of the injection tube. Then, by changing the composition, flow rate, or inner diameter of the collection tube of each phase fluid, bullet-shaped polyvinyl alcohol embolization microparticles of the same uniform size can be obtained, thereby achieving precise control over the size and morphology of the bullet-shaped polyvinyl alcohol embolization microparticles.

[0015] 4. The bullet-shaped polyvinyl alcohol embolization microparticles provided by this invention have better biocompatibility, which can better improve the embolization performance of embolization materials and greatly benefit tumor treatment. Attached Figure Description

[0016] Figure 1 This is a schematic diagram of a two-stage capillary microfluidic device; In the diagram, 1-injection tube, 2-first connecting tube, 3-transition tube, 4-second connecting tube, 5-collection tube, and 6-ultraviolet light source.

[0017] Figure 2 This is a SEM image of the bullet-shaped polyvinyl alcohol embolization microparticles prepared in Example 1 after air drying.

[0018] Figure 3 This is an optical image of the bullet-shaped polyvinyl alcohol embolization microparticles prepared in Example 2.

[0019] Figure 4 This is a comparison chart of the movement velocities of the polyvinyl alcohol spherical microparticles prepared in Comparative Example 1 and the bullet-shaped polyvinyl alcohol embolization microparticles prepared in Example 1.

[0020] Figure 5 This is a comparison chart of the embolization effects of polyvinyl alcohol spherical microparticles prepared in Comparative Example 1 and bullet-shaped polyvinyl alcohol embolization microparticles prepared in Example 1. Detailed Implementation

[0021] The technical solution of the present invention will be further described in detail below with reference to specific embodiments, but the implementation of the present invention is not limited thereto.

[0022] The following embodiments use a schematic diagram of the two-stage capillary microfluidic device. Figure 1 As shown, it includes an injection tube 1, a first connecting tube 2, a transition tube 3, a second connecting tube 4, a collection tube 5, and an ultraviolet light source 6, as well as an injection pump.

[0023] Injection tube 1 is made of cylindrical glass capillary tube. The head of the cylindrical glass capillary tube is drawn into a conical shape using a needle puller, and then polished on sandpaper until the inner diameter of the conical opening is approximately 60-200 μm. The outer diameter of its cylindrical section is 960 μm and the inner diameter is 600 μm. Transition tube 3 is made of cylindrical glass capillary tube, obtained by polishing both ends of the cylindrical glass capillary tube flat. The outer diameter of the transition tube is 960 μm and the inner diameter is 200-700 μm. Collection tube 5 is made of cylindrical glass capillary tube, obtained by polishing both ends of the cylindrical glass capillary tube flat. The outer diameter of the collection tube is 960 μm and the inner diameter is 100-700 μm. First connecting tube 2 and second connecting tube 4 are both square glass tubes, obtained by polishing both ends of the square glass tube smooth. A square through-hole with a size of 1×1 mm is provided in the center of each tube. After fabrication, the injection tube 1, first connecting tube 2, transition tube 3, second connecting tube 4, and collection tube 5 need to be ultrasonically cleaned in anhydrous ethanol and then dried. The head of the injection tube 1 is inserted into the tail of the transition tube 3 and connected through the first connecting tube 2. The head of the transition tube 3 is inserted into the second connecting tube 4 from one end, and the tail of the collection tube 5 is inserted into the second connecting tube 4 from the other end. The first transition tube and the collection tube 5 are connected through the second connecting tube 4. The ultraviolet light source 6 is placed near the end of the collection tube 5, and a collection container is placed at the outlet end of the collection tube 5. The injection tube 1, first connecting tube 2, transition tube 3, second connecting tube 4, and collection tube 5 are coaxially arranged and fixed to the glass slide with AB glue. The non-inlet ends of the first connecting tube 2 and the second connecting tube 4 are sealed with AB glue. Flat-headed needles are fixed to the inlet ends of the first connecting tube 2 and the second connecting tube 4 with AB glue, and each flat-headed needle is connected to the injection pump through a fitting.

