Medical hydrogel containing ultrasonically-developable bubble microspheres and preparation method therefor

Abstract

The present invention relates to the technical field of pharmaceutical formulations. Particularly provided are a medical hydrogel containing ultrasonically-developable bubble microspheres and a preparation method therefor. Said medical hydrogel is formed by in-situ crosslinking of a polyethylene glycol precursor solution and a multi-amino crosslinking agent solution containing bubble microspheres, the polyethylene glycol precursor solution consisting of a multi-arm polyethylene glycol derivative and a buffer A solution. While not affecting the gelling performance of the hydrogel, the provided medical hydrogel can be clearly ultrasonically developed, so as to enable real-time observation of the hydrogel in human bodies; in addition, the medical hydrogel is completely degradable without residues.

Description

Medical hydrogel containing ultrasonic imaging bubble microspheres and preparation method thereof

[0001] This application claims priority to the Chinese patent application filed with the State Intellectual Property Office on November 3, 2023, with application number CN202310973760.X and invention name “A medical hydrogel containing ultrasonic imaging bubble microspheres and its preparation method”, the entire contents of which are incorporated by reference into this application. Technical Field

[0002] The present application relates to the technical field of pharmaceutical preparations, and in particular to a medical hydrogel containing ultrasound-developable bubble microspheres and a preparation method thereof. Background Art

[0003] Hydrogel is a soft material containing a large amount of water obtained by cross-linking hydrophilic polymers. It has excellent physical and chemical properties and biological characteristics, including strong conformability, degradability, and good biocompatibility. Therefore, hydrogel products have attracted much attention in the field of biomedicine, including the application of implantable interventions such as drug delivery, isolation protection, and vascular embolization.

[0004] However, after hydrogels are implanted in the body, they cannot be visualized by conventional ultrasound imaging, which makes it difficult for researchers to conveniently and effectively observe the location, shape, and degradation of the implanted hydrogels in the body. Although there are many research and developments on the imaging properties of hydrogels, there are currently very few effective methods. The main method is to achieve ultrasound imaging by introducing materials with a density different from that of water, such as introducing water-insoluble imaging particles into the hydrogel. Chinese patent application (publication number CN116077744A) discloses an absorbable self-imaging hydrogel and its preparation method and application. The imaging function of the hydrogel is derived from inorganic nanoparticles generated by the in situ combination of anions and salt ions in the buffer component. However, this method has some problems, such as poor imaging effect, a period of time for imaging after implantation, and changes in hydrogel properties. Pre-introducing imaging particles into the hydrogel can give the hydrogel a better imaging effect, but the imaging particles are generally dense and settle quickly, resulting in unstable use. Moreover, the most controversial issue is that the water-insoluble imaging particles will remain in the human body for a long time after the hydrogel degrades and may migrate, which may cause foreign body reactions and thrombosis.

[0005] Summary of the Invention

[0006] In order to solve the above problems, the present application provides a medical hydrogel containing ultrasound-developable bubble microspheres and a preparation method thereof. Without affecting the gelling properties of the hydrogel, the provided medical hydrogel can be clearly developed under ultrasound, realizing real-time observation of the hydrogel in the human body, and can be completely degraded without residue.

[0007] On the one hand, the present application provides a medical hydrogel containing ultrasound-developable bubble microspheres, which is formed by in situ cross-linking of a polyethylene glycol precursor solution and a polyamino cross-linker solution containing bubble microspheres, wherein the polyethylene glycol precursor solution is composed of a multi-arm polyethylene glycol derivative and a buffer A solution.

[0008] As a preferred technical solution, the multi-arm polyethylene glycol derivative is selected from at least one of a three-arm polyethylene glycol derivative, a four-arm polyethylene glycol derivative, a six-arm polyethylene glycol derivative, and an eight-arm polyethylene glycol derivative.

[0009] Preferably, the multi-arm polyethylene glycol derivative is an aldehyde-terminated multi-arm polyethylene glycol derivative, and the aldehyde group of the aldehyde-terminated multi-arm polyethylene glycol derivative is connected to the multi-arm polyethylene glycol through an ether bond, an amide bond, a urethane bond, an imine bond or a urea bond.

[0010] Preferably, the number average molecular weight of the multi-arm polyethylene glycol derivative is 10 to 20 kDa.

[0011] Preferably, the multi-arm polyethylene glycol derivative is a four-arm polyethylene glycol terminated with benzaldehyde groups connected by amide bonds, and has a number average molecular weight of 10 kDa.

[0012] As a preferred technical solution, the mass fraction of the multi-arm polyethylene glycol derivative in the polyethylene glycol precursor solution is 10 to 24%, preferably 10 to 20%.

[0013] As a preferred technical solution, the raw materials for preparing the polyamino cross-linking agent solution containing bubble microspheres include at least polyamino polymer, serum albumin, and buffer B solution.

[0014] As a preferred technical solution, the polyamino polymer is composed of one or more of trilysine, polyethyleneimine, and polylysine, preferably a combination of polyethyleneimine and polylysine.

[0015] As a preferred technical solution, the mass fraction of the polyamino polymer in the polyamino crosslinker solution containing bubble microspheres is 9-17%, preferably 9.128-16.13%. Preferably, the concentration ratio of polyethyleneimine to polylysine is 4-7:5-11.

[0016] The medical hydrogel provided in the present application is prepared by cross-linking and curing four-arm polyethylene glycol terminated with benzaldehyde groups connected by amide bonds with a number average molecular weight of 10kDa with polyethyleneimine and polylysine. The mass fraction of the multi-arm polyethylene glycol derivative in the polyethylene glycol precursor solution is further controlled to be 10-24%. After mixing with a polyamino crosslinker solution containing bubble microspheres with a mass fraction of 9-17% of the polyamino polymer, the hydrogel is gelled in a relatively short time, ensuring that the average gelation time is less than 10 seconds. At the same time, the cured hydrogel has good stability and a low swelling rate. However, the mass fraction of the polyamino polymer is low, resulting in an excessively long gelation time, which cannot meet the actual application requirements.

[0017] As a preferred technical solution, the mass fraction of serum albumin in the polyamino cross-linking agent solution containing bubble microspheres is 10 to 30%, preferably 10 to 20%. The serum albumin is preferably bovine serum albumin.

[0018] To address the limitations of current technology, the present invention preferably prepares a polyamino crosslinker solution containing bovine serum albumin bubble microspheres by adding bovine serum albumin to a crosslinking system. After mixing with a polyethylene glycol precursor solution, the solution is cured by two-component in-situ crosslinking to form an ultrasound-developable medical hydrogel. The low density of the gas allows the hydrogel to be clearly developed under ultrasound. Furthermore, during their research, the inventors discovered that by controlling the mass fraction of serum albumin in the polyamino crosslinker solution containing the bubble microspheres to 10-20%, the hydrogel can be completely degraded without residue without affecting the gelation properties of the hydrogel, while also improving the stability of the hydrogel. The inventors believe that this may be due to the amino groups contained in the bovine serum albumin shell of the bubble microspheres chemically bonding with the multi-arm polyethylene glycol derivative. This allows the bubble microspheres to be stably loaded into the hydrogel through chemical bonding for a long time and gradually degraded and released as the hydrogel degrades. This ensures the stability of the hydrogel during ultrasound development and synchronizes its degradation with the hydrogel, facilitating real-time observation of the hydrogel in the human body. However, excessive BSA addition accelerates the degradation rate, while excessive BSA addition affects the development performance.

[0019] As a preferred technical solution, the buffer A solution and the buffer B solution are phosphate buffer or borax buffer with a pH of 4 to 10; preferably, the buffer A solution is a phosphate buffer with a pH of 5.6; and the buffer B solution is a borax buffer with a pH of 9.2.

[0020] On the other hand, the present application provides a preparation method of a medical hydrogel containing ultrasound-developable bubble microspheres and a preparation method thereof, which comprises at least the following steps:

[0021] (1) dissolving the multi-arm polyethylene glycol derivative in buffer A to prepare a polyethylene glycol precursor solution;

[0022] (2) The polyethylene glycol precursor solution and the polyamino crosslinker solution containing the bubble microspheres are mixed and injected through a double syringe according to the volume ratio.

[0023] Preferably, the preparation method of the polyamino crosslinker solution containing bubble microspheres is as follows: dissolving the polyamino polymer in buffer B to prepare a polyamino crosslinker solution base liquid; controlling the temperature, dissolving serum albumin in the polyamino crosslinker solution base liquid, and after complete dissolution, simultaneously subjecting the solution to ultrasonic treatment and nitrogen treatment, immediately placing the solution in a constant temperature water bath for low-temperature treatment, then taking it out and restoring it to 20-30°C to obtain a polyamino crosslinker solution containing bubble microspheres.

[0024] Further preferably, the method for preparing the medical hydrogel containing ultrasound-developable bubble microspheres specifically comprises the following steps:

[0025] S1: dissolving the multi-arm polyethylene glycol derivative in a phosphate buffer solution at pH 5.6 to prepare a polyethylene glycol precursor solution;

[0026] S2: dissolving the polyamino polymer in a borax buffer solution at pH 9.2 to prepare a polyamino crosslinker solution base;

[0027] S3: Controlling the temperature, dissolving bovine serum albumin in the polyamino crosslinker solution base solution, and simultaneously ultrasonically treating and nitrogen-gasing the solution after complete dissolution. Immediately placing the solution in a constant temperature water bath for low-temperature treatment, then removing the solution and returning it to 20-30° C., thereby obtaining a polyamino crosslinker solution containing bovine serum albumin bubble microspheres;

[0028] S4: The polyethylene glycol precursor solution and the polyamino cross-linking agent solution containing the bubble microspheres are mixed and injected according to the volume ratio through a double syringe.

[0029] As a preferred technical solution, the temperature in step S3 is controlled to be 55-65°C.

[0030] As a preferred technical solution, the ultrasonic treatment and nitrogen treatment in step S3 are performed for 10 to 30 seconds, and the treatment times are both 1 to 5 times.

[0031] As a preferred technical solution, the temperature of the low-temperature treatment in step S3 is -5 to 0°C, and the time is 40 to 60 minutes.

[0032] As a preferred technical solution, the volume ratio of the polyethylene glycol precursor solution to the polyamino cross-linking agent solution containing bubble microspheres is 1:1.

[0033] This application uses a specific process to creatively introduce serum albumin (such as bovine serum albumin) bubble microspheres into a two-component gel system, solving many problems existing in the existing water-insoluble developing particle development system. The provided ultrasound-developable hydrogel material is expected to provide new materials for the fields of medicine and tissue engineering, and can be used in implantable medical devices, permanent embolisms, artificial tissue scaffolds, etc., to achieve clear ultrasound development observation during and after the implantation process.

[0034] The third aspect of the present application provides an application of a medical hydrogel containing ultrasound-developable bubble microspheres, which can be used in implantable medical devices, permanent embolisms, and artificial tissue scaffolds. Beneficial effects

[0035] 1. The present application provides a medical hydrogel containing ultrasound-developable bubble microspheres. Without affecting the gelling properties of the hydrogel, the provided medical hydrogel can be clearly developed under ultrasound, enabling real-time observation of the hydrogel in the human body, and can be completely degraded without residue.

[0036] 2. In the present application, the mass fraction of the multi-arm polyethylene glycol derivative in the polyethylene glycol precursor solution is controlled to be 10-24%, and after mixing with the polyamino crosslinker solution with a mass fraction of the polyamino polymer of 9-17%, gelation is achieved in a relatively short time, ensuring that the average gelation time is less than 10 seconds. At the same time, the cured hydrogel has good stability and a low swelling rate.

[0037] 3. In this application, a polyamino crosslinker solution containing bovine serum albumin bubble microspheres is prepared by adding bovine serum albumin to a crosslinking system. After mixing with a polyethylene glycol precursor solution, an ultrasound-developable medical hydrogel is formed by in-situ crosslinking and curing of the solution through two components. The low density of the gas is utilized to enable the hydrogel to be clearly developed under ultrasound.

[0038] 4. The present application controls the mass fraction of serum albumin in the polyamino crosslinker solution to 10-30%, thereby achieving the goal of not affecting the gelling properties of the hydrogel, while being able to be completely degraded without residue, and also contributing to the stability of the hydrogel.

[0039] 5. This application creatively introduces bovine serum albumin bubble microspheres into a two-component gel system through a specific process, solving many problems existing in the existing water-insoluble developing particle development system. The provided ultrasound-developable hydrogel material is expected to provide new materials for the fields of medicine and tissue engineering, and can be used in implantable medical devices, permanent embolisms, artificial tissue scaffolds, etc., to achieve clear ultrasound development observation during and after the implantation process. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] FIG1 is a comparison chart showing the changes in swelling ratio over time for Example 3, Examples 1, 2, 4, and Comparative Example 2;

[0041] FIG2 is a comparison chart showing the changes in swelling ratio over time for Example 3, Examples 5 and 6, and Comparative Example 2;

[0042] FIG3 is a comparison of the swelling ratio changes over time of Example 3, Examples 9, 10, and Comparative Example 2;

[0043] FIG4 is a shape characterization diagram of bovine serum albumin bubble microspheres in Example 3 and Example 9 under an optical fiber microscope at 10 times and 20 times magnification, wherein a) is Example 3 (10 times magnification), b) is Example 3 (20 times magnification), c) is Example 9 (10 times magnification), and d) is Example 9 (20 times magnification);

[0044] Figure 5 shows the ultrasound imaging effects of Example 3, Example 9, and Comparative Example 2, wherein the red circles indicate the implant materials. In the figure, a) is the ultrasound imaging effect of Comparative Example 2, b) is the ultrasound imaging effect of Example 3, and c) is the ultrasound imaging effect of Example 9. DETAILED DESCRIPTION

[0045] Example 1

[0046] Example 1 of the present application provides, on the one hand, a medical hydrogel containing ultrasound-developable bubble microspheres, which is formed by in situ cross-linking of a polyethylene glycol precursor solution and a polyamino cross-linker solution containing bubble microspheres, wherein the polyethylene glycol precursor solution is composed of a multi-arm polyethylene glycol derivative and a buffer A solution.

[0047] The multi-arm polyethylene glycol derivative is a four-arm polyethylene glycol terminated with benzaldehyde groups connected by amide bonds, and has a number average molecular weight of 10 kDa (purchased from Beijing Jiankai Technology Co., Ltd.).

[0048] The mass fraction of the multi-arm polyethylene glycol derivative in the polyethylene glycol precursor solution is 10%.

[0049] The raw materials for preparing the polyamino crosslinking agent solution containing bubble microspheres include polyamino polymer, serum albumin and buffer B solution.

[0050] The mass fraction of the polyamino polymer in the polyamino crosslinker solution containing bubble microspheres is 16.13%. The polyamino polymer is a combination of polylysine and polyethyleneimine. The concentration ratio of polyethyleneimine to polylysine is 6.078:10.052.

[0051] The mass fraction of serum albumin in the polyamino cross-linking agent solution containing bubble microspheres is 20%, and the serum albumin is bovine serum albumin.

[0052] The buffer A solution is a phosphate buffer solution with a pH of 5.6; the buffer B solution is a borax buffer solution with a pH of 9.2.

[0053] On the other hand, Example 1 of the present application provides a method for preparing a medical hydrogel containing ultrasound-developable bubble microspheres, which specifically comprises the following steps:

[0054] S1: Dissolve the polyethylene glycol derivative in 1 mL of buffer A to prepare a polyethylene glycol precursor solution;

[0055] S2: Dissolve the polyamino polymer in 1 mL of buffer B to prepare a polyamino crosslinker base solution;

[0056] S3: Controlling the temperature, dissolving bovine serum albumin in the polyamino crosslinker solution base solution, and simultaneously subjecting the solution to ultrasonic treatment and nitrogen treatment after complete dissolution. Immediately placing the solution in a constant temperature water bath for low-temperature treatment, the solution is taken out and returned to 25°C to obtain a polyamino crosslinker solution containing bovine serum albumin bubble microspheres;

[0057] S4: The polyethylene glycol precursor solution and the polyamino cross-linking agent solution are mixed and injected according to the volume ratio through a double syringe.

