A hydrogel for tissue adhesion

Abstract

The present invention discloses a hydrogel for tissue adhesion and its uses. The hydrogel uses two polymer compounds grafted with dopamine, one containing aldehyde groups and the other containing amino groups, acrylic acid monomers, N-hydroxy succinimide acrylate, and a photoinitiator as raw materials. After mixing evenly, it is irradiated with ultraviolet light for sufficient polymerization to obtain a hydrogel material. Among them, a reaction occurs between the dopamine-grafted polymer containing aldehyde groups and the dopamine-grafted polymer containing amino groups to form a Schiff base. The acrylic acid monomers and N-hydroxy succinimide acrylate polymerize under the action of the photoinitiator to form a copolymer. At the same time, the active ester groups of N-hydroxy succinimide acrylate undergo a chemical reaction with the dopamine-grafted polymer containing amino groups, making the hydrogel have a high crosslinking density. This hydrogel has good skin affinity and high tissue adhesion strength.

Description

Technical Field

[0001] This application is a divisional application of patent application No. 2021100931022. The application date of the original application is January 25, 2021. The name of the invention is: a tissue adhesion hydrogel and its preparation method and use. The present invention relates to a hydrogel for tissue adhesion, which belongs to the field of functional polymer materials. Background Art

[0002] Traditional methods for closing wounds on human tissues are mainly surgical sutures and mechanical fixation with rivets, but these methods are cumbersome to operate and may cause infection due to poor wound sealing. As a result, another material for treating wounds has emerged: viscous hydrogel. This adhesive is easy and quick to operate. It only needs to be applied to the wound, without the need for suturing or removing stitches. It will not harm the tissues around the wound, and the wound sealing effect is much better than traditional methods. It can effectively prevent the leakage of body fluids and air and prevent wound infection.

[0003] Polymer materials such as sodium alginate, chitosan and gelatin have good biocompatibility and are commonly used materials in human tissue engineering. However, when these natural polymer materials are used alone as the main component of hydrogels, their adhesion ability often does not meet people's expectations. For example, in the invention patent with application number 201510891554.X, a medical adhesive and its preparation method are disclosed. The preparation method is to mix equal volumes of aldehyde-modified sodium alginate solution with a concentration of 10% to 50% (w / v) and amino-modified carboxymethyl chitosan solution with a concentration of 1% to 6% (w / v), and the Schiff base reaction forms a hydrogel. The pig skin bonding strength of the hydrogel is 10 to 30 gfcm -2 , the adhesion strength is not prominent enough.

[0004] In the invention patent with application number 201810746272.4, an antibacterial adhesive injectable hydrogel dressing and its preparation method and application are disclosed. The preparation method of the antibacterial adhesive injectable hydrogel dressing is to prepare a quaternized chitosan polymer and an aldehyde-terminated Pluronic The polymers are respectively prepared into solutions, and cross-linked at 20-45°C for 5-400s to obtain an antibacterial adhesive injectable hydrogel dressing, wherein the quaternized chitosan polymer and the aldehyde-terminated Pluronic The mass ratio of the polymers is (1-20):(50-200). The modified Pluronic The aldehyde groups of the polymer chemically interact with the tissue, and the electrostatic and hydrophobic interactions of chitosan. These interactions together endow the hydrogel with certain adhesion properties. However, the adhesion strength of this hydrogel is 4.4 kPa to 6.1 kPa, and there is a drawback of insufficient adhesion ability. In addition, acetone and dichloromethane used in the preparation of the two components are both toxic and harmful substances. Therefore, in the actual application process, it is very easy to cause toxic effects on organisms due to incomplete purification.

[0005] Therefore, there is a need in clinical practice for a tissue-adhesive hydrogel with strong tissue adhesion performance, simple preparation, low cost, and fast operation. Summary of the Invention

[0006] The object of the present invention is to provide a tissue-adhesive hydrogel with strong tissue adhesion performance, simple preparation, low cost, and fast operation.

[0007] The present invention provides a tissue-adhesive hydrogel, characterized in that: it has a hydrogel with the structure of formula (I).

[0008]

[0009] In the structure of formula (I), G1 is one of sodium alginate oxide, dextran oxide, and cellulose oxide.

[0010] In the structure of formula (I), G2 is one of chitosan, gelatin, and chitosan.

[0011] In the structure of formula (I), m is the degree of polymerization of N-hydroxysuccinimide acrylate, and n is the degree of polymerization of acrylic acid.

[0012] In the structure of formula (I), the molecular weight of G1 is 10,000 to 200,000, and the degree of oxidation is 30% to 80%.

[0013] In the structure of formula (I), the molecular weight of G2 is 10,000 to 200,000.

[0014] In the structure of formula (I), G1 is grafted with dopamine, and the content of dopamine is 0.1 mmol / g to 1 mmol / g.