[0024] Example 1 In this embodiment, the bullet-shaped polyvinyl alcohol embolization microparticles are prepared by the following steps: (1) Preparation of modified polyvinyl alcohol polymer 5 g of polyvinyl alcohol was dissolved in 25 mL of dimethyl sulfoxide (DMSO) solution under a nitrogen atmosphere, with a mass fraction of 20%. Then, ethyl 2-isocyanate methacrylate was added dropwise while stirring vigorously. The reaction temperature was 60 °C and the reaction time was 4 hours. The resulting solution was then added dropwise to 500 mL of toluene until no more precipitate formed, at which point the reaction was stopped. The precipitate was then dissolved in water, washed with a 10 kDa filtration membrane, and finally lyophilized to obtain the modified polyvinyl alcohol polymer. (2) Prepare the dispersed phase fluid, continuous phase 1 fluid, and continuous phase 2 fluid. Preparation of the dispersed phase fluid: The modified polyvinyl alcohol polymer and HMPP were dissolved in water to obtain the dispersed phase fluid; in the dispersed phase fluid, the mass fraction of the modified polyvinyl alcohol polymer was 5% and the mass fraction of HMPP was 0.5%; Preparation of continuous phase 1 fluid: PGPR was dissolved in soybean oil to obtain continuous phase 1 fluid, wherein the mass fraction of oil-soluble surfactant in continuous phase 1 fluid was 1%; Preparation of continuous phase 2 fluid: PGPR was dissolved in soybean oil to obtain continuous phase 2 fluid, wherein the mass fraction of oil-soluble surfactant in continuous phase 2 fluid was 1%; (3) Preparation of bullet-shaped non-spherical microparticles Adopting such Figure 1 The microfluidic device shown has an injection tube with a conical inlet diameter of 60 μm, a transition tube with an inner diameter of 550 μm, and a collection tube with an inner diameter of 300 μm. The dispersed phase fluid, continuous phase 1 fluid, and continuous phase 2 fluid are injected into the injection tube, transition tube, and collection tube of the microfluidic device respectively using an injection pump. At the conical inlet of the injection tube, the continuous phase 1 fluid shears the dispersed phase fluid to form a monodisperse water-in-oil emulsion. The water-in-oil emulsion droplets flow with the continuous phase 1 through the transition tube and enter the downstream collection tube. Under the combined action of the spatial confinement of the collection tube wall and the shear force of the fluid in the collection tube, they are deformed into bullet-shaped droplet templates. Then, the bullet-shaped droplet templates in the collection tube are irradiated with an ultraviolet light source. The modified polyvinyl alcohol polymer inside the bullet-shaped droplets is polymerized and cured to obtain bullet-shaped polyvinyl alcohol embolization microparticles. In this step, the flow rate of the dispersed phase fluid is controlled at 100 μL / h, the flow rate of the continuous phase 1 fluid is 200 μL / h, and the flow rate of the continuous phase 2 fluid is 400 μL / h. (4) Washing The obtained bullet-shaped polyvinyl alcohol embolization microparticles were washed with ethanol to remove the continuous phase 1 and continuous phase 2 solutions from their surfaces. The washed bullet-shaped polyvinyl alcohol embolization microparticles were then stored in pure water.

[0025] The bullet-shaped polyvinyl alcohol embolic microparticles prepared in this embodiment, after being air-dried, are shown in the SEM image below. Figure 2 As shown.

[0026] As can be seen from the figure, the bullet-shaped polyvinyl alcohol embolization microparticles are uniform in size and have an overall bullet-shaped shape, consisting of a hemispherical head and a cylindrical tail that are smoothly connected as one piece; the diameter of the cylindrical tail is approximately 220 μm; the length ratio of the hemispherical head to the cylindrical tail is approximately 1:2, and the length direction is along the axis of the cylinder.

