阅读说明：本技术 一种生物医用组织粘合剂的制备方法 (Preparation method of biomedical tissue adhesive ) 是由 孙乐青 周慧丽 张婷婷 赵瑾 柳仁民 于 2021-10-11 设计创作，主要内容包括：本发明公开一种生物医用组织粘合剂的制备方法,利用氧化葡聚糖的醛基与ε-聚赖氨酸的氨基发生亲核加成反应来制备水凝胶,通过调控葡聚糖的氧化程度以及ε-聚赖氨酸的酰化程度来实现成胶时间和粘合强度的可控性。本发明所得生物医用组织粘合剂具备低细胞毒性、良好的黏附性能,成胶工艺简单、可控。(The invention discloses a preparation method of a biomedical tissue adhesive, which is characterized in that the aldehyde group of oxidized glucan and the amino group of epsilon-polylysine are subjected to nucleophilic addition reaction to prepare hydrogel, and the controllability of gelling time and bonding strength is realized by regulating and controlling the oxidation degree of glucan and the acylation degree of epsilon-polylysine. The biomedical tissue adhesive prepared by the invention has low cytotoxicity, good adhesion performance and simple and controllable gel forming process.)

1. A preparation method of a biomedical tissue adhesive is characterized in that aldehyde groups of oxidized glucan and amino groups of epsilon-polylysine are subjected to nucleophilic addition reaction to prepare hydrogel, and the controllability of gelling time and adhesive strength is realized by regulating and controlling the oxidation degree of the glucan and the acylation degree of the epsilon-polylysine.

2. The preparation method of claim 1, wherein the aldehyde dextran is prepared by oxidizing dextran with sodium periodate, and the method comprises the following steps:

preparing 5-30% dextran water solution, mixing with 0-20% sodium periodate water solution at a volume ratio of 1:1-5:1, and stirring at 30-70 deg.C for 30-90 min; after the reaction is finished, dialyzing the mixed solution for 12-24h by using running water, further dialyzing the mixed solution for 2 times by using deionized water, wherein the dialysis time is 1-2h, finally drying to obtain aldehyde group glucan, grinding the aldehyde group glucan into powder, performing vacuum drying, and refrigerating for later use.

3. The method of claim 2, wherein the epsilon-polylysine is amidated with an anhydride, comprising the steps of:

preparing an epsilon-polylysine aqueous solution with the mass fraction of 15-30%, diluting acid anhydride with deionized water to obtain an acid anhydride aqueous solution with the concentration of 1-10%, mixing the two solutions according to a certain volume ratio (1:1-3:1), and reacting for 45-90min under the condition of stirring at constant temperature (30-60 ℃); after the reaction is finished, deionized water is used for dialyzing and purifying the reaction solution for 12-36h, and finally, amidated epsilon-polylysine is obtained by freeze drying.

4. The method according to claim 3, wherein the acid anhydride is one of acetic anhydride and succinic anhydride.

5. The method of claim 4, wherein the hydrogel adhesive is formed by the steps of: preparing 10-30% of aldehyde group dextran aqueous solution, preheating the aldehyde group dextran aqueous solution to a certain temperature (20-40 ℃), then adding 5-25% of amidated epsilon-polylysine aqueous solution according to the volume ratio (1:5-5:1) at the temperature, and magnetically stirring for 0.1-10min to finally prepare the hydrogel adhesive.

Technical Field

The invention belongs to the field of clinical medicine, and particularly relates to a preparation method of a biomedical tissue adhesive.

Background

At present, the wound is usually repaired by mechanical fixation treatment by surgical suture, rivets, medical adhesive tapes and other articles, and the mechanical fasteners are required to firmly fix the connected wound tissues and prevent the leakage of gas, blood and tissue fluid. At the same time, the fastener must resist a certain mechanical tensile load in order to achieve the goal of sufficient wound healing and restoration of its structure and function. Although the application of these conventional methods is well established, the limitations have not been able to meet the increasingly high clinical needs, such as time-consuming suturing procedures, risk of susceptibility to infection by stitches removing and dressing changing, and aesthetic problems of scarring.

With the continuous development of modern medical technology and treatment concept, medical tissue adhesives are produced. The method has the characteristics of simple and convenient operation, noninvasive adhesion, instant sealing and hemostasis, effective shortening of the operation time, wide attention in the medical field, and gradual effective assistance or substitution means of the traditional operation suture line. The ideal medical tissue adhesive should have good biocompatibility, biodegradability, safety, nontoxicity, certain mechanical strength and adhesive strength. However, the current tissue adhesives do not fully meet the above requirements, and the preparation of ideal tissue adhesives is of great practical significance.

