Injectable expansion composite hydrogel as well as preparation method and application thereof

Abstract

The invention belongs to the field of biological medicine, and particularly relates to injectable expansion composite hydrogel and a preparation method and application thereof.The preparation method comprises the steps that chitosan is dissolved in an acetic acid solution, and a uniform chitosan solution is obtained; the preparation method comprises the following steps: sequentially adding a calcium chloride solution and an MXene dispersion liquid into a chitosan solution, and uniformly mixing to obtain a solution A; preparing a sodium alginate solution, adding sodium bicarbonate into the sodium alginate solution, and uniformly mixing to obtain a solution B; and mixing the solution A and the solution B, and expanding through a cross-linking reaction to form the injectable expanded composite hydrogel. The hydrogel can support the uterine cavity form through the expansion characteristic, and intrauterine adhesion is prevented.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and particularly relates to an injectable swelling composite hydrogel, a preparation method thereof, and an application thereof. Background Art

[0002] The endometrium is a highly dynamic tissue structure with extremely strong regenerative ability. It consists of a functional layer and a basal layer. The functional layer grows, transforms, exfoliates, and regenerates and repairs during the menstrual cycle. This regenerative ability is mainly regulated by ovarian hormones (estrogen and progesterone). However, the endometrium is severely damaged under some specific circumstances, such as curettage, uterine cavity cleaning, intrauterine infection, and other gynecological surgical operations. These operations will damage the structures of the functional layer and basal layer of the endometrium, resulting in a decline in the regenerative ability of the endometrium and causing problems such as intrauterine adhesion, abnormal menstruation, embryo implantation failure, and infertility.

[0003] Intrauterine adhesion (IUA) is one of the common complications of endometrial injury. Its main feature is that the endometrium fibroses and thickens after injury, forming adhesions on the inner wall of the uterine cavity. Severe intrauterine adhesions may completely close the uterine cavity, preventing normal embryo implantation, and are one of the important causes of female infertility and recurrent miscarriage. With the increase in uterine cavity operations, the incidence of IUA has been increasing year by year, especially in women who have experienced multiple abortions and uterine cavity surgeries. Currently, the treatment methods for intrauterine adhesions include surgical lysis, hormone therapy, and placement of intrauterine devices, etc. Adhesion lysis under hysteroscopy is the most common treatment method, directly separating the adhesion tissue through surgery to restore the shape of the uterine cavity. However, the surgery itself is a traumatic treatment, which often further damages the endometrial tissue, resulting in a relatively high risk of re-adhesion after surgery. In addition, estrogen is usually used as an adjuvant after surgery to promote endometrial hyperplasia, but this method requires long-term treatment and has side effects related to hormone therapy, such as weight gain, thrombosis, etc. In order to prevent the recurrence of postoperative adhesions, an intrauterine device (such as a balloon or other support devices) is often placed in the uterine cavity to maintain the open state of the uterine cavity, but these devices may cause local irritation and even lead to secondary inflammation, making the treatment effect unsatisfactory. Summary of the Invention

[0004] Aiming at the deficiencies in the prior art, the present invention innovatively develops an injectable swelling composite hydrogel, a preparation method thereof, and an application thereof. The present invention uses the hydrogel to expand and support the shape of the uterine cavity to prevent intrauterine fibrous tissue adhesion. The hydrogel is jointly prepared from chitosan, MXene, acetic acid, calcium chloride, sodium alginate, and sodium bicarbonate, and has good injectability, in-situ and timely swelling property, and biocompatibility. It can be directly injected into the uterine cavity through a minimally invasive method to quickly form a three-dimensional scaffold structure, thereby effectively preventing the occurrence of intrauterine adhesions.

[0005] To achieve the above object, the present invention is realized through the following technical solutions:

[0006] In a first aspect, the present invention provides a method for preparing an injectable swelling composite hydrogel, and the preparation method includes:

[0007] Dissolve chitosan in an acetic acid solution to obtain a uniform chitosan solution;

[0008] Sequentially add a calcium chloride solution and an MXene dispersion to the chitosan solution, and after mixing evenly, obtain solution A;

[0009] Prepare a sodium alginate solution, and add sodium bicarbonate thereto, and after mixing evenly, obtain solution B;

[0010] Mix solution A and solution B, and form an injectable swelling composite hydrogel through a cross-linking reaction and swelling.

