Solid-liquid two-phase embolism agent with surface cilium structure and preparation method of solid-liquid two-phase embolism agent

Abstract

The invention relates to the technical field of biomedical materials, in particular to a solid-liquid two-phase embolism agent with a surface cilium structure and a preparation method thereof. Comprising an oil-phase liquid embolism material and a Janus cilia microsphere with a hydrophilic cilia structure, the oil-phase liquid embolism material is wrapped by the Janus cilia microspheres, and during wrapping, hydrophilic cilia structures in the Janus cilia microspheres are outwards exposed in a water phase, so that the surface of the solid-liquid dual-phase embolism agent has cilia structures; the cilia structure can improve the interaction force between embolism material particles and between the embolism material particles and a blood vessel wall, has excellent viscoelasticity and deformability, can reach finer artery blood vessels, realizes efficient thick and thin artery embolism, and improves the tumor embolism chemotherapy efficiency; the cilia structure is combined with a solid-liquid two-phase system, so that the embolism effect is improved, the stability of the embolism agent is enhanced, the action time is prolonged, the biocompatibility is optimized, and the application prospect is wide.

Description

Technical Field

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

[0002] With the rapid development of medical imaging technology, interventional therapy is increasingly used in the fields of tumors, vascular diseases, etc. Embolization therapy mainly blocks blood flow by delivering embolic materials. It is a minimally invasive treatment method and is currently considered to be one of the preferred treatment strategies for certain diseases, such as bleeding, hepatocellular carcinoma and renal tumors. The development of traditional embolic agents mainly focuses on their blocking effect on blood vessels, but with the development of medical technology, patients' requirements for embolic therapy are also increasing. Embolic agents are not only required to have efficient embolic effects, but also require them to have better biocompatibility, targeting and controllability.

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

[0004] In arterial chemoembolization of tumors, in addition to embolizing large-sized arterial vessels, embolic materials also need to move distally to embolize smaller arterial vessels to achieve distal embolization to improve the efficiency of chemoembolization, which is crucial for the treatment of tumors. However, solid embolic microspheres usually have a large diameter, poor viscoelasticity and deformation ability, and are difficult to effectively embolize smaller arterial vessels. Liquid embolic materials, such as iodized oil, are expected to flow to smaller blood vessels and show good radiographic imaging and drug loading capacity. In the past few decades, they have attracted special attention, especially in tumor chemoembolization. However, these iodized oils are highly unstable in the blood, easy to clear again, have poor specificity, and are partially toxic, resulting in high requirements and limited use in tumor chemoembolization.

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

[0006] Therefore, the present application proposes a solid-liquid biphasic embolic agent with a surface ciliary 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 technology, the present invention proposes a solid-liquid biphasic embolic agent with a surface ciliary structure and a preparation method thereof.

[0008] The present invention is achieved through the following technical solutions: A solid-liquid biphasic embolic agent with a surface ciliary structure comprises a liquid embolic material in an oil phase and Janus ciliary microspheres with a hydrophilic ciliary structure; the Janus ciliary microspheres encapsulate the liquid embolic material in the oil phase, and during encapsulation, the hydrophilic ciliary structure in the Janus ciliary microspheres is exposed outwardly to the water phase, so that the surface of the solid-liquid biphasic embolic agent has abundant ciliary structures.

[0009] The oil phase inside each embolic agent is liquid embolic material, and the outside is tightly wrapped by solid Janus ciliary microspheres, so that it can simultaneously exert the advantages of liquid embolic material and solid embolic microspheres.

[0010] Preferably, the Janus ciliary microspheres are composed of high molecular polymers with a diameter between 2-10 microns, 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; one side is a smooth structure corresponding to half of the Janus ciliary microspheres being smooth, and the other side is a ciliary structure corresponding to half being a ciliary structure, so that it can tightly wrap the oil phase liquid embolic material.

[0011] Preferably, the diameter of the cilia in the cilia structure is 30-500 nanometers, the length is greater than 500 nanometers, and it has good flexibility, so as to enhance the interaction between embolic agents and between embolic agents and cell walls, thereby improving the embolization efficiency.