[0015] In the structure of formula (I), G2 is grafted with dopamine, and the content of dopamine is 0.001 mmol / g to 0.02 mmol / g.

[0016] In the structure of formula (I), the mass ratio of G1, G2, polyacrylic acid, and poly-N-hydroxysuccinimide acrylate is (1 to 10):(2 to 15):(50 to 200):(1 to 10).

[0017] The present invention also provides a method for preparing a tissue adhesion hydrogel, and the preparation steps are as follows:

[0018] (1) adding DOPA-grafted G1 and DOPA-grafted G2 into distilled water in a certain ratio and fully mixing and dissolving them. The total volume concentration of G1 and G2 in water is 15-45 mg / mL;

[0019] (2) then adding acrylic acid and N-hydroxysuccinimide acrylate, mixing and stirring to dissolve;

[0020] (3) adding a photoinitiator and stirring to dissolve;

[0021] (4) Finally, the polymerized product is irradiated under ultraviolet light to obtain a tissue adhesion hydrogel.

[0022] The photoinitiator is selected from one of 2-hydroxy-methylphenylpropane-1-one, 1-hydroxycyclohexyl phenyl ketone, 2-methyl-1-(4-methylthiophenyl)-2-morpholinyl-1-propanone, methyl o-benzoylbenzoate, 2-hydroxy-4′-(2-hydroxyethoxy)-2-methylpropiophenone, and α-ketoglutaric acid.

[0023] The mass ratio of the sum of the masses of G1 and G2 to the added photoinitiator is (6-18):5.

[0024] Compared with the prior art, the advantages of the present invention are:

[0025] (1) The tissue adhesion hydrogel of the present invention is mainly composed of acrylic acid, which can ensure certain mechanical properties when polymerized under the action of a photoinitiator. It contains a large number of carboxyl groups and can form a large number of hydrogen bonds with tissues, thus having good skin affinity, so that the gel has certain adhesion ability.

[0026] (2) In the present invention, G1 and G2 undergo a Schiff base reaction to be cross-linked, and acrylic acid and N-hydroxysuccinimide acrylate undergo free radical polymerization under the action of a photoinitiator to be cross-linked. At the same time, the active ester group of N-hydroxysuccinimide acrylate undergoes a chemical reaction with the amino group of G2 to be cross-linked, so that the hydrogel has a multi-dimensional cross-linking mode with a high cross-linking density, thereby ensuring that the hydrogel has high mechanical strength and adhesion strength.

[0027] (3) The dynamic Schiff base generated by the reaction of aldehyde groups and amino groups in the present invention enables the hydrogel to have a certain self-healing ability and to adhere to tissues for a long time.

[0028] (4) Both G1 and G2 in the tissue adhesion hydrogel of the present invention are grafted with dopa groups, which can form a large number of hydrogen bonds with tissues, thereby increasing the hydrogen bond density of the hydrogel and further increasing the adhesion strength of the hydrogel.

[0029] (5) The tissue-adhesive hydrogel of the present invention has inexpensive and easily available raw materials, is simple to manufacture and has a short production cycle, and can be directly used when applied to a wound surface. Detailed implementation manners

[0030] The technical solutions of the present invention will be further described below in conjunction with specific embodiments, but these embodiments do not limit the present invention in any form. Unless otherwise specified in the embodiments, all are conventional reagents and conventional methods.

[0031] Example 1

[0032] 4 mg of dopamine-grafted oxidized sodium alginate (relative molecular weight of 10,000 - 200,000, oxidation degree of 54.48%, dopamine grafting content of 0.72 mmol / g) and 20 mg of dopamine-grafted gelatin (relative molecular weight of 10,000 - 200,000, dopamine grafting content of 0.013 mmol / g) were added to 1.6 mL of distilled water, mixed and dissolved by ultrasonic wave. After dissolution, stirring was continued for 10 minutes, then 420 mg of acrylic acid and 20 mg of N-hydroxysuccinimide acrylate were added, mixed and stirred for dissolution, and then 0.118 mmol of 2-hydroxy-4′-(2-hydroxyethoxy)-2-methylpropiophenone was added and mixed and stirred for dissolution. This mixed solution was placed in a mold and then polymerized under an ultraviolet lamp for 3 hours to obtain a tissue-adhesive hydrogel.