[0027] Example 2 In this embodiment, bullet-shaped polyvinyl alcohol microparticles are prepared using the following steps: (1) Preparation of modified polyvinyl alcohol polymer 5 g of polyvinyl alcohol was dissolved in 25 mL of dimethyl sulfoxide (DMSO) solution under a nitrogen atmosphere, with a mass fraction of 20%. Then, ethyl isocyanate methacrylate was added dropwise while stirring vigorously. The reaction temperature was 60 °C and the reaction time was 4 hours. The resulting solution was then added dropwise to 1500 mL of toluene until no more precipitate formed, at which point the reaction was stopped. The precipitate was then dissolved in water, washed with a 10 kDa filtration membrane, and finally lyophilized to obtain the modified polyvinyl alcohol polymer. (2) Prepare the dispersed phase fluid, continuous phase 1 fluid, and continuous phase 2 fluid. Preparation of the dispersed phase fluid: The modified polyvinyl alcohol polymer, photoinitiator 2959, and SDS were dissolved in water to obtain the dispersed phase fluid; in the dispersed phase fluid, the mass fraction of the modified polyvinyl alcohol polymer was 1%, the mass fraction of the photoinitiator 2959 was 10%, and the mass fraction of the SDS was 10%. Preparation of continuous phase 1 fluid: Span 80 was dissolved in soybean oil to obtain continuous phase 1 fluid, and the mass fraction of oil-soluble surfactant in continuous phase 1 fluid was 0.5%; Preparation of continuous phase 2 fluid: Span80 was dissolved in soybean oil to obtain continuous phase 2 fluid, and the mass fraction of oil-soluble surfactant in continuous phase 2 fluid was 5%; (3) Preparation of bullet-shaped non-spherical microparticles Adopting such Figure 1 The microfluidic device shown has an injection tube with a conical inlet diameter of 60 μm, a transition tube with an inner diameter of 200 μm, and a collection tube with an inner diameter of 200 μm. The dispersed phase fluid, continuous phase 1 fluid, and continuous phase 2 fluid are injected into the injection tube, transition tube, and collection tube of the microfluidic device respectively using an injection pump. At the conical inlet of the injection tube, the continuous phase 1 fluid shears the dispersed phase fluid to form a monodisperse water-in-oil emulsion. The water-in-oil emulsion droplets flow with the continuous phase 1 through the transition tube and enter the downstream collection tube. Under the combined action of the spatial confinement of the collection tube wall and the shear force of the fluid in the collection tube, they are deformed into bullet-shaped droplet templates. Then, the bullet-shaped droplet templates in the collection tube are irradiated with an ultraviolet light source. The modified polyvinyl alcohol polymer inside the bullet-shaped droplets is polymerized and cured to obtain bullet-shaped polyvinyl alcohol embolization microparticles. In this step, the flow rate of the dispersed phase fluid is controlled at 50 μL / h, the flow rate of the continuous phase 1 fluid is 80 μL / h, and the flow rate of the continuous phase 2 fluid is 100 μL / h. (4) Washing The obtained bullet-shaped polyvinyl alcohol embolization microparticles were washed with isopropanol to remove the continuous phase 1 and continuous phase 2 solutions from their surfaces. The washed bullet-shaped polyvinyl alcohol embolization microparticles were then stored in pure water.

[0028] Optical images of the bullet-shaped polyvinyl alcohol embolization microparticles obtained in this embodiment are shown below. Figure 3 As shown.

[0029] As can be seen from the figure, the bullet-shaped polyvinyl alcohol embolization microparticles are uniform in size and have an overall bullet-shaped shape, consisting of a hemispherical head and a cylindrical tail that are smoothly connected as one piece; the diameter of the cylindrical tail is about 100 μm; the length ratio of the hemispherical head to the cylindrical tail is about 1:1, and the length direction is along the axis of the cylinder.

