Multi-component microcapsule with multiple ultrasonic responses as well as preparation method and application of multi-component microcapsule

Abstract

The invention belongs to the field of biological materials, and particularly discloses a multi-component microcapsule with multiple ultrasonic responses as well as a preparation method and application of the multi-component microcapsule with the multiple ultrasonic responses, and a hydrogel microcapsule with structural and functional design is prepared through a microfluidic double-emulsion technology on the basis of light-cured methacrylic anhydride gelatin hydrogel and liquid decafluoropentane. According to the prepared multi-ultrasonic-responsive multi-component microcapsule, ultrasonic-responsive oxygen release and controllable generation of reactive oxygen free radicals are realized on the basis of curcumin loaded in methacrylic anhydride gelatin and oxygen dissolved in decafluoropentane; the released oxygen provides an oxygen raw material for sonodynamic therapy while relieving a hypoxic environment in an articular cavity, so that generation of reactive oxygen free radicals is enhanced, apoptosis of pathological synovial fibroblasts is induced, and synovial proliferation in the pathological articular cavity is inhibited.

Description

Technical Field

[0001] The present invention belongs to the field of biomaterials, and in particular relates to a multi-component microcapsule with multiple ultrasonic responses, and a preparation method and application thereof. Background Art

[0002] Rheumatoid arthritis is a chronic autoimmune disease with a high morbidity rate. Early pathological changes in rheumatoid arthritis primarily include excessive proliferation of synovial fibroblasts, invasion of synovial pannus, and accumulation of inflammatory cells. Clinically, drug therapy is the mainstay of managing early symptoms of rheumatoid arthritis, including disease-modifying antirheumatic drugs, nonsteroidal anti-inflammatory drugs, and glucocorticoids. In addition, several traditional Chinese medicines, such as curcumin, have been shown to have therapeutic efficacy. To maintain optimal drug concentrations and achieve long-term therapeutic effects, these drugs should be administered systemically at high doses. While symptom relief is achieved, systemic side effects are unavoidable, and severe complications can even lead to death. Currently, microcarrier-based drug delivery systems have attracted significant attention due to their potential to enhance drug efficacy. By encapsulating drugs within microcarriers, sustained release can be achieved through carrier degradation, enabling long-term treatment. However, controlling the release of active compounds to achieve optimal drug concentrations remains challenging. Furthermore, numerous drug-drug interactions can significantly enhance therapeutic efficacy, while the simplistic structure and composition of existing drug carriers limit their potential therapeutic efficacy. Summary of the Invention

[0003] Purpose of the invention: The technical problem to be solved by the present invention is to address the deficiencies of the existing technology and provide a novel multi-component microcapsule with multiple ultrasound responses and a preparation method thereof to enhance the therapeutic effect of curcumin on rheumatoid arthritis.

[0004] In order to achieve the above object, the technical solution adopted by the present invention is as follows: A method for preparing multi-component microcapsules with multiple ultrasonic responses comprises the following steps: S1. Coaxially assemble three glass tubes with different inner diameters as the fluid input channel. The glass tube with the largest inner diameter serves as the external phase channel, the glass tube with a medium inner diameter serves as the intermediate phase channel, and the glass tube with the smallest inner diameter serves as the internal phase channel. S2, adding methacrylic anhydride gelatin, 2-hydroxy-2-methyl-1-phenyl-1-propanone and curcumin to deionized water to prepare a mixed pre-gel solution; introducing oxygen into liquid decafluoropentane to obtain an oxygen-enriched fluorocarbon liquid after treatment; S3. Silicone oil is introduced into the external phase channel, and the mixed pre-gel solution and oxygen-rich fluorocarbon liquid obtained by S2 are introduced into the intermediate phase channel and the internal phase channel respectively. The three-phase liquids are injected simultaneously by three microfluidic pumps and flow through the three channels. After microfluidic emulsification, core-shell structured microdroplets are obtained. The liquid is quickly irradiated with ultraviolet light and washed to remove the silicone oil.

[0005] Preferably, in step S1, the inner diameter of the glass tube used in the outer phase channel is 550-600 microns, preferably 580 microns; the inner diameter of the glass tube used in the middle phase channel is 75-100 microns; and the inner diameter of the glass tube used in the inner phase channel is 50-75 microns.

[0006] Preferably, in step S2, the concentration of methacrylic anhydride gelatin in the mixed pre-gel solution is 6-8 wt %, preferably 7 wt %; the concentration of 2-hydroxy-2-methyl-1-phenyl-1-propanone is 0.05-0.1 vol %, preferably 0.1 vol %; and the concentration of curcumin is 0.05-0.1 M, preferably 0.05 M.

[0007] Preferably, in step S2, the dissolved oxygen content in the oxygen-enriched fluorocarbon liquid is 40-50 mg / L.

[0008] Preferably, in step S3, the flow rate of the silicone oil in the external phase channel is 300-600 μL / min; the flow rate of the mixed pregel solution in the intermediate phase channel is 40-100 μL / min; and the flow rate of the oxygen-rich fluorocarbon liquid in the inner phase channel is 5-35 μL / min.

[0009] Preferably, in step S3, the collection liquid is the same as the silicone oil introduced into the external phase channel, and is solidified by ultraviolet light irradiation for at least 2 minutes.

[0010] Furthermore, the present invention also claims protection for the multi-component microcapsules with multiple ultrasonic responses prepared by the above preparation method.

[0011] The present invention utilizes multi-component, ultrasound-responsive microcapsules to enhance the therapeutic efficacy of curcumin for rheumatoid arthritis. Ultrasound waves can efficiently transmit energy over long distances through complex media, making them an ideal tool for internal stimulation. Incorporating ultrasound-responsive components has led to numerous therapeutic strategies, such as sonodynamic therapy. Notably, curcumin is a sonosensitizer that can be used in sonodynamic therapy. Under specific ultrasound stimulation, it catalyzes oxygen in the surrounding environment to generate large quantities of reactive oxygen species (ROS) free radicals. Research conducted by the present invention has demonstrated that this ROS burst can cause irreversible oxidative damage to abnormal cells and lead to apoptosis, demonstrating its effectiveness in eliminating the overproliferation of fibroblast-like synoviocytes in rheumatoid arthritis-affected joints. Furthermore, given the high oxygen consumption during sonodynamic therapy and the hypoxic microenvironment within the rheumatoid arthritis joint cavity, additional oxygen supply is crucial for enhancing the therapeutic effect of sonodynamic therapy. Furthermore, microfluidic technology offers unique advantages in fabricating microcarriers with complex structures, enabling the loading of different active substances into distinct regions of the carrier. Therefore, the present invention utilizes microfluidic technology to construct multi-component, ultrasound-responsive microcapsules with specific structures, which are expected to enhance the efficacy of sonodynamic therapy for rheumatoid arthritis.

[0012] Further preferably, the core-shell diameter ratio of the multiple ultrasound-responsive multi-component microcapsules prepared by the present invention is 0.3-0.9.

[0013] Furthermore, the present invention also claims to protect the use of the above-mentioned multi-component microcapsules with multiple ultrasonic responses in the preparation of drugs for treating rheumatoid arthritis.

[0014] Furthermore, the multi-component microcapsules with multiple ultrasonic responses are ruptured by ultrasonic stimulation to release active substances.

[0015] Compared with the prior art, the present invention has the following beneficial effects: (1) The multi-component microcapsules with multiple ultrasound responses prepared by the present invention are used in the preparation and enhancement of sonodynamic therapy for rheumatoid arthritis. Specifically, by combining microfluidic double emulsion technology, the hydrogel microcapsules with a core-shell structure are prepared, which can release oxygen and generate reactive oxygen free radicals under the irradiation of ultrasound of a specific frequency, thereby alleviating the hypoxic environment in the joint cavity and inducing apoptosis of diseased synovial fibroblasts, providing a new strategy for the treatment of rheumatoid arthritis.

