Injection type in-situ wet adhesion hemostatic hydrogel and application thereof

Abstract

The invention discloses an injection type in-situ wet adhesion hemostasis hydrogel and application thereof. The injection type in-situ wet adhesion hemostasis hydrogel comprises a solution A, a solution B, a solution C and a solution D, the solute of the solution A is a first high polymer material containing an aldehyde group or an aldehyde group precursor; the solute of the solution B is a water-based polymer material containing amino; the solute of the solution C is a thickening high polymer material containing amino; the solute of the solution D is a second high polymer material for improving the rheological property of the solution. The injection type in-situ wet adhesion hemostatic hydrogel is a gel material with good biocompatibility, degradability and wet adhesion performance.

Description

Technical Field

[0001] The invention belongs to the technical field of hemostatic gels, and in particular relates to an injectable in-situ wet-adhesive hemostatic hydrogel and an application thereof. Background Art

[0002] At present, all kinds of surgery have the risk of bleeding. Taking liver surgery as an example, inappropriate hemostasis methods may cause secondary damage or affect the recovery of liver function. The current hemostasis methods mainly include mechanical compression, electrocoagulation hemostasis, suturing, ligation and the use of various hemostatic materials. Early commercial hemostatic materials are mainly gelatin sponges, oxidized cellulose sponges, animal-derived collagen or fibrin glue. Although these materials have certain hemostatic effects in clinical applications, they often have the following limitations: (1) Insufficient or insufficient hemostasis efficiency. In the case of large wounds in tissues such as the liver, traditional materials are difficult to achieve rapid hemostasis. Moreover, when the amount of bleeding is excessive, the adsorption and cross-linking speed of these materials are limited, and they cannot form a solid gel or coagulation layer in time; (2) Limited adhesion and blocking ability. Because the surface of organ tissues is rich in blood and body fluids, and is constantly peristaltic or affected by respiratory movement, traditional hemostatic materials often cannot flexibly adhere to the tissue surface well and are easily detached due to local scouring or mechanical disturbance. In addition, existing commercial hemostatic materials have no or weak adhesion and cannot provide effective wound sealing during or after surgery, resulting in bleeding or body fluid leakage; (3) The operation is complicated and the cost is high. Some hemostatic products require the simultaneous preparation of other auxiliary materials or mixed liquids, and the operation process is relatively complicated; due to the limitations of production costs or storage conditions, the price is relatively expensive or clinical applications are not popular enough. Summary of the Invention

[0003] In order to solve the above technical problems, the purpose of the present invention is to provide an injectable in situ wet-adhesive hemostatic hydrogel that is easy to use, can quickly gel on the wet tissue surface, and has good adhesion to the wet tissue surface and excellent hemostatic performance after gelation.

[0004] In order to achieve the above object, the technical solution of the present invention is as follows: an injectable in situ wet adhesion hemostatic hydrogel, characterized by comprising solution A, solution B, solution C and solution D;

[0005] The solute of solution A is a first polymer material containing an aldehyde group or an aldehyde group precursor;

[0006] The solute of solution B is an aqueous polymer material containing amino groups;

[0007] The solute of solution C is a thickening polymer material containing amino groups;

[0008] The solute of solution D is a second polymer material that improves the rheological properties of the solution.

[0009] In the above technical solution, the solution A and the solution D are miscible as the first component, and the solution B and the solution C are miscible as the second component;

[0010] Alternatively, the solution A is used as the first component, and the solution B, solution C, and solution D are mixed and used as the second component.

[0011] In the above technical solution, the first polymer material is at least one of oxidized dialdehyde starch, oxidized hyaluronic acid, oxidized sodium alginate, oxidized dextran, oxidized chondroitin sulfate and oxidized hydroxyethyl cellulose;

[0012] The aqueous polymer material is at least one of PEG-NH2, polyetherimide, dopamine, deacetylated hyaluronic acid, deacetylated chondroitin sulfate, deacetylated dermatan sulfate, deacetylated keratan sulfate, amino-modified sericin and amino-modified collagen;

[0013] The thickening polymer material is at least one of carboxymethyl chitosan, gelatin, chitosan, carboxyethyl chitosan, chitosan hydrochloride, chitosan quaternary ammonium salt, chitosan lactate, chitosan glutamate and chitosan sulfate;

[0014] The second polymer material is at least one of xanthan gum, hydroxyethyl cellulose, guar gum, locust bean gum, konjac gum, carrageenan and hydroxypropyl methylcellulose.

[0015] In the above technical solution, the first polymer material includes oxidized dialdehyde starch, and the aldehyde group oxidation degree of the oxidized dialdehyde starch is 20-80% (it can be any value among 20%, 30%, 40%, 50%, 60%, 70% and 80% or the range corresponding to any two values). The aldehyde group oxidation degree of the oxidized dialdehyde starch is limited to the above range because sufficient aldehyde group density (≥20%) can maintain effective cross-linking ability. Excessive oxidation (>80%) will cause starch chain breakage and induce excessive cross-linking, making the material more brittle.

[0016] The molecular weight range of the PEG-NH2 in the above technical scheme is 1000-100000Da (it can be any value of 1000Da, 2000Da, 3000Da, 4000Da, 5000Da, 6000Da, 7000Da, 8000Da, 9000Da and 100000Da, or the range corresponding to any two values). The molecular weight range of the PEG-NH2 is limited to 1000-100000Da, mainly because PEG-NH2 below 1000Da is easily cleared quickly by the kidneys, and the high density of terminal amino groups may lead to excessive cross-linking. If the PEG is higher than 100000Da, it will induce antibody response and the processing difficulty will increase.

[0017] The degree of deacetylation of the carboxymethyl chitosan in the above technical solution is 40-85% (it can be any value among 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80% and 85% or the range corresponding to any two values). If the degree of deacetylation of the carboxymethyl chitosan is lower than 40%, the amino content is too low and the antibacterial property is significantly weakened. If it is higher than 85%, although the amino content is high, the rigidity of the molecular chain increases, the solubility decreases, and the high charge density destroys the membrane integrity, resulting in an increased risk of cytotoxicity.

[0018] In the above technical solution, the molar ratio of the aldehyde group in solution A to the amino group in solution B is 0.5-8:1 (it can be any ratio of 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1 and 8:1 or the corresponding range between any two ratios), and the molar ratio of the aldehyde group in solution A to the amino group in solution B is limited to 0.5-8:1. This is because under this functional group molar ratio, the two are more conducive to the in situ formation of tissue glue and have a certain adhesion.

[0019] In the above technical solution, the molar ratio of the aldehyde groups in solution A to the sum of the amino groups in solution B and solution C is 1-5.5:1 (which can be any ratio of 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, 5:1 and 5.5:1, or a range corresponding to any two ratios). The molar ratio of the aldehyde groups in solution A to the sum of the amino groups in solution B and solution C is limited to 1-5.5:1 because the tissue glue formed at this ratio can have stronger adhesion and strength.

[0020] In the above technical solution, the sum of the masses of the first polymer material, the aqueous polymer material and the thickening polymer material is 5-30% of the sum of the masses of solution A, solution B, solution C and solution D (it can be any value of 5%, 10%, 15%, 20%, 25% and 30% or the corresponding range between any two values). The sum of the masses of the first polymer material, the aqueous polymer material and the thickening polymer material is limited to 5-30% of the sum of the masses of solution A, solution B, solution C and solution D. This is because if it is less than 5%, it will lead to insufficient mechanical properties, insignificant thickening / rheological effects, and poor dispersibility. If it is higher than 30%, it will lead to problems such as excessive viscosity, processing difficulties and cost waste.

[0021] The solvents of solution A, solution B, solution C and solution D in the above technical solution are deionized water, physiological saline or phosphate buffer.

[0022] A second object of the present invention is to provide a use of the injectable in situ wet adhesion hemostatic hydrogel as described above in the preparation of hemostatic preparations.

[0023] The beneficial effects of the present invention are: 1. In situ wet adhesion gelation: the hemostatic hydrogel after compounding the first polymer material, the aqueous polymer material and the thickening polymer material has the characteristics of in situ wet adhesion gelation, that is, it can quickly adhere and solidify into gel when it contacts moist tissue or bleeding wound, and can complete hemostasis and wound sealing in time. Compared with traditional hemostatic materials and means, this wet adhesion can replace suture, electrocoagulation and other treatment methods, and during the application process, it can be directly injected without external assistance and initiation; 2. Injectability and rapid gelation: the low viscosity of the pre-crosslinked solution allows it to be injected into the wound by injection, which can quickly form a physical hemostatic barrier at the site of the trauma, thereby stopping bleeding and sealing the wound. In addition, the thickening polymer material promotes blood The aggregation and activation of platelets can also increase the speed of hemostasis. The amino groups in the thickening polymer material can interact with the protein of the tissue to further improve the adhesion and sealing strength, ensuring the sustainability of the hemostatic effect. 3. Degradability: The degradation characteristics of the wet-adhesive hemostatic hydrogel are another significant advantage. The thickening polymer material is a degradable polysaccharide or protein, which can be gradually degraded in the body, avoiding the health risks that may be caused by long-term residue in the body. The aqueous polymer material can also be gradually decomposed in the body by hydrolysis or biodegradation due to its excellent water solubility and low immunogenicity. Therefore, the prepared hemostatic hydrogel will not cause a burden on the body after the hemostatic effect is completed, and can be safely excreted from the body or absorbed by the tissue, reducing the trouble of secondary surgery for removal. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 Schematic diagram of the gelation mechanism of the injectable in situ wet adhesion hemostatic hydrogel of the present invention;

[0025] Figure 2 Schematic diagram of the injectable in situ wet adhesion hemostatic hydrogel before and after gelation of the present invention;

[0026] Figure 3 Schematic diagram of the hemostatic hydrogel corresponding to Example 4 of the present invention;

[0027] Figure 4 Schematic diagram of the liver of SD rats after being treated in Example 1, Example 2 and Example 4 of the present invention;

[0028] Figure 5 This is a schematic diagram of the liver of SD rats after being treated with Examples 1, 2 and 4 of the present invention for 10 days;

[0029] Figure 6 This is a schematic diagram of a New Zealand white rabbit liver being treated with hemostatic hydrogel corresponding to Example 4 of the present invention;

[0030] Figure 7This is the second schematic diagram of the hemostatic hydrogel corresponding to Example 4 of the present invention after hemostasis treatment on the liver of a New Zealand white rabbit;

[0031] Figure 8 Schematic diagram of underwater adhesion of the hemostatic hydrogel corresponding to Example 4 of the present invention. DETAILED DESCRIPTION

[0032] The principles and features of the present invention are described below with reference to the accompanying drawings. The examples given are only used to explain the present invention and are not intended to limit the scope of the present invention. The following paragraphs describe the present invention in more detail by way of example with reference to the accompanying drawings. The advantages and features of the present invention will become more apparent from the following description and claims. It should be noted that the drawings are all in a very simplified form and are not in exact proportions. They are only used to facilitate and clearly illustrate the purpose of the embodiments of the present invention.

[0033] The present invention provides an injectable in-situ wet-adhesive hemostatic hydrogel comprising solution A, solution B, solution C, and solution D. The solute of solution A is a first polymer material containing an aldehyde group or an aldehyde group precursor; the solute of solution B is an aqueous polymer material containing an amino group; the solute of solution C is a thickening polymer material containing an amino group; and the solute of solution D is a second polymer material that improves the rheological properties of the solution. The solutions A and D are miscible as a first component, and the solutions B and C are miscible as a second component; alternatively, solution A is the first component, and the solutions B, C, and D are miscible as a second component; and before use, the first and second components are injected through a double-tube. The first polymer material is at least one of oxidized dialdehyde starch, oxidized hyaluronic acid, oxidized sodium alginate, oxidized dextran, oxidized chondroitin sulfate and oxidized hydroxyethyl cellulose; the aqueous polymer material is at least one of PEG-NH2, polyetherimide, dopamine, deacetylated hyaluronic acid, deacetylated chondroitin sulfate, deacetylated dermatan sulfate, deacetylated keratan sulfate, amino-modified sericin and amino-modified collagen; the thickening polymer material is at least one of carboxymethyl chitosan, gelatin, chitosan, carboxyethyl chitosan, chitosan hydrochloride, chitosan quaternary ammonium salt, chitosan lactate, chitosan glutamate and chitosan sulfate; the second polymer material is at least one of xanthan gum, hydroxyethyl cellulose, guar gum, locust bean gum, konjac gum, carrageenan and hydroxypropyl methylcellulose. This in-situ injectable hemostatic hydrogel is formulated using the Schiff base reaction as its primary mechanism, blending aldehyde groups from oxidized natural polysaccharides, amino groups or derivatives from natural polymers, and natural materials that modify the solution's rheological properties. Double-tube injection of the tissue adhesive allows for underwater wet adhesion, boasting high colloid strength and excellent fluidity. It can be injected into the gel under hemostatic and specialized underwater laparoscopic conditions.

