A solid-liquid biphasic embolizing agent with a surface cilia structure and its preparation method

Abstract

The present invention relates to the technical field of biomedical materials, and particularly to a solid-liquid biphasic embolic agent with a surface cilia structure and a preparation method thereof; it includes a liquid embolic material in the oil phase and Janus cilia microspheres with hydrophilic cilia structures; the Janus cilia microspheres encapsulate the liquid embolic material in the oil phase, and when encapsulating, the hydrophilic cilia structures in the Janus cilia microspheres are exposed outward in the aqueous phase, so that the surface of the solid-liquid biphasic embolic agent has a cilia structure; the cilia structure can improve the interaction force between embolic material particles and between embolic material particles and the blood vessel wall, has excellent viscoelasticity and deformation ability, can reach finer arterial blood vessels, realize efficient embolization of thick and thin arteries, and improve the efficiency of tumor embolization chemotherapy; and the cilia structure is combined with the solid-liquid biphasic system, which not only improves the embolization effect, but also enhances the stability of the embolic agent, prolongs the action time, and optimizes the biocompatibility, and will have broad application prospects.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedical materials, and particularly to a solid-liquid biphasic embolization agent with a surface cilia structure and a preparation method thereof. Background Art

[0002] With the rapid development of medical imaging technology, interventional therapy has been increasingly widely applied in the fields of tumors, vascular diseases, etc. Embolization therapy mainly blocks blood flow by delivering embolization materials, which is a minimally invasive treatment method and is currently considered one of the preferred treatment strategies for treating certain diseases, such as bleeding, hepatocellular tumors, and renal tumors. The development of traditional embolization agents mainly focuses on their occlusion effect on blood vessels. However, with the development of medical technology, patients' requirements for embolization therapy are also increasing day by day. They not only require the embolization agent to have an efficient embolization effect, but also need it to have better biocompatibility, targeting, and controllability.

[0003] Existing embolization materials are divided into solid embolization microspheres and liquid embolization agents. These two types of embolization materials have been widely used in clinical practice, especially in tumor chemoembolization. However, due to the different sizes and complex structures of blood vessels, most embolization materials are limited in effective chemoembolization.

[0004] In arterial chemoembolization of tumors, in addition to embolizing large-sized arterial blood vessels, the embolization material also needs to move distally to embolize finer arterial blood vessels to achieve distal embolization and improve the efficiency of chemoembolization, which is crucial for the treatment of tumors. However, solid embolization microspheres usually have a relatively large diameter, poor viscoelasticity and deformation ability, and are difficult to effectively embolize finer arterial blood vessels. Liquid embolization materials, such as lipiodol, are expected to flow into finer blood vessels and exhibit good radiological imaging and drug loading capabilities, and have attracted particular attention in the past few decades, especially in tumor chemoembolization. However, these lipiodols are highly unstable in the blood, are prone to re-canalization, have poor specificity, and some are toxic, resulting in high requirements and limited use in tumor chemoembolization.

[0005] Therefore, there is an urgent need to develop new embolization materials that can adapt to the vascular structure to achieve effective embolization of thick and fine arteries, which can not only expand the application scope of embolization therapy, improve the treatment effect, but also reduce the incidence of complications, and has important clinical significance and market value.

[0006] Therefore, the present application proposes a solid-liquid biphasic embolization agent with a surface cilia structure and a preparation method thereof. Summary of the Invention

[0007] In order to make up for the deficiencies of the prior art and solve the technical problems existing in the background art, the present invention proposes a solid-liquid biphasic embolization agent with a surface cilia structure and a preparation method thereof.

[0008] The present invention is realized through the following technical solutions:

[0009] A solid-liquid biphasic embolic agent with a surface cilia structure, comprising a liquid embolic material in the oil phase and Janus cilia microspheres with hydrophilic cilia structures; the Janus cilia microspheres encapsulate the liquid embolic material in the oil phase, and when encapsulating, the hydrophilic cilia structures in the Janus cilia microspheres are exposed outward in the water phase, so that the surface of the solid-liquid biphasic embolic agent has abundant cilia structures.

[0010] The oil phase in each embolic agent is the liquid embolic material, and the outside is tightly encapsulated by solid Janus cilia microspheres, enabling it to simultaneously exert the advantages of the liquid embolic material and the solid embolic microspheres.