[0030] Example 3 In this embodiment, bullet-shaped polyvinyl alcohol microparticles are prepared using the following steps: (1) Preparation of modified polyvinyl alcohol polymer 5 g of polyvinyl alcohol was dissolved in 50 mL of dimethyl sulfoxide (DMSO) solution under a nitrogen atmosphere, with a mass fraction of 10%. Then, ethyl 2-isocyanate methacrylate was added dropwise while stirring vigorously. The reaction temperature was 60 °C and the reaction time was 4 hours. The resulting solution was then added dropwise to 1000 mL of toluene until no more precipitate formed, at which point the reaction was stopped. The precipitate was then dissolved in water, washed with a 10 kDa cutoff dialysis membrane by ultrafiltration, and finally lyophilized to obtain the modified polyvinyl alcohol polymer. (2) Prepare the dispersed phase fluid, continuous phase 1 fluid, and continuous phase 2 fluid. Preparation of the dispersed phase fluid: The modified polyvinyl alcohol polymer, HMPP, and SDS were dissolved in water to obtain the dispersed phase fluid; in the dispersed phase fluid, the mass fraction of the modified polyvinyl alcohol polymer was 8%, the mass fraction of HMPP was 10%, and the mass fraction of SDS was 5%. Preparation of continuous phase 1 fluid: Span40 was dissolved in soybean oil to obtain continuous phase 1 fluid, and the mass fraction of oil-soluble surfactant in continuous phase 1 fluid was 0.5%; Preparation of continuous phase 2 fluid: Span40 was dissolved in soybean oil to obtain continuous phase 2 fluid, and the mass fraction of oil-soluble surfactant in continuous phase 2 fluid was 2%; (3) Preparation of bullet-shaped non-spherical microparticles Adopting such Figure 1The microfluidic device shown has an injection tube with a conical inlet diameter of 200 μm, a transition tube with an inner diameter of 700 μm, and a collection tube with an inner diameter of 700 μm. The dispersed phase fluid, continuous phase 1 fluid, and continuous phase 2 fluid are injected into the injection tube, transition tube, and collection tube of the microfluidic device respectively using an injection pump. At the conical inlet of the injection tube, the continuous phase 1 fluid shears the dispersed phase fluid to form a monodisperse water-in-oil emulsion. The water-in-oil emulsion droplets flow with the continuous phase 1 through the transition tube and enter the downstream collection tube. Under the combined action of the spatial confinement of the collection tube wall and the shear force of the fluid in the collection tube, they are deformed into bullet-shaped droplet templates. Then, the bullet-shaped droplet templates in the collection tube are irradiated with an ultraviolet light source. The modified polyvinyl alcohol polymer inside the bullet-shaped droplets is polymerized and cured to obtain bullet-shaped polyvinyl alcohol embolization microparticles. In this step, the flow rate of the dispersed phase fluid is controlled at 600 μL / h, the flow rate of the continuous phase 1 fluid is 1200 μL / h, and the flow rate of the continuous phase 2 fluid is 1000 μL / h. (4) Washing The obtained bullet-shaped polyvinyl alcohol embolization microparticles were washed with ethanol to remove the continuous phase 1 and continuous phase 2 solutions from their surfaces. The washed bullet-shaped polyvinyl alcohol embolization microparticles were then stored in pure water.

[0031] The bullet-shaped polyvinyl alcohol embolization microparticles prepared in this embodiment are bullet-shaped in overall shape, consisting of a hemispherical head and a cylindrical tail that are smoothly connected as one piece; wherein, the diameter of the cylindrical tail is about 600 μm; the length ratio of the hemispherical head to the cylindrical tail is about 1:2, and the length direction is along the axis of the cylinder.

[0032] Example 4 In this embodiment, bullet-shaped polyvinyl alcohol microparticles are prepared using the following steps: (1) Preparation of modified polyvinyl alcohol polymer 3 g of polyvinyl alcohol was dissolved in 20 mL of dimethyl sulfoxide (DMSO) solution under a nitrogen atmosphere, with a mass fraction of 15%. Then, ethyl 2-isocyanate methacrylate was added dropwise while stirring vigorously. The reaction temperature was 60 °C and the reaction time was 4 hours. The resulting solution was then added dropwise to 800 mL of toluene until no more precipitate formed, at which point the reaction was stopped. The precipitate was then dissolved in water, washed with a 10 kDa filtration membrane, and finally lyophilized to obtain the modified polyvinyl alcohol polymer. (2) Prepare the dispersed phase fluid, continuous phase 1 fluid, and continuous phase 2 fluid. Preparation of the dispersed phase fluid: The modified polyvinyl alcohol polymer and HMPP were dissolved in water to obtain the dispersed phase fluid; in the dispersed phase fluid, the mass fraction of the modified polyvinyl alcohol polymer was 5% and the mass fraction of HMPP was 20%; Preparation of continuous phase 1 fluid: Tween 85 was dissolved in soybean oil to obtain continuous phase 1 fluid, and the mass fraction of oil-soluble surfactant in continuous phase 1 fluid was 20%; Preparation of continuous phase 2 fluid: Tween 85 was dissolved in soybean oil to obtain continuous phase 2 fluid, and the mass fraction of oil-soluble surfactant in continuous phase 2 fluid was 20%; (3) Preparation of bullet-shaped non-spherical microparticles Adopting such Figure 1 The microfluidic device shown has an injection tube with a conical inlet diameter of 100 μm, a transition tube with an inner diameter of 700 μm, and a collection tube with an inner diameter of 300 μm. The dispersed phase fluid, continuous phase 1 fluid, and continuous phase 2 fluid are injected into the injection tube, transition tube, and collection tube of the microfluidic device respectively using an injection pump. At the conical inlet of the injection tube, the continuous phase 1 fluid shears the dispersed phase fluid to form a monodisperse water-in-oil emulsion. The water-in-oil emulsion droplets flow with the continuous phase 1 through the transition tube and enter the downstream collection tube. Under the combined action of the spatial confinement of the collection tube wall and the shear force of the fluid in the collection tube, they are deformed into bullet-shaped droplet templates. Then, the bullet-shaped droplet templates in the collection tube are irradiated with an ultraviolet light source. The modified polyvinyl alcohol polymer inside the bullet-shaped droplets is polymerized and cured to obtain bullet-shaped polyvinyl alcohol embolization microparticles. In this step, the flow rate of the dispersed phase fluid is controlled at 200 μL / h, the flow rate of the continuous phase 1 fluid is 1200 μL / h, and the flow rate of the continuous phase 2 fluid is 1000 μL / h. (4) Washing The obtained bullet-shaped polyvinyl alcohol embolization microparticles were washed with isopropanol to remove the continuous phase 1 and continuous phase 2 solutions from their surfaces. The washed bullet-shaped polyvinyl alcohol embolization microparticles were then stored in pure water.

[0033] The bullet-shaped polyvinyl alcohol embolization microparticles prepared in this embodiment are bullet-shaped in overall shape, consisting of a hemispherical head and a cylindrical tail that are smoothly connected as one piece; wherein, the diameter of the cylindrical tail is about 220 μm; the length ratio of the hemispherical head to the cylindrical tail is about 1:5, and the length direction is along the axis of the cylinder.

[0034] Example 5 In this embodiment, bullet-shaped polyvinyl alcohol microparticles are prepared using the following steps: (1) Preparation of modified polyvinyl alcohol polymer The modified polyvinyl alcohol polymer was prepared using the same method as in Example 1. (2) Prepare the dispersed phase fluid, continuous phase 1 fluid, and continuous phase 2 fluid. Preparation of the dispersed phase fluid: The modified polyvinyl alcohol polymer, HMPP, and F-127 were dissolved in water to obtain the dispersed phase fluid; in the dispersed phase fluid, the mass fraction of the modified polyvinyl alcohol polymer was 5%, the mass fraction of HMPP was 10%, and the mass fraction of F-127 was 5%. Preparation of continuous phase 1 fluid: Span20 was dissolved in soybean oil to obtain continuous phase 1 fluid, and the mass fraction of oil-soluble surfactant in continuous phase 1 fluid was 0.5%; Preparation of continuous phase 2 fluid: Span20 was dissolved in soybean oil to obtain continuous phase 2 fluid, and the mass fraction of oil-soluble surfactant in continuous phase 2 fluid was 0.5%; (3) Preparation of bullet-shaped non-spherical microparticles Adopting such Figure 1 The microfluidic device shown has an injection tube with a conical inlet diameter of 200 μm, a transition tube with an inner diameter of 700 μm, and a collection tube with an inner diameter of 600 μm. The dispersed phase fluid, continuous phase 1 fluid, and continuous phase 2 fluid are injected into the injection tube, transition tube, and collection tube of the microfluidic device respectively using an injection pump. At the conical inlet of the injection tube, the continuous phase 1 fluid shears the dispersed phase fluid to form a monodisperse water-in-oil emulsion. The water-in-oil emulsion droplets flow with the continuous phase 1 through the transition tube and enter the downstream collection tube. Under the combined action of the spatial confinement of the collection tube wall and the shear force of the fluid in the collection tube, they are deformed into bullet-shaped droplet templates. Then, the bullet-shaped droplet templates in the collection tube are irradiated with an ultraviolet light source. The modified polyvinyl alcohol polymer inside the bullet-shaped droplets is polymerized and cured to obtain bullet-shaped polyvinyl alcohol embolization microparticles. In this step, the flow rate of the dispersed phase fluid is controlled at 500 μL / h, the flow rate of the continuous phase 1 fluid is 1200 μL / h, and the flow rate of the continuous phase 2 fluid is 2000 μL / h. (4) Washing The obtained bullet-shaped polyvinyl alcohol embolization microparticles were washed with ethanol to remove the continuous phase 1 and continuous phase 2 solutions from their surfaces. The washed bullet-shaped polyvinyl alcohol embolization microparticles were then stored in pure water.

[0035] The bullet-shaped polyvinyl alcohol embolization microparticles prepared in this embodiment are bullet-shaped in overall shape, consisting of a hemispherical head and a cylindrical tail that are smoothly connected as one piece; wherein, the diameter of the cylindrical tail is about 550 μm; the length ratio of the hemispherical head to the cylindrical tail is about 1:3, and the length direction is along the axis of the cylinder.

[0036] Example 6 In this embodiment, bullet-shaped polyvinyl alcohol microparticles are prepared using the following steps: (1) Preparation of modified polyvinyl alcohol polymer The modified polyvinyl alcohol polymer was prepared using the same method as in Example 1. (2) Prepare the dispersed phase fluid, continuous phase 1 fluid, and continuous phase 2 fluid. Preparation of the dispersed phase fluid: The modified polyvinyl alcohol polymer, photoinitiator 2959, and F-127 were dissolved in water to obtain the dispersed phase fluid; in the dispersed phase fluid, the mass fraction of the modified polyvinyl alcohol polymer was 1%, the mass fraction of the photoinitiator 2959 was 10%, and the mass fraction of F-127 was 20%. Preparation of continuous phase 1 fluid: Span 60 was dissolved in soybean oil to obtain continuous phase 1 fluid, and the mass fraction of oil-soluble surfactant in continuous phase 1 fluid was 0.5%; Preparation of continuous phase 2 fluid: Soybean oil is used directly as continuous phase 2 fluid without adding oil-soluble surfactants; (3) Preparation of bullet-shaped non-spherical microparticles Adopting such Figure 1 The microfluidic device shown has an injection tube with a conical inlet diameter of 100 μm, a transition tube with an inner diameter of 300 μm, and a collection tube with an inner diameter of 100 μm. The dispersed phase fluid, continuous phase 1 fluid, and continuous phase 2 fluid are injected into the injection tube, transition tube, and collection tube of the microfluidic device respectively using an injection pump. At the conical inlet of the injection tube, the continuous phase 1 fluid shears the dispersed phase fluid to form a monodisperse water-in-oil emulsion. The water-in-oil emulsion droplets flow with the continuous phase 1 through the transition tube and enter the downstream collection tube. Under the combined action of the spatial confinement of the collection tube wall and the shear force of the fluid in the collection tube, they are deformed into bullet-shaped droplet templates. Then, the bullet-shaped droplet templates in the collection tube are irradiated with an ultraviolet light source. The modified polyvinyl alcohol polymer inside the bullet-shaped droplets is polymerized and cured to obtain bullet-shaped polyvinyl alcohol embolization microparticles. In this step, the flow rate of the dispersed phase fluid is controlled at 100 μL / h, the flow rate of the continuous phase 1 fluid is 200 μL / h, and the flow rate of the continuous phase 2 fluid is 100 μL / h. (4) Washing The obtained bullet-shaped polyvinyl alcohol embolization microparticles were washed with ethanol to remove the continuous phase 1 and continuous phase 2 solutions from their surfaces. The washed bullet-shaped polyvinyl alcohol embolization microparticles were then stored in pure water.

[0037] The bullet-shaped polyvinyl alcohol embolization microparticles prepared in this embodiment are bullet-shaped in overall shape, consisting of a hemispherical head and a cylindrical tail that are smoothly connected as one piece; wherein, the diameter of the cylindrical tail is about 50 μm; the length ratio of the hemispherical head to the cylindrical tail is about 1:3, and the length direction is along the axis of the cylinder.

[0038] Comparative Example 1 In this comparative example, the spherical polyvinyl alcohol microparticles were prepared using the following steps: (1) Preparation of modified polyvinyl alcohol polymer The modified polyvinyl alcohol polymer was prepared using the same method as in Example 1. (2) Preparation of dispersed phase fluid and continuous phase fluid Preparation of the dispersed phase fluid: The modified polyvinyl alcohol polymer and HMPP were dissolved in water to obtain the dispersed phase fluid; in the dispersed phase fluid, the mass fraction of the modified polyvinyl alcohol polymer was 5% and the mass fraction of HMPP was 0.5%; Preparation of continuous phase fluid: PGPR is dissolved in soybean oil to obtain a continuous phase fluid, wherein the mass fraction of oil-soluble surfactant in the continuous phase fluid is 1%; (3) Preparation of spherical microparticles Spherical microparticles were prepared using a primary microfluidic device, which differs from the secondary microfluidic device used in Example 1 in that it does not include the second connecting tube 4 and the collection tube 5. The dispersed phase fluid and the continuous phase fluid were injected into the injection tube 1 and the transition tube 3 of the microfluidic device, respectively, using a syringe pump. At the conical opening of the injection tube, the continuous phase fluid sheared the dispersed phase fluid to form a monodisperse water-in-oil emulsion. The water-in-oil emulsion droplets flowed with the continuous phase into the transition tube 3. The droplets were collected in a culture dish and irradiated with ultraviolet light, causing the modified polyvinyl alcohol polymer inside the spherical droplets to polymerize and solidify, resulting in spherical polyvinyl alcohol microparticles with a diameter of approximately 285 μm. In this step, the flow rate of the dispersed phase fluid is controlled at 100 μL / h, and the flow rate of the continuous phase fluid is controlled at 600 μL / h. (4) Washing The obtained spherical polyvinyl alcohol microparticles were washed with ethanol to remove the continuous phase solution on the surface, and the washed spherical polyvinyl alcohol microparticles were stored in pure water.

