CN113292671B

CN113292671B - High molecular cross-linking agent containing phenylboronic acid group, biological adhesive prepared from high molecular cross-linking agent, preparation method and application of biological adhesive

Info

Publication number: CN113292671B
Application number: CN202110773090.8A
Authority: CN
Inventors: 刘吉; 薛羽; 张俊; 张加俊; 陈兴梅
Original assignee: Southwest University of Science and Technology
Current assignee: Southwest University of Science and Technology
Priority date: 2021-07-08
Filing date: 2021-07-08
Publication date: 2023-09-05
Anticipated expiration: 2041-07-08
Also published as: CN113292671A

Abstract

The invention provides a polymer cross-linking agent containing phenylboronic acid groups, a biological adhesive prepared from the polymer cross-linking agent, and a preparation method and application of the biological adhesive. The cross-linking agent is prepared from acrylic acid, monomer containing phenylboronic acid groups and other acrylic acid monomers or polymers containing hydroxyl or amino groups, and can be used for preparing biological adhesives. The raw materials for preparing the biological adhesive comprise acrylic acid, acrylic acid-N-succinimidyl ester, a macromolecular crosslinking agent containing phenylboronic acid groups, a polyalcohol polymer, a photoinitiator, an acidity regulator and water. The crosslinking agent is mixed with the acrylic acid with succinimidyl ester group and the polyalcohol polymer for reaction, and the obtained biological adhesive has excellent comprehensive performance, can show good adhesive performance and mechanical performance in a wet environment, and can be relatively simple and convenient for de-adhesion.

Description

High molecular cross-linking agent containing phenylboronic acid group, biological adhesive prepared from high molecular cross-linking agent, preparation method and application of biological adhesive

Technical Field

The invention belongs to the field of medical material preparation, and particularly relates to a bioadhesive, in particular to a polymer cross-linking agent containing phenylboronic acid groups, a bioadhesive prepared from the same, and a preparation method and application of the bioadhesive.

Background

Bioadhesives (including tissue adhesives, hemostatic agents, and tissue sealants) are biomedical materials used to prevent tissue adhesions, hemostasis, and leakage of air and body fluids during surgery. In terms of postoperative wound suturing and tissue adhesion, the biological adhesive is an ideal substitute for traditional sutures, rivets and other mechanical fixing materials, has the advantages of convenience in use, noninvasive closure, less pain, capability of inhibiting body fluid leakage, additional injury caused by wound suturing and the like, thus meeting the modern medical concept and high requirements on surgical operation, and having wide application prospect in clinic. However, the bioadhesives used in the market at present, such as cyanoacrylates, fibrin adhesives and the like, generally have the defects of poor elasticity, weak wet-adhesion resistance, poor antibacterial and antiviral properties and the like, and cannot meet the clinical actual demands.

In addition, in many medical applications, the wound or tissue often requires removal of the adhesive after healing. Particularly for delicate or important biological tissue sites, the adhesive must be removed without damaging the body, thus placing higher demands on the bioadhesive de-adhesion method. In general, the strong adhesive properties of adhesives are contradictory to easy adhesion. Strong adhesion is typically achieved by covalent bonds, physical interactions or a combination thereof. Covalent bonding, while having extremely high adhesion, is very difficult to break the chemical bonding of the adhesive and tissue surfaces; strong adhesion by physical action makes it possible to achieve de-adhesion, but requires solvent treatment before adhesion, which is cumbersome and not environmentally friendly.

Some conventional adhesives are chemically modified to allow for de-adhesion under changes in temperature (epoxy) or light (pressure sensitive adhesives), but such materials are generally biotoxic with little adhesion to wet surfaces.

Therefore, designing a biological adhesive with excellent comprehensive performance and strong adhesion and easy adhesion is a problem to be solved by scientific researchers in the field.

Disclosure of Invention

In view of the problems in the prior art, the invention provides a polymer cross-linking agent containing phenylboronic acid groups, a biological adhesive prepared from the polymer cross-linking agent, a preparation method and application of the biological adhesive.

To achieve the purpose, the invention adopts the following technical scheme:

in a first aspect, the present invention provides a polymeric crosslinker containing phenylboronic acid groups, the polymeric crosslinker having a structure according to formula I:

wherein x is an integer greater than or equal to 1, y is an integer greater than or equal to zero, and m is an integer greater than or equal to zero.

The R1 contains phenylboronic acid groups.

The R2 contains any one group or a combination of at least two groups of carboxyl, ester group or acyl chloride.

The R3Wherein->Indicating the access position of the group.

The side chain of the high molecular cross-linking agent provided by the invention contains phenylboronic acid groups, has glucose responsiveness, is used for preparing the biological adhesive, and can overcome the contradiction between the adhesive property and the anti-adhesive property of the biological adhesive.

As a preferable technical scheme of the invention, the R is as follows ₁ The R is ₁ Is that Any one or a combination of at least two of the above, wherein +.>Indicating the access position of the group.

Preferably, said R ₂ Is that Any one or a combination of at least two of the above, wherein +.>Indicating the access position of the group.

Preferably, the polymer crosslinking agent is poly (acrylic acid-co-vinylphenylboronic acid-co-methacrylic acid (ethyl isocyanate, ethyl acrylate)), and has a structure shown in formula II:

wherein x is an integer of 1 or more, y is an integer of zero or more, and m is an integer of zero or more, and the number average molecular weight of the polymer crosslinking agent is in the range of 600 to 1000000g/mol, and may be, for example, 600g/mol, 700g/mol, 800g/mol, 1000g/mol, 2000g/mol, 5000g/mol, 8000g/mol, 10000g/mol, 50000g/mol, 100000g/mol, 500000g/mol, 1000000g/mol, or the like.

In a second aspect, the present invention provides a method for preparing the polymeric crosslinker according to the first aspect, the method comprising the steps of:

dissolving a raw material I, a raw material II and a raw material III, adding an initiator to perform polymerization reaction, and then adding a modifier to perform modification to obtain the high polymer cross-linking agent;

wherein, the raw material I is acrylic acid, the raw material II is monomer containing phenylboronic acid group, and the raw material III is acrylamide and/or acrylic ester containing hydroxyl and/or amino.

Preferably, the monomer containing phenylboronic acid group comprises any one or a combination of at least two of 2-vinylphenylboronic acid, 3-vinylphenylboronic acid, 4-vinylphenylboronic acid, 2- (2-carboxyvinyl) phenylboronic acid, 3- (2-carboxyvinyl) phenylboronic acid or 4- (2-carboxyvinyl) phenylboronic acid.

Preferably, the raw material III is a monomer and/or a polymer.

Preferably, the raw material III comprises hydroxyethyl methacrylate and/or hydroxyethyl acrylate; .

Preferably, the initiator comprises azobisisobutyronitrile.

Preferably, the modifier comprises isocyanate ethyl acrylate.

Preferably, the molar ratio of the raw materials I, II and III is (80-100): (10-20): 1, for example, 80:10:1, 80:15:1, 80:18:1, 80:20:1, 85:10:1, 90:10:1, 95:10:1, 100:10:1, 85:15:1, 90:20:1 or 100:20:1, etc., preferably 85:15:1.

Preferably, the molar ratio of the raw material III to the modifier is 1 (1-1.2), for example, 1:1.05, 1:1.08, 1:1.1, 1:1.12, 1:1.15, 1:1.18, etc.

Preferably, the polymerization reaction time is 3 to 5 hours, and may be, for example, 3.2 hours, 3.4 hours, 3.5 hours, 3.6 hours, 3.8 hours, 4 hours, 4.2 hours, 4.5 hours, 4.6 hours, or 4.8 hours.

Preferably, the molar ratio of the initiator to the starting material III is (0.5-0.8): 1, which may be, for example, 0.55:1, 0.6:1, 0.65:1, 0.7:1, or 0.75:1, etc.

Preferably, the molar ratio of the azodiisobutyronitrile to the hydroxyethyl methacrylate is (0.5-0.8): 1, for example, 0.55:1, 0.6:1, 0.65:1, 0.7:1, 0.75:1, or the like.

In a third aspect, the present invention provides a releasable bioadhesive comprising a polymeric crosslinker according to the first aspect.

Preferably, the bioadhesive comprises: acrylic acid, acrylic acid-N-succinimidyl ester, a macromolecular crosslinking agent as described in the first aspect, a polyol polymer, a photoinitiator, an acidity regulator and water.

In the present invention, the bioadhesive comprises acrylic acid having a succinimidyl ester group, a crosslinking agent containing a phenylboronic acid group, and a polyol polymer, which is chemically bonded and adhered to the surface of biological tissue through the succinimidyl ester group, and at the same time, the acrylic polymer and the polyol are chemically connected through a boric acid ester bond having a glucose response; under the synergistic effect of succinimidyl ester group, phenylboronic acid group and polyalcohol, the obtained biological adhesive has excellent comprehensive performance, can show good adhesion performance in a wet environment, and has mechanical performance matched with tissues, good biocompatibility and good adhesion-resolvable performance.

Preferably, the biological adhesive is prepared from the following raw materials in parts by weight:

wherein, the weight part of the acrylic acid can be 11 parts, 12 parts, 13 parts, 14 parts, 15 parts, 16 parts, 17 parts, 18 parts or 19 parts, etc.; the weight part of the acrylic acid-N-succinimidyl ester can be 1.2 parts, 1.4 parts, 1.5 parts, 1.6 parts or 1.8 parts, etc.; the weight part of the cross-linking agent can be 2 parts, 3 parts, 4 parts or 4.5 parts, etc.; the weight parts of the polyol polymer may be 1 part, 1.5 parts, 2 parts, 2.5 parts, 3 parts, 3.5 parts, 4 parts, 4.5 parts, etc.; the weight portion of the photoinitiator can be 0.6 portion, 0.7 portion, 0.8 portion or 0.9 portion, etc.; the acidity regulator may be 4.2 parts, 4.5 parts, 4.8 parts, 5 parts, 5.2 parts, 5.4 parts, 5.5 parts, 5.6 parts, 5.8 parts, etc.

As a preferable technical scheme of the invention, the polyol polymer has various types, and comprises synthetic polymers such as polyvinyl alcohol, synthetic polymers containing dihydric alcohol or polyalcohol side chains such as polyvinyl alcohol copolymer, or natural polymers such as sodium alginate, chitosan, cellulose, hyaluronic acid, hydroxyethyl cellulose, gelatin, carrageenan, agar, hyaluronic acid and the like.

Preferably, the photoinitiator comprises any one or a combination of at least two of alpha-ketoglutarate, alpha-hydroxyalkyl benzophenone or alpha-aminoalkylbenzophenone.

Preferably, the acidity regulator comprises any one or a combination of at least two of acetic acid, lactic acid or hydrochloric acid.

In a fourth aspect, the present invention also provides a method for preparing a bioadhesive as described in the third aspect, comprising the steps of:

mixing the formula amount of acrylic acid, acrylic acid-N-succinimidyl ester, the cross-linking agent, the photoinitiator, the polyalcohol polymer and the acidity regulator, photo-crosslinking, and performing post-treatment to obtain the biological adhesive.

As a preferred embodiment of the present invention, the solvent used in the mixing includes water.

Preferably, the photo-crosslinking method comprises an ultraviolet curing method.

Preferably, the photocrosslinking temperature is 18 to 30 ℃, for example, 19 ℃, 20 ℃, 22 ℃, 24 ℃, 25 ℃, 26 ℃, 28 ℃, 29 ℃ or the like, preferably 25 ℃. Preferably, the photo-crosslinking time is 0.5 to 1h, for example, 0.6h, 0.7h, 0.8h, 0.9h, or the like.

Preferably, the post-treatment comprises immersing the photo-crosslinked material in an aqueous solution of PBS.

As a preferable technical scheme of the invention, the preparation method comprises the following steps:

(1) Dissolving acrylic acid, vinylphenylboronic acid and hydroxyethyl methacrylate in a dimethyl sulfoxide (DMSO) solvent, adding an initiator azodiisobutyronitrile, reacting for 3-5 h, and adding isocyanate ethyl acrylate for modification to obtain a high molecular cross-linking agent;

(2) Dissolving formula amount of acrylic acid, acrylic acid-N-succinimidyl ester, a high molecular cross-linking agent and a photoinitiator in water to obtain a solution I, and dispersing and dissolving formula amount of polyol polymer and an acidity regulator in water to obtain a solution II;

and mixing the solution I and the solution II, pouring into a mold, solidifying under ultraviolet irradiation, placing into air for volatilizing, and soaking in PBS aqueous solution to obtain the biological adhesive.

In a fifth aspect, the present invention also provides a method of using the bioadhesive of the third aspect, the method of using comprising the steps of adhering and de-adhering.

The adhering step includes: and coating buffer solution on the surface of the biological tissue, adhering the biological adhesive on the surface of the biological tissue, and pressing.

The step of deadhesing comprises: coating the bioadhesive surface with the deadhesive solution, and standing.

Preferably, the buffer comprises an aqueous PBS solution.

Preferably, the pH of the aqueous PBS solution is 7.2 to 7.6, and may be, for example, 7.2, 7.3, 7.4, or 7.6.

Preferably, the pressing time is 4 to 10s, and may be, for example, 5s, 6s, 7s, 8s, 9s, or the like.

Preferably, the debonding solution comprises any one or a combination of at least two of a glucose solution, a fructose solution, a sucrose solution, a maltose solution or glycerol.

Preferably, the mass concentration in the debonding solution is 5 to 30wt%, for example, 6wt%, 8wt%, 10wt%, 12wt%, 15wt%, 18wt%, 20wt%, 22wt%, 25wt%, 28wt%, etc.

Preferably, the time for the standing is 8 to 15s, and may be, for example, 9s, 10s, 11s, 12s, 13s, 14s, or the like.

In a sixth aspect, the present invention also provides the use of a polymeric crosslinker as described in the first aspect or a bioadhesive as described in the third aspect in the preparation of a biomedical material.

The numerical ranges recited herein include not only the recited point values, but also any point values between the recited numerical ranges that are not recited, and are limited to, and for the sake of brevity, the invention is not intended to be exhaustive of the specific point values that the recited range includes.

Compared with the prior art, the invention has at least the following beneficial effects:

(1) The invention provides a polymer cross-linking agent containing phenylboronic acid groups, which has glucose responsiveness and can help the bioadhesive to overcome the contradiction between the adhesive property and the anti-adhesion property of the bioadhesive;

(2) Mixing the cross-linking agent with an acrylic acid and polyalcohol polymer with a succinimidyl ester group, and then carrying out photo-crosslinking curing reaction to obtain a biological adhesive, wherein the acrylic acid polymer and the polyalcohol are chemically connected through a borate ester bond with glucose response; the obtained biological adhesive contains a double-network structure constructed by the acrylic polymer and the polyalcohol, and can be chemically bonded and adhered with the surface of biological tissues, so that the biological adhesive has the effects of strong adhesion and easy adhesion, and meanwhile, the method for adhering the biological adhesive is simple and convenient, the process is mild and safe, and the biological adhesive has good biomedical prospect.

Drawings

FIG. 1 is a nuclear magnetic spectrum of a polymer crosslinking agent poly (acrylic acid-co-vinylphenylboronic acid-co-methacrylic acid (ethyl isocyanate-ethyl acrylate)) prepared in example 1.

FIG. 2 is a graph of stress-strain curve control of the bioadhesive PBAc/SA before and after treatment with a 20wt% dextrose solution.

FIG. 3 is a graph showing the comparison of the bioadhesive PBAc/SA to pigskin tissue adhesion rheology curves before and after treatment with a 20wt% dextrose solution.

FIG. 4 is a graph showing a 180℃peel curve of the bioadhesive PBAc/SA adhered to pigskin tissue before and after treatment with a 20wt% dextrose solution.

FIG. 5 is a graph of the biocompatibility spectrum of the bioadhesive PBAc/SA.

FIG. 6 is a graph showing the comparison of the toughness of the adhesive interface between various bioadhesives and pigskin.

Detailed Description

The following embodiments are further described with reference to the accompanying drawings, but the following examples are merely simple examples of the present invention and do not represent or limit the scope of the invention, which is defined by the claims.

Example 1

The embodiment provides a polymer cross-linking agent with phenylboronic acid groups, and the preparation method specifically comprises the following steps:

the method comprises the steps of dissolving reaction raw materials of acrylic acid, 4-vinylphenylboronic acid, hydroxyethyl methacrylate and an initiator azodiisobutyronitrile in a molar ratio of 85:15:1:0.5 in 20mL of dried dimethyl sulfoxide (DMSO) solution;

continuously introducing nitrogen for 10min, and reacting for 3h at 80 ℃;

after the reaction is finished, the obtained polymer solution is settled in anhydrous diethyl ether to obtain a polymer with pendant phenylboronic acid;

dissolving the polymer in a dry DMSO solution, adding an equivalent amount of isocyanate ethyl acrylate solution, and sealing for continuous reaction for 12 hours;

the obtained reaction solution is settled in anhydrous diethyl ether and dried in vacuum, and a light yellow sticky substance is obtained, namely the macromolecule crosslinking agent poly (acrylic acid-co-vinylphenylboronic acid-co-methacrylic acid (ethyl isocyanate and ethyl acrylate)), the chemical formula is shown as a formula II, the number average molecular weight is 7031g/mol, and the nuclear magnetic resonance spectrum is shown as a figure 1.

Example 2

This example provides a polymer crosslinking agent with phenylboronic acid groups, and the preparation method is different from example 1 in that:

the reaction materials of acrylic acid, 4-vinylphenylboronic acid, hydroxyethyl methacrylate and azo-bis-isobutyronitrile as initiator are dissolved according to the molar ratio of 80:10:1:0.5, and the rest operation and treatment method are the same as those of the example 1.

Example 3

the reaction materials of acrylic acid, 4-vinylphenylboronic acid, hydroxyethyl methacrