Adhesive hydrogel patch as well as preparation method and application thereof

Abstract

The invention provides an adhesive hydrogel patch and a preparation method and application thereof.The preparation method comprises the steps that firstly, polyglutamic acid connected with double bonds and water-soluble hydroxypropyl chitosan are coagulated and settled through electrostatic interaction, and then obtained coagulated gel is freeze-dried and ground to obtain powder similar to natural flour ingredients; and after hydration with a hydrating agent, repeated stirring and kneading and one-step chemical crosslinking are performed to obtain the stable adhesive hydrogel patch. The hydrogel patch prepared by the method disclosed by the invention is simple in preparation method and appropriate in modulus, and has wet tissue adhesiveness; in addition, the hydrating agent selected by the system can select different drug solutions or nanoparticle solutions according to application scenes, endows the hydrogel patch with corresponding biological activity functions, and can be applied to the field of tissue engineering.

Description

Technical Field

[0001] The present invention relates to the technical field of hydrogels, and more particularly to an adhesion hydrogel patch inspired by kneading dough, its preparation method and application. Background Art

[0002] Hydrogels are three-dimensional polymer network structures with certain mechanical properties and similar structures to the extracellular matrix, facilitating the transport of nutrients and the diffusion of gases with the surrounding environment. Therefore, they are usually used as controlled delivery systems for cells, drug molecules, and growth factors in the field of tissue engineering. Among them, hydrogel patches with good adhesion to tissues have more operability advantages in practical applications and can reduce unnecessary invasive injuries. To achieve adhesion to wet tissues, a common current method is to use dry gel powder, which hydrates by absorbing the moisture in the tissue site and achieves adhesion to the tissue while gelifying. However, the gel powder prepared from natural polymers has low strength after re-gelification and is difficult to match the dynamic tissue surface (such as the surface of a beating heart). Summary of the Invention

[0003] The purpose of the present invention is to overcome the deficiencies in the prior art and provide an adhesion hydrogel patch inspired by kneading dough, its preparation method and application. First, polyglutamic acid grafted with double bonds and hydroxypropyl chitosan are respectively prepared. After mixing the two solutions, a condensate is obtained through electrostatic interaction. Then, the condensate is freeze-dried and ground to prepare gel powder. The gel powder is hydrated with a hydrating agent and kneaded repeatedly to form a dough-like gel. Finally, an adhesion hydrogel patch is obtained through one-step chemical cross-linking. By changing the kneading time and the components of the hydrating agent, a hydrogel patch with adjustable mechanical strength and biological functions can be obtained.

[0004] The technical object of the present invention is achieved through the following technical solutions.

[0005] An adhesion hydrogel patch and its preparation method are carried out according to the following steps:

[0006] Step 1, mix an aqueous solution of γ-polyglutamic acid grafted with glycidyl methacrylate and hydroxypropyl chitosan, obtain a condensate through electrostatic interaction, precipitate, and then freeze-dry and grind it into powder to obtain double-bond polyglutamic acid / hydroxypropyl chitosan gel powder; the mass ratio of hydroxypropyl chitosan to γ-polyglutamic acid grafted with glycidyl methacrylate is (1-6):(4-10); in the aqueous solution, the total solid content of γ-polyglutamic acid grafted with glycidyl methacrylate and hydroxypropyl chitosan is 10-15 wt% (that is, the sum of the masses of γ-polyglutamic acid grafted with glycidyl methacrylate and hydroxypropyl chitosan / the mass of water × 100%);

[0007] In step 1, the mass ratio of hydroxypropyl chitosan to γ-polyglutamic acid grafted with glycidyl methacrylate is (2-4):(6-8).

[0008] In step 1, in an aqueous solution, the total solid content of γ-polyglutamic acid grafted with glycidyl methacrylate and hydroxypropyl chitosan is 10 wt%.

[0009] Step 2: Add a hydrating agent to the double-bond polyglutamic acid / hydroxypropyl chitosan gel powder for infiltration, and knead repeatedly until a smooth-surfaced dough gel is formed. Then add an aqueous solution with a uniformly dispersed initiator, continue kneading and then press into tablets, and carry out chemical cross-linking through free radical polymerization to obtain an adhesive gel patch. The mass ratio of the double-bond polyglutamic acid / hydroxypropyl chitosan gel powder to the hydrating agent is 1:(1-6), and the hydrating agent is ultrapure water, a drug solution with biological functions, or a solution dispersing nanoparticles.

[0010] In step 2, after infiltration, the time for repeated stirring and kneading is 10-15 min to form a smooth-surfaced dough gel.

[0011] In step 2, the time for continuing kneading after adding the aqueous solution with a uniformly dispersed initiator is 3-6 min.

[0012] In step 2, press the dough gel into a sheet material with a thickness of 1-2 mm.

[0013] In step 2, the initiator is a thermal initiator such as potassium persulfate, and the dosage is 1-5% of the sum of the masses of γ-polyglutamic acid grafted with glycidyl methacrylate and hydroxypropyl chitosan; free radical initiation and polymerization are carried out by placing the kneaded material in an oven above the initiation temperature; the initiation temperature is 50-80 °C, and the polymerization time is 10-30 min.

[0014] In step 2, the mass ratio of the double-bond polyglutamic acid / hydroxypropyl chitosan gel powder to the hydrating agent is 1:(1-4).

[0015] The adhesive hydrogel patch of the present invention is used in the field of tissue engineering and in the preparation of drugs or devices for treating myocardial infarction. By regulating the kneading time of the dough gel, a hydrogel patch with adjustable mechanical strength and adhesion strength can be formed under mild conditions. The mechanical strength can be adjusted to 200 Pa-3000 Pa, and the adhesion strength can be adjusted to 5 kPa-15 kPa.

[0016] The formation of hydrogen bonds between molecular chains promoted by repeated stirring and kneading in the present invention is an effective strengthening means, and at the same time, the tissue adhesion of the patch can be maintained. The hydrogel patch prepared by the method of the present invention has a simple preparation method, appropriate modulus, and wet tissue adhesion; in addition, the hydrating agent selected in this system can be different drug solutions or nanoparticle solutions according to the application scenario, endowing the hydrogel patch with corresponding bioactive functions and can be applied to the field of tissue engineering. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 It is the schematic preparation process and nuclear magnetic resonance hydrogen spectrum of grafting double bonds on polyglutamic acid prepared in the present invention.

[0018] Figure 2 It is the schematic preparation process and nuclear magnetic resonance hydrogen spectrum of hydroxypropyl chitosan prepared in the present invention.

[0019] Figure 3 It is the diagram of the change of the N-H stretching vibration peak on the amide bond during the kneading process of the hydrogel patch prepared in the present invention.

[0020] Figure 4 It is the adhesion display picture of the hydrogel patch prepared in the present invention on the surface of the chicken heart.

[0021] Figure 5 It is the column chart of the adhesion strength characterization results of the hydrogel patch prepared in the present invention.

[0022] Figure 6 It is the test result diagram of the change of the modulus of the gel during the kneading process of the hydrogel patch prepared in the present invention

[0023] Figure 7 It is the observation and characterization diagram for 28 days after the hydrogel patches prepared with different hydrating agents in the present invention are respectively adhered to the myocardial lesion site of rats. DETAILED DESCRIPTION OF THE INVENTION

[0024] The technical solutions of the present invention will be further described below through specific examples.

[0025] In the present invention, the synthesis steps of double bond grafted polyglutamic acid (γ-polyglutamic acid grafted with glycidyl methacrylate) refer to the following literature: R. Yang, X. X. Wang, S. Liu, W. J. Zhang, P. H. Wang, X. Liu, Y. H. Ren, X. Y. Tan, B. Chi, International Journal of Biological Macromolecules 2020, 142, 332.

[0026] Dissolve γ-polyglutamic acid completely in an appropriate amount of water, add a certain amount of glycidyl methacrylate, adjust the pH of the reaction solution to weakly acidic with 1M hydrochloric acid, react in a 60°C water bath for 6h, then dialyze with ultrapure water for three days, and obtain polyglutamic acid grafted with double bonds after freeze-drying. The molar ratio of glycidyl methacrylate to polyglutamic acid in the feed is (2:1)-(0.5:1), and the pH of the reaction solution is 3.5-5.

[0027] Figure 1 Shown is the synthesis process and nuclear magnetic resonance hydrogen spectrum of polyglutamic acid grafted with double bonds, as Figure 1 shown. Nuclear magnetic resonance hydrogen spectrum characterization was performed on the prepared polyglutamic acid grafted with double bonds. The figure shows an obvious -C=C- peak at 5.5-6.5 ppm, indicating that glycidyl methacrylate was grafted onto the side chain of polyglutamic acid, demonstrating the successful synthesis of the polyglutamic acid monomer grafted with double bonds.

[0028] In the present invention, the synthesis steps of hydroxypropyl chitosan refer to the following literature: D.Y. Zhu, Z.P. Chen, Z.P. Hong, L. Zhang, X. Liang, Y. Li, X. Duan, H. Luo, J. Peng, J. Guo, Acta Biomaterialia 2022, 143, 203.

[0029] Disperse a certain amount of chitosan in isopropanol, stir at room temperature for 30 min to make it disperse evenly, add a certain amount of concentrated sodium hydroxide solution, continue to stir at room temperature for 1 h, place the above solution in a refrigerator at -20°C overnight, and after restoring to room temperature the next day, add a certain amount of 10 wt% tetramethylammonium chloride solution and a certain amount of propylene oxide, slowly dropwise add for 1 h, react the mixed solution in a 45°C water bath for 10 h, filter by suction after the reaction, wash the filter cake with ethanol 2-3 times, then redissolve it in deionized water, adjust the pH to about 7 with 1M hydrochloric acid, dialyze in pure water for 3 days and freeze-dry. The amount of isopropanol used is 50-150 ml, the amount of tetramethylammonium chloride used is 5-20 ml, and the amount of propylene oxide used is 20-100 ml.

[0030] Figure 2 Shown is the synthesis process and nuclear magnetic resonance hydrogen spectrum of hydroxypropyl chitosan, as Figure 2 shown. Nuclear magnetic resonance hydrogen spectrum characterization was performed on the prepared hydroxypropyl chitosan. The figure shows an obvious methyl peak at 1.0 ppm and a significant enhancement of the methylene peak at 3.0-4.0 ppm, indicating that propylene oxide was grafted onto the side chain of chitosan, demonstrating the successful synthesis of the hydroxypropyl chitosan monomer.

[0031] Example 1

[0032] Step 1: Weigh 1 g of γ-polyglutamic acid on a balance and dissolve it in 100 ml of ultrapure water. Add 490 μL of glycidyl methacrylate, and adjust the pH of the reaction solution to about 4.5 with 1 M hydrochloric acid. React in a 60°C water bath for 6 h, then dialyze with ultrapure water for three days, and obtain polyglutamic acid grafted with double bonds after freeze-drying.

[0033] Step 2: Weigh 5 g of chitosan and disperse it in 50 ml of isopropanol. Stir at room temperature for 30 min to make it disperse evenly. Add 30 ml of sodium hydroxide solution with a mass fraction of 33 wt%, and continue to stir at room temperature for 1 h. Place the above solution in a refrigerator at -20°C overnight. After restoring to room temperature the next day, add 10 ml of tetramethylammonium chloride solution with a mass fraction of 10 wt% and 50 ml of propylene oxide, and slowly drip for 1 h. React the mixed solution in a 45°C water bath for 10 h. After the reaction, filter by suction, wash the filter cake with ethanol 2 - 3 times, then redissolve it in deionized water, adjust the pH to about 7 with 1 M hydrochloric acid, dialyze in pure water for 3 days and freeze-dry to obtain hydroxypropyl chitosan.

[0034] Step 3: Weigh 0.2 g of hydroxypropyl chitosan and dissolve it in 10 ml of water to prepare a 2 wt% aqueous solution of hydroxypropyl chitosan (0.2 g of hydroxypropyl chitosan / 10 g of water). Weigh 0.8 g of polyglutamic acid with double bonds and dissolve it in 10 ml of water to prepare an 8 wt% aqueous solution of polyglutamic acid with double bonds (0.8 g of polyglutamic acid with double bonds / 10 g of water). Mix the two solutions evenly at room temperature, stir for 1 h to make the gel fully sediment, then perform freeze-drying, and grind the product into powder to obtain polyglutamic acid with double bonds / hydroxypropyl chitosan gel powder.

[0035] Step 4: Weigh 0.2 g of polyglutamic acid with double bonds / hydroxypropyl chitosan gel powder, add 400 μL of ultrapure water. After the powder is fully wetted by water, stir and knead repeatedly for 15 min to gradually form a smooth dough-like gel on the surface.

[0036] Step 5: Add 10 μL of 10 wt% aqueous solution of potassium persulfate (mass of potassium persulfate / mass of water) to the dough-like gel, and continue to knead for 3 min.

[0037] Step 6: Press the kneaded dough-like gel into a sheet with a thickness of 1 mm, and perform chemical cross-linking by free radical polymerization in a 60°C oven to finally obtain an adhesive hydrogel patch.

[0038] Example 2

[0039] Step 1: Weigh 1 g of γ-polyglutamic acid with a balance and dissolve it in 100 ml of ultrapure water. Add 980 μL of glycidyl methacrylate, and adjust the pH of the reaction solution to about 4.5 with 1 M hydrochloric acid. React in a 60 °C water bath for 6 h, then dialyze with ultrapure water for three days, and obtain polyglutamic acid grafted with double bonds after freeze-drying.

[0040] Step 2: Weigh 5 g of chitosan with a balance and disperse it in 50 ml of isopropanol. Stir at room temperature for 30 min to make it disperse evenly. Add 30 ml of sodium hydroxide solution with a mass fraction of 33 wt%, and continue to stir at room temperature for 1 h. Place the above solution in a refrigerator at -20 °C overnight. After returning to room temperature the next day, add 10 ml of tetramethylammonium chloride solution with a mass fraction of 10 wt% and 50 ml of propylene oxide, and slowly dropwise add for 1 h. React the mixed solution in a 45 °C water bath for 10 h. After the reaction, filter by suction, wash the filter cake with ethanol 2 - 3 times, then redissolve it in deionized water, adjust the pH to about 7 with 1 M hydrochloric acid, dialyze in pure water for 3 days and freeze-dry to obtain hydroxypropyl chitosan.

[0041] Step 3: Weigh 0.3 g of hydroxypropyl chitosan and dissolve it in 10 ml of water to prepare a 3 wt% aqueous solution of hydroxypropyl chitosan. Weigh 0.7 g of polyglutamic acid with double bonds and dissolve it in 10 ml of water to prepare a 7 wt% aqueous solution of polyglutamic acid with double bonds. Mix the two solutions evenly at room temperature, stir for 1 h to make the gel fully sediment, then perform freeze-drying, and grind the product into powder to obtain polyglutamic acid with double bonds / hydroxypropyl chitosan gel powder.

[0042] Step 4: Weigh 0.2 g of polyglutamic acid with double bonds / hydroxypropyl chitosan gel powder, add 300 μL of ultrapure water. After the powder is fully wetted by water, stir and knead repeatedly for 15 min to make the powder gradually form a smooth dough-like gel.

[0043] Step 5: Add 10 μL of 10 wt% potassium persulfate solution to the dough-like gel, and continue to knead for 3 min.

[0044] Step 6: Press the kneaded dough-like gel into a sheet with a thickness of 1 mm, and perform chemical cross-linking by free radical polymerization in a 60 °C oven to finally obtain an adhesive hydrogel patch.

[0045] Example 3

[0046] Step 1: Weigh 1 g of γ-polyglutamic acid with a balance and dissolve it in 100 ml of ultrapure water. Add 490 μL of glycidyl methacrylate, and adjust the pH of the reaction solution to about 4.5 with 1 M hydrochloric acid. React in a 60 °C water bath for 6 h, then dialyze with ultrapure water for three days, and obtain polyglutamic acid grafted with double bonds after freeze-drying.

[0047] Step 2: Weigh 5 g of chitosan and disperse it in 50 ml of isopropanol. Stir at room temperature for 30 min to make it evenly dispersed. Add 30 ml of sodium hydroxide solution with a mass fraction of 33 wt%, and continue to stir at room temperature for 1 h. Place the above solution in a refrigerator at -20 °C overnight. After restoring to room temperature the next day, add 10 ml of tetramethylammonium chloride solution with a mass fraction of 10 wt% and 50 ml of propylene oxide, and slowly dropwise add for 1 h. The mixed solution reacts in a 45 °C water bath for 10 h. After the reaction, filter by suction, wash the filter cake with ethanol 2 - 3 times, then redissolve it in deionized water, adjust the pH to about 7 with 1 M hydrochloric acid, dialyze in pure water for 3 days, and freeze-dry to obtain hydroxypropyl chitosan.

[0048] Step 3: Weigh 0.2 g of hydroxypropyl chitosan and dissolve it in 10 ml of water to prepare a 2 wt% aqueous solution of hydroxypropyl chitosan. Weigh 0.8 g of polyglutamic acid with double bonds and dissolve it in 10 ml of water to prepare an 8 wt% aqueous solution of polyglutamic acid with double bonds. Mix the two solutions evenly at room temperature, stir for 1 h to allow the gel to fully settle, then perform freeze-drying, and grind the product into a powder to obtain polyglutamic acid with double bonds / hydroxypropyl chitosan gel powder.

[0049] Step 4: Weigh 0.2 g of polyglutamic acid with double bonds / hydroxypropyl chitosan gel powder, add 400 μL of rutin aqueous solution (500 μM). After the powder is fully wetted by the solution, stir and knead repeatedly for 15 min to gradually form a gel similar to dough with a smooth surface.

[0050] Step 5: Add 10 μL of 10 wt% potassium persulfate solution to the dough-like gel and continue to knead for 3 min.

[0051] Step 6: Press the kneaded dough-like gel into a sheet with a thickness of 1 mm, and perform chemical cross-linking by free radical polymerization in an oven at 60 °C to finally obtain an adhesive hydrogel patch.

[0052] Example 4

[0053] Step 1: Weigh 1 g of γ-polyglutamic acid and dissolve it in 100 ml of ultrapure water. Add 490 μL of glycidyl methacrylate, adjust the pH of the reaction solution to about 4.5 with 1 M hydrochloric acid, react in a 60 °C water bath for 6 h, then dialyze with ultrapure water for three days, and obtain polyglutamic acid grafted with double bonds after freeze-drying.

[0054] Step 2: Weigh 5 g of chitosan and disperse it in 50 ml of isopropanol. Stir at room temperature for 30 min to make it evenly dispersed. Add 30 ml of sodium hydroxide solution with a mass fraction of 33 wt%, and continue to stir at room temperature for 1 h. Place the above solution in a refrigerator at -20 °C overnight. After restoring to room temperature the next day, add 10 ml of tetramethylammonium chloride solution with a mass fraction of 10 wt% and 50 ml of propylene oxide, and slowly drip for 1 h. The mixed solution reacts in a 45 °C water bath for 10 h. After the reaction, filter by suction, wash the filter cake with ethanol 2 - 3 times, then redissolve it in deionized water, adjust the pH to about 7 with 1 M hydrochloric acid, dialyze in pure water for 3 days, and freeze-dry to obtain hydroxypropyl chitosan.

[0055] Step 3: Weigh 0.2 g of hydroxypropyl chitosan and dissolve it in 10 ml of water to prepare a 2 wt% aqueous solution of hydroxypropyl chitosan. Weigh 0.8 g of double-bonded polyglutamic acid and dissolve it in 10 ml of water to prepare an 8 wt% aqueous solution of double-bonded polyglutamic acid. Mix the two solutions evenly at room temperature, stir for 1 h to allow the gel to fully settle, then perform freeze-drying, and grind the product into a powder to obtain double-bonded polyglutamic acid / hydroxypropyl chitosan gel powder.

[0056] Step 4: Weigh 0.2 g of double-bonded polyglutamic acid / hydroxypropyl chitosan gel powder, add 400 μL of hyaluronic acid nanogel solution loaded with hypoxanthine (the preparation process refers to the literature: C. Yang, C. Li, P. Zhang, W. Wu, X. Jiang, Theranostics 2017, 7, 1719.). After the powder is fully wetted by the solution, stir and knead repeatedly for 15 min until the powder gradually forms a smooth dough-like gel.

[0057] Step 5: Add 10 μL of 10 wt% potassium persulfate solution to the dough-like gel and continue to knead for 3 min.

[0058] Step 6: Press the kneaded dough-like gel into a sheet with a thickness of 1 mm, and perform chemical cross-linking by free radical polymerization in an oven at 60 °C to finally obtain an adhesive hydrogel patch.

[0059] Example 5

[0060] Step 1: Weigh 1 g of γ-polyglutamic acid and dissolve it in 100 ml of ultrapure water. Add 490 μL of glycidyl methacrylate, adjust the pH of the reaction solution to about 4.5 with 1 M hydrochloric acid, react in a 60 °C water bath for 6 h, then dialyze with ultrapure water for three days, and obtain polyglutamic acid grafted with double bonds after freeze-drying.

[0061] Step 2: Weigh 5 g of chitosan and disperse it in 50 ml of isopropanol. Stir at room temperature for 30 min to make it evenly dispersed. Then add 30 ml of sodium hydroxide solution with a mass fraction of 33 wt%, and continue to stir at room temperature for 1 h. The above solution is placed in a refrigerator at -20 °C overnight. After returning to room temperature the next day, add 10 ml of tetramethylammonium chloride solution with a mass fraction of 10 wt% and 50 ml of propylene oxide, and slowly drip them for 1 h. The mixed solution reacts in a 45 °C water bath for 10 h. After the reaction, filter by suction, wash the filter cake with ethanol 2 - 3 times, then redissolve it in deionized water, adjust the pH to about 7 with 1 M hydrochloric acid, dialyze in pure water for 3 days, and freeze-dry to obtain hydroxypropyl chitosan.

[0062] Step 3: Weigh 0.2 g of hydroxypropyl chitosan and dissolve it in 10 ml of water to prepare a 2 wt% aqueous solution of hydroxypropyl chitosan. Weigh 0.8 g of double-bonded polyglutamic acid and dissolve it in 10 ml of water to prepare an 8 wt% aqueous solution of double-bonded polyglutamic acid. Mix the two solutions evenly at room temperature, stir for 1 h to allow the gel to fully settle, then perform freeze-drying, and grind the product into a powder to obtain double-bonded polyglutamic acid / hydroxypropyl chitosan gel powder.

[0063] Step 4: Weigh 0.2 g of double-bonded polyglutamic acid / hydroxypropyl chitosan gel powder, add 200 μL of rutin aqueous solution (concentration: 500 μM) and 200 μL of hyaluronic acid nanogel solution loaded with hypoxanthine (the preparation process refers to the literature: C. Yang, C. Li, P. Zhang, W. Wu, X. Jiang, Theranostics 2017, 7, 1719.). After the powder is fully wetted by the solution, stir and knead it repeatedly for 15 min until the powder gradually forms a smooth dough-like gel.

[0064] Step 5: Add 10 μL of 10 wt% potassium persulfate solution to the dough-like gel and continue to knead for 3 min.

[0065] Step 6: Press the kneaded dough-like gel into a sheet with a thickness of 1 mm, and perform chemical cross-linking by free radical polymerization in an oven at 60 °C to finally obtain an adhesive hydrogel patch.

[0066] Figure 3 Shown is the change in the N-H stretching vibration peak of the amide bond during the kneading process of the hydrogel patch, as Figure 3 Shown is the characterization of the change in the N-H stretching vibration peak of the amide bond during the kneading process of the hydrogel patch by infrared spectroscopy. As the stirring and kneading time increases, the position of the N-H stretching vibration peak shows a red shift, which also proves that the formation of hydrogen bonds between molecular chains is accelerated during the stirring and kneading process, corresponding to the result of the increase in its modulus.

[0067] Figure 4The adhesion of the hydrogel patch prepared by the present invention on the surface of the chicken heart is shown. The patch cannot adhere to the surface of dry tissue, but can adhere well to the surface of wet tissue and can withstand torsion, bending and water flow impact.

[0068] The lap shear test was used to measure the adhesion strength of the hydrogel patch. The lap shear test was carried out at room temperature using a universal electronic tensile testing machine (Legend 2344, Instron). The patch was cut into a size of 1 cm × 1 cm and pasted on the surface of a piece of pigskin, making it contact with another piece of pigskin and overlapping with the same area. The adhesion strength calculation formula is F / S, where F is the maximum load (N) and S is the contact area of each sample (cm 2 ), and the specific reference is the following literature: C.Y. Cui, Y.G. Sun, X.F. Nie, X.X. Yang, F.S. Wang, W.G. Liu, Advanced Functional Materials 2023, 2307543. As Figure 5 shown in the characterization of the adhesion strength of the hydrogel patch, compared with the gel powder and the dough-like gel without chemical crosslinking, the adhesion strength of the hydrogel patch of the present invention is increased to about 15 kPa, indicating that the improvement of the strength of the patch body helps to improve the adhesion performance of the patch.

[0069] As Figure 6 shown is the change in the modulus of the gel during the kneading process of the hydrogel patch. As the stirring and kneading time increases (from left to right in the figure), the hydrated powder gradually becomes viscoelastic from the viscous flow state, indicating the formation of the hydrogel. Subsequently, the modulus continues to increase, proving that the formation of hydrogen bonds between molecular chains is accelerated during the stirring and kneading process.

[0070] The animal experiment model was a male SD rat myocardial infarction model with left anterior descending artery ligation. The hydrogel patches prepared with different hydrating agents were respectively adhered to the myocardial lesion sites of the rats, and observation and characterization were carried out for 28 days after the operation, as Figure 7 shown. The patch prepared in Example 1 was named Patch A, the patch prepared in Example 3 was named Patch B, the patch prepared in Example 4 was named Patch C, the patch prepared in Example 5 was named Patch D. In addition, a sham operation group was set and named Sham, and an untreated model group was named MI.

[0071] Among them, (a)-(c) are the echocardiogram images of rats and the corresponding statistical analysis of left ventricular ejection fraction and fractional shortening. Compared with the model group, in the rats treated with the hydrogel patch, by releasing drugs at the lesion site, the cardiac function of the rats was gradually improved after the operation; (d)-(f) are the HE staining and Masson staining results of rat myocardium and the corresponding statistical analysis of left ventricular wall thickness and fibrosis area. The results show that through the synergistic effect of the two drugs, Patch D group can maintain the normal morphology of rat myocardium, significantly increase the left ventricular wall thickness of rats after myocardial infarction, reduce the fibrosis area, and effectively reduce the risk of heart failure after myocardial infarction; (g) is the immunofluorescence staining of type I collagen, type III collagen and WGA on rat myocardium, further confirming that the application of Patch D can reduce the excessive deposition of extracellular matrix, reduce the degree of myocardial fibrosis and the occurrence of myocardial hypertrophy.

[0072] According to the content of the present invention, the adjustment of process parameters can realize the preparation of the hydrogel. After testing, it shows basically the same performance as the present invention. The above is an exemplary description of the present invention. It should be noted that any simple deformation, modification or equivalent substitution that can be made by those skilled in the art without creative labor falls within the protection scope of the present invention without departing from the core of the present invention.

Claims

1. An adhesive hydrogel patch, characterized in that, it is carried out according to the following steps: Step 1, Mix an aqueous solution of glycidyl methacrylate-grafted γ-polyglutamic acid and hydroxypropyl chitosan to obtain a condensate through electrostatic interaction. After precipitation, it is freeze-dried and ground into a powder to obtain a double-bond polyglutamic acid / hydroxypropyl chitosan gel powder; the mass ratio of hydroxypropyl chitosan to glycidyl methacrylate-grafted γ-polyglutamic acid is (1-6):(4-10); in the aqueous solution, the total solid content of glycidyl methacrylate-grafted γ-polyglutamic acid and hydroxypropyl chitosan is 10-15 wt%; Step 2, Add a hydrating agent to the double-bond polyglutamic acid / hydroxypropyl chitosan gel powder for infiltration, and knead repeatedly until the gel powder forms a smooth dough gel. Then add an aqueous solution in which the initiator is uniformly dispersed, continue to knead and then press into tablets, and carry out chemical cross-linking through free radical polymerization to obtain an adhesive gel patch. The mass ratio of the double-bond polyglutamic acid / hydroxypropyl chitosan gel powder to the hydrating agent is 1:(1-6), and the hydrating agent is ultrapure water, a drug solution with biological functions or a solution dispersing nanoparticles.

2. An adhesive hydrogel patch according to claim 1, characterized in that, in Step 1, the mass ratio of hydroxypropyl chitosan to glycidyl methacrylate-grafted γ-polyglutamic acid is (2-4):(6-8); in the aqueous solution, the total solid content of glycidyl methacrylate-grafted γ-polyglutamic acid and hydroxypropyl chitosan is 10 wt%.

3. An adhesive hydrogel patch according to claim 1, characterized in that, in Step 2, after infiltration, the time of repeated stirring and kneading is 10-15 min to form a smooth dough gel; the time of continued kneading after adding the aqueous solution in which the initiator is uniformly dispersed is 3-6 min.

4. An adhesive hydrogel patch according to claim 1, characterized in that, in Step 2, the initiator is a thermal initiator such as potassium persulfate, and free radical initiation and polymerization are carried out by placing the kneaded material in an oven above the initiation temperature.

5. An adhesive hydrogel patch according to claim 4, characterized in that, in Step 2, the initiation temperature is 50-80 °C, and the polymerization time is 10-30 min.

6. An adhesive hydrogel patch according to claim 1, characterized in that, in Step 2, the mass ratio of the double-bond polyglutamic acid / hydroxypropyl chitosan gel powder to the hydrating agent is 1:(1-4).

7. A preparation method of an adhesive hydrogel patch, characterized in that, it is carried out according to the following steps: Step 1: Mix an aqueous solution of glycidyl methacrylate-grafted γ-polyglutamic acid and hydroxypropyl chitosan to obtain a coacervate through electrostatic interaction. After precipitation, it is freeze-dried and ground into a powder to obtain a double-bonded polyglutamic acid / hydroxypropyl chitosan gel powder; the mass ratio of hydroxypropyl chitosan to glycidyl methacrylate-grafted γ-polyglutamic acid is (1-6):(4-10); in the aqueous solution, the total solid content of glycidyl methacrylate-grafted γ-polyglutamic acid and hydroxypropyl chitosan is 10-15 wt%. Step 2: Add a hydrating agent to the double-bonded polyglutamic acid / hydroxypropyl chitosan gel powder for infiltration, and knead repeatedly until a smooth-surfaced dough gel is formed. Then add an aqueous solution in which an initiator is uniformly dispersed, continue kneading and then press into tablets, and carry out chemical cross-linking through free radical polymerization to obtain an adhesive gel patch. The mass ratio of the double-bonded polyglutamic acid / hydroxypropyl chitosan gel powder to the hydrating agent is 1:(1-6), and the hydrating agent is ultrapure water, a drug solution with biological functions or a solution dispersing nanoparticles.

8. The preparation method of an adhesive hydrogel patch according to claim 7, characterized in that, in Step 1, the mass ratio of hydroxypropyl chitosan to glycidyl methacrylate-grafted γ-polyglutamic acid is (2-4):(6-8); in the aqueous solution, the total solid content of glycidyl methacrylate-grafted γ-polyglutamic acid and hydroxypropyl chitosan is 10 wt%.

9. The preparation method of an adhesive hydrogel patch according to claim 7, characterized in that, in Step 2, after infiltration, the time for repeated stirring and kneading is 10-15 min to form a smooth-surfaced dough gel; when adding the aqueous solution in which an initiator is uniformly dispersed, the time for continued kneading is 3-6 min, and the initiator is a thermal initiator such as potassium persulfate. Free radical initiation and polymerization are carried out by placing the kneaded material in an oven above the initiation temperature, the initiation temperature is 50-80 °C, and the polymerization time is 10-30 min; the mass ratio of the double-bonded polyglutamic acid / hydroxypropyl chitosan gel powder to the hydrating agent is 1:(1-4).

10. The application of an adhesive hydrogel patch according to any one of claims 1-6 in the field of tissue engineering, the preparation of drugs or devices for treating myocardial infarction.

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