[0034] In order to improve the underwater viscosity and injectability of the gel, a second polymer material is added to the hemostatic hydrogel system in this embodiment. The second polymer material can effectively adjust the rheological properties of the tissue glue, ensuring that it maintains appropriate fluidity and high adhesion during the injection process, thereby enhancing its adhesion and sealing effect in the target tissue area.

[0035] The first polymer material in the present invention contains an aldehyde group, which can undergo a cross-linking reaction with an aqueous polymer material and a thickening polymer material with an amino group. The first polymer material in the present invention is preferably oxidized dialdehyde starch. At this time, the first polymer material, the aqueous polymer material and the thickening polymer material are cross-linked to form a three-dimensional network structure. Among them, the pre-cross-linked system of the first polymer material and the aqueous polymer material has low viscosity and high fluidity. In order to improve the flexible fit to irregular tissue wounds in a wet environment, a thickening polymer material is introduced. This makes the pre-cross-linked system less likely to be dispersed in a wet environment, especially during underwater injection, thereby increasing its viscous resistance and improving the strength and toughness of the finally cured hemostatic hydrogel, making it more suitable as a hemostatic hydrogel in a wet environment.

[0036] The aqueous polymer material in this embodiment enables the injectable in situ wet adhesion hemostatic hydrogel to quickly spread and form a film on the organ wound surface after in situ injection, while the thickening polymer material enables the pre-cross-linked injection system before film formation to better adhere to the wound surface, reduce the adhesion time, and improve the gel strength after curing.

[0037] Example 1

[0038] This embodiment provides an injectable in situ wet adhesion hemostatic hydrogel, the preparation method of which is as follows:

[0039] Step 1: 6 g of corn starch was added to 15 g of deionized water and stirred to form a paste, followed by the addition of 3.22 g of a sodium periodate solution having an oxidation degree of 75%, and the mixture was stirred in a water bath for 12 h (the water bath temperature was 37° C. and the stirring frequency was 500 rpm). The mixture was then cooled to room temperature, centrifuged, and freeze-dried to obtain aldehyde starch, which was then dissolved in water to obtain a reactant (the concentration of the aldehyde starch in the reactant was 3 wt%).

[0040] Step 2: Add 0.6 g of xanthan gum to 20 g of PBS solution under stirring and mix well, then add 3 g of 4arm-PEG-NH2 and 1 g of carboxymethyl chitosan to prepare a second reactant having an amino material;

[0041] Step 3: Mix reactant 1 and reactant 2 in a volume ratio of 1:1 and inject into gel (such as Figure 1 shown).

[0042] Among them, reactant 1 and reactant 2 have a certain fluidity immediately after mixing, such as Figure 2 As shown in Figure A, after mixing and fully cross-linking, Figure 2 As shown in Figure B.

[0043] Example 2

[0044] The same as Example 1, except that in step 1, the amount of sodium periodate added is 2.5 g, and the degree of oxidation is 50%.

[0045] Example 3

[0046] The same as Example 1, except that in step 1, the amount of sodium periodate added is 1.1 g, and the degree of oxidation is 30%.

[0047] Example 4

[0048] The same as Example 1, except that in step 2, the amount of 4arm-PEG-NH2 added is 0.4 g, and the amount of carboxymethyl chitosan added is 0.8 g.

[0049] Example 5

[0050] The same as Example 1, except that in step 2, carboxymethyl chitosan is replaced by polyetherimide (PEI), PBS solution is replaced by deionized water, and the added amount of 4arm-PEG-NH2 is 2 g and the added amount of polyetherimide is 2 g.

[0051] Example 6

[0052] The same as Example 5, except that in step 2, the amount of 4arm-PEG-NH2 added is 0.8 g, and the amount of polyetherimide added is 0.2 g.

[0053] Comparative Example 1

[0054] The same as Example 1, except that carboxymethyl chitosan was not added in step 2, deionized water was used instead of PBS solution, and the added amount of 4arm-PEG-NH2 was 2 g.

[0055] Comparative Example 2

[0056] The same as Example 1, except that 4arm-PEG-NH2 was not added in step 2, deionized water was used instead of PBS solution, and the amount of carboxymethyl chitosan used was 0.5 g.

[0057] Comparative Example 3

[0058] The same as Example 5, except that 4arm-PEG-NH2 was not added in step 2, deionized water was used instead of PBS solution, and the amount of polyetherimide used was 1 g.