[0011] As a further optimized scheme of the present invention, the mass ratio of chitosan, calcium chloride and MXene is (1.5 - 3.0):(0.5 - 1.5):(0.5 - 1.5), the chitosan concentration is 1.5 - 3.0 g / 100 mL, the calcium chloride concentration is 2 - 4% w / v, and the MXene concentration is 0.5 - 1.5% w / v; the mass ratio of sodium alginate and sodium bicarbonate is (1.0 - 3.0):(0.5 - 1.5), the sodium alginate concentration is 1 - 2% w / v, and the sodium bicarbonate concentration is 0.3 - 1.0% w / v.

[0012] Further, the mass ratio of chitosan, calcium chloride and MXene is 2:1:1, the chitosan concentration is 1.8 g / 100 mL, the MXene concentration is 0.75% w / v, and the calcium chloride concentration is 3.0% w / v; the mass ratio of sodium alginate and sodium bicarbonate is 2:1, the sodium alginate concentration is 1.2% w / v, and the sodium bicarbonate concentration is 0.4% w / v.

[0013] As a further optimized scheme of the present invention, the pH value of the cross-linked injectable swelling composite hydrogel is between 6.8 and 7.4.

[0014] As a further optimized scheme of the present invention, solution A and solution B are mixed according to a volume ratio of 1:1, and the cross-linking reaction time is 30 - 60 s.

[0015] As a further optimized scheme of the present invention, the volume of the cross-linked injectable swelling composite hydrogel is 2 - 5 times the original volume before cross-linking.

[0016] Second aspect, the present invention provides an injectable swelling composite hydrogel, and the injectable swelling composite hydrogel is prepared by the above-mentioned preparation method.

[0017] Third aspect, the present invention provides an application of the injectable swelling composite hydrogel in the preparation of products for preventing intrauterine adhesions.

[0018] As a further optimized solution of the present invention, the method for in-situ mixing and injecting the injectable swelling composite hydrogel into the uterine cavity includes: first, separately filling solution A and solution B into two chambers of a double-chamber syringe, and then using the double-chamber syringe to in-situ mix solution A and solution B at a specified position (such as in the uterine cavity), and forming an injectable swelling composite hydrogel with a three-dimensional network structure through cross-linking reaction and swelling, so as to provide mechanical support for the damaged endometrium.

[0019] As a further optimized solution of the present invention, when the solution A and solution B are in-situ mixed and injected at a specified position, the pH value at the specified position is between 6.5 and 7.5.

[0020] As a further optimized solution of the present invention, when the solution A and solution B are in-situ mixed and injected at a specified position, the temperature at the specified position is between 35 and 40 °C.

[0021] Compared with the prior art, the beneficial effects achieved by the present invention are as follows:

[0022] (1) The present invention uses natural or biocompatible materials such as chitosan, MXene, and sodium alginate to prepare an injectable swelling composite hydrogel. Among them, chitosan is used to form the main structure of the hydrogel, MXene is used to enhance the anti-inflammatory and pro-angiogenic effects, calcium chloride is used as a cross-linking agent, and sodium alginate and sodium bicarbonate jointly provide swelling regulation characteristics. The hydrogel is cross-linked by in-situ mixing with a double-chamber syringe and forms a swelling structure scaffold in the endometrial injury area to provide functions of mechanical support, anti-inflammatory and promoting endometrial regeneration, effectively filling the injury area and preventing intrauterine adhesions.

[0023] (2) The prepared injectable swelling composite hydrogel has good biocompatibility and degradability, is gradually degraded in vivo, has no obvious toxicity, and is suitable for long-term implantation to achieve long-term repair of the endometrium.

[0024] (3) The pH value of the injectable swelling composite hydrogel is between 6.8 and 7.4 to ensure adaptation to the physiological environment and reduce irritation to surrounding tissues. It has stable swelling performance in an environment with a pH of 6.5 - 7.5 in the uterine cavity, and the volume swelling rate is 2 - 5 times the original volume, and it can adapt to the swelling requirements of different shapes (such as spherical, sheet-like, columnar), ensuring effective support and repair functions in a complex uterine cavity environment.

[0025] (4) Compared with traditional intrauterine adhesion treatment methods, the present invention can complete the treatment through a single minimally invasive injection, eliminating the need for multiple surgeries or long-term drug treatments, thus reducing the pain and economic burden on patients. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 Schematic diagram of injectable swelling hydrogel for endometrial injury treatment.

[0027] Figure 2 pH value curve of hydrogels with different concentrations of acetic acid and sodium bicarbonate after crosslinking.

[0028] Figure 3 Gas pressure values generated by hydrogels with different concentrations of acetic acid and sodium bicarbonate after crosslinking.

[0029] Figure 4 Gas pressure values generated by hydrogels with different concentrations of acetic acid after crosslinking.

[0030] Figure 5 Volume swelling rate of hydrogels with different concentrations of acetic acid after crosslinking.

[0031] Figure 6 Fluorescence image of internal bubble distribution of injectable swelling hydrogel after crosslinking.

[0032] Figure 7 Scanning electron micrograph of injectable swelling hydrogel after crosslinking.

[0033] Figure 8 Photos of conforming to different shapes of injectable swelling hydrogel after crosslinking.

[0034] Figure 9 Photos of conforming to the complex shape of the human uterine model of injectable swelling hydrogel after crosslinking.

[0035] Figure 10 Cell viability images of injectable swelling hydrogel after crosslinking and co-cultured with mesenchymal stem cells for different times.

[0036] Figure 11 Fluorescence images of cell adhesion of injectable swelling hydrogel after crosslinking and co-cultured with mesenchymal stem cells. Among them, a is a 10-fold magnified fluorescence image of biocompatible cell adhesion, and b is a 20-fold magnified fluorescence image of biocompatible cell adhesion.

[0037] Figure 12 Photos of volume swelling of injectable swelling hydrogel after injection into the rat uterus. Among them, a is the image of the rat uterus without injecting hydrogel, and b is the image of the rat uterus after injecting hydrogel.

[0038] Figure 13This is a HE staining image of the adhesion of an injectable swelling hydrogel to the rat uterus after injection. Among them, a is the H&E staining morphological image of the rat uterus after injecting the hydrogel, and b is the partial enlarged H&E staining image of the rat uterus after injecting the hydrogel. Detailed implementation mode

[0039] In order to enable those skilled in the art to better understand the technical solution of the present invention, the preferred implementation modes of the present invention will be described below in conjunction with specific embodiments. However, it should not be understood as a limitation of the present invention, and it is only for example.

[0040] MXene in the present invention, as a two-dimensional transition metal carbide and nitride, has good biological activity and can significantly improve the microenvironment in the uterus. First of all, MXene has excellent anti-inflammatory properties, can effectively inhibit the inflammatory reaction in the uterine cavity, reduce the damage of inflammatory factors to the endometrial tissue, and prevent fibrous adhesions and tissue necrosis caused by inflammation. Secondly, MXene can promote angiogenesis, form a new capillary network in the damaged area, thereby improving the blood supply of the endometrial tissue and promoting tissue regeneration and repair. Angiogenesis is crucial for the health of the endometrium because rich blood supply can provide sufficient oxygen and nutrients for the regenerated endometrial cells, thus accelerating the repair process.

[0041] In order to ensure the retention time and swelling effect of the hydrogel in the uterine cavity, acetic acid and sodium bicarbonate are used as foaming agents in the present invention. The hydrogel formed by cross-linking calcium chloride and sodium alginate has strong mechanical properties and can maintain the supporting effect in the uterine cavity for a long time. The addition of sodium bicarbonate enables the hydrogel to expand moderately after injection, so as to fit more closely to the inner wall of the uterine cavity and provide more stable physical support for damage repair.

[0042] The present invention provides a preparation method of an injectable swelling composite hydrogel based on chitosan, MXene, acetic acid, calcium chloride, sodium alginate and sodium bicarbonate, including the following steps:

[0043] Take 1.5 - 3.0 g of chitosan and add it to a 1 - 2% (v / v) acetic acid solution, stir until the chitosan is completely dissolved to obtain a uniform chitosan solution, and control the chitosan concentration at 1.5 - 3.0 g / 100 mL. Appropriately adjusting the concentrations of chitosan and acetic acid helps to control the mechanical strength and swelling property of the gel.

[0044] Take 0.5 - 1.5 g of calcium chloride, add it to deionized water and mix evenly, control the concentration of calcium chloride between 2 - 4% (w / v), and then add it to the above chitosan solution. The concentration of calcium chloride affects the cross-linking degree and swelling strength, and the appropriate range ensures that the cross-linked hydrogel has appropriate mechanical properties.

[0045] Take 0.5 - 1.5 g of MXene and add it to deionized water. Treat it with ultrasonic waves for 30 minutes to obtain a uniform MXene dispersion. The concentration of MXene is controlled between 0.5 - 1.5% (w / v) to ensure its dispersibility and biological functionality. Then add it to the above-mentioned mixed solution of chitosan and calcium chloride. After mixing evenly, stir magnetically at room temperature for 8 hours to obtain Solution A.

[0046] Take 1.0 - 3.0 g of sodium alginate and add it to 100 mL of deionized water. Continuously stir until it is completely dissolved to form a 1.0 - 2.0% (w / v) sodium alginate solution. The appropriate concentration range helps to ensure that the hydrogel has a stable structure and mechanical strength during the swelling process.

[0047] Take 0.5 - 1.5 g of sodium bicarbonate and add it to deionized water and mix evenly. The concentration of sodium bicarbonate is controlled between 0.3 - 1.0% (w / v). Then add it to the above-mentioned sodium alginate solution and mix evenly to obtain Solution B. The concentration of sodium bicarbonate regulates the swelling characteristics and pH value of the hydrogel to ensure that the hydrogel can adapt to the biological environment after formation, such as Figure 2 shown.

[0048] Fill Solution A and Solution B into the two chambers of a double-lumen syringe respectively, ensuring that the syringe maintains a sterile environment. Solution A contains chitosan, MXene, acetic acid, and calcium chloride, and Solution B contains sodium alginate and sodium bicarbonate. Among them, the double-lumen syringe is purchased from Suzhou Shenglong Precision Plastic & Hardware Co., Ltd., and the model is 50ML AB glue cylinder.

[0049] Using the double-lumen syringe, during the injection process, Solution A and Solution B are in-situ mixed through the mixing head of the double-lumen syringe (mixed at a volume ratio of 1:1), and the cross-linking reaction and swelling process occur simultaneously in vivo. Calcium chloride in Solution A acts as a cross-linking agent and undergoes an ionic cross-linking reaction with sodium alginate in Solution B to form a three-dimensional hydrogel network structure. At the same time, the presence of sodium bicarbonate promotes the appropriate swelling of the hydrogel to better fit the inner wall of the uterine cavity and provide mechanical support for the damaged endometrium. Control the cross-linking time within 30 - 60 seconds to ensure that the hydrogel quickly forms and swells after injection.

[0050] During the injection process, Solution A and Solution B are mixed through the mixing head of the double-lumen syringe and then undergo cross-linking and gelation reactions in vivo. The hydrogel fits the inner wall of the uterine cavity through swelling to form a three-dimensional structure with a stable supporting effect. The swelling volume of the cross-linked hydrogel is controlled between 2 - 5 times the initial volume to ensure sufficient support for the uterine cavity without generating excessive swelling pressure.

[0051] The combination of acetic acid in Solution A and sodium bicarbonate in Solution B regulates the pH value of the final gel, such that the pH value of the hydrogel is between 6.8 and 7.4 to ensure adaptation to the physiological environment and reduce irritation to the surrounding tissues.

[0052] Example 1: Preparation of Solution A and Solution B

[0053] Preparation of Solution A: (1) Take 2.0 g of chitosan and add it to 100 mL of 1.5% (v / v) acetic acid solution. Stir for 4 hours until the chitosan is completely dissolved to obtain a uniform chitosan solution. (2) Take 1.0 g of calcium chloride and add it to deionized water to prepare a calcium chloride solution with a concentration of 2.5% (w / v). Add it to the chitosan solution and mix evenly. (3) Take 1.0 g of MXene and add it to deionized water and sonicate for 30 minutes to form an MXene dispersion with a concentration of 0.5% (w / v). (4) Mix the chitosan solution, calcium chloride solution and MXene dispersion to obtain Solution A.