[0011] Preferably, the Janus cilia microspheres are composed of a polymer, with a diameter between 2 and 10 microns, and one side of the Janus cilia microspheres is a smooth structure, and the other side is a cilia structure, and the smooth side has lipophilicity, and the cilia side has hydrophilicity; one side being a smooth structure corresponds to half being smooth in the Janus cilia microspheres, and the other side being a cilia structure corresponds to half being a cilia structure, enabling it to tightly encapsulate the liquid embolic material in the oil phase.

[0012] Preferably, the diameter of the cilia in the cilia structure is between 30 and 500 nanometers, and the length is greater than 500 nanometers, having good flexibility, so as to enhance the interaction force between embolic agents and between embolic agents and cell walls, and improve the embolization efficiency.

[0013] Preferably, the solid-liquid biphasic embolic agent can maintain a spherical shape and exist stably under normal conditions, and will transform into an ellipsoidal shape, a cylindrical shape, a dumbbell shape or a snowman shape when subjected to external forces.

[0014] Compared with its solid embolic microspheres, this solid-liquid biphasic embolic agent exhibits a larger encapsulation coefficient and will accumulate more tightly in blood vessels; moreover, this solid-liquid biphasic embolic agent can reach thinner blood vessels, thereby simultaneously embolizing thick and thin arterial blood vessels and improving the embolization efficiency.

[0015] In addition, the solid-liquid biphasic embolic agent with a surface cilia structure can simultaneously take into account the advantages of the liquid embolic material and the solid embolic microspheres, has excellent viscoelasticity and deformation ability, will transform from a spherical shape to an ellipsoidal shape, a cylindrical shape, a dumbbell shape and a snowman shape, etc. under the action of external forces, and can generate deformation to reach thinner arterial blood vessels. At the same time, the cilia structures on the surface of the embolic agent particles can increase the interaction between embolic agents and between embolic agents and the blood vessel wall. Therefore, this solid-liquid biphasic embolic agent can simultaneously and efficiently embolize thick and thin arterial blood vessels and improve the embolization chemotherapy efficiency.

[0016] Preferably, the particle size of the solid-liquid biphasic embolizing agent is 10-1000 microns, and the size is adjustable;

[0017] According to the needs of clinical applications, the particle size can be adjusted simply and quickly by changing the concentration of the Janus ciliated microsphere dispersion during emulsification, or the volume ratio of the liquid embolizing material to the Janus ciliated dispersion, or the emulsification rotation speed. It is easy to prepare on a large scale, providing convenience for clinical embolization treatment.

[0018] Preferably, by adding functional units to the liquid embolizing material and / or Janus ciliated microspheres, the solid-liquid biphasic embolizing agent can have different functions.

[0019] Adding cisplatin to the liquid embolizing material and adding doxorubicin, paclitaxel, etc. to the Janus ciliated microspheres can achieve the effect of killing tumor cancer cells;

[0020] Adding fluorescent dyes, quantum dots, etc. to the liquid embolizing material or Janus ciliated microspheres can achieve the effect of blood vessel imaging, especially having important research value in the imaging of thinner lymphatic vessels;

[0021] After adding magnetic iron oxide nanoparticles to the Janus ciliated microspheres, the movement of the embolizing agent can be controlled under a magnetic field, thus achieving the effect of precise targeted therapy.

[0022] Different applications such as cancer cell killing, lymphatic vessel imaging, and precise targeted therapy are achieved by adding some functional units to the solid-liquid biphasic embolizing agent, and its preparation method is simple and fast.

[0023] A preparation method suitable for the above-mentioned solid-liquid biphasic embolizing agent with a surface ciliated structure, the method comprising the following steps:

[0024] Step 1: Prepare Janus ciliated microspheres:

[0025] Step 2: Hydrophilic treatment of Janus ciliated microspheres:

[0026] Take 100-500 mg of Janus ciliated microspheres in a 50 mL centrifuge tube, add 20-40 mL of 2 M hydrochloric acid solution, mix well and hydrolyze on a rotary shaker for 4 hours. After completion, wash three times with deionized water and set aside;

[0027] Step 3: Prepare the solid-liquid biphasic embolizing agent:

[0028] Prepare an aqueous dispersion of Janus ciliated microspheres with a concentration of 0.5-20 mg / mL;

[0029] Slowly add 0.05-2 mL of the liquid embolizing material to the Janus ciliated microsphere dispersion;

[0030] Then insert the cutter head of the disperser into the oil-water interface, emulsify for 5 - 30 minutes under the condition of 200 - 4000 rpm, and let it stand for 30 minutes after completion.

[0031] Step Four: Clean the solid-liquid biphasic embolization agent:

[0032] Shake and disperse the solid-liquid biphasic embolization agent, after standing for 1 minute, suck off the supernatant, then add deionized water and shake to disperse it. Repeat the cleaning 3 - 5 times to remove the excess Janus cilia microspheres, and then a clean solid-liquid biphasic embolization agent can be obtained.

[0033] Preferably, the specific steps in Step One are as follows:

[0034] First, blend the block copolymer and the homopolymer in a ratio of 1:7 and dissolve them in an organic solvent to prepare a polymer solution with a concentration of 1 - 5 wt%;

[0035] Next, under a high-speed disperser, add 5 - 15 mL of the polymer solution to 150 - 300 mL of the surfactant aqueous solution and emulsify for 10 minutes;

[0036] Then cover the emulsion with tin foil and place it on a flat table, and let it stand at room temperature for 4 hours;

[0037] Finally, remove the tin foil, heat the emulsion to 40 °C, stir at 400 rpm for 2 hours to evaporate the solvent, then centrifuge at 6000 rpm and wash three times with water to obtain white Janus cilia microspheres.

[0038] In addition, there are alternative solutions for preparing Janus cilia microspheres. For example, adjusting the type, molecular weight, composition, and concentration of the block copolymer can also achieve similar effects; adjusting the type, molecular weight, composition, and concentration of the surfactant can also achieve similar effects; adjusting the type and composition of the organic solvent can also achieve similar effects.

[0039] There are also alternative solutions for the hydrophilic treatment of Janus cilia microspheres. For example, changing the hydrolysis conditions, changing the type, concentration, rotation speed, and hydrolysis time of the acid or base during hydrolysis can also achieve similar effects.

[0040] There are also alternative solutions for preparing the solid-liquid biphasic embolization agent. For example, changing the emulsification method, changing the disperser, ultrasonic cell disruptor, stirrer, membrane emulsifier, and microfluidic chip used during emulsification can also achieve similar effects.

[0041] Preferably, the block copolymer is a triblock copolymer with a hydrophobic segment and a hydrophilic segment;

[0042] Among them, the hydrophobic chain segment includes polylactic acid, poly(lactide), poly(lactic acid / glycolic acid) copolymer, or polystyrene;

[0043] The hydrophilic chain segment includes polyethylene glycol, poly(4-vinylpyridine), or polyacrylic acid;

[0044] The organic solvent includes one or more of dichloromethane, chloroform, benzene, toluene, xylene, 1,2-dichloroethane, trichloroethane, and carbon tetrachloride.

[0045] Preferably, the surfactant aqueous solution includes one or more of sodium dodecyl sulfate, cetyltrimethylammonium bromide, and polyvinyl alcohol;

[0046] The liquid embolization material includes one or more of polyacrylate, polyethylene glycol, polyacrylonitrile, and iodized oil.

[0047] The beneficial effects of the present invention are as follows:

[0048] 1. The surface of the solid-liquid biphasic embolizing agent of the present invention has a rich cilia structure. The cilia structure can improve the interaction force between the embolization material particles and between the embolization material particles and the blood vessel wall. It has excellent viscoelasticity and deformation ability, can reach finer arterial blood vessels, achieve efficient embolization of thick and thin arteries, and thus improve the efficiency of tumor embolization chemotherapy; in addition, the combination of the cilia structure and the solid-liquid biphasic system can not only enhance the embolization effect, but also improve the stability of the embolizing agent, extend the action time, and optimize its biocompatibility. It will have broad application prospects and can provide better curative effects and patient experiences in clinical treatment.

