A tissue adhesive and its preparation method and application

Abstract

The application discloses a tissue adhesive and a preparation method and application thereof, and belongs to the field of medical materials.The tissue adhesive comprises a copolymer composed of at least one of acrylic acid and methacrylic acid and a hydrochloride salt, the hydrochloride salt is at least one of 2-aminoethyl methacrylic acid ester hydrochloride and 2-aminoethyl acrylic acid ester hydrochloride, and the tissue adhesive can further comprise a crosslinked polymer formed by crosslinking at least one of polyacrylic acid and polymethacrylic acid with a polymer, and the polymer is formed by polymerization of the hydrochloride salt and a zwitterionic betaine.The copolymer can quickly absorb moisture on a wet tissue surface to form a gel and adhere to the tissue surface, so that a soft tissue wound, especially a low-pH microenvironment soft tissue wound, is closed; and the crosslinked polymer can be firmly combined on the surface of the copolymer and quickly form an anti-adhesion gel, which effectively prevents the surrounding tissue from being adhered after an operation as a physical barrier.

Description

Technical Field

[0001] The present invention belongs to the field of polymer materials, and in particular relates to a tissue adhesive and a preparation method and application thereof. Background Art

[0002] Tissue adhesives are clinical examples used to close wounds non-invasively, prevent body fluid leakage, and promote wound healing, such as Bioglue™, Coseal™, Tisseel™ and other surgical sealants.

[0003] Common adhesive at present is by the physical interactions such as hydrogen bond, electrostatic action, intermolecular action, or by chemical crosslinking with the functional groups such as tissue surface amino, sulfhydryl, adheres to tissue surface and as physical barrier, closes wound, prevents liquid or gas leakage.As disclosed in the Chinese patent of publication number CN114848668A, a kind of composition with promoting wound healing and hemostasis function is disclosed, comprising polyacrylic acid and polyethyleneimine, can effectively promote the healing of gastrointestinal perforation, quickly and effectively stops bleeding.But this powder is respectively mixed by two kinds of polymers, contains two kinds of components, can not reach the effect of molecular level in mixing process, there is uneven situation, the adhesive force to tissue is weak, and stable gel can not be formed and adheres to tissue surface, can not be long-acting, stable sealing tissue wound, can not meet clinical demand well.

[0004] In addition, most tissue adhesives have double-sided adhesion properties. After being applied to the target tissue, they will adhere to the surrounding tissues, causing adverse postoperative adhesions, leading to serious consequences such as chronic pelvic pain, intestinal obstruction, and infertility. To address this problem, a Chinese patent with publication number CN113577370A discloses a Janus hydrogel adhesive and its preparation method and application. The Janus hydrogel adhesive contains an acrylic acid hydrogel as an adhesion layer and an acrylamide hydrogel as an anti-adhesion layer. It can not only adhere to the tissue surface and seal the wound, but also effectively prevent its adhesion to the surrounding tissues and prevent postoperative adhesions. However, this block-shaped hydrogel adhesive cannot fit well on tissues with uneven surfaces, and the unreacted small molecules remaining in the hydrogel have toxic side effects on biological tissues and are difficult to biodegrade. When applied to the human body, it may not be degraded for a long time and may be coated and turned into a foreign body, causing an inflammatory reaction. Summary of the Invention

[0005] Purpose of the invention: The first purpose of the present invention is to provide a tissue adhesive that is stable and uniform, has high adhesion strength, is suitable for irregular wounds, and has good biocompatibility, as well as a preparation method and application thereof; the second purpose of the present invention is to provide a tissue adhesive that has both tissue adhesion and anti-tissue adhesion properties, as well as a preparation method and application thereof.

[0006] Technical solution: The tissue adhesive comprises a copolymer composed of at least one of acrylic acid and methacrylic acid and a hydrochloride, wherein the hydrochloride is at least one of 2-aminoethyl methacrylate hydrochloride and 2-aminoethyl acrylate hydrochloride.

[0007] Preferably, the mass ratio of the at least one of acrylic acid and methacrylate acid to the hydrochloride is 1:3-19:1.

[0008] Preferably, the surface of the copolymer further comprises a cross-linked polymer formed by cross-linking at least one of polyacrylic acid and polymethacrylic acid with a polymer formed by polymerization of the hydrochloride and a zwitterionic betaine.

[0009] Preferably, the zwitterionic betaine is at least one of sulfobetaine, carboxybetaine and phosphorylcholine.

[0010] Preferably, the mass percentage of the zwitterionic betaine in the polymer is 15-70%, and the mass percentage of the at least one of polyacrylic acid and polymethacrylic acid in the cross-linked polymer is 10-30%.

[0011] The preparation method of the tissue adhesive comprises the following steps: taking at least one of acrylic acid and methacrylic acid and a hydrochloride, adding an initiator and a solvent, initiating a polymerization reaction, purifying the solution after the reaction, freeze-drying and grinding to obtain a copolymer powder.

[0012] Preferably, the mass percentage of the at least one of acrylic acid and methacrylic acid and the at least one of 2-aminoethyl methacrylate hydrochloride and 2-aminoethyl acrylate hydrochloride in the solvent is 5-25%, the percentage of the initiator in the solvent is 0.05-2%, the reaction time of the polymerization reaction is 10 min-48 h, and the polymerization reaction is carried out at a reaction temperature of 20-85°C or under irradiation of ultraviolet light with an intensity of 10-500 mW / cm 2 .

[0013] Preferably, after obtaining the copolymer powder, a hydrochloride and a zwitterionic betaine are taken, an initiator and a solvent are added, a polymerization reaction is initiated, the solution after the reaction is purified to obtain a polymer, at least one of polyacrylic acid and polymethacrylic acid and the polymer are taken, a solvent is added for dissolution, under stirring, an alkali is added to adjust the pH of the solution to be between 6.5 and 7.5, and the obtained solid is subjected to freeze-drying and grinding to obtain a cross-linked polymer powder.

[0014] Preferably, the mass percentage of at least one of the 2-aminoethyl methacrylate hydrochloride, 2-aminoethyl acrylate hydrochloride and zwitterionic betaine in the solvent is 5-25%; the percentage of the initiator in the solvent mass is 0.05-2%; the reaction time of the polymerization reaction is 10 min-48 h; the polymerization reaction is carried out at a reaction temperature of 20-85℃ or under the irradiation of ultraviolet light with an intensity of 10-500 mW / cm 2 Preferably, the percentage of at least one of the polyacrylic acid, polymethacrylic acid and the copolymer in the solvent mass is 1-20%.

[0015] The application of the tissue adhesive in medical adhesives.

[0016] Preferably, the tissue adhesive is used for various soft tissue wounds with uneven surfaces and soft tissue wounds in low-pH microenvironments.

[0017] Preferably, the specific application method is to apply the copolymer on the surface of the soft tissue wound, and then apply the cross-linked polymer on the surface of the copolymer.

[0018] Preferably, the specific application method is to apply the copolymer powder on the surface of the soft tissue wound, and then apply the cross-linked polymer powder on the surface of the copolymer powder.

[0019] Preferably, the specific application method is to apply the copolymer powder on the surface of the soft tissue wound, and then add water to the cross-linked polymer powder to form a gel and then adhere to the surface of the copolymer powder.

[0020] The application principle is that 2-aminoethyl methacrylate hydrochloride and 2-aminoethyl acrylate hydrochloride contain double bonds and can participate in polymerization for molecular design, and are commonly used for polymer synthesis or as pH buffering materials, and there is no related report on the preparation of gels for tissue adhesion. In the present application, at least one of acrylic acid, methacrylic acid and at least one of 2-aminoethyl methacrylate hydrochloride and 2-aminoethyl acrylate hydrochloride are combined to form a copolymer, and the carboxylic acid groups contained in acrylic acid and methacrylic acid and the rich primary amine groups contained in 2-aminoethyl methacrylate hydrochloride and 2-aminoethyl acrylate hydrochloride are cross-linked to form a microgel, which has high reactivity. After contacting with a wet tissue, the copolymer can quickly absorb water, cross-link to form a stable and uniform gel, and adhere to the surface of the tissue through the excess carboxylic acid groups to seal the tissue wound. In addition, the carboxyl / amino groups in the cross-linked polymer can cross-link with the carboxyl / amino groups in the copolymer to produce a stable bond, and at the same time, the gel formed by the water absorption of the cross-linked polymer can act as a non-adhesive physical barrier to isolate the surrounding tissue. In addition, the zwitterionic polymer material contained in the gel further improves its anti-cell / tissue adhesion function, thereby exhibiting good anti-tissue adhesion effect.

[0021] Advantages: Compared with the prior art, the present application has the following remarkable advantages:

[0022] (1) The tissue adhesive prepared by the present application is stable and uniform, has high adhesion strength to wet tissues (more than 40 kPa), and a burst pressure of more than 200 mmHg, which is higher than that of commercially available fibrin glue products (adhesion strength of about 20-30 kPa), and can be used to seal soft tissue wounds and promote wound healing; it is suitable for soft tissue wounds in low-pH microenvironment (such as gastric perforation); it is suitable for various irregular tissue wounds, is easy to use, and closely adheres to the tissue without the need for external conditions (such as ultraviolet light) to assist gelation; it also has broad-spectrum antibacterial activity and can reduce the incidence of wound infection.

[0023] (2) The tissue adhesive prepared by the present application further comprises an anti-adhesion cross-linked polymer, and the copolymer and the cross-linked polymer are firmly and stably combined, and have both tissue adhesion and anti-adhesion functions, and can provide long-acting anti-adhesion effect during the wound healing period.

[0024] (3) The components and storage conditions of the present application are simple, the preparation process is simple and easy to implement, and the present application is easy to mass-produce and has great application value; the present application does not use organic solvents, and all components are macromolecular polymers, and have good cell compatibility. BRIEF DESCRIPTION OF DRAWINGS

[0025] Figure 1 Figure 4 is a graph showing the adhesion strength of the copolymer powder prepared in Example 4 to different tissues;

[0026] Figure 2 Figure 5 is a graph showing the adhesion strength of the copolymer powder prepared in Comparative Example 1 to different tissues;

[0027] Figure 3 Figure 6 is a graph showing the sealing capacity of the copolymer powder prepared in Example 4 to different defect tissues;

[0028] Figure 4 Figure 7 is a graph showing the long-term adhesion of the copolymer powder prepared in Example 4 to different wet tissues;

[0029] Figure 5 Figure 8 is a graph showing the bactericidal effect of the copolymer powder prepared in Example 4;

[0030] Figure 6 Figure 9 is a graph showing the stable combination of the copolymer powder prepared in Example 5 and the cross-linked polymer powder;

[0031] Figure 7 Figure 10 is a graph showing the cytotoxicity of the copolymer powder and the cross-linked polymer powder prepared in Example 5;

[0032] Figure 8Preparation of copolymer powder of Example 5 before and after adding cross-linking polymer powder for anti-adhesion of tissue;

[0033] Figure 9 Pictures of tissue repair after treatment of gastric perforation using suture, commercial fibrin sealant and tissue adhesive of Example 5, respectively. DETAILED DESCRIPTION

[0034] The technical solutions of the present application are further described below with reference to the drawings.

[0035] Example 1

[0036] A tissue adhesive comprises a copolymer of acrylic acid and 2-aminoethyl methacrylate hydrochloride. The preparation method of the tissue adhesive comprises the following steps: weighing 0.25 g of acrylic acid, 0.75 g of 2-aminoethyl methacrylate hydrochloride and 0.01 g of potassium persulfate, dissolving in 20 mL of deionized water, reacting at 85°C for 48 h, dialyzing the reacted solution, freeze-drying and grinding the dialyzed solution to obtain copolymer powder.

[0037] Example 2

[0038] A tissue adhesive comprises a copolymer of methacrylic acid and 2-aminoethyl acrylate hydrochloride. The preparation method of the tissue adhesive comprises the following steps: weighing 4.75 g of methacrylic acid, 0.25 g of 2-aminoethyl acrylate hydrochloride and 0.01 g of potassium persulfate, dissolving in 20 mL of deionized water, reacting at 75°C for 24 h, dialyzing the reacted solution, freeze-drying and grinding the dialyzed solution to obtain copolymer powder.

[0039] Example 3

[0040] A tissue adhesive comprises a copolymer of acrylic acid and 2-aminoethyl methacrylate hydrochloride. The preparation method of the tissue adhesive comprises the following steps: weighing 0.5 g of acrylic acid, 0.5 g of 2-aminoethyl methacrylate hydrochloride and 0.01 g of potassium persulfate, dissolving in 20 mL of deionized water, reacting at 65°C for 48 h, dialyzing the reacted solution, freeze-drying and grinding the dialyzed solution to obtain copolymer powder.

[0041] Example 4

[0042] A tissue adhesive comprising a copolymer of acrylic acid and 2-aminoethyl methacrylate hydrochloride. A method for preparing the tissue adhesive, comprising the steps of: weighing 0.635 g of acrylic acid and 0.365 g of 2-aminoethyl methacrylate hydrochloride, 0.033 g of ammonium persulfate, dissolving in 10 mL of deionized water, reacting at 75°C for 24 h, dialyzing the reacted solution, and freeze-drying and grinding the dialyzed solution to obtain a copolymer powder.

[0043] Example 5

[0044] A tissue adhesive comprising a copolymer of acrylic acid and 2-aminoethyl methacrylate hydrochloride, and a cross-linked polymer of polyacrylic acid cross-linked 2-aminoethyl methacrylate hydrochloride / sulfobetaine polymer. A method for preparing the tissue adhesive, comprising the steps of:

[0045] (1) Weighing 0.635 g of acrylic acid and 0.365 g of 2-aminoethyl methacrylate hydrochloride, 0.033 g of ammonium persulfate, dissolving in 10 mL of deionized water, reacting at 75°C for 24 h, dialyzing the reacted solution, and freeze-drying and grinding the dialyzed solution to obtain a copolymer powder.

[0046] (2) Weighing 0.5 g of sulfobetaine, 0.5 g of 2-aminoethyl methacrylate hydrochloride, 0.0075 g of 2,2'-azobis(2-methyl-N-(2-hydroxyethyl)propionamide), dissolving in 4.5 mL of deionized water, and reacting under ultraviolet light (60 mW / cm2) for 1 h, dialyzing the reacted solution, and freeze-drying and grinding the dialyzed solution to obtain a copolymer of 2-aminoethyl methacrylate hydrochloride and sulfobetaine;

[0047] (3) Weighing 0.174 g of polyacrylic acid and 0.8 g of the copolymer obtained in step (2), dissolving in 20 mL of deionized water, adding sodium hydroxide solution under stirring to adjust the pH of the solution to about 7, freeze-drying the obtained solid, and grinding to obtain a cross-linked polymer powder.

[0048] Example 6

[0049] A tissue adhesive comprising a copolymer of acrylic acid and 2-aminoethyl methacrylate hydrochloride, and a cross-linked polymer of polyacrylic acid cross-linked 2-aminoethyl methacrylate hydrochloride / sulfobetaine polymer. A method for preparing the tissue adhesive, comprising the steps of:

[0050] (1) Take 0.9 g of acrylic acid, 0.1 g of 2-aminoethyl methacrylate hydrochloride, 0.08 g of α-ketoglutaric acid, dissolve in 4 mL of deionized water, react under ultraviolet light (500 mW / cm2) for 10 min, dialyze the solution after reaction, and freeze-dry, grind the dialyzed solution to obtain a copolymer powder.

[0051] (2) Take 0.7 g of phosphocholine zwitterion, 0.3 g of 2-aminoethyl acrylate hydrochloride, 0.066 g of potassium persulfate, dissolve in 6.6 mL of deionized water, react at 60°C for 48 h, dialyze the solution after reaction, and freeze-dry, grind the dialyzed solution to obtain a copolymer of 2-aminoethyl acrylate hydrochloride and phosphocholine zwitterion;

[0052] (3) Take 0.3 g of polymethacrylic acid and 0.7 g of the copolymer obtained in step (2), dissolve in 100 mL of deionized water, add sodium bicarbonate solution to adjust the solution pH to 7.5 under stirring, freeze-dry the obtained solid, and grind to obtain a cross-linked polymer powder.

[0053] Example 7

[0054] A tissue adhesive comprising a copolymer of acrylic acid and 2-aminoethyl methacrylate hydrochloride copolymer, and further comprising a cross-linked polymer of 2-aminoethyl acrylate hydrochloride / carboxybetaine polymer cross-linked with polymethacrylic acid. A method for preparing the tissue adhesive, comprising the following steps:

[0055] (1) Take 0.7 g of acrylic acid, 0.3 g of 2-aminoethyl methacrylate hydrochloride, 0.08 g of α-ketoglutaric acid, dissolve in 4 mL of deionized water, react under ultraviolet light (500 mW / cm2) for 30 min, dialyze the solution after reaction, and freeze-dry, grind the dialyzed solution to obtain a copolymer powder.

[0056] (2) Take 0.15 g of carboxybetaine, 0.85 g of 2-aminoethyl acrylate hydrochloride, 0.066 g of potassium persulfate, dissolve in 6.6 mL of deionized water, react at 60°C for 48 h, dialyze the solution after reaction, and freeze-dry, grind the dialyzed solution to obtain a copolymer of 2-aminoethyl acrylate hydrochloride and carboxybetaine;

[0057] (3) Take 0.1 g of polymethacrylic acid and 0.9 g of the copolymer obtained in step (2), dissolve in 20 mL of deionized water, add sodium bicarbonate solution to adjust the solution pH to 6.5 under stirring, freeze-dry the obtained solid, and grind to obtain a cross-linked polymer powder.

[0058] Example 8

[0059] A tissue adhesive comprising a copolymer of acrylic acid and 2-aminoethyl methacrylate hydrochloride, further comprising a cross-linked polymer of polyacrylic acid cross-linked 2-aminoethyl methacrylate hydrochloride / sulfobetaine. A method of preparing the tissue adhesive comprising the steps of:

[0060] (1) Weigh 0.7 g of acrylic acid, 0.3 g of 2-aminoethyl methacrylate hydrochloride, 0.08 g of alpha-ketoglutaric acid, dissolve in 4 mL of deionized water, react under ultraviolet light (500 mW / cm2) for 30 min, dialyze the solution after reaction, and freeze-dry the dialyzed solution to obtain a copolymer powder.

[0061] (2) Weigh 0.425 g of sulfobetaine, 0.575 g of 2-aminoethyl methacrylate hydrochloride, 0.066 g of potassium persulfate, dissolve in 6.6 mL of deionized water, react at 60°C for 48 h, dialyze the solution after reaction, and freeze-dry the dialyzed solution to obtain a copolymer of 2-aminoethyl methacrylate hydrochloride and sulfobetaine.

[0062] (3) Weigh 0.2 g of polyacrylic acid and 0.8 g of the copolymer obtained in step (2), dissolve in 20 mL of deionized water, add sodium bicarbonate solution to adjust the pH of the solution to 7.5 under stirring, freeze-dry the obtained solid, and grind to obtain a cross-linked polymer powder.

[0063] Comparative Example 1

[0064] A tissue adhesive comprising a copolymer of acrylic acid and acrylamide. A method of preparing the tissue adhesive comprising the steps of: weighing 0.5 g of acrylic acid and 0.5 g of acrylamide, 0.01 g of ammonium persulfate, dissolving in 10 mL of deionized water, reacting at 75°C for 24 h, dialyzing the solution after reaction, and freeze-drying the dialyzed solution to obtain a copolymer powder.

[0065] Comparative Example 2

[0066] A tissue adhesive comprising a copolymer of acrylic acid and 2-aminoethyl methacrylate hydrochloride. A method of preparing the tissue adhesive comprising the steps of: weighing 0.1 g of acrylic acid and 0.9 g of 2-aminoethyl methacrylate hydrochloride, 0.02 g of ammonium persulfate, dissolving in 10 mL of deionized water, reacting at 75°C for 24 h, dialyzing the solution after reaction, and freeze-drying the dialyzed solution to obtain a copolymer powder.

[0067] The copolymer powder prepared in Example 4 was subjected to lap shear test to test the adhesion strength of the copolymer powder. 25 mg of the copolymer powder was coated on the surface of two pieces of wet chicken skin, pig liver, pig heart, pig stomach and pig small intestine tissue respectively, and the coating area was 180 mm 2 After lapping, the copolymer was fully contacted with the adherend by pressing at 8 kPa for 5 minutes at 37°C. The adhesion performance of the copolymer powder to the wet tissue was measured using a universal testing machine by using a lap shear test model. The adhesion strength = F max / S, F max is the maximum force during the measurement, and S is the area of the adhesion region. The experimental results are shown in Table 1. Figure 1 The adhesion strength of the copolymer powder to different wet biological tissues was between 40-65 kPa, indicating that the copolymer powder as a tissue adhesive had strong adhesion performance to different wet biological tissues.

[0068] The copolymer powder prepared in Comparative Example 1 was subjected to lap shear test to test the adhesion strength of the copolymer powder, and the test parameters were the same as the above lap shear test. The experimental results are shown in Table 2. Figure 2 The adhesion strength of the copolymer powder prepared in Comparative Example 2 to different biological tissues was less than 5 kPa, which was significantly lower than the adhesion strength of the copolymer powder prepared in Example 4, indicating that the copolymer powder prepared in Comparative Example 1 had poor adhesion performance to tissues.

[0069] The copolymer powder prepared in Example 4 was subjected to burst pressure test to test the sealing performance of the copolymer powder to the damaged tissue. The burst pressure test model was used to measure the sealing ability of the copolymer powder to the wounds of chicken skin, pig small intestine and pig stomach. 40 mg of the copolymer powder was scattered on the wound with a diameter of 3 mm, and then pressed at 8 kPa for 5 minutes at 37°C. Then the sealed tissue was placed on the burst pressure test device, and the maximum pressure during the measurement was recorded as the burst pressure. The experimental results are shown in Table 3. Figure 3 The copolymer powder could withstand a burst pressure higher than 200 mmHg after sealing the damaged tissue, indicating that the copolymer powder as a tissue adhesive had strong wound sealing performance.

[0070] Take the copolymer powder prepared in Example 4 and test its long-term adhesion performance to different wet biological tissues. Take an appropriate amount of copolymer powder and apply it to the surface of chicken skin and pig heart. After pressing at a pressure of 8kPa at 37°C for 5 minutes, immerse it in PBS for 12 hours, and rinse it with high-flow water to observe whether the copolymer powder falls off. Use copolymer powder to seal pig small intestine and pig stomach with liquid leakage (artificial intestinal juice, artificial gastric juice (pH=1.5)). The pig small intestine is immersed in artificial intestinal juice for 12 hours, and the pig stomach is immersed in artificial gastric juice (pH=1.5) for 12 hours to observe whether the copolymer powder falls off. The experimental results are as follows. Figure 4 As shown, after the copolymer powder contacts wet biological tissue, it forms a stable gel and adheres to the tissue surface, which can seal tissue wounds in a long-term and stable manner.

[0071] The copolymer powder prepared in Example 4 was used for antibacterial performance test. 40 mg of the copolymer powder was taken and formed into a gel after contact with water. The gel was sterilized with 75% alcohol. The washed gel was then mixed with a bacterial solution (Staphylococcus aureus: 10 5 CFU / mL, methicillin-resistant Staphylococcus aureus: 10 5 CFU / mL; Escherichia coli: 10 4 CFU / mL) were co-cultured for 24 h, and then the number of residual bacteria was detected by plate counting method. Figure 5 As shown, after the copolymer powder forms a gel, the sterilization rates against Staphylococcus aureus, Escherichia coli and methicillin-resistant Staphylococcus aureus are 99.4%, 96.2% and 99.9% respectively, showing a broad-spectrum and highly effective sterilization activity.

[0072] The copolymer powder and cross-linked polymer powder prepared in Example 5 were used to test their binding ability. After using the copolymer powder to seal the leaking small intestinal tissue, the cross-linked polymer powder was applied to the surface of the copolymer powder. The small intestinal tissue was immersed in phosphate buffer solution for 12 hours to observe whether the gel formed by the cross-linked polymer powder was firmly bound to the surface of the gel formed by the copolymer powder. The experimental results are shown in Figure 2. Figure 6 As shown, the gel formed by the cross-linked polymer powder can be stably and firmly bound to the surface of the gel formed by the copolymer powder and serve as a physical barrier to isolate the gel formed by the copolymer powder.

[0073] The copolymer powder and cross-linked polymer powder prepared in Example 5 were subjected to cytotoxicity test. Cell viability test and cell live / death observation test were used to test the cell compatibility of the copolymer powder and cross-linked polymer powder. Figure 7As shown, the copolymer powder and the cross-linked polymer powder have no obvious cytotoxicity to the mouse fibroblasts, and the cells grow well, indicating that the copolymer powder and the cross-linked polymer powder have good cell compatibility.

[0074] The copolymer powder and the cross-linked polymer powder prepared in Example 5 were taken for in vivo anti-adhesion test. The control group was only applied with the copolymer powder subcutaneously on the rat, and the experimental group was applied with the copolymer powder subcutaneously on the rat first, and then applied with the gel formed by the cross-linked polymer powder on the surface of the copolymer powder, and after one week of implantation, the subcutaneous tissue adhesion of the rat was observed. The experimental results are shown in Figure 8 As shown, the muscle tissue and the skin tissue of the rat in the control group were obviously adhered, while in the experimental group, the gel formed by the cross-linked polymer powder effectively prevented the copolymer powder from adhering to the skin tissue of the rat, and no obvious tissue adhesion was observed, indicating that the cross-linked polymer powder has good anti-adhesion performance.

[0075] The copolymer powder and the cross-linked polymer powder prepared in Example 5 were taken for in vivo gastric perforation repair experiment (low pH microenvironment). A gastric perforation model was established in the rat stomach, and the gastric perforation diameter was 5 mm. One group was sutured at the perforation site with a suture, one group was sealed with a commercial fibrin tissue sealant, one group was sealed with the copolymer powder, and then the copolymer powder was covered with the cross-linked polymer powder, and after seven days, the gastric perforation repair was observed. The experimental results are shown in Figure 9 As shown, the sutured site was obviously adhered and the tissue was not completely healed, and the wounds sealed with the fibrin sealant and the copolymer powder / cross-linked polymer powder were almost completely healed, and compared with the fibrin sealant, the copolymer powder / cross-linked polymer powder showed better anti-adhesion performance, which indicates that the tissue adhesive composed of the copolymer powder / cross-linked polymer powder can be used to seal the tissue wounds in the low pH microenvironment, promote wound healing, and prevent tissue adhesion.

Claims

1. A tissue adhesive, characterized in that The invention relates to a copolymer comprising at least one of acrylic acid and methacrylic acid and hydrochloride, wherein the hydrochloride is at least one of 2-aminoethyl methacrylate hydrochloride and 2-aminoethyl acrylate hydrochloride; the surface of the copolymer further comprises a cross-linked polymer, wherein the cross-linked polymer is formed by cross-linking at least one of polyacrylic acid and polymethacrylic acid with a polymer, wherein the polymer is formed by polymerizing the hydrochloride and zwitterionic betaine.

2. The tissue adhesive according to claim 1, characterized in that The mass ratio of at least one of the acrylic acid and methacrylic acid to the hydrochloride is 1:3 to 19:

1.

3. The tissue adhesive according to claim 1, characterized in that The mass percentage of the zwitterionic betaine in the polymer is 15-70%; the mass percentage of at least one of polyacrylic acid and polymethacrylic acid in the cross-linked polymer is 10-30%.

4. A method for preparing the tissue adhesive according to claim 1, characterized in that: The following steps are involved: The method comprises the following steps: taking at least one of acrylic acid and methacrylic acid and hydrochloride, adding an initiator and a solvent, initiating a polymerization reaction, purifying the post-reaction solution, freeze-drying, and grinding to obtain a copolymer powder; after obtaining the copolymer powder, taking the hydrochloride and zwitterionic betaine, adding an initiator and a solvent, initiating a polymerization reaction, and purifying the post-reaction solution to obtain a polymer; taking at least one of polyacrylic acid and polymethacrylic acid and the polymer, adding a solvent to dissolve the polymer, adding a base to adjust the pH of the solution to between 6.5 and 7.5 under stirring conditions, and freeze-drying and grinding the obtained solid to obtain a cross-linked polymer powder.

5. Use of the tissue adhesive according to any one of claims 1 to 3 in the preparation of a medical adhesive.

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