[0058] The temperature in step S3 is controlled to be 60° C.; the time for ultrasonic treatment and nitrogen treatment in step S3 is 15 seconds, and the number of treatments is 1.

[0059] The temperature of the low temperature treatment in step S3 is -5°C and the time is 45 minutes.

[0060] The volume ratio of the polyethylene glycol precursor solution to the polyamino crosslinker solution containing bovine serum albumin bubble microspheres is 1:1.

[0061] Example 2

[0062] Example 2 of the present application provides a medical hydrogel containing ultrasound-developable bubble microspheres and a preparation method thereof. The specific implementation method is the same as that of Example 1, except that the mass fraction of the multi-arm polyethylene glycol derivative in the polyethylene glycol precursor solution is 13%.

[0063] Example 3

[0064] Example 3 of the present application provides a medical hydrogel containing ultrasound-developable bubble microspheres and a preparation method thereof. The specific implementation method is the same as that of Example 1, except that the mass fraction of the multi-arm polyethylene glycol derivative in the polyethylene glycol precursor solution is 20%.

[0065] Example 4

[0066] Example 4 of the present application provides a medical hydrogel containing ultrasound-developable bubble microspheres and a preparation method thereof. The specific implementation method is the same as that of Example 1, except that the mass fraction of the multi-arm polyethylene glycol derivative in the polyethylene glycol precursor solution is 24%.

[0067] Example 5

[0068] Example 5 of the present application provides a medical hydrogel containing ultrasound-developable bubble microspheres and a preparation method thereof. The specific implementation method is the same as that of Example 1, except that the mass fraction of the polyamino polymer in the polyamino crosslinker solution containing bubble microspheres is 13.153%, the polyamino polymer is a combination of polylysine and polyethyleneimine, and the concentration ratio of polyethyleneimine to polylysine is 5.539:7.614.

[0069] Example 6

[0070] Example 6 of the present application provides a medical hydrogel containing ultrasound-developable bubble microspheres and a preparation method thereof. Its specific implementation method is the same as that of Example 1, except that the mass fraction of the polyamino polymer in the polyamino crosslinker solution containing bubble microspheres is 9.128%, the polyamino polymer is a combination of polylysine and polyethyleneimine, and the concentration ratio of polyethyleneimine to polylysine is 4.052:5.076.

[0071] Example 7

[0072] Example 7 of the present application provides a medical hydrogel containing ultrasound-developable bubble microspheres and a preparation method thereof. The specific implementation method is the same as that of Example 1, except that the mass fraction of the polyamino polymer in the polyamino crosslinker solution containing bubble microspheres is 8.065%, the polyamino polymer is a combination of polylysine and polyethyleneimine, and the concentration ratio of polyethyleneimine to polylysine is 3.039:5.026.

[0073] Example 8

[0074] Example 8 of the present application provides a medical hydrogel containing ultrasound-developable bubble microspheres and a preparation method thereof. Its specific implementation method is the same as that of Example 1, except that the mass fraction of the polyamino polymer in the polyamino crosslinker solution containing bubble microspheres is 6.515%, the polyamino polymer is a combination of polylysine and polyethyleneimine, and the concentration ratio of polyethyleneimine to polylysine is 2.076:4.439.

[0075] Example 9

[0076] Example 9 of the present application provides a medical hydrogel containing ultrasound-developable bubble microspheres and a preparation method thereof. The specific implementation method is the same as that of Example 1, except that the mass fraction of serum albumin in the polyamino cross-linker solution containing the bubble microspheres is 10%.

[0077] Example 10

[0078] Example 10 of the present application provides a medical hydrogel containing ultrasound-developable bubble microspheres and a preparation method thereof. The specific implementation method is the same as that of Example 1, except that the mass fraction of serum albumin in the polyamino cross-linker solution containing the bubble microspheres is 30%.

[0079] Comparative Example 1

[0080] Comparative Example 1 of the present application provides a medical hydrogel containing ultrasound-developable bubble microspheres and a preparation method thereof. The specific implementation manner is the same as that of Example 1, except that the mass fraction of serum albumin in the polyamino cross-linker solution containing the bubble microspheres is 40%.

[0081] Comparative Example 2

[0082] Comparative Example 2 of the present application provides a medical hydrogel containing ultrasound-developable bubble microspheres and a preparation method thereof. The specific implementation manner is the same as that of Example 1, except that the mass fraction of serum albumin in the polyamino cross-linker solution containing the bubble microspheres is 0%.

[0083] Performance testing methods

[0084] 1. Gelation time: Take 0.6 mL of each of the polyethylene glycol precursor solution and the polyamino crosslinker solution containing bubble microspheres in Example 2 and Comparative Example 2, and place a 2.5 mL vial in a 37 ± 0.5 ° C water bath. After standing for 5 minutes, use a pipette to take 200 μL of the polyethylene glycol precursor solution into a 2.5 mL vial. Then, use a different pipette tip to take 200 μL of the polyamino crosslinker solution containing bubble microspheres. Add the polyamino crosslinker solution containing bubble microspheres to the vial containing the polyethylene glycol precursor solution. Vibrate the vial with your wrist at a frequency of 3 times / s for 3 seconds, then repeatedly tilt the vial at a frequency of 1 time / s and observe until the liquid stops flowing. Start adding the polyethylene glycol precursor solution and start timing until the liquid stops flowing. The timing is the gelation time. Three sets of samples are measured in parallel, and the average value is taken. The results are recorded in Table 1.

[0085] Table 1 Gelation time of polyethylene glycol precursor solution in Example and Comparative Example 2

[0086] 2. Degradation performance: The hydrogels provided in the examples and comparative example 2, except for Examples 7, 8 and Comparative Example 1, were subjected to accelerated aging experiments (in vitro degradation simulation experiments, incubated in a 60°C constant temperature box), and the time for complete degradation of the hydrogel was recorded. The results are shown in Table 2. The data in Table 2 show that the complete degradation time of the provided hydrogel product ranges from 7 to 14 days (60°C, 7 days is approximately equal to 37°C, 34 days; 60°C, 9 days is approximately equal to 37°C, 44 days; 60°C, 11 days is approximately equal to 37°C, 54 days; 60°C, 14 days is approximately equal to 37°C, 69 days), which can meet the requirements of various clinical application scenarios for different degradation times.

[0087] Table 2 Complete degradation time of the hydrogels provided in Examples 1 to 6, 9 to 10 and Comparative Example 2

[0088] 3. Hydrogel Swelling Rate: The hydrogel swelling rate was calculated based on the hydrogel degradation performance data provided in Example and Comparative Example 2. The results are shown in Figures 1, 2, 3, and Table 3. Comparison shows that the products provided in Example 3 and Example 9 have better hydrogel stability and lower hydrogel swelling rate.

[0089] Table 3 Swelling ratio of the hydrogels provided in Examples 1 to 6, 9 to 10 and Comparative Example 2

[0090] (Note: “-” means not tested)

[0091] 4. The hydrogels provided in Examples 3 and 9 were placed under an optical microscope to observe the shapes of the bovine serum albumin bubble microspheres. The bovine serum albumin bubble microspheres formed in Example 3 were significantly more than those in Example 9. The results are shown in FIG4 .

[0092] 5. The hydrogels provided by Example 3(b), Example 9(c) and Comparative Example 2(a) were respectively implanted subcutaneously in rats and subjected to ultrasound imaging. Comparative Example 2(a) did not develop under ultrasound, while Example 3(b) had a better ultrasound imaging effect than Example 9(c). See Figure 5 for the ultrasound imaging effect.

Claims

1. A medical hydrogel containing ultrasound-developable bubble microspheres, characterized in that: The invention is composed of air bubble microspheres and cross-linked products on the surface of the air bubble microspheres; the cross-linked products are cross-linked products of multi-arm polyethylene glycol derivatives cross-linked by multi-amino cross-linking agents.

2. A medical hydrogel containing ultrasound-developable bubble microspheres, characterized in that: The polyethylene glycol precursor solution and the polyamino cross-linking agent solution containing the bubble microspheres are in situ cross-linked, wherein the polyethylene glycol precursor solution is composed of a multi-arm polyethylene glycol derivative and a buffer A solution; The pH value of the buffer A solution is 4-10.

3. The medical hydrogel containing ultrasound-developable bubble microspheres according to claim 2, characterized in that: The raw materials for preparing the polyamino crosslinking agent solution containing bubble microspheres at least include polyamino polymer, serum albumin and buffer B solution; the pH value of the buffer B solution is 4-10.

4. The medical hydrogel containing ultrasound-developable bubble microspheres according to claim 1 or 2, characterized in that: The multi-arm polyethylene glycol derivative is selected from at least one of a three-arm polyethylene glycol derivative, a four-arm polyethylene glycol derivative, a six-arm polyethylene glycol derivative, and an eight-arm polyethylene glycol derivative.

5. The medical hydrogel containing ultrasound-developable bubble microspheres according to claim 1 or 2, characterized in that: The multi-arm polyethylene glycol derivative is an aldehyde-terminated multi-arm polyethylene glycol derivative, and the aldehyde group of the aldehyde-terminated multi-arm polyethylene glycol derivative is connected to the multi-arm polyethylene glycol through an ether bond, an amide bond, an urethane bond, an imine bond or a urea bond.

6. The medical hydrogel containing ultrasound-developable bubble microspheres according to claim 2, characterized in that: The mass fraction of the multi-arm polyethylene glycol derivative in the polyethylene glycol precursor solution is 10-24%.

7. The medical hydrogel containing ultrasound-developable bubble microspheres according to claim 3, characterized in that: The polyamino polymer is composed of one or more of trilysine, polyethyleneimine and polylysine.

8. The medical hydrogel containing ultrasound-developable bubble microspheres according to claim 3 or 7, characterized in that: The mass fraction of the polyamino polymer in the polyamino crosslinking agent solution containing bubble microspheres is 9-17%.

9. The medical hydrogel containing ultrasound-developable bubble microspheres according to claim 3, characterized in that: The mass fraction of serum albumin in the polyamino cross-linking agent solution containing bubble microspheres is 10-30%.

10. The medical hydrogel containing ultrasound-developable bubble microspheres according to claim 2, characterized in that: The buffer A solution and the buffer B solution are independently a phosphate buffer solution with a pH value of 4 to 10 or a borax buffer solution with a pH value of 4 to 10.

11. The method for preparing the medical hydrogel containing ultrasound-developable bubble microspheres according to any one of claims 1 to 10, characterized in that: At least the following steps are included: (1) dissolving the multi-arm polyethylene glycol derivative in buffer A to obtain a polyethylene glycol precursor solution; (2) The polyethylene glycol precursor solution and the polyamino crosslinker solution containing the bubble microspheres are mixed and injected by a double syringe according to a volume ratio to obtain a medical hydrogel containing ultrasound-developable bubble microspheres.

12. The preparation method according to claim 11, characterized in that: The preparation method of the polyamino crosslinker solution containing bubble microspheres is as follows: dissolving a polyamino polymer in a buffer B solution to prepare a polyamino crosslinker solution base solution; controlling the temperature to be 55-65° C., dissolving serum albumin in the polyamino crosslinker solution base solution, and simultaneously subjecting the solution to ultrasonic treatment and nitrogen treatment after complete dissolution, and then placing the solution in a constant temperature water bath for low temperature treatment, and then taking it out and restoring the temperature to 20-30° C. to obtain the polyamino crosslinker solution containing bubble microspheres.

13. The preparation method according to claim 12, characterized in that: The ultrasonic treatment and nitrogen treatment are performed for 10 to 30 seconds, and the number of treatments is 1 to 5 times.

14. The preparation method according to claim 12, characterized in that: The temperature of the low temperature treatment is -5 to 0°C and the time is 40 to 60 minutes.

15. Use of the medical hydrogel containing ultrasound-developable bubble microspheres according to any one of claims 1 to 9 or the medical hydrogel containing ultrasound-developable bubble microspheres prepared by the preparation method according to any one of claims 10 to 14 in medical devices.

16. The use according to claim 15, characterized in that The medical device includes a permanent embolic material or an artificial tissue scaffold.

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