[0016] (2) The present invention is based on photocurable methacrylic anhydride gelatin hydrogel and liquid decafluoropentane, and uses microfluidic double emulsion technology to prepare hydrogel microcapsules with structural and functional designs. The mixed pregel solution is prepared from 7% methacrylic anhydride gelatin, 0.1% 2-hydroxy-2-methyl-1-phenyl-1-propanone and 0.05 M curcumin; the oxygen-enriched fluorocarbon liquid is obtained by oxygen treatment. The hydrogel materials methacrylic anhydride gelatin, curcumin and decafluoropentane used have good biosafety and stability. Using microfluidic double emulsion technology, core-shell structured microcapsules with controllable structure and size can be obtained.

[0017] (3) The multi-component ultrasound-responsive microcapsules prepared by the present invention achieve ultrasound-responsive oxygen release and controllable generation of reactive oxygen free radicals based on the curcumin loaded in the methacrylic anhydride gelatin and the oxygen dissolved in decafluoropentane. The released oxygen not only alleviates the hypoxic environment in the joint cavity but also provides oxygen raw materials for sonodynamic therapy, thereby enhancing the generation of reactive oxygen free radicals, which meets the conditions for correcting the pathological changes in the joint cavity affected by rheumatoid arthritis. The results showed that the oxygen-rich fluorocarbon liquid in the core of the microcapsule undergoes a liquid-gas phase transition under the action of ultrasound, and releases a large amount of oxygen after breaking through the hydrogel shell. In addition, the curcumin encapsulated in the methacrylic anhydride gelatin exerts an anti-inflammatory effect after release. Under additional ultrasound stimulation, it can generate reactive oxygen free radicals and induce apoptosis of diseased synovial fibroblasts, thereby inhibiting the proliferation of the synovial membrane in the diseased joint cavity.

[0018] (4) The multi-component microcapsules with multiple ultrasound responses prepared by the present invention were further verified to be able to effectively induce apoptosis of diseased synovial fibroblasts under external ultrasound stimulation in the treatment of collagen-induced rheumatoid arthritis rats. The subsequent sustained release of curcumin continued to exert anti-inflammatory and antioxidant effects, promoting the treatment of rheumatoid arthritis. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments, and the above and / or other advantages of the present invention will become more apparent.

[0020] Figure 1 A capillary glass microfluidic chip prepared for the present invention (a) and a detailed view of its outlet (b).

[0021] Figure 2 High-speed camera image (a) of the process of preparing core-shell structure droplets by double emulsion of the microfluidic chip prepared for the application of the present invention, light microscopy image (b) and electron scanning microscope image (c) of the prepared multi-component microcapsules.

[0022] Figure 3Figure 3. Multi-component microcapsules with multiple ultrasonic responses and different core-shell ratios prepared in the present invention (a) and the relationship between the microcapsule particle size and core diameter and the middle phase flow rate (b), outer phase flow rate (c) and inner phase flow rate (d).

[0023] Figure 4 Light microscopy images of the multi-component microcapsules with multiple ultrasonic responses prepared in the present invention before ultrasonic stimulation (a), after ultrasonic stimulation for 30 seconds (b), after ultrasonic stimulation for 60 seconds (c), and after ultrasonic stimulation for 90 seconds (d), as well as statistics on ultrasonic stimulation rupture rate (e), oxygen release (f), and curcumin release (g) of microcapsules with four different core-shell ratios.

[0024] Figure 5 This is a graph showing the degradation efficiency of methylene blue by the multi-component microcapsules with multiple ultrasonic responses used in the present invention at different ultrasonic stimulation times.

[0025] Figure 6 Biocompatibility (a, b) and optimal curcumin dosage (cf) of the multi-component microcapsules with multiple ultrasound responses prepared by the present invention.

[0026] Figure 7 The fluorescence staining image (a) and quantitative statistical results (b) of the multi-component microcapsules with multiple ultrasound responses prepared by the present invention that enhance the activity of reactive oxygen free radicals in synovial fibroblast-like cells under ultrasound stimulation.

[0027] Figure 8 Fluorescence staining image (a) and quantitative statistical results (b) of the multi-component microcapsules with multiple ultrasound responses prepared by the present invention to alleviate the hypoxic environment in synovial fibroblast-like cells under ultrasound stimulation; Figure 9 Live-dead staining fluorescence image (a) and quantitative statistical results (b) of the multi-component microcapsules with multiple ultrasound responses prepared by the present invention that induce apoptosis of synovial fibroblasts under ultrasound stimulation.

[0028] Figure 10 The multi-component microcapsules with multiple ultrasound responses prepared by the present invention induce macrophages to change from M1 type (a) to M2 type (b) under ultrasound stimulation.

[0029] Figure 11 Fluorescence staining images (ae) and quantitative statistical results (f) of the multi-component microcapsules with multiple ultrasound responses prepared by the present invention inhibiting the tube formation of human umbilical vein endothelial cells under ultrasound stimulation.

[0030] Figure 12Thermal imaging images (a), temperature change statistics (b), swelling degree statistics (c) and clinical index statistics (d) of rat rheumatoid arthritis diseased joints after the multi-component microcapsules with multiple ultrasound responses prepared by the present invention were combined with ultrasound-mediated sonodynamic therapy.

[0031] Figure 13 Microcomputed tomography images (a), bone volume statistics (b), tissue volume statistics (c), bone surface area statistics (d), trabecular number statistics (e), trabecular thickness statistics (f) and trabecular separation statistics (g) of rat rheumatoid arthritis diseased joints after the multi-component microcapsules prepared by the present invention were applied in combination with ultrasound-mediated sonodynamic therapy.

[0032] Figure 14 Hematoxylin-eosin staining results, safranin fast green staining results (a), CD31, HIF-1α, TNF-α, IL-6 fluorescence staining results (b) and related quantitative statistical results (ce) after the multi-component microcapsules with multiple ultrasound responses prepared by the present invention were combined with ultrasound-mediated sonodynamic therapy on rat rheumatoid arthritis diseased joints.

[0033] Figure 15 This is a diagram showing the hematoxylin-eosin staining results of the main organs of rats treated with the multi-component microcapsules with multiple ultrasound responses prepared by the present invention combined with ultrasound-mediated sonodynamic therapy. DETAILED DESCRIPTION

[0034] The present invention can be better understood with reference to the following examples.

[0035] Example 1: Preparation of microfluidic chip: Prepare three capillary glass tubes with an inner diameter of 580 microns. Use epoxy resin glue to fix one capillary glass tube (capillary glass tube 1) on a glass slide; place the other two capillary glass tubes on an alcohol lamp to heat and stretch them to both sides, cut them with a glass cutter, and then use sandpaper to polish the cut ends under a microscope, and polish the inner diameters of the ports to 75-100 microns (capillary glass tube 2) and 50-75 microns (capillary glass tube 3). Place capillary glass tube 2 coaxially in capillary glass tube 1 and fix it on a glass slide with epoxy resin glue; then place capillary glass tube 3 coaxially in capillary glass tube 2 and fix it on a glass slide with epoxy resin glue. The entrances of the three capillaries are all fixed with flat needles, and finally a microfluidic chip is prepared, as shown in FIG. Figure 1 shown.

[0036] Example 2: Preparation of multi-component microcapsules with multiple ultrasonic responses: (1) Using deionized water as solvent, 7 wt% methacrylic anhydride gelatin, 0.1 vol% 2-hydroxy-2-methyl-1-phenyl-1-propanone and 0.05 M curcumin were prepared into a mixed pre-gel solution, which was then placed in a syringe and stored in the dark. Oxygen was introduced into the liquid decafluoropentane, and the dissolved oxygen content in the liquid decafluoropentane was detected using a dissolved oxygen meter. When the dissolved oxygen content reached 40-50 mg / L, the oxygen was stopped and the solution was immediately placed in a syringe and stored in the dark and at low temperature. Silicone oil at room temperature was placed in a syringe.

[0037] (2) Connect the syringe filled with silicone oil to the flat needle connected to the external phase channel through a hose; connect the syringe filled with the mixed and gel solution to the flat needle connected to the intermediate phase channel through a hose; connect the syringe filled with the oxygen-rich fluorocarbon liquid to the flat needle connected to the internal phase channel through a hose. The three syringes are placed on three microfluidic pumps respectively, and the flow rate of the external phase microchannel is adjusted to 300-600 μL / min, the flow rate of the intermediate phase microchannel is adjusted to 40-100 μL / min, and the flow rate of the internal phase microchannel is adjusted to 5-35 μL / min. The obtained microcapsules have uniform size, high monodispersity, and a clear core-shell structure, such as Figure 2 By collecting microcapsules at different flow rates and counting their particle size and core diameter, we obtained microcapsules with different core-shell ratios, which showed that the microfluidic technology has strong controllability in preparing drug-loaded microcapsules and can be used to prepare microcarriers with different functions and drug loading amounts, such as Figure 3 shown.

[0038] Example 3: Ultrasonic responsiveness and biosafety testing of multi-component microcapsules with multiple ultrasonic responses: (1) The four core-shell ratio multi-component ultrasound-responsive microcapsules prepared in Example 2 were subjected to ultrasound treatment at an ultrasound power of 1.2 W / cm 2 , center frequency 1.0 MHz, duty cycle 80%. A stereo microscope was used to record the morphological changes of the microcapsules under different ultrasound stimulation times, and the rupture rate, oxygen release, and curcumin release of the microcapsules were statistically analyzed. The results showed that the microcapsules with a core-shell ratio of 0.7 had sensitive ultrasound-triggered oxygen release ability, and their drug loading and drug release capacity were more efficient than those of microcapsules with other core-shell ratios. Therefore, microcapsules with a core-shell ratio of 0.7 were used for subsequent in vitro and in vivo experiments. The results are as follows Figure 4As shown. Methylene blue was used to detect the efficiency of multiple ultrasound-responsive multi-component microcapsules in generating reactive oxygen free radicals under ultrasound. First, it was confirmed that curcumin could generate reactive oxygen free radicals and degrade methylene blue under ultrasound triggering with specific parameters. Secondly, we found that under the condition of additional oxygen supply, curcumin could generate more reactive oxygen free radicals under ultrasound triggering. The same experimental results were obtained in the experimental group of multi-component microcapsules encapsulating curcumin and oxygen, verifying that oxygen-carrying ultrasound-responsive microcapsules can significantly improve the efficiency of curcumin in generating reactive oxygen free radicals under ultrasound triggering. The results are shown as follows. Figure 5 shown.

[0039] (2) The microcapsules were co-cultured with normal synovial fibroblasts and diseased synovial fibroblasts to verify their biosafety. Live-dead fluorescence staining and quantitative statistics showed that the microcapsule materials and ultrasound used in the present invention had no significant effect on cell activity. By loading different doses of curcumin into the microcapsules and applying additional ultrasound stimulation, we found that 40-50 μM curcumin had a significant inhibitory effect on the activity of diseased synovial fibroblasts, and under the additional triggering of ultrasound, 30-50 μM curcumin had a significant inhibitory effect on the activity of diseased synovial fibroblasts, while 50 μM curcumin had a significant inhibitory effect on the activity of normal synovial fibroblasts. Therefore, the present invention selected 40 μM curcumin for subsequent experiments, and the results are as follows. Figure 6 shown.

[0040] Example 4: Effects of multi-component microcapsules with multiple ultrasound responses on cells: 1) The microcapsules with the best ultrasound responsiveness screened out in Example 3 were co-cultured with diseased synovial fibroblasts and subjected to ultrasonic stimulation. The content of reactive oxygen free radicals in the cells was detected (green fluorescence) and quantified. The results showed that under ultrasound triggering, the content of reactive oxygen free radicals in the cells increased significantly, especially in the group with additional oxygen supply. This confirmed that the multi-component microcapsules with multiple ultrasound responses of the present invention can significantly increase the content of reactive oxygen free radicals in diseased synovial fibroblasts under ultrasound triggering. Figure 7 As shown; the multi-component microcapsules with multiple ultrasound responses were co-cultured with diseased synovial fibroblasts and ultrasonic stimulation was applied to detect the hypoxia in the cells (red fluorescence) and quantify the results. The results showed that under ultrasound triggering, the multi-component microcapsules of the present invention can release oxygen and significantly alleviate the hypoxic microenvironment in the cells. The results are shown in FIG. Figure 8As shown; the multi-component microcapsules with multiple ultrasound responses were co-cultured with diseased synovial fibroblasts and ultrasonic stimulation was applied to detect the changes in cell viability (live cells were green fluorescence, dead cells were red fluorescence), and quantitative statistics were performed. The results showed that under ultrasound triggering, the multi-component microcapsules of the present invention can induce apoptosis of diseased synovial fibroblasts by causing the outbreak of reactive oxygen free radicals in the cells. The results are shown in FIG. Figure 9 shown.

[0041] 2) The multi-component microcapsules with multiple ultrasound responses were co-cultured with lipopolysaccharide-induced inflammatory macrophages and ultrasonic stimulation was applied to detect the polarization of macrophages. The results showed that the multi-component microcapsules with multiple ultrasound responses of the present invention can effectively induce the polarization change of macrophages from M1 to M2. At the same time, the burst of reactive oxygen free radicals produced by them can cause apoptosis of inflammatory macrophages. The results are as follows Figure 10 As shown; the multi-component microcapsules with multiple ultrasound responses were co-cultured with human umbilical vein endothelial cells, the number and tube formation of human umbilical vein endothelial cells were detected, and quantitative statistics were performed. The results showed that the multi-component microcapsules with multiple ultrasound responses of the present invention can effectively inhibit the proliferation and tube formation of human umbilical vein endothelial cells. The results are shown in FIG. Figure 11 shown.

[0042] Example 5: Application of multi-component microcapsules with multiple ultrasound responses in rheumatoid arthritis: Sprague-Dawley rats weighing approximately 200 grams were anesthetized and an emulsion containing porcine type II collagen was injected into the base of the rat's tail. Arthritis symptoms developed 3 to 4 weeks after injection, and when the clinical score reached 4, the rats were divided into groups and further tested. The multi-component microcapsules prepared by the present invention were injected into the toe joint spaces and ankle joint cavities of the rats every three days, with a power of 1.2 W / cm for 2 minutes each day. 2 Ultrasound treatment with a center frequency of 1.0 MHz and a duty cycle of 80% was performed. The treatment was terminated after 21 days. During the treatment, a near-infrared thermal imager was used to photograph and record the diseased toes. Changes in joint temperature, toe swelling, and clinical index were also recorded. The results showed that simple ultrasound stimulation had no significant effect on the condition. Curcumin could effectively alleviate the inflammatory response, while the multi-component microcapsules of the present invention with multiple ultrasound responses could more effectively inhibit the inflammatory response and alleviate joint swelling. The results are shown in Figure 2. Figure 12As shown in the figure; after the treatment, the rat hind leg tissue was taken for micro-computed tomography and the bone volume, tissue volume, bone surface area, trabecular number, trabecular thickness and trabecular separation were counted. The results showed that compared with the other groups, the joints of the multi-component microcapsule combined with ultrasound treatment group had larger bone volume, smaller tissue volume, less bone surface area, more trabecular number and trabecular thickness, and lower trabecular separation, indicating that bone damage was alleviated. The results are shown in the figure. Figure 13 As shown; the ankle joint tissue of the rats was stained with hematoxylin-eosin and safranin fast green to observe the damage of the cartilage and bone tissue; the synovial tissue of the rats was stained with CD31, HIF-1α, TNF-α, and IL-6 fluorescence and quantified. The results showed that compared with the other groups, the joint cavity of the multi-component microcapsule combined with ultrasound treatment group had more complete cartilage tissue and bone tissue, less blood vessels in the synovium, alleviated the hypoxic environment, and significantly reduced the expression of inflammatory factors, indicating that joint verification and osteochondritis damage were effectively controlled and alleviated. The results are shown in Figure 14 As shown; At the same time, the main organs of the rats, kidneys, lungs, hearts, livers, and spleens were stained with hematoxylin-eosin. The results showed that there was no significant difference between the groups, indicating that the multi-component microcapsules with multiple ultrasound responses combined with ultrasound treatment of the invention have good biosafety. The results are shown Figure 15 shown.

[0043] The present invention provides a multi-component microcapsule with multiple ultrasonic responses, as well as a method for preparing and applying the microcapsules. Numerous methods and approaches exist for implementing this technical solution. The foregoing description is merely a preferred embodiment of the present invention. It should be noted that those skilled in the art may make various improvements and modifications without departing from the principles of the present invention, and such improvements and modifications are considered within the scope of the present invention. Any components not specified in this embodiment may be implemented using existing technologies.

Claims

1. A method for preparing multi-component microcapsules with multiple ultrasonic responses, characterized in that: The steps include: S1. Coaxially assemble three glass tubes with different inner diameters as the fluid input channel. The glass tube with the largest inner diameter serves as the external phase channel, the glass tube with a medium inner diameter serves as the intermediate phase channel, and the glass tube with the smallest inner diameter serves as the internal phase channel. S2, adding methacrylic anhydride gelatin, 2-hydroxy-2-methyl-1-phenyl-1-propanone and curcumin to deionized water to prepare a mixed pre-gel solution; introducing oxygen into liquid decafluoropentane to obtain an oxygen-enriched fluorocarbon liquid after treatment; S3. Silicone oil is introduced into the external phase channel, and the mixed pre-gel solution and oxygen-rich fluorocarbon liquid obtained by S2 are introduced into the intermediate phase channel and the internal phase channel respectively. The three-phase liquids are injected simultaneously by three microfluidic pumps and flow through the three channels. After microfluidic emulsification, core-shell structured microdroplets are obtained. The liquid is quickly irradiated with ultraviolet light and washed to remove the silicone oil.

2. The method for preparing multi-component microcapsules with multiple ultrasonic responses according to claim 1, characterized in that: In step S1, the inner diameter of the glass tube used in the outer phase channel is 550-600 microns; the inner diameter of the glass tube used in the middle phase channel is 75-100 microns; and the inner diameter of the glass tube used in the inner phase channel is 50-75 microns.

3. The method for preparing multi-component microcapsules with multiple ultrasonic responses according to claim 1, characterized in that: In step S2, the concentration of methacrylic anhydride gelatin in the mixed pre-gel solution is 6-8 wt %, the concentration of 2-hydroxy-2-methyl-1-phenyl-1-propanone is 0.05-0.1 vol %, and the concentration of curcumin is 0.05-0.1 M.

4. The method for preparing multi-component microcapsules with multiple ultrasonic responses according to claim 1, characterized in that: In step S2, the dissolved oxygen content in the oxygen-enriched fluorocarbon liquid is 40-50 mg / L.

5. The method for preparing multi-component microcapsules with multiple ultrasonic responses according to claim 1, characterized in that: In step S3, the flow rate of the silicone oil in the external phase channel is 300-600 μL / min; the flow rate of the mixed pregel solution in the intermediate phase channel is 40-100 μL / min; and the flow rate of the oxygen-rich fluorocarbon liquid in the inner phase channel is 5-35 μL / min.

6. The method for preparing multi-component microcapsules with multiple ultrasonic responses according to claim 1, characterized in that: In step S3, the collected liquid is the same as the silicone oil introduced into the external phase channel and is solidified by ultraviolet light irradiation for at least 2 minutes.

7. Multi-component microcapsules with multiple ultrasonic responses prepared by the preparation method according to any one of claims 1 to 6.

8. The multi-component microcapsule with multiple ultrasonic responses according to claim 7, characterized in that: The core-shell diameter ratio is 0.3~0.

9.

9. Use of the multi-component microcapsule with multiple ultrasound responses according to claim 7 or 8 in the preparation of a drug for treating rheumatoid arthritis.

10. The use according to claim 9, characterized in that The multi-component microcapsules with multiple ultrasonic responses are ruptured by ultrasonic stimulation to release active substances.

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