[0049] 2. The present invention uses the method of self-assembly of block copolymer emulsion to obtain amphiphilic Janus cilia microspheres. The Janus cilia microsphere dispersion is used as the aqueous phase, and the liquid embolization material of the oil phase is added to the aqueous phase. After emulsification with a disperser and washing away the excess Janus cilia microspheres, a solid-liquid biphasic embolizing agent with a surface cilia structure can be obtained. Description of the Drawings

[0050] Figure 1 It is a schematic diagram of the solid-liquid biphasic embolizing agent with a surface cilia structure prepared by the present invention;

[0051] Figure 2 It is a characteristic diagram of the Janus cilia microspheres prepared in Example 1 of the present invention;

[0052] Among them, Figure 2 A is the EDX element distribution diagram of the Janus cilia microspheres; Figure 2 B is the SEM diagram of the Janus cilia microspheres; Figure 2 C is the diameter distribution diagram of the prepared Janus cilia microspheres;Figure 2 D is the coverage area diagram of cilia in the prepared Janus cilia microspheres;

[0053] Figure 3 It is the characteristic diagram of the solid-liquid biphasic embolization agent with a surface cilia structure prepared in Example 2 of the present invention;

[0054] Among them, Figure 3 A is the camera diagram of the solid-liquid biphasic embolization agent with a surface cilia structure; Figure 3 B is the fluorescence microscope diagram of the solid-liquid biphasic embolization agent with a surface cilia structure; Figure 3 C is the particle size distribution diagram of the prepared solid-liquid biphasic embolization agent with a surface cilia structure; Figure 3 D is the confocal scanning diagram of the solid-liquid biphasic embolization agent with a surface cilia structure;

[0055] Figure 4 It is the particle size regulation diagram of the solid-liquid biphasic embolization agent with a surface cilia structure prepared in Example 3 of the present invention;

[0056] Among them, Figure 4 A is the influence curve diagram of the rotation speed during emulsification on the particle size of the solid-liquid biphasic embolization agent; Figure 4 B is the influence curve diagram of the oil-water ratio during preparation on the particle size of the solid-liquid biphasic embolization agent; Figure 4 C is the influence curve diagram of the concentration of the Janus cilia microsphere dispersion liquid during preparation on the particle size of the solid-liquid biphasic embolization agent;

[0057] Figure 5 It is the viscoelasticity and deformation ability characteristic diagram obtained by characterizing the solid-liquid biphasic embolization agent with a surface cilia structure in Example 4 of the present invention;

[0058] Among them, Figure 5 A is the viscosity change curve diagram of the solid-liquid biphasic embolization agent with respect to the shear rate; Figure 5 B is the storage modulus change curve diagram of the solid-liquid biphasic embolization agent with respect to the shear strain; Figure 5 C is the injection force curve diagram of the solid-liquid biphasic embolization agent; Figure 5 D is the embolization effect display diagram of the solid-liquid biphasic embolization agent in the capillary; Figure 5 E is the encapsulation coefficient diagram of different embolization materials; Figure 5 F is the fluorescence microscope diagram of solid-liquid biphasic embolization agents with different shapes; Figure 5 G is the deformation ability display diagram of the solid-liquid biphasic embolization agent;

[0059] Figure 6 It is the embolization performance diagram obtained by characterizing the solid-liquid biphasic embolization agent with a surface cilia structure in Example 5 of the present invention;

[0060] Among them, Figure 6 A is the embolization mechanism diagram of the solid-liquid biphasic embolization agent;Figure 6 Figure B shows the display of the solid-liquid biphasic embolization agent passing through the artificial blood vessel; Figure 6 Figure C shows the interaction force diagram between the solid-liquid biphasic embolization agent and the blood vessel wall; Figure 6 Figure D shows the embolization effect diagram of the solid-liquid biphasic embolization agent with surface cilia structure in capillaries of different thicknesses;

[0061] Figure 7 This is the embolization performance diagram of the solid-liquid biphasic embolization agent with surface cilia structure in the branched microfluidic channel in Example 6 of the present invention;

[0062] Figure 8 This is the embolization performance diagram of the solid-liquid biphasic embolization agent with surface cilia structure in the liver of SD rats in Example 7 of the present invention.

[0063] Among them, Figure 8 Figure A is an optical photograph of the liver of an SD rat after being cleared; Figure 8 Figure B is an optical photograph of the transparent liver of an SD rat after injecting the solid-liquid biphasic embolization agent with surface topography structure through the blood vessel; Figure 8 C-8H is Figure 8 The confocal microscope images of different blood vessel parts in B. Detailed implementation manners

[0064] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are usually carried out according to conventional conditions or according to the conditions recommended by the manufacturer.