At present, natural biological materials and synthetic materials are often adopted to develop various novel medical tissue adhesives. CN 113088247A discloses a natural polymer antibacterial tissue adhesive and a preparation method thereof, wherein the tissue adhesive is prepared by adopting 100 parts of gelatin, 5-30 parts of oxidized sodium alginate and 5-50 parts of antibacterial material, and the tissue adhesive prepared by the method has good biocompatibility, but has poor adhesive strength, is easy to fall off in practical clinical application and has no application value. CN 112826976A discloses a preparation method of a low-whitening cyanoacrylate medical adhesive, wherein a synthetic tissue adhesive is prepared by adopting cyanoacrylate, a thickening agent, a free radical stabilizer, an acidic stabilizer and a silicone modifier, and the tissue adhesive prepared by the method has excellent adhesive strength, but shows certain inflammatory reaction and high cytotoxicity in clinical application. At present, the preparation of a composite tissue adhesive having both high adhesive strength and low cytotoxicity is of great significance for practical clinical applications.

Disclosure of Invention

Aiming at the problem of high cytotoxicity of most of the existing synthetic adhesives, the invention provides a preparation method of an oxidized glucan/epsilon-polylysine hydrogel tissue adhesive, which is green and environment-friendly in material selection and low in product cytotoxicity.

Aiming at the problems that the existing natural tissue adhesive has good biocompatibility and poor adhesion strength and is easy to fall off in practical clinical application, the invention adopts green and environment-friendly glucan and epsilon-polylysine to prepare the composite tissue adhesive with excellent adhesion strength.

Aiming at the problems of long preparation process and uncontrollable product performance of the composite tissue adhesive, the invention provides a simple and controllable process for preparing the hydrogel adhesive.

The invention provides a preparation method of oxidized dextran/epsilon-polylysine hydrogel tissue adhesive, which is characterized in that the aldehyde group of oxidized dextran and the amino group of epsilon-polylysine are subjected to nucleophilic addition reaction to prepare hydrogel, and the controllability of gelling time and bonding strength is realized by regulating and controlling the oxidation degree of dextran and the acylation degree of epsilon-polylysine. The specific operation steps are as follows:

(1) preparing aldehyde group glucan by using a method of oxidizing glucan by sodium periodate: preparing 5-30% dextran water solution, mixing with 0-20% sodium periodate water solution at a volume ratio of 1:1-5:1, and stirring at 30-70 deg.C for 30-90 min; after the reaction is finished, dialyzing the mixed solution for 12-24h by using running water, further dialyzing the mixed solution for 2 times by using deionized water, wherein the dialysis time is 1-2h, finally drying to obtain aldehyde group glucan, grinding the aldehyde group glucan into powder, performing vacuum drying, and refrigerating for later use.

(2) Amidation of epsilon-polylysine with anhydride: preparing an epsilon-polylysine aqueous solution with the mass fraction of 15-30%, diluting acid anhydride with deionized water to obtain an acid anhydride aqueous solution with the concentration of 1-10%, mixing the two solutions according to a certain volume ratio (1:1-3:1), and reacting for 45-90min under the condition of stirring at constant temperature (30-60 ℃); after the reaction is finished, deionized water is used for dialyzing and purifying the reaction solution for 12-36h, and finally, amidated epsilon-polylysine is obtained by freeze drying. Wherein the anhydride is one of acetic anhydride and succinic anhydride.

(3) Formation of hydrogel adhesive: preparing 10-30% of aldehyde group dextran aqueous solution, preheating the aldehyde group dextran aqueous solution to a certain temperature (20-40 ℃), then adding 5-25% of amidated epsilon-polylysine aqueous solution according to the volume ratio (1:5-5:1) at the temperature, and magnetically stirring for 0.1-10min to finally prepare the hydrogel adhesive.

Compared with the prior art, the invention has the characteristics and beneficial effects that:

1. low cytotoxicity: the glucan is biosynthesized by Leuconostoc mesenteroides and is a glucose polymer with good biocompatibility. And epsilon-polylysine is a homopolymer biosynthesized by streptomyces, and belongs to a green environment-friendly reagent. The invention successfully synthesizes the oxidized dextran/epsilon-polylysine hydrogel adhesive without using a cross-linking agent with cytotoxicity.

2. High adhesive strength: the hydrogel adhesive prepared by the invention has the adhesion strength which is 10 times of that of the traditional commercial fibrin glue, has good adhesion performance and has practical application prospect in the field of clinical adhesives.

3. The gelling process is simple and controllable: the gel forming time and the viscosity characteristic of the hydrogel can be controlled by adjusting the oxidation degree of glucan and the acylation degree of epsilon-polylysine. In addition, the oxidized dextran aqueous solution and the acylated epsilon-polylysine aqueous solution can be easily gelatinized by stirring.

Detailed Description

The present invention will be further described with reference to the following embodiments. The following description is given for the purpose of explanation and not limitation. Unless otherwise specified, the contents of the respective components used below are weight percent contents.

The experimental materials and equipment sources used in the examples are shown in tables 1 and 2

TABLE 1 Main test materials and specifications

TABLE 2 Main experimental facilities and specifications

Example 1

(1) Preparing 20% dextran water solution, mixing with 1% sodium periodate water solution at a volume ratio of 2:1, and stirring at 30 deg.C for 60 min; after the reaction is finished, dialyzing the mixed solution for 18h by using running water, further dialyzing the mixed solution for 2 times by using deionized water, wherein the dialysis time is 1.5h, finally drying to obtain aldehyde group glucan, grinding the aldehyde group glucan into powder, performing vacuum drying for 24h, and refrigerating at-15 ℃ for later use;

(2) preparing an epsilon-polylysine aqueous solution with the mass fraction of 25%, diluting acetic anhydride with deionized water to an acetic anhydride aqueous solution with the concentration of 6%, mixing the two solutions according to the volume ratio of 2:1, reacting for 60min under the condition of stirring at the constant temperature of 45 ℃, dialyzing and purifying the reaction liquid for 24h with deionized water after the reaction is finished, and finally freeze-drying for 24h to obtain amidated epsilon-polylysine;

(3) preparing 20% aldehyde dextran aqueous solution, preheating the aqueous solution to 37 ℃, then adding 10% amidated epsilon-polylysine aqueous solution in percentage by mass at the temperature in an equal proportion, and magnetically stirring for 3min to finally prepare the hydrogel adhesive.

Example 2

(1) Preparing 20% dextran water solution, mixing with 1% sodium periodate water solution at a volume ratio of 2:1, and stirring at 70 deg.C for 60 min; after the reaction is finished, dialyzing the mixed solution for 18h by using running water, further dialyzing the mixed solution for 2 times by using deionized water, wherein the dialysis time is 1.5h, finally drying to obtain aldehyde group glucan, grinding the aldehyde group glucan into powder, performing vacuum drying for 24h, and refrigerating at-15 ℃ for later use;

(2) preparing an epsilon-polylysine aqueous solution with the mass fraction of 25%, diluting acetic anhydride with deionized water to an acetic anhydride aqueous solution with the concentration of 6%, mixing the two solutions according to the volume ratio of 2:1, reacting for 60min under the condition of stirring at the constant temperature of 45 ℃, dialyzing and purifying the reaction liquid for 24h with deionized water after the reaction is finished, and finally freeze-drying for 24h to obtain amidated epsilon-polylysine;

(3) preparing 20% aldehyde dextran aqueous solution, preheating the aqueous solution to 37 ℃, then adding 10% amidated epsilon-polylysine aqueous solution in percentage by mass at the temperature in an equal proportion, and magnetically stirring for 3min to finally prepare the hydrogel adhesive.

Example 3

(1) Preparing 20% dextran water solution, mixing with 20% sodium periodate water solution at a volume ratio of 2:1, and stirring at 30 deg.C for 60 min; after the reaction is finished, dialyzing the mixed solution for 18h by using running water, further dialyzing the mixed solution for 2 times by using deionized water, wherein the dialysis time is 1.5h, finally drying to obtain aldehyde group glucan, grinding the aldehyde group glucan into powder, performing vacuum drying for 24h, and refrigerating at-15 ℃ for later use;

(2) preparing an epsilon-polylysine aqueous solution with the mass fraction of 25%, diluting acetic anhydride with deionized water to an acetic anhydride aqueous solution with the concentration of 6%, mixing the two solutions according to the volume ratio of 2:1, reacting for 60min under the condition of stirring at the constant temperature of 45 ℃, dialyzing and purifying the reaction liquid for 24h with deionized water after the reaction is finished, and finally freeze-drying for 24h to obtain amidated epsilon-polylysine;

(3) preparing 20% aldehyde dextran aqueous solution, preheating the aqueous solution to 37 ℃, then adding 10% amidated epsilon-polylysine aqueous solution in percentage by mass at the temperature in an equal proportion, and magnetically stirring for 3min to finally prepare the hydrogel adhesive.

Example 4

(1) Preparing 20% dextran water solution, mixing with 20% sodium periodate water solution at a volume ratio of 2:1, and stirring at 70 deg.C for 60 min; after the reaction is finished, dialyzing the mixed solution for 18h by using running water, further dialyzing the mixed solution for 2 times by using deionized water, wherein the dialysis time is 1.5h, finally drying to obtain aldehyde group glucan, grinding the aldehyde group glucan into powder, performing vacuum drying for 24h, and refrigerating at-15 ℃ for later use;

(2) preparing an epsilon-polylysine aqueous solution with the mass fraction of 25%, diluting acetic anhydride with deionized water to an acetic anhydride aqueous solution with the concentration of 6%, mixing the two solutions according to the volume ratio of 2:1, reacting for 60min under the condition of stirring at the constant temperature of 45 ℃, dialyzing and purifying the reaction liquid for 24h with deionized water after the reaction is finished, and finally freeze-drying for 24h to obtain amidated epsilon-polylysine;

(3) preparing 20% aldehyde dextran aqueous solution, preheating the aqueous solution to 37 ℃, then adding 10% amidated epsilon-polylysine aqueous solution in percentage by mass at the temperature in an equal proportion, and magnetically stirring for 3min to finally prepare the hydrogel adhesive.

Example 5

(1) Preparing 20% dextran water solution, mixing with 5% sodium periodate water solution at volume ratio of 2:1, and stirring at 50 deg.C for 60 min; after the reaction is finished, dialyzing the mixed solution for 18h by using running water, further dialyzing the mixed solution for 2 times by using deionized water, wherein the dialysis time is 1.5h, finally drying to obtain aldehyde group glucan, grinding the aldehyde group glucan into powder, performing vacuum drying for 24h, and refrigerating at-15 ℃ for later use;

(2) preparing an epsilon-polylysine aqueous solution with the mass fraction of 25%, diluting acetic anhydride with deionized water to obtain an acetic anhydride aqueous solution with the concentration of 1%, mixing the two solutions according to the volume ratio of 1:1, reacting for 60min under the condition of stirring at the constant temperature of 45 ℃, dialyzing and purifying the reaction solution for 24h with deionized water after the reaction is finished, and finally freeze-drying for 24h to obtain amidated epsilon-polylysine;

(3) preparing 20% aldehyde dextran aqueous solution, preheating the aqueous solution to 37 ℃, then adding 10% amidated epsilon-polylysine aqueous solution in percentage by mass at the temperature in an equal proportion, and magnetically stirring for 3min to finally prepare the hydrogel adhesive.

Example 6

(1) Preparing 20% dextran water solution, mixing with 5% sodium periodate water solution at volume ratio of 2:1, and stirring at 50 deg.C for 60 min; after the reaction is finished, dialyzing the mixed solution for 18h by using running water, further dialyzing the mixed solution for 2 times by using deionized water, wherein the dialysis time is 1.5h, finally drying to obtain aldehyde group glucan, grinding the aldehyde group glucan into powder, performing vacuum drying for 24h, and refrigerating at-15 ℃ for later use;

(2) preparing an epsilon-polylysine aqueous solution with the mass fraction of 25%, diluting succinic anhydride with deionized water to obtain a 1% succinic anhydride aqueous solution, mixing the two solutions according to the volume ratio of 3:1, reacting for 60min under the condition of stirring at the constant temperature of 45 ℃, dialyzing and purifying the reaction solution for 24h with deionized water after the reaction is finished, and finally freeze-drying for 24h to obtain amidated epsilon-polylysine;

(3) preparing 20% aldehyde dextran aqueous solution, preheating the aqueous solution to 37 ℃, then adding 10% amidated epsilon-polylysine aqueous solution in percentage by mass at the temperature in an equal proportion, and magnetically stirring for 3min to finally prepare the hydrogel adhesive.