[0054] Preparation of Solution B: (1) Take 1.5 g of sodium alginate and add it to 100 mL of deionized water. Stir until completely dissolved to form a 1.5% (w / v) sodium alginate solution. (2) Take 0.75 g of sodium bicarbonate and add it to deionized water to prepare a sodium bicarbonate solution with a concentration of 0.5% (w / v). Then add it to the sodium alginate solution and mix evenly to obtain Solution B. Load Solution A and Solution B into a double-chamber syringe respectively, ensuring aseptic operation, and set aside for use.

[0055] Example 2: Preparation of Solution A and Solution B with different concentrations

[0056] Preparation of Solution A: (1) Take 1.8 g of chitosan and add it to 100 mL of 2% (v / v) acetic acid solution. Stir for 3 hours until the chitosan is completely dissolved to obtain a uniform chitosan solution. (2) Take 0.9 g of calcium chloride and add it to deionized water to prepare a calcium chloride solution with a concentration of 3.0% (w / v). Add it to the chitosan solution and mix evenly. (3) Take 0.9 g of MXene and add it to deionized water and sonicate for 20 minutes to form an MXene dispersion with a concentration of 0.75% (w / v). (4) Mix the chitosan solution, calcium chloride solution and MXene dispersion to obtain Solution A.

[0057] Preparation of Solution B: (1) Take 1.2 g of sodium alginate and add it to 100 mL of deionized water. Stir until completely dissolved to form a 1.2% (w / v) sodium alginate solution. (2) Take 0.6 g of sodium bicarbonate and add it to deionized water to prepare a sodium bicarbonate solution with a concentration of 0.4% (w / v). Then add it to the sodium alginate solution and mix evenly to obtain Solution B. Filling of the dual-chamber syringe: Fill Solution A and Solution B into the dual-chamber syringe respectively, ensuring aseptic operation, and set aside for use.

[0058] Example 3: Preparation of Solution A and Solution B with adjusted MXene concentration

[0059] Preparation of Solution A: (1) Take 2.5 g of chitosan and add it to 100 mL of 1.0% (v / v) acetic acid solution. Stir for 5 hours until the chitosan is completely dissolved to obtain a uniform chitosan solution. (2) Take 1.2 g of calcium chloride and add it to deionized water to prepare a calcium chloride solution with a concentration of 3.5% (w / v). Add it to the chitosan solution and mix evenly. (3) Take 1.2 g of MXene and add it to deionized water. Sonicate for 25 minutes to form a 1% (w / v) MXene dispersion. (4) Mix the chitosan solution, calcium chloride solution and MXene dispersion to obtain Solution A.

[0060] Preparation of Solution B: (1) Take 1.8 g of sodium alginate and add it to 100 mL of deionized water. Stir until completely dissolved to form a 1.8% (w / v) sodium alginate solution. (2) Take 0.9 g of sodium bicarbonate and add it to deionized water to prepare a sodium bicarbonate solution with a concentration of 0.6% (w / v). Then add it to the sodium alginate solution and mix evenly to obtain Solution B. Filling of the dual-chamber syringe: Fill Solution A and Solution B into the dual-chamber syringe respectively, ensuring aseptic operation, and set aside for use.

[0061] Example 4: Preparation of Solution A and Solution B with increased calcium chloride concentration

[0062] Preparation of Solution A: (1) Take 2.2 g of chitosan and add it to 100 mL of 1.2% (v / v) acetic acid solution. Stir for 3 hours until the chitosan is completely dissolved to obtain a uniform chitosan solution. (2) Take 1.1 g of calcium chloride and add it to deionized water to prepare a calcium chloride solution with a concentration of 4.0% (w / v). Add it to the chitosan solution and mix evenly. (3) Take 1.0 g of MXene and add it to deionized water. Sonicate for 30 minutes to form a 1.25% (w / v) MXene dispersion. (4) Mix the chitosan solution, calcium chloride solution and MXene dispersion to obtain Solution A.

[0063] Preparation of Solution B: (1) Take 1.6 g of sodium alginate and add it to 100 mL of deionized water. Stir until completely dissolved to form a 1.6% (w / v) sodium alginate solution. (2) Take 0.8 g of sodium bicarbonate and add it to deionized water to prepare a 0.7% (w / v) sodium bicarbonate solution, and then add it to the sodium alginate solution and mix evenly to obtain Solution B. Loading of double-barrel syringe: Fill Solution A and Solution B into a double-barrel syringe respectively, ensuring aseptic operation, and set aside for use.

[0064] Example 5: Preparation of Solution A and Solution B of low-concentration chitosan and high-concentration sodium alginate

[0065] Preparation of Solution A: (1) Take 1.0 g of chitosan and add it to 100 mL of 1.8% (v / v) acetic acid solution. Stir for 3 hours until the chitosan is completely dissolved to obtain a uniform chitosan solution. (2) Take 0.5 g of calcium chloride and add it to deionized water to prepare a 2.0% (w / v) calcium chloride solution, and add it to the chitosan solution and mix evenly. (3) Take 0.9 g of MXene and add it to deionized water and ultrasonically treat for 20 minutes to form a 1.5% (w / v) MXene dispersion. (4) Mix the chitosan solution, calcium chloride solution and MXene dispersion to obtain Solution A.

[0066] Preparation of Solution B: (1) Take 2.0 g of sodium alginate and add it to 100 mL of deionized water. Stir until completely dissolved to form a 2.0% (w / v) sodium alginate solution. (2) Take 1.0 g of sodium bicarbonate and add it to deionized water to prepare a 0.8% (w / v) sodium bicarbonate solution, and then add it to the sodium alginate solution and mix evenly to obtain Solution B. Loading of double-barrel syringe: Fill Solution A and Solution B into a double-barrel syringe respectively, ensuring aseptic operation, and set aside for use.

[0067] The unit (w / v) in Examples 1 - 5 can be expressed as (mg / ml).

[0068] The hydrogels used in Examples 6 - 9 are all products prepared based on Example 2.

[0069] Example 6: In-situ crosslinking and swelling performance test of hydrogel

[0070] In-situ crosslinking: Use a double-barrel syringe filled with Solution A and Solution B for in-vivo injection. In-situ mix Solution A and Solution B (mixed at a volume ratio of 1:1) through the mixing head of the double-barrel syringe to achieve in-situ crosslinking and swelling of the hydrogel in the endometrial injury area.

[0071] The volume expansion test was carried out by placing the prepared hydrogel in a water bath at 37 °C to simulate the in vivo environment and recording the volume change of the hydrogel. The results showed that the volume expansion rate of the hydrogel was 2-5 times the original volume, and the expansion pressure was moderate, which could effectively fill the endometrial injury area.( Figure 4 , Figure 5 , Figure 6 , Figure 7 ) - The gas pressure of the crosslinked hydrogel increased with the concentration, and the volume expansion also increased linearly. The uniform distribution of air bubbles generated in the hydrogel after expansion was the important reason for maintaining expansion and support.

[0072] Example 7: pH Stability and Conformability Tests

[0073] For the pH stability test, the hydrogel was placed in buffer solutions with pH values of 6.5, 7.0, and 7.5 respectively, and the swelling performance and morphological changes of the hydrogel were observed. The results showed that the hydrogel maintained stable swelling performance in different pH environments. When the pH value was between 6.5 and 7.5, the hydrogel could maintain good structure and morphology. Figure 3 - pH distribution.

[0074] For the conformability test, the hydrogel was injected into structures with different shapes and placed in an environment at 37 °C to observe its morphology retention. The results showed that the hydrogel had excellent conformability and could maintain stable expansion and support performance according to different shapes. Such as Figure 8 , Figure 9 .

[0075] Example 8: Biocompatibility Tests

[0076] For the in vitro biocompatibility test, human mesenchymal stem cells (MSCs) were co-cultured with the prepared hydrogel, and the survival rate and proliferation rate of the cells in the hydrogel were observed. The in vitro co-culture process: The crosslinked composite hydrogel was irradiated with ultraviolet light for 12 h and placed in a 24-well plate. Mesenchymal stem cells were inoculated into the 24-well plate based on the hydrogel. After culturing for 48 hours, DAPI and FITC staining were performed and photographed under an inverted fluorescence microscope. The trypan blue staining method and MTT method were used for detection. The results showed that the hydrogel had no obvious toxicity to the cells, and the cells had good adhesion and proliferation ability in the hydrogel. According to Figure 10 and Figure 11 the results showed that the hydrogel of the present invention had good biocompatibility.