[0065] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. The reagents or raw materials used in the present invention can be obtained through conventional channels. Unless otherwise specified, the reagents or raw materials used in the present invention are used in the conventional manner in the art or according to the product instructions. In addition, any methods and materials similar or equivalent to the recorded content can be applied to the method of the present invention. The present invention will be further described below according to the accompanying drawings of the specification and the detailed implementation manners. The preferred implementation methods and materials described in the present invention are only for demonstration purposes.

[0066] Example 1:

[0067] a) Blend and dissolve the triblock polymer and the homopolymer in a mass ratio of 1:7 in dichloromethane to obtain a 5 w / v% polymer solution, and add 5 μg of beihong fluorescent dye thereto;

[0068] b) Under a high-speed disperser, add 10 mL of the polymer solution to 200 mL of the surfactant aqueous solution and emulsify for 10 minutes. Then cover the emulsion with tin foil and place it on a flat tabletop, and let it stand still at room temperature for 4 hours;

[0069] c) After 4 hours, remove the tin foil, heat the emulsion to 40 °C, and stir at 400 rpm for 2 hours to volatilize the solvent and grow the cilia structure;

[0070] d) After completion, centrifuge the dispersion at 6000 rpm and wash it three times with water to obtain pink Janus cilia microspheres, which are freeze-dried and stored after centrifugation and washing with water.

[0071] Characterized by SEM and EDX, the prepared Janus cilia-structured microspheres exhibit a morphological feature of being half smooth and half ciliated. Moreover, one side of the cilia is rich in O element and has hydrophilicity, while the smooth side has lipophilicity, and there are no obvious defects in the microspheres. The results are as shown in the appendix Figure 2 as follows.

[0072] Among them, as can be seen from Figure 2 A, the O element is mainly distributed on one side of the cilia, making it hydrophilic after hydrolysis, while the smooth side is mainly composed of C element, making it lipophilic; as can be seen from Figure 2 B, the Janus cilia microspheres are half smooth and half ciliated; as can be seen from Figure 2 C, the particle size distribution of the Janus cilia microspheres is between 2 - 8 microns; as can be seen from Figure 2 D, the coverage area of the cilia is about 50%, showing a morphological feature of being half smooth and half ciliated.

[0073] Example 2:

[0074] a) Take 200 mg of the Janus cilia microspheres prepared in Example 1 in a 50 mL centrifuge tube, add 30 mL of 2 M hydrochloric acid, shake well, and place it on a rotary shaker for hydrolysis for 4 hours. After completion, wash it three times with deionized water and set it aside for use;

[0075] b) Add 40 mL of deionized water to the hydrolyzed Janus cilia microspheres to prepare a microsphere dispersion with a concentration of 5 mg / mL. Then slowly add 500 μL of iodized oil liquid embolization material to the Janus cilia microsphere dispersion;

[0076] c) Insert the cutter head of the disperser into the oil-water interface, emulsify at 1000 rpm for 10 minutes, and let it stand still for 30 minutes after completion;

[0077] d) Shake and disperse the solid-liquid biphasic embolization agent, let it stand for 1 minute, carefully suck off the supernatant, then add deionized water and shake to disperse it. Repeat the washing 3 - 5 times, and then remove the excess Janus ciliated microspheres to obtain a clean solid-liquid biphasic embolization agent;

[0078] The prepared solid-liquid biphasic embolization agent particles with surface cilia structure were characterized by fluorescence microscopy and confocal microscopy. The particles were of uniform size and had no obvious defects. The results are shown in the Figure 3 attachment.

[0079] Among them, Figure 3 as can be seen from Figure 3 A, the prepared solid-liquid biphasic embolization agent particles with surface cilia structure were pink, the supernatant was clear and transparent, and there were no excess Janus ciliated microspheres mixed in it; as can be seen from Figure 3 B, the solid-liquid biphasic embolization agent particles were of uniform size and could emit red fluorescence; as can be seen from Figure 3 C, the prepared solid-liquid biphasic embolization agent particles with surface cilia structure had a uniform particle size distribution, and the size was between 60 - 240 microns; as can be seen from

[0080] Example 3:

[0081] a) Adjust the rotation speed during emulsification in Example 2 to 500 rpm, 1000 rpm, 1500 rpm, 2000 rpm, and 2500 rpm respectively to prepare a solid-liquid biphasic embolization agent with surface cilia structure;

[0082] b) Adjust the oil-water ratio (volume ratio of iodized oil to Janus ciliated microsphere dispersion) in Example 2 to 1:30, 1:60, 1:90, 1:120, and 1:150 respectively to prepare a solid-liquid biphasic embolization agent with surface cilia structure;

[0083] c) Adjust the concentration of the Janus ciliated microsphere dispersion in Example 2 to 1 mg / mL, 2 mg / mL, 4 mg / mL, 6 mg / mL, 8 mg / mL, and 10 mg / mL respectively to prepare a solid-liquid biphasic embolization agent with surface cilia structure;

[0084] The prepared solid-liquid biphasic embolization agent particles with surface cilia structure were characterized by fluorescence microscopy, and the particle size was statistically analyzed using ImageJ software. The results are shown in the Figure 4 attachment.

[0085] Among them, Figure 4A shows the effect of the rotation speed during emulsification on the particle size of the solid-liquid biphasic embolization agent. It can be seen that as the emulsification rotation speed increases, the particle size of the solid-liquid biphasic embolization agent gradually decreases; Figure 4 B shows the effect of the oil-water ratio during preparation on the particle size of the solid-liquid biphasic embolization agent. It can be seen that as the oil-water ratio decreases, the particle size of the solid-liquid biphasic embolization agent will decrease; Figure 4 C shows the effect of the concentration of the Janus ciliated microsphere dispersion during preparation on the particle size of the solid-liquid biphasic embolization agent. Similarly, it can be found that as the concentration of the dispersion increases, the particle size of the prepared solid-liquid biphasic embolization agent also shows a downward trend.

[0086] Example 4:

[0087] a) Respectively take 500 μL of lipiodol and the solid-liquid biphasic embolization agent prepared in Example 2 on a rheometer, and measure the change in viscosity with shear rate and the change in storage modulus with shear strain;

[0088] b) Take 1 mL of the solid-liquid biphasic embolization agent prepared in Example 2 in a 1 mL BD syringe, and measure the injection force on a force measuring machine at a rate of 1 mL / min;

[0089] c) Take 1 mL of the solid-liquid biphasic embolization agent prepared in Example 2 in a 1 mL BD syringe, and slowly add it to a glass capillary. Observe the stacking situation of the solid-liquid biphasic embolization agent in the capillary with a fluorescence microscope, and calculate the encapsulation coefficient;

[0090] d) Take a glass capillary with thick ends and a thin middle, and inject the solid-liquid biphasic embolization agent particles prepared in Example 2 from one end of the capillary with a microfluidic injection pump, and observe the deformation ability under a microscope;

[0091] The results are as shown in the appendix Figure 5 as follows.

[0092] Among them, it can be seen from Figure 5 A that as the shear rate increases, the viscosity of the solid-liquid biphasic embolization agent gradually decreases, showing the characteristic of shear thinning, while lipiodol does not have this characteristic; it can be seen from Figure 5 B that compared with lipiodol, the solid-liquid biphasic embolization agent has a higher storage modulus, showing excellent viscoelasticity; Figure 5 It can be seen from C that the injection force of the solid-liquid biphasic embolization agent with a surface ciliated structure is all below 10 N, indicating that this solid-liquid biphasic embolization agent can stably exist during injection and is relatively easy to inject into animals for embolization chemotherapy; Figure 5 It can be seen from D that each embolization particle of the solid-liquid biphasic embolization agent in the glass capillary is tightly pushed together with each other, and some have deformed; it can be seen from Figure 5It can be seen from the encapsulation coefficient diagram of E that the solid-liquid biphasic embolic agent encapsulated by Janus ciliated microspheres has a high encapsulation coefficient, indicating that it can be packed more tightly and has better embolization ability; Figure 5 F is a fluorescence microscope image of solid-liquid biphasic embolic agent particles with different shapes in a glass capillary. It can be seen that these solid-liquid biphasic embolic agents can exhibit various shapes, mainly including spherical, cylindrical, ellipsoidal, dumbbell-shaped, and snowman-shaped, etc.; From Figure 5 G, it can be seen that this solid-liquid biphasic embolic agent can deform and pass through a thinner capillary, and then gradually return to its original spherical shape.

[0093] Example 5:

[0094] a) Prepare a single-channel microfluidic chip using the methods of 3D printing and PDMS template replication;

[0095] b) Grow HUVEC cells in the prepared microfluidic chip to mimic artificial blood vessels;

[0096] c) Use a syringe to flow the solid-liquid biphasic embolic agent prepared in Example 2 through the artificial blood vessel, and observe the remaining embolic agent in the artificial blood vessel with a fluorescence microscope;

[0097] d) Use a syringe to flow the solid-liquid biphasic embolic agent prepared in Example 2 through the artificial blood vessel, and measure the interaction force of the embolic agent flowing through the artificial blood vessel with a force measuring machine;

[0098] e) Use a syringe to inject the solid-liquid biphasic embolic agent prepared in Example 2 into glass capillaries of different thicknesses, and observe the embolization effect of the solid-liquid biphasic embolic agent particles in capillaries of different thicknesses with a fluorescence microscope.

[0099] The results are as shown in the appendix Figure 6 as follows.

[0100] Among them, from Figure 6 A, it can be seen that the cilia on the surface of the solid-liquid biphasic embolic agent with surface cilia structure can entangle with each other, have topological matching, and increase the interaction force between embolic agent particles and between embolic agent particles and the blood vessel wall, while the solid-liquid biphasic embolic agent with a smooth surface shows a weak interaction force; From Figure 6 B, it can be seen that this solid-liquid biphasic embolic agent with surface cilia structure will remain more on HUVEC cells after passing through the artificial blood vessel, while the solid-liquid biphasic embolic agent with a smooth surface remains less; From Figure 6 C, in the diagram of the interaction force between the biphasic embolic agent and the blood vessel wall, it can be seen that compared with pure iodized oil and the solid-liquid biphasic embolic agent with a smooth surface, this solid-liquid biphasic embolic agent with surface cilia structure has a greater interaction force, indicating that this kind of solid-liquid biphasic embolic agent particles can produce a stronger interaction with the blood vessel wall; From Figure 6D It can be seen that this solid-liquid biphasic embolic agent can achieve good embolization in capillaries of 1000μm, 500μm, 300μm and 100μm.

[0101] Embodiment 6:

[0102] a) Preparation of microfluidic channel core with cross-structure using 3D printing and PDMS template replication method;

[0103] b) blocking the main outlet of the microfluidic chip, and injecting the solid-liquid biphasic embolic agent prepared in Example 2 into the artificial blood vessel using a syringe;

[0104] c) Observe the embolization of the solid-liquid biphasic embolic agent using a camera and a fluorescence microscope;

[0105] The results are attached Figure 7 shown.

[0106] Among them, Janus ciliary microspheres have red fluorescence, and iodized oil droplets are dyed green fluorescence. From the figure, it can be seen that whether it is a thick microfluidic channel, a thin microfluidic channel or a cross-section, red fluorescence and green fluorescence can be produced, indicating that this solid-liquid biphasic embolic agent can stably exist in the cross-multi-channel microfluidic chip and can achieve good embolization.

[0107] Embodiment 7:

[0108] a) The liver of the SD rat was completely removed, and SDS rinse solution and saline were perfused from the arterial inlet of the liver until the liver was completely transparent;

[0109] b) using a syringe to carefully inject the solid-liquid biphasic embolic agent prepared in Example 2 into the transparently treated liver organ until it is completely filled;

[0110] c) Confocal microscopy was used to observe the embolization of solid-liquid biphasic embolic agent particles in the liver of SD rats;

[0111] The results are attached Figure 8 shown.

[0112] Among them, from Figure 8 A shows that the liver of SD rat is completely transparent, and the blood vessels inside are clearly visible. Figure 8 As can be seen in B, after the transparent SD rat liver was injected with this solid-liquid biphasic embolic agent with a surface morphology structure through the artery, both the thick and thin blood vessels were filled with the solid-liquid embolic agent, showing good embolic performance; Figure 8 It can be seen from C-8H that the solid and liquid embolic agents inside can still exist stably and push each other tightly, achieving good embolic effects in both thick and thin blood vessels.

[0113] Those parts not described in the present invention are applicable to the prior art.

Claims

1. A solid-liquid biphasic embolic agent with a surface ciliary structure, characterized in that: It comprises an oil phase liquid embolic material and a Janus ciliary microsphere with a hydrophilic ciliary structure; the Janus ciliary microsphere encapsulates the oil phase liquid embolic material, and during encapsulation, the hydrophilic ciliary structure in the Janus ciliary microsphere is exposed to the outside in the water phase, so that the surface of the solid-liquid biphasic embolic agent has a ciliary structure; The Janus ciliary microspheres are composed of high molecular polymers, and one side of the Janus ciliary microspheres is a smooth structure and the other side is a ciliary structure, and the smooth side is lipophilic and the ciliary side is hydrophilic; The diameter of the cilia in the cilia structure is 30-500 nanometers, and the length is greater than 500 nanometers.

2. The solid-liquid biphasic embolic agent with a surface ciliary structure according to claim 1, characterized in that: The solid-liquid biphasic embolic agent can maintain a spherical shape and exist stably under normal circumstances, and can be transformed into an ellipsoid, a cylinder, a dumbbell or a snowman shape when subjected to external force.

3. The solid-liquid biphasic embolic agent with a surface ciliary structure according to claim 1, characterized in that: Said The particle size of the solid-liquid biphasic embolic agent is 10-1000 microns, and the size is adjustable; The size can be adjusted by changing the concentration of the Janus ciliary microsphere dispersion during emulsification, the volume ratio of the liquid embolic material and the Janus ciliary dispersion, or the emulsification speed.

4. The solid-liquid biphasic embolic agent with a surface ciliary structure according to claim 1, characterized in that: By adding functional units to liquid embolic materials and / or Janus ciliary microspheres, solid-liquid biphasic embolic agents can have different effects.

5. A method for preparing the solid-liquid biphasic embolic agent with a surface ciliary structure suitable for use in any one of claims 1 to 4, characterized in that: The method comprises the following steps: Step 1: Preparation of Janus ciliary microspheres: Step 2: Hydrophilic treatment of Janus ciliary microspheres: Take 100-500 mg of Janus ciliary microspheres in a 50 mL centrifuge tube, add 20-40 mL of 2M hydrochloric acid solution, mix well and place on a rotating rocker for hydrolysis for 4 hours. After the end, wash three times with deionized water for later use; Step 3: Preparation of solid-liquid biphasic embolic agent: The Janus ciliary microspheres were prepared into an aqueous dispersion with a concentration of 0.5-20 mg / mL; Slowly add 0.05-2 mL of liquid embolic material into the Janus ciliary microsphere dispersion; Then insert the blade of the disperser into the oil-water interface and emulsify for 5-30 minutes at 200-4000rpm, and then let it stand for 30 minutes; Step 4: Cleaning the solid-liquid biphasic embolic agent: The solid-liquid biphasic embolic agent was shaken to disperse, allowed to stand for 1 minute, the supernatant was aspirated, and then deionized water was added and shaken to disperse it. After repeated washing 3-5 times, the excess Janus ciliary microspheres were removed to obtain a clean solid-liquid biphasic embolic agent.

6. The method for preparing a solid-liquid biphasic embolic agent with a surface ciliary structure according to claim 5, characterized in that: The specific steps in step one are as follows: First, the block copolymer and the homopolymer are blended in a ratio of 1:7 and dissolved in an organic solvent to prepare a polymer solution with a concentration of 1-5wt%; Next, add 5-15 mL of the polymer solution to 150-300 mL of the surfactant aqueous solution in a high-speed disperser and emulsify for 10 minutes; Then cover the emulsion with tin foil and place it on a flat table, leaving it at room temperature for 4 hours; Finally, the tin foil was removed, the emulsion was heated to 40°C, stirred at 400 rpm for 2 hours to evaporate the solvent, centrifuged at 6000 rpm and washed with water three times to obtain white Janus ciliary microspheres.

7. The method for preparing a solid-liquid biphasic embolic agent with a surface ciliary structure according to claim 6, characterized in that: The block copolymer is a triblock copolymer having a hydrophobic segment and a hydrophilic segment; Wherein, the hydrophobic segment comprises polylactic acid or polylactide or polylactic acid / glycolic acid copolymer or polystyrene; The hydrophilic segment includes polyethylene glycol or poly-4-vinylpyridine or polyacrylic acid; The organic solvent includes one or more of dichloromethane, chloroform, benzene, toluene, xylene, 1,2-dichloroethane, trichloroethane, and carbon tetrachloride.

8. The method for preparing a solid-liquid biphasic embolic agent with a surface ciliary structure according to claim 7, characterized in that: The surfactant aqueous solution includes one or more of sodium dodecyl sulfate, hexadecyltrimethylammonium bromide, and polyvinyl alcohol; The liquid embolic material includes one or more of polyacrylates, polyethylene glycols, polyacrylonitrile, and iodized oils.

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