[0033] Example 2

[0034] 8 mg of dopamine-grafted oxidized sodium alginate (relative molecular weight of 10,000 - 200,000, oxidation degree of 54.48%, dopamine grafting content of 0.72 mmol / g) and 40 mg of dopamine-grafted gelatin (relative molecular weight of 10,000 - 200,000, dopamine grafting content of 0.013 mmol / g) were added to 1.6 mL of distilled water, mixed and dissolved by ultrasonic wave. After dissolution, stirring was continued for 10 minutes, then 420 mg of acrylic acid and 20 mg of N-hydroxysuccinimide acrylate were added, mixed and stirred for dissolution, and then 20 mg of 2-hydroxy-4′-(2-hydroxyethoxy)-2-methylpropiophenone was added and mixed and stirred for dissolution. This mixed solution was placed in a mold and then polymerized under an ultraviolet lamp for 3 hours to obtain a tissue-adhesive hydrogel.

[0035] Example 3

[0036] 12 mg of dopamine-grafted sodium alginate (with a relative molecular mass of 10,000 - 200,000, an oxidation degree of 54.48%, and a dopamine grafting content of 0.72 mmol / g) and 60 mg of dopamine-grafted gelatin (with a relative molecular mass of 10,000 - 200,000 and a dopamine grafting content of 0.013 mmol / g) were added to 1.6 mL of distilled water, mixed and dissolved by ultrasonic treatment. After dissolution, stirring was continued for 10 minutes. Then, 420 mg of acrylic acid and 20 mg of N-hydroxysuccinimide acrylate were added, and the mixture was stirred and dissolved. Next, 20 mg of 2-hydroxy-4′-(2-hydroxyethoxy)-2-methylpropiophenone was added and stirred until dissolved. This mixed solution was placed in a mold and then polymerized under an ultraviolet lamp for 3 hours to obtain a tissue-adhesive hydrogel.

[0037] Performance testing

[0038] The hydrogels prepared in Examples 1 - 3 above were respectively applied to the surface of porcine skin. The sizing area was 15 mm × 15 mm, and the sizing thickness was 1 mm. After the two pieces of porcine skin were bonded, they were pressed by hand for 20 seconds, and then the shear strength was tested using a universal testing machine. The test results of the shear strength are shown in the following table.

[0039]

[0040]

Claims

1. A tissue-adhesive hydrogel, characterized in that: The preparation steps are as follows: Add 4 mg of dopamine-grafted oxidized sodium alginate and 20 mg of dopamine-grafted gelatin into 1.6 mL of distilled water, mix and dissolve by ultrasonic treatment. After stirring for 10 minutes, add 420 mg of acrylic acid and 20 mg of N-hydroxysuccinimide acrylate. After stirring and dissolving, add 0.118 mmol of 2-hydroxy-4′-(2-hydroxyethoxy)-2-methylpropiophenone. After stirring and dissolving, place this mixed solution in a mold and polymerize it under ultraviolet light for 3 hours; The oxidized sodium alginate has a relative molecular weight of 10,000 - 200,000, an oxidation degree of 54.48%, and a dopamine grafting content of 0.72 mmol / g; The gelatin has a relative molecular weight of 10,000 - 200,000 and a dopamine grafting content of 0.013 mmol / g.

2. A tissue-adhesive hydrogel, characterized in that: The preparation steps are as follows: Add 8 mg of dopamine-grafted oxidized sodium alginate and 40 mg of dopamine-grafted gelatin into 1.6 mL of distilled water, mix and dissolve by ultrasonic treatment. After stirring for 10 minutes, add 420 mg of acrylic acid and 20 mg of N-hydroxysuccinimide acrylate. After stirring and dissolving, add 20 mg of 2-hydroxy-4′-(2-hydroxyethoxy)-2-methylpropiophenone. After stirring and dissolving, place this mixed solution in a mold and polymerize it under ultraviolet light for 3 hours; The oxidized sodium alginate has a relative molecular weight of 10,000 - 200,000, an oxidation degree of 54.48%, and a dopamine grafting content of 0.72 mmol / g; The gelatin has a relative molecular weight of 10,000 - 200,000 and a dopamine grafting content of 0.013 mmol / g.

3. A tissue-adhesive hydrogel, characterized in that: The preparation steps are as follows: Add 12 mg of dopamine-grafted oxidized sodium alginate and 60 mg of dopamine-grafted gelatin into 1.6 mL of distilled water, mix and dissolve by ultrasonic treatment. After stirring for 10 minutes, add 420 mg of acrylic acid and 20 mg of N-hydroxysuccinimide acrylate. After stirring and dissolving, add 20 mg of 2-hydroxy-4′-(2-hydroxyethoxy)-2-methylpropiophenone. After stirring and dissolving, place this mixed solution in a mold and polymerize it under ultraviolet light for 3 hours; The oxidized sodium alginate has a relative molecular weight of 10,000 - 200,000, an oxidation degree of 54.48%, and a dopamine grafting content of 0.72 mmol / g; The gelatin has a relative molecular weight of 10,000 - 200,000 and a dopamine grafting content of 0.013 mmol / g.

4. Use of the tissue adhesion hydrogel according to any one of claims 1 - 3 in the preparation of a medical adhesive.

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