Example 7

(1) Preparing 20% dextran water solution, mixing with 5% sodium periodate water solution at volume ratio of 2:1, and stirring at 50 deg.C for 60 min; after the reaction is finished, dialyzing the mixed solution for 18h by using running water, further dialyzing the mixed solution for 2 times by using deionized water, wherein the dialysis time is 1.5h, finally drying to obtain aldehyde group glucan, grinding the aldehyde group glucan into powder, performing vacuum drying for 24h, and refrigerating at-15 ℃ for later use;

(2) preparing an epsilon-polylysine aqueous solution with the mass fraction of 25%, diluting succinic anhydride with deionized water to obtain a succinic anhydride aqueous solution with the concentration of 10%, mixing the two solutions according to the volume ratio of 1:1, reacting for 60min under the condition of stirring at the constant temperature of 45 ℃, dialyzing and purifying the reaction solution for 24h with deionized water after the reaction is finished, and finally freeze-drying for 24h to obtain amidated epsilon-polylysine;

(3) preparing 20% aldehyde dextran aqueous solution, preheating the aqueous solution to 37 ℃, then adding 10% amidated epsilon-polylysine aqueous solution in percentage by mass at the temperature in an equal proportion, and magnetically stirring for 3min to finally prepare the hydrogel adhesive.

Example 8

(1) Preparing 20% dextran water solution, mixing with 5% sodium periodate water solution at volume ratio of 2:1, and stirring at 50 deg.C for 60 min; after the reaction is finished, dialyzing the mixed solution for 18h by using running water, further dialyzing the mixed solution for 2 times by using deionized water, wherein the dialysis time is 1.5h, finally drying to obtain aldehyde group glucan, grinding the aldehyde group glucan into powder, performing vacuum drying for 24h, and refrigerating at-15 ℃ for later use;

(2) preparing an epsilon-polylysine aqueous solution with the mass fraction of 25%, diluting succinic anhydride with deionized water to obtain a succinic anhydride aqueous solution with the concentration of 10%, mixing the two solutions according to the volume ratio of 3:1, reacting for 60min under the condition of stirring at the constant temperature of 45 ℃, dialyzing and purifying the reaction solution for 24h with deionized water after the reaction is finished, and finally freeze-drying for 24h to obtain amidated epsilon-polylysine;

(3) preparing 20% aldehyde dextran aqueous solution, preheating the aqueous solution to 37 ℃, then adding 10% amidated epsilon-polylysine aqueous solution in percentage by mass at the temperature in an equal proportion, and magnetically stirring for 3min to finally prepare the hydrogel adhesive.

Example 9

(1) Preparing 20% dextran water solution, mixing with 5% sodium periodate water solution at volume ratio of 2:1, and stirring at 50 deg.C for 60 min; after the reaction is finished, dialyzing the mixed solution for 18h by using running water, further dialyzing the mixed solution for 2 times by using deionized water, wherein the dialysis time is 1.5h, finally drying to obtain aldehyde group glucan, grinding the aldehyde group glucan into powder, performing vacuum drying for 24h, and refrigerating at-15 ℃ for later use;

(2) preparing an epsilon-polylysine aqueous solution with the mass fraction of 25%, diluting succinic anhydride with deionized water to a succinic anhydride aqueous solution with the concentration of 6%, mixing the two solutions according to the volume ratio of 2:1, reacting for 60min under the condition of stirring at the constant temperature of 45 ℃, dialyzing and purifying the reaction solution for 24h with deionized water after the reaction is finished, and finally freeze-drying for 24h to obtain amidated epsilon-polylysine;

(3) preparing 20% aldehyde dextran aqueous solution, preheating the aqueous solution to 20 ℃, then adding 5% amidated epsilon-polylysine aqueous solution at the temperature in an equal proportion, and magnetically stirring for 3min to finally prepare the hydrogel adhesive.

Example 10

(1) Preparing 20% dextran water solution, mixing with 5% sodium periodate water solution at volume ratio of 2:1, and stirring at 50 deg.C for 60 min; after the reaction is finished, dialyzing the mixed solution for 18h by using running water, further dialyzing the mixed solution for 2 times by using deionized water, wherein the dialysis time is 1.5h, finally drying to obtain aldehyde group glucan, grinding the aldehyde group glucan into powder, performing vacuum drying for 24h, and refrigerating at-15 ℃ for later use;

(2) preparing an epsilon-polylysine aqueous solution with the mass fraction of 25%, diluting succinic anhydride with deionized water to a succinic anhydride aqueous solution with the concentration of 6%, mixing the two solutions according to the volume ratio of 2:1, reacting for 60min under the condition of stirring at the constant temperature of 45 ℃, dialyzing and purifying the reaction solution for 24h with deionized water after the reaction is finished, and finally freeze-drying for 24h to obtain amidated epsilon-polylysine;

(3) preparing 20% aldehyde dextran aqueous solution, preheating the aqueous solution to 20 ℃, then adding 25% amidated epsilon-polylysine aqueous solution in mass fraction at the temperature in an equal proportion, and magnetically stirring for 3min to finally prepare the hydrogel adhesive.

Test example 1

Evaluation of adhesion Performance: the shear bond strength of the hydrogel adhesive was tested using a tensile Strength Meter (RTC-1210) by the following procedure: cutting collagen casing with diameter of 40mm into 60 × 15mm²And storing in deionized water at 2 ℃ for later use. The surface of the casing was wiped free of water and 0.1mL of the hydrogel adhesive of examples 1-10 was dropped onto the swollen casingCovering another piece of sausage casing on the upper part, and controlling the bonding area to be 15 multiplied by 15mm²After 200g had been loaded for 2min, a shear adhesion strength test was carried out at a speed of 10mm/min using a tensile strength tester. Commercial fibrin glue and cyanoacrylate adhesives were numbered 11 and 12, respectively, for comparison. The bond strength results are shown in table 3.

TABLE 3 Table of adhesive Strength data for each sample

The hydrogel adhesives prepared in examples 1-10 exhibited excellent adhesion as high as 8.688MPa, ten times the bond strength of the commercial fibrin glue (sample 11, 0.841MPa), and slightly higher than the bond strength of the commercial synthetic cyanoacrylate (sample 12, 6.211 MPa). This is attributed to the sufficient gelation between oxidized dextran and amidated epsilon-polylysine, and the inter-entangled structure of macromolecules gives it high adhesive strength.

Test example 2

Evaluation of cytotoxicity: in vitro cytotoxicity test was performed by referring to MTT method provided in GB/T16886.5-2017 (ISO 10993-5:2009), L929 mouse fibroblast was used as a cell line, and 10% fetal bovine serum MEM culture solution was used to treat silk fibroin in examples 1-10 by 3cm²Leaching at 37 deg.C for 24 hr to obtain solution to be tested. Commercial fibrin glue and cyanoacrylate adhesives are used as evaluation comparison, the numbers are 11 and 12 respectively, and the extraction is carried out by the same method; the same batch of MEM culture solution containing 10% fetal calf serum is used as a blank control solution; laminating high density polyethylene film by 3cm²Adding 10% fetal calf serum-containing MEM culture solution into the extract at a ratio of/mL to obtain a negative control solution; 10% dimethyl sulfoxide (DMSO) was used as a positive control. Experimentally determined cell presenceThe viability and toxicity ratings are shown in table 4. If the survival rate drops below 70% of the blank, potential cytotoxicity is indicated. Cytotoxicity ratings were graded 0-4: where 0 represents no toxicity, 1 represents mild, 2 represents mild, 3 represents moderate, and 4 represents severe.

TABLE 4 cell viability and toxicity ratings for various concentrations of the example samples and the control samples

As can be seen from the data in table 4, the cell survival rate of the commercial fibrin glue 11 is 98.23%, which has good biocompatibility, while the cell survival rate of the synthetic cyanoacrylate-based adhesive 12 is 71.25%, which has mild cytotoxicity, which is consistent with that described in the background art. The hydrogel adhesives prepared in examples 1-10 of the present invention have a cell survival rate ranging from 93.39% to 98.31%, a cytotoxicity of 0 grade, and a high biosafety, which is attributed to that dextran and epsilon-polylysine are both green-friendly reagents, and no crosslinking agent having cytotoxicity is used in the preparation process of the hydrogel adhesives.

In conclusion, the hydrogel adhesive prepared by the invention has high adhesive strength and low cytotoxicity, and has a profound prospect in the clinical medical field.

It should be understood that the above-described embodiments of the present invention are only examples for illustrating the present invention, and are not intended to limit the specific embodiments of the present invention. It will be apparent to those skilled in the art that other variations and modifications can be made on the above examples. Not all embodiments are exemplified in detail herein. All obvious changes and modifications of the present invention are within the scope of the present invention.