[0059] Comparative Example 4

[0060] Same as Example 5, except that PBS solution is used instead of deionized water in step 2.

[0061] 1. Initial adhesion test

[0062] The performance of the injectable in situ wet adhesion hemostatic hydrogels prepared in Examples 1-6 and Comparative Examples 1-4 was evaluated. The results are shown in Table 1 below:

[0063] Table 1 is the test results of the performance of the injectable in situ wet adhesion hemostatic hydrogel

[0064]

[0065]

[0066] Note: The initial adhesion test is carried out according to the method disclosed in GB / T4852-2002.

[0067] The overall adhesion of Examples 1 to 6 of the present invention is stronger than that of Control Examples 1 to 4. The hemostatic hydrogel corresponding to Example 4 is as follows: Figure 3 As shown, the viscosity is high and the elasticity is good. The reactants of Examples 1 to 6 of the present invention all use a double amino component (i.e., a water-based polymer material containing amino groups and a thickening polymer material containing amino groups) to mix, and the overall initial adhesion is greater than 80%. Comparative Examples 1 to 3 all use a single amino component, and their initial adhesion is poor (Comparative Example 3 uses a single amino component polyetherimide for cross-linking, resulting in a soft gel feeling and poor strength of the hemostatic hydrogel prepared therefrom). Although Comparative Example 4 uses a double amino component, it does not add xanthan gum, resulting in an overall weak initial adhesion.

[0068] Hemostasis ability test.

[0069] 2. Hemostasis ability test

[0070] Specifically, a mouse hemorrhagic liver model was used to study the potent hemostatic ability of the hemostatic hydrogels corresponding to Example 1, Example 2, Example 4, and Control Example 4 in vivo.

[0071] Healthy SD female rats weighing 200-250 g were selected and kept in an environmental temperature of 22±2°C and a humidity of 50±5%. The experimental animals were adapted to the environment before the experiment and fasted for 12 hours before the experiment, with free access to drinking water.

[0072] Experimental method: 70 vol% ethanol was used to disinfect the rat liver surgical area (abdomen) and maintain aseptic operation. The specific operation was as follows:

[0073] Step 1: The rats were anesthetized by intraperitoneal injection of 10 vol% chloral hydrate (0.6 mL per 100 g of SD rat body weight);

[0074] Step 2: A midline incision was then made on the right side of the anesthetized rat's abdomen using a scalpel to expose the liver. A transverse incision was made on the surface of the liver (the incision should be made at the edge of the liver to avoid damaging important blood vessels. Hemostasis was performed during the incision, and the depth and size of the incision were recorded). The incision length was 1.5-2.0 cm.

[0075] Step 3: Immediately inject 200 μL of hemostatic hydrogel on the surface of the bleeding site as a hemostatic agent and observe the liver bleeding.

[0076] The hemostatic hydrogels corresponding to Example 1, Example 2, Example 4 and Control Example 4 were respectively subjected to parallel experiments using multiple mice.

[0077] Experimental results: Figure 4 The liver conditions of SD rats after being treated with the corresponding hemostatic hydrogels of Example 1, Example 2 and Example 4 respectively. It can be clearly seen that the liver wound is covered and the bleeding is stopped in time, while the bleeding in the liver of the SD rat of Control Example 4 cannot be stopped. Figure 5 This is the colloid retention in the livers of the experimental rats corresponding to Examples 1, 2, and 4 after ten days of hemostatic treatment. It was found that the hemostatic hydrogel was retained, and it was found that the liver began to repair on the 10th day.

[0078] Similarly, this embodiment also uses New Zealand white rabbits to replace mice for testing (New Zealand white rabbit livers are as follows Figure 6 As shown), only Example 4 was found to be able to stop bleeding (as shown Figure 7 As shown, the hemostatic ability is strong (Example 1, Example 2, and Control Example 4 all failed to achieve hemostasis). This is because the ratio of liver blood flow to cardiac output in rabbits (approximately 25%-30%) is significantly higher than that in rats (approximately 20%). The portal vein and hepatic artery systems in rabbit livers are larger, with denser vascular branches, particularly forming a more developed microcirculatory network between the hepatic lobules. Therefore, the same degree of injury can result in more severe bleeding.

[0079] 3. Underwater Adhesion Ability

[0080] The experiment was conducted using a sheep vertebra model to simulate the human spine to verify the underwater adhesion ability of the hemostatic hydrogel provided by the present invention. The hemostatic hydrogels corresponding to Example 1, Example 4, Control Example 1, Control Example 2, and Control Example 3 were selected for the experiment. A defect model was created on the spinal section, and the bone defect was immersed in physiological saline to simulate the water environment under arthroscopy. Figure 8As shown in the figure, the adhesion of the hemostatic hydrogel to the defective bone surface after injection is observed. Only Examples 1 and 4 can achieve underwater wet adhesion and do not fall off after immersion in water for 2 hours. While Control Examples 1 to 3 can also adhere, they all fall off within 2 hours of immersion in water.

[0081] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form. Any ordinary technician in this industry can smoothly implement the present invention as shown in the drawings and described above. However, any equivalent changes, modifications and evolutions made by technicians familiar with this profession without departing from the scope of the technical solution of the present invention using the technical content disclosed above are all equivalent embodiments of the present invention. At the same time, any equivalent changes, modifications and evolutions made to the above embodiments based on the essential technology of the present invention are still within the scope of protection of the technical solution of the present invention.

Claims

1. An injectable in situ wet adhesion hemostatic hydrogel, characterized in that: Including solution A, solution B, solution C and solution D; The solute of solution A is a first polymer material containing an aldehyde group or an aldehyde group precursor; The solute of solution B is an aqueous polymer material containing amino groups; The solute of solution C is a thickening polymer material containing amino groups; The solute of solution D is a second polymer material that improves the rheological properties of the solution.

2. The injectable in situ wet adhesion hemostatic hydrogel according to claim 1, characterized in that: The A solution and the D solution are miscible as a first component, and the B solution and the C solution are miscible as a second component; Alternatively, the solution A is used as the first component, and the solution B, solution C, and solution D are mixed and used as the second component.

3. The injectable in situ wet adhesion hemostatic hydrogel according to claim 1 or 2, characterized in that: The first polymer material is at least one of oxidized dialdehyde starch, oxidized hyaluronic acid, oxidized sodium alginate, oxidized dextran, oxidized sulfur chondroitin and oxidized hydroxyethyl cellulose; The aqueous polymer material is at least one of PEG-NH2, polyetherimide, dopamine, deacetylated hyaluronic acid, deacetylated chondroitin sulfate, deacetylated dermatan sulfate, deacetylated keratan sulfate, amino-modified sericin and amino-modified collagen; The thickening polymer material is at least one of carboxymethyl chitosan, gelatin, chitosan, carboxyethyl chitosan, chitosan hydrochloride, chitosan quaternary ammonium salt, chitosan lactate, chitosan glutamate and chitosan sulfate; The second polymer material is at least one of xanthan gum, hydroxyethyl cellulose, guar gum, locust bean gum, konjac gum, carrageenan and hydroxypropyl methylcellulose.

4. The injectable in situ wet adhesion hemostatic hydrogel according to claim 1 or 2, characterized in that: The first polymer material includes oxidized dialdehyde starch, and the aldehyde oxidation degree of the oxidized dialdehyde starch is 20-80%.

5. The injectable in situ wet adhesion hemostatic hydrogel according to claim 3, characterized in that: The molecular weight of the PEG-NH2 is in the range of 1000-100000 Da, and the deacetylation degree of the carboxymethyl chitosan is in the range of 40-85%.

6. The injectable in situ wet adhesion hemostatic hydrogel according to claim 1 or 2, characterized in that: The molar ratio of the aldehyde groups in the solution A to the amino groups in the solution B is 0.5-8:

1.

7. The injectable in situ wet adhesion hemostatic hydrogel according to claim 1 or 2, characterized in that: The molar ratio of the aldehyde groups in the solution A to the sum of the amino groups in the solutions B and C is 1-5.5:

1.

8. The injectable in situ wet adhesion hemostatic hydrogel according to claim 1 or 2, characterized in that: The total solid content of the A solution, the B solution, the C solution and the D solution is 5-30%.

9. The injectable in situ wet adhesion hemostatic hydrogel according to claim 1 or 2, characterized in that: The solvents of the solution A, solution B, solution C and solution D are deionized water, physiological saline or phosphate buffer.

10. Use of the injectable in situ wet adhesion hemostatic hydrogel according to any one of claims 1 to 9, characterized in that: Used to prepare hemostatic preparations.

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