[0039] Experimental Example 1 This experimental example compares the flowability of bullet-shaped polyvinyl alcohol embolization microparticles (Example 1) and spherical polyvinyl alcohol microparticles (Comparative Example 1). The experimental apparatus provided in patent CN109482111B (see Figure 12 of the patent) was used, and the experiment was conducted according to the method described in paragraphs [0210-0213] of its specification.

[0040] In this experimental example, the movement velocities of bullet-shaped and spherical polyvinyl alcohol (PVA) embolization microparticles in the channel are as follows: Figure 4 As shown, by Figure 4 It can be seen that the velocity of bullet-shaped polyvinyl alcohol embolized microparticles is greater than that of spherical polyvinyl alcohol microparticles, and the velocity of bullet-shaped polyvinyl alcohol embolized microparticles increases more than that of spherical polyvinyl alcohol microparticles as the fluid velocity increases.

[0041] Experiment Example 2 This experimental example compares the embolization effect of bullet-shaped polyvinyl alcohol embolization microparticles (Example 1) and spherical polyvinyl alcohol microparticles (Comparative Example 1). The experimental apparatus provided in patent CN109482111B (see Figure 14 of the patent) was used, and the experiment was conducted according to the method described in paragraphs [0217-0218] of its specification.

[0042] In this experimental example, the flux comparison results of each experimental group are as follows: Figure 5 As shown, by Figure 5 It can be seen that both bullet-shaped and spherical polyvinyl alcohol embolization microparticles have good embolization effects. At the same time, we also noticed that the water flux of the microchannel where the bullet-shaped polyvinyl alcohol embolization microparticles are located is always close to zero, showing a better embolization effect.