[0077] Example 9: Test for the Effect of Preventing Intrauterine Adhesions

[0078] Inject 4 ml of the hydrogel of the present invention into the uterus of rats using a double-lumen syringe. For in vivo effect observation, remove the uterine tissue of the rats on the 7th day after injection and perform hematoxylin-eosin (H&E) staining to observe the morphology of the uterine tissue. According to Figure 12 and Figure 13 The results show that the hydrogel of the present invention can effectively prevent intrauterine adhesions.

[0079] The above are only the preferred embodiments of the present invention. It should be noted that the above preferred embodiments should not be regarded as limitations on the present invention. The protection scope of the present invention should be subject to the scope defined by the claims. For those of ordinary skill in the art, without departing from the spirit and scope of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be regarded as within the protection scope of the present invention.

Claims

1. A preparation method of an injectable expandable composite hydrogel, characterized in that, The preparation method includes: Dissolving chitosan in an acetic acid solution to obtain a uniform chitosan solution; Sequentially adding a calcium chloride solution and an MXene dispersion to the chitosan solution, and mixing evenly to obtain Solution A; Preparing a sodium alginate solution, and adding sodium bicarbonate thereto, and mixing evenly to obtain Solution B; Mixing Solution A and Solution B, and swelling through a cross-linking reaction to form an injectable swelling composite hydrogel.

2. The preparation method of the injectable expandable composite hydrogel according to claim 1, wherein The mass ratio of the chitosan, calcium chloride, and MXene is (1.5 - 3.0):(0.5 - 1.5):(0.5 - 1.5), the concentration of the chitosan is 1.5 - 3.0 g / 100 mL, the concentration of the calcium chloride is 2 - 4% w / v, and the concentration of the MXene is 0.5 - 1.5% w / v; the mass ratio of the sodium alginate and sodium bicarbonate is (1.0 - 3.0):(0.5 - 1.5), the concentration of the sodium alginate is 1 - 2% w / v, and the concentration of the sodium bicarbonate is 0.3 - 1.0% w / v.

3. The preparation method of the injectable expandable composite hydrogel according to claim 2, characterized in that, The mass ratio of the chitosan, calcium chloride, and MXene is 2:1:1, the concentration of the chitosan is 1.8 g / 100 mL, the concentration of the MXene is 0.75% w / v, and the concentration of the calcium chloride is 3.0% w / v; the mass ratio of the sodium alginate and sodium bicarbonate is 2:1, the concentration of the sodium alginate is 1.2% w / v, and the concentration of the sodium bicarbonate is 0.4% w / v.

4. The preparation method of the injectable expandable composite hydrogel according to claim 1, characterized in that, The pH value of the cross-linked injectable swelling composite hydrogel is between 6.8 and 7.

4.

5. The preparation method of the injectable expandable composite hydrogel according to claim 1, wherein Solution A and Solution B are mixed in a volume ratio of 1:1, and the time of the cross-linking reaction is 30 - 60 s.

6. The preparation method of the injectable expandable composite hydrogel according to claim 1, characterized in that, The volume of the cross-linked injectable swelling composite hydrogel is 2 - 5 times the original volume before cross-linking.

7. An injectable expandable composite hydrogel, characterized in that, The injectable swelling composite hydrogel is prepared by the preparation method according to any one of claims 1 - 6.

8. Use of an injectable swelling composite hydrogel according to claim 7 in the preparation of a product for preventing intrauterine adhesions.

9. The application according to claim 8, characterized in that, The injection method of the injectable swelling composite hydrogel includes: first filling Solution A and Solution B into two chambers of a double-chamber syringe respectively, and then using the double-chamber syringe to in-situ mix Solution A and Solution B at a specified position, and swelling through a cross-linking reaction to form a three-dimensional network structure of the injectable swelling composite hydrogel.

10. The application according to claim 8, wherein When Solution A and Solution B are in-situ mixed and injected at a specified position, the pH value at the specified position is between 6.5 and 7.5, and the temperature at the specified position is between 35 and 40 °C.

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