[0012] Preferably, the solid-liquid biphasic embolic agent can maintain a spherical shape under normal circumstances, and can be transformed into an ellipsoid, a cylinder, a dumbbell, or a snowman shape when subjected to external force.

[0013] Compared with its solid embolic microspheres, the solid-liquid biphasic embolic agent exhibits a larger encapsulation coefficient and accumulates more densely in the blood vessels. Moreover, the solid-liquid biphasic embolic agent can reach thinner blood vessels, thereby embolizing thick and thin arteries at the same time, improving the embolization efficiency.

[0014] In addition, the solid-liquid biphasic embolic agent with a surface ciliary structure can take into account the advantages of both liquid embolic materials and solid embolic microspheres, and has excellent viscoelasticity and deformation ability. Under the action of external force, it will change from a spherical shape to an ellipsoid, a cylinder, a dumbbell, a snowman, etc., and can deform to reach thinner arteries. At the same time, the ciliary structure on the surface of the embolic agent particles can increase the interaction between the embolic agents and between the embolic agents and the blood vessel walls. Therefore, this solid-liquid biphasic embolic agent can simultaneously and efficiently embolize thick and thin arterial vessels, thereby improving the efficiency of embolic chemotherapy.

[0015] Preferably, the particle size of the solid-liquid biphasic embolic agent is 10-1000 microns, and the size is adjustable; According to the needs of clinical applications, the particle size can be adjusted simply and quickly 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. This makes large-scale preparation easy and provides convenience for clinical embolization therapy.

[0016] Preferably, by adding functional units to the liquid embolic material and / or the Janus ciliary microspheres, the solid-liquid biphasic embolic agent can have different effects.

[0017] Adding cisplatin to liquid embolic materials and adding doxorubicin and paclitaxel to Janus ciliated microspheres can kill tumor cancer cells. Adding fluorescent dyes, quantum dots, etc. to liquid embolic materials or Janus ciliated microspheres can achieve the effect of vascular imaging, especially in the imaging of thin lymphatic vessels, which has important research value; After adding ferroferric oxide magnetic nanoparticles to Janus ciliary microspheres, the movement of embolic agents can be controlled under a magnetic field, thereby achieving precise targeted therapy.

[0018] Different applications, such as cancer cell killing, lymphatic vascular imaging, and precise targeted therapy, can be achieved by adding some functional units into the solid-liquid biphasic embolic agent, and the preparation method is simple and fast.

[0019] A method for preparing the solid-liquid biphasic embolic agent with a surface ciliary structure, the method comprising 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 formulated 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 at 200-4000rpm for 5-30 minutes, and then let it stand for 30 minutes.

[0020] 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.

[0021] Preferably, 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.

[0022] In addition, there are alternative solutions for preparing Janus ciliary microspheres, such as: adjusting the type, molecular weight, composition and concentration of block copolymers can also achieve similar effects; adjusting the type, molecular weight, composition and concentration of surfactants can also achieve similar effects; adjusting the type and composition of organic solvents can also achieve similar effects.

[0023] There are also alternative solutions for the hydrophilic treatment of Janus ciliary microspheres, such as: changing the hydrolysis conditions, changing the acid and alkali type, concentration, rotation speed and hydrolysis time during hydrolysis can also achieve similar effects.

[0024] There are also alternative solutions for preparing solid-liquid biphasic embolic agents, such as: changing the emulsification method, changing the disperser used in emulsification, ultrasonic cell disruptor, stirrer, membrane emulsifier and microfluidic chip can also achieve similar effects.

[0025] Preferably, 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.

[0026] Preferably, 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.

[0027] The beneficial effects of the present invention are: 1. The surface of the solid-liquid biphasic embolic agent of the present invention has a rich ciliary structure, which can enhance the interaction between the embolic material particles and between the embolic material particles and the blood vessel wall. It has excellent viscoelasticity and deformation ability, can reach thinner arterial vessels, and achieve efficient embolization of thick and thin arteries, thereby improving the efficiency of tumor embolization chemotherapy; in addition, the combination of the ciliary structure and the solid-liquid biphasic system can not only enhance the embolic effect, but also enhance the stability of the embolic agent, prolong the action time, and optimize its biocompatibility. It will have broad application prospects and can provide better efficacy and patient experience in clinical treatment.

[0028] 2. The present invention adopts the block copolymer emulsion self-assembly method to obtain amphiphilic Janus ciliary microspheres, uses the Janus ciliary microsphere dispersion as the aqueous phase, adds the oil phase liquid embolic material into the aqueous phase, uses a disperser to emulsify and then washes away the excess Janus ciliary microspheres to obtain a solid-liquid biphasic embolic agent with a surface ciliary structure. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 A schematic diagram of a solid-liquid biphasic embolic agent with a surface ciliary structure prepared in the present invention; Figure 2 This is a characteristic diagram of the Janus ciliary microspheres prepared in Example 1 of the present invention; in, Figure 2 A is the EDX element distribution map of Janus ciliary microspheres; Figure 2 B is the SEM image of Janus ciliary microspheres; Figure 2 C is the diameter distribution diagram of the prepared Janus ciliary microspheres; Figure 2 D is the coverage area of ​​cilia in the prepared Janus cilia microspheres; Figure 3 This is a characteristic diagram of the solid-liquid biphasic embolic agent with a surface ciliary structure prepared in Example 2 of the present invention; in, Figure 3 A is a camera image of a solid-liquid biphasic embolic agent with a surface ciliary structure; Figure 3 B is a fluorescence microscopy image of a solid-liquid biphasic embolic agent with a surface ciliary structure; Figure 3 C is the particle size distribution diagram of the prepared solid-liquid biphasic embolic agent with surface ciliary structure; Figure 3 D is a confocal scan of a solid-liquid biphasic embolic agent with a surface ciliary structure; Figure 4This is a graph showing the particle size control of the solid-liquid biphasic embolic agent with a surface ciliary structure prepared in Example 3 of the present invention; in, Figure 4 A is the curve diagram showing the effect of rotation speed on the particle size of solid-liquid biphasic embolic agent during emulsification; Figure 4 B is the curve diagram showing the effect of oil-water ratio on the particle size of solid-liquid biphasic embolic agent during preparation; Figure 4 C is a curve showing the effect of the concentration of the Janus ciliary microsphere dispersion on the particle size of the solid-liquid biphasic embolic agent during preparation; Figure 5 This is a characteristic diagram of viscoelasticity and deformation capacity obtained by characterizing the solid-liquid biphasic embolic agent with a surface ciliary structure in Example 4 of the present invention; in, Figure 5 A is the curve of the viscosity of the solid-liquid biphasic embolic agent changing with the shear rate; Figure 5 B is the curve of storage modulus of solid-liquid biphasic embolic agent changing with shear strain; Figure 5 C is the injection force curve of the solid-liquid biphasic embolic agent; Figure 5 D is a diagram showing the embolic effect of the solid-liquid biphasic embolic agent in the capillary; Figure 5 E is the encapsulation factor diagram of different embolic materials; Figure 5 F is the fluorescence microscopy image of solid-liquid biphasic embolic agents with different shapes; Figure 5 G is a graph showing the deformation ability of the solid-liquid biphasic embolic agent; Figure 6 This is a graph of embolic performance obtained by characterizing the solid-liquid biphasic embolic agent with a surface ciliary structure according to Example 5 of the present invention; in, Figure 6 A is the embolization mechanism diagram of the solid-liquid biphasic embolic agent; Figure 6 B is a diagram showing the solid-liquid biphasic embolic agent passing through an artificial blood vessel; Figure 6 C is the interaction diagram between the solid-liquid biphasic embolic agent and the vascular wall; Figure 6 D is a diagram showing the embolization effect of a solid-liquid biphasic embolic agent with a surface ciliary structure in capillaries of different thicknesses; Figure 7 This is a diagram showing the embolic performance of the solid-liquid biphasic embolic agent with a surface ciliary structure in a branched microfluidic channel in Example 6 of the present invention; Figure 8 This is a graph showing the embolic performance of the solid-liquid biphasic embolic agent with a surface ciliary structure in Example 7 of the present invention in the liver of SD rats.

[0030] in, Figure 8 A is an optical photograph of the liver of SD rat after transparent treatment; Figure 8 B is an optical photograph of the transparent SD rat liver after intravascular injection of a solid-liquid biphasic embolic agent with a surface morphology structure; Figure 8 C-8H Figure 8Confocal microscopy images of different vascular sites in B. DETAILED DESCRIPTION

[0031] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or according to the conditions recommended by the manufacturer.

[0032] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. The reagents or raw materials used in the present invention can be purchased through conventional channels. Unless otherwise specified, the reagents or raw materials used in the present invention are used in a conventional manner in the art or in accordance with the product instructions. In addition, any method and material similar to or equivalent to the described content can be applied to the method of the present invention. The present invention is further described according to the accompanying drawings and specific embodiments of the present invention, and the preferred implementation methods and materials described in the present invention are only for demonstration purposes.

[0033] Embodiment 1:

[0034] a) The triblock polymer and the homopolymer were mixed and dissolved in dichloromethane at a mass ratio of 1:7 to obtain a 5 w / v% polymer solution, and 5 μg of Beihong fluorescent dye was added thereto; b) Add 10 mL of polymer solution to 200 mL of 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 and let it stand at room temperature for 4 hours. c) After 4 hours, remove the tin foil, heat the emulsion to 40°C, and stir at 400 rpm for 2 hours to evaporate the solvent and allow the ciliary structure to grow; d) After the end, the dispersion was centrifuged at 6000 rpm and washed with water three times to obtain pink Janus ciliary microspheres, which were then freeze-dried and stored after centrifugation and washing.

[0035] The Janus cilia structure microspheres prepared by SEM and EDX characterization showed a morphological feature of half smooth and half cilia, and the cilia side was rich in O elements and hydrophilic, while the smooth side was lipophilic, and the microspheres had no obvious defects. The results are shown in the attached Figure 2 shown.

[0036] Among them, from Figure 2 A shows that the O element is mainly distributed on one side of the cilium, which makes it hydrophilic after hydrolysis, while the smooth side is mainly composed of the C element, which makes it lipophilic. Figure 2 In B, we can see that the Janus ciliary microsphere is half smooth and half ciliary structure; Figure 2In C, we can see that the particle size distribution of Janus ciliary microspheres is between 2 and 8 microns. Figure 2 D shows that the coverage area of ​​cilia is about 50%, showing a morphology of half smooth and half ciliated.

[0037] Embodiment 2:

[0038] a) 200 mg of the Janus ciliary microspheres prepared in Example 1 were placed in a 50 mL centrifuge tube, 30 mL of 2M hydrochloric acid was added, and the mixture was shaken evenly and then placed on a rotating rocker for hydrolysis for 4 hours. After the hydrolysis was completed, the microspheres were washed three times with deionized water and then used for later use; b) Add 40 mL of deionized water to the hydrolyzed Janus microspheres to prepare a microsphere dispersion with a concentration of 5 mg / mL, and then slowly add 500 μL of iodized oil liquid embolic material to the Janus microsphere dispersion; c) Insert the blade of the disperser into the oil-water interface and emulsify at 1000 rpm for 10 minutes, then let it stand for 30 minutes; d) Shake the solid-liquid biphasic embolic agent to disperse it, let it stand for 1 minute, carefully aspirate the supernatant, then add deionized water and shake it to disperse it, repeat the washing 3-5 times and remove the excess Janus ciliary microspheres to obtain a clean solid-liquid biphasic embolic agent; Fluorescence microscopy and confocal microscopy showed that the solid-liquid biphasic embolic agent particles with surface ciliary structure were uniform in size and had no obvious defects. Figure 3 shown.

[0039] Among them, from Figure 3 A shows that the solid-liquid biphasic embolic agent particles with surface ciliary structure are pink, the supernatant is clear and transparent, and there are no extra Janus ciliary microspheres mixed in it; Figure 3 From B, we can see that the solid-liquid biphasic embolic agent has uniform particle size and can emit red fluorescence. Figure 3 It can be seen from Figure C that the particle size distribution of the prepared solid-liquid biphasic embolic agent particles with surface ciliary structure is uniform, ranging from 60 to 240 microns; Figure 3 In D, we can see that Janus ciliary microspheres tightly wrap the liquid embolic material to form spherical biphasic embolic agent particles, with the ciliary structure facing outward, making its surface rich in cilia.

[0040] Embodiment 3:

[0041] a) adjusting 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 embolic agent with a surface ciliary structure; b) adjusting the oil-water ratio (volume ratio of iodized oil to Janus ciliary microsphere dispersion) in Example 2 to 1:30, 1:60, 1:90, 1:120, and 1:150, respectively, to prepare a solid-liquid biphasic embolic agent with a surface ciliary structure; c) adjusting the concentration of the Janus ciliary 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 embolic agent with a surface ciliary structure; The solid-liquid biphasic embolic agent particles with surface ciliary structure were characterized by fluorescence microscopy, and the particle size was calculated using ImageJ software. The results are shown in the attached figure. Figure 4 shown.

[0042] in, Figure 4 A is the effect of the rotation speed during emulsification on the particle size of the solid-liquid biphasic embolic agent. It can be seen that with the increase of the emulsification rotation speed, the particle size of the solid-liquid biphasic embolic agent gradually decreases; Figure 4 B is the effect of oil and water on the particle size of the solid-liquid biphasic embolic agent during preparation. It can be seen that as the oil-water ratio decreases, the particle size of the solid-liquid biphasic embolic agent decreases; Figure 4 C is the effect of the concentration of the Janus ciliary microsphere dispersion on the particle size of the solid-liquid biphasic embolic agent during preparation. It can also be found that with the increase of the concentration of the dispersion, the particle size of the prepared solid-liquid biphasic embolic agent also shows a downward trend.

[0043] Embodiment 4:

[0044] a) taking 500 μL of iodized oil and the solid-liquid biphasic embolic agent prepared in Example 2 respectively on a rheometer to measure the change of viscosity with shear rate and the change of storage modulus with shear strain; b) taking 1 ml of the solid-liquid biphasic embolic agent prepared in Example 2 into a 1 ml BD syringe, and measuring the injection force at a rate of 1 ml / min on a force measuring machine; c) taking 1 ml of the solid-liquid biphasic embolic agent prepared in Example 2 into a 1 ml BD syringe, slowly adding it into the glass capillary, observing the accumulation of the solid-liquid biphasic embolic agent in the capillary with a fluorescence microscope, and calculating the packing coefficient; d) Take a glass capillary tube with thick ends and thin middle, inject the solid-liquid biphasic embolic agent particles prepared in Example 2 from one end of the capillary tube using a microfluidic syringe pump, and observe the deformation ability under a microscope; The results are attached Figure 5 shown.

[0045] Among them, from Figure 5 It can be seen from A that as the shear rate increases, the viscosity of the solid-liquid biphasic embolic agent gradually decreases, showing a shear-thinning characteristic, while iodized oil does not have this characteristic; Figure 5 B shows that compared with iodized oil, the solid-liquid biphasic embolic agent has a higher storage modulus and exhibits excellent viscoelasticity; Figure 5 C shows that the injection force of the solid-liquid biphasic embolic agent with a surface ciliary structure is below 10N, indicating that this solid-liquid biphasic embolic agent can be stable during injection and is relatively easy to be injected into animals for embolic chemotherapy. Figure 5 D shows that each embolic particle of the solid-liquid biphasic embolic agent in the glass capillary is tightly squeezed together and partially deformed. Figure 5 From the encapsulation coefficient diagram E, it can be seen that the solid-liquid biphasic embolic agent encapsulated by Janus ciliary microspheres has a higher encapsulation coefficient, indicating that it can be stacked more densely and has better embolic ability; Figure 5 F is a fluorescence microscope image of solid-liquid biphasic embolic agent particles of different shapes in a glass capillary. It can be seen that these solid-liquid biphasic embolic agents can present a variety of shapes, mainly spherical, cylindrical, ellipsoidal, dumbbell-shaped and snowman-shaped. Figure 5 G It can be seen that this solid-liquid biphasic embolic agent can deform and pass through thinner capillaries, and then gradually restore its original spherical shape.

[0046] Embodiment 5:

[0047] a) Preparation of a single-channel microfluidic chip using 3D printing and PDMS template replication; b) HUVEC cells are grown in the prepared microfluidic chip to mimic artificial blood vessels; c) using a syringe to flow the solid-liquid biphasic embolic agent prepared in Example 2 through the artificial blood vessel, and observing the embolic agent remaining in the artificial blood vessel with a fluorescence microscope; d) using a syringe to flow the solid-liquid biphasic embolic agent prepared in Example 2 through the artificial blood vessel, and using a dynamometer to measure the interaction force of the embolic agent flowing through the artificial blood vessel; e) The solid-liquid biphasic embolic agent prepared in Example 2 was injected into glass capillaries of different thicknesses using a syringe, and the embolic effects of the solid-liquid biphasic embolic agent particles in capillaries of different thicknesses were observed using a fluorescence microscope.

[0048] The results are attached Figure 6 shown.

[0049] Among them, from Figure 6 It can be seen from A that the cilia on the surface of the solid-liquid biphasic embolic agent with a surface ciliary structure can entangle with each other and topologically match, thereby increasing the interaction between the embolic agent particles and between the embolic agent particles and the vascular wall, while the solid-liquid biphasic embolic agent with a smooth surface exhibits weak interaction. Figure 6As can be seen in B, the solid-liquid biphasic embolic agent with a surface ciliary structure will remain more on the HUVEC cells after passing through the artificial blood vessel, while the solid-liquid biphasic embolic agent with a smooth surface will remain less; Figure 6 It can be seen from the interaction force diagram between C biphasic embolic agent and vascular wall that compared with pure iodized oil and solid-liquid biphasic embolic agent with smooth surface, this solid-liquid biphasic embolic agent with surface ciliary structure has greater interaction force, and the solid-liquid biphasic embolic agent particles can produce stronger interaction with the vascular wall; Figure 6 D It can be seen that this solid-liquid biphasic embolic agent can achieve good embolization in capillaries of 1000μm, 500μm, 300μm and 100μm.

[0050] Embodiment 6:

[0051] a) Preparation of microfluidic channel core with cross-structure using 3D printing and PDMS template replication method; 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; c) Observe the embolization of the solid-liquid biphasic embolic agent using a camera and a fluorescence microscope; The results are attached Figure 7 shown.

[0052] 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.

[0053] Embodiment 7:

[0054] 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; 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; c) Confocal microscopy was used to observe the embolization of solid-liquid biphasic embolic agent particles in the liver of SD rats; The results are attached Figure 8 shown.

[0055] 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 8As 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.

[0056] Any matters 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 Janus ciliary microspheres with a hydrophilic ciliary structure; the Janus ciliary microspheres encapsulate the oil phase liquid embolic material, and during encapsulation, the hydrophilic ciliary structure in the Janus ciliary microspheres is exposed outwardly to the water phase, so that the surface of the solid-liquid dual-phase embolic agent has a ciliary structure.

2. The solid-liquid biphasic embolic agent with a surface ciliary structure according to claim 1, characterized in that: 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.

3. The solid-liquid biphasic embolic agent with a surface ciliary structure according to claim 1, characterized in that: The diameter of the cilia in the cilia structure is 30-500 nanometers, and the length is greater than 500 nanometers.

4. 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.

5. 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.

6. 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.

7. A method for preparing a solid-liquid biphasic embolic agent having a surface ciliary structure applicable to any one of claims 1 to 6, 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.

8. The method for preparing a solid-liquid biphasic embolic agent with a surface ciliary structure according to claim 7, 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.

9. The method for preparing a solid-liquid biphasic embolic agent with a surface ciliary structure according to claim 8, 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.

10. The method for preparing a solid-liquid biphasic embolic agent having a surface ciliary structure according to claim 9, 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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