[0043] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Any simple modifications or equivalent changes 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 method for preparing bullet-shaped polyvinyl alcohol embolic microparticles, characterized in that, Includes the following steps: A. Preparation of modified polyvinyl alcohol polymer Polyvinyl alcohol was dissolved in dimethyl sulfoxide solution at a mass fraction of 10%–20% under a nitrogen atmosphere. Then, ethyl 2-isocyanate methacrylate was added dropwise while stirring vigorously. The reaction temperature was 60°C and the reaction time was 4 hours. The resulting solution was then added dropwise to toluene, with the volume of toluene being 20–60 times the volume of DMSO, until no more precipitate was formed. The reaction was then stopped. The precipitate was then dissolved in water, washed with a 10 kDa filtration membrane, and finally lyophilized to obtain the modified polyvinyl alcohol polymer. B. Preparation of dispersed phase fluid, continuous phase 1 fluid, and continuous phase 2 fluid. Preparation of dispersed phase fluid The modified polyvinyl alcohol polymer, water-soluble photoinitiator, and water-soluble surfactant obtained in step A are dissolved in water to obtain a dispersed phase fluid; in the dispersed phase fluid, the mass fraction of the modified polyvinyl alcohol polymer is 1%~8%, the mass fraction of the water-soluble photoinitiator is 0.5%~20%, and the mass fraction of the water-soluble surfactant is 0%~20%; Preparation of continuous phase 1 fluid: Dissolve an oil-soluble surfactant in soybean oil to obtain continuous phase 1 fluid, wherein the mass fraction of the oil-soluble surfactant in continuous phase 1 fluid is 0.5%~20%; Preparation of continuous phase 2 fluid: Dissolve oil-soluble surfactant in soybean oil to obtain continuous phase 2 fluid, wherein the mass fraction of oil-soluble surfactant in continuous phase 2 fluid is 0%~20%; C. Preparation of bullet-shaped non-spherical microparticles The dispersed phase fluid, continuous phase 1 fluid, and continuous phase 2 fluid obtained in step B are injected into the injection tube (1), transition tube (3), and collection tube (5) of the microfluidic device using a syringe pump. The injection tube (1) is made of cylindrical glass capillary tube, and its head is drawn into a cone shape using a needle puller and the cone tip is polished flat on sandpaper. The transition tube (3) and collection tube (5) are both cylindrical glass capillary tubes. The head of the injection tube (1) is inserted into the tail of the transition tube (3) and connected through the first connecting tube (2). The head of the transition tube (3) is inserted into the second connecting tube (4) from one end, and the tail of the collection tube (5) is inserted into the second connecting tube (4) from the other end. The transition tube (3) and collection tube (5) are connected through the second connecting tube (4). The first connecting tube (2) and the second connecting tube (4) are both square glass tubes with a square through hole in the center. The injection tube (1), the first connecting tube (2), the first connecting tube (3), the second connecting tube (4), the second connecting tube (4), the second connecting tube (5), the second connecting tube (2), the second connecting tube (3), the second connecting tube (4), the second connecting tube (4), the second connecting tube (5), the second connecting tube (2), the second connecting tube (3), the second connecting tube (4), the second connecting tube (5), the second connecting tube (4), the second connecting tube (3), the second connecting tube (4), the second connecting tube (5), the second connecting tube (2 ... The connecting pipe (2), transition pipe (3), second connecting pipe (4) and collecting pipe (5) are coaxially arranged; the non-inlet ends of the first connecting pipe (2) and the second connecting pipe (4) are sealed with glue; the dispersed phase fluid is injected by the injection pipe (1), and is sheared by the continuous phase 1 fluid injected through the transition pipe (3) at the conical opening of the injection pipe (1) via the first connecting pipe (2) to form a monodisperse water-in-oil emulsion. The water-in-oil emulsion droplets flow with the continuous phase 1 through the transition pipe (3) and the second connecting pipe (4) into the downstream collecting pipe (5). Under the combined action of the spatial restriction of the collecting pipe (5) wall and the shearing force of the continuous phase 2 fluid injected in the collecting pipe (5), the droplets are transformed into bullet-shaped water-in-oil emulsion droplet templates. Then, the bullet-shaped droplet templates in the collecting pipe (5) are irradiated by an ultraviolet light source (6) located near the end of the collecting pipe (5). The modified polyvinyl alcohol polymer inside the bullet-shaped droplets is polymerized and cured to obtain bullet-shaped polyvinyl alcohol embolization microparticles. The flow rate of the dispersed phase fluid is controlled at 50~600 μL / h, the flow rate of the continuous phase 1 fluid is 80~1200 μL / h, and the flow rate of the continuous phase 2 fluid is 100~2000 μL / h. D. Washing The bullet-shaped polyvinyl alcohol embolization microparticles obtained in step C were washed with detergent to remove the continuous phase 1 and continuous phase 2 solutions from their surfaces. The washed bullet-shaped polyvinyl alcohol embolization microparticles were then stored in pure water.

2. The method for preparing bullet-shaped polyvinyl alcohol embolic microparticles according to claim 1, characterized in that, The water-soluble photoinitiator mentioned in step B is one of 2-hydroxy-2-methyl-1-phenyl-1-propanone and photoinitiator 2959.

3. The method for preparing bullet-shaped polyvinyl alcohol embolic microparticles according to claim 1, characterized in that, The water-soluble surfactant mentioned in step B is one of Pluronic F-127 and sodium dodecyl sulfonate.

4. The method for preparing bullet-shaped polyvinyl alcohol embolic microparticles according to claim 1, characterized in that, The oil-soluble surfactant used in continuous phase 1 and continuous phase 2 in step B is the same, which is one of polyricinoleic acid glycerol ester, Span20, Span40, Span60, Span80, and Tween85.

5. The method for preparing bullet-shaped polyvinyl alcohol embolic microparticles according to claim 1, characterized in that, The detergent mentioned in step D is ethanol or isopropanol.

6. A bullet-shaped polyvinyl alcohol embolization microparticle, prepared by the method of claim 1, wherein the matrix of the embolization microparticle is polyvinyl alcohol, and the overall shape is bullet-shaped, consisting of a hemispherical head and a cylindrical tail smoothly connected as one piece; wherein, The diameter of the cylindrical tail is 50~600μm; the ratio of the length of the hemispherical head to the length of the cylindrical tail is 1:1~5, and the length direction is along the axis of the cylinder.

7. The application of the bullet-shaped polyvinyl alcohol embolization microparticles as described in claim 6 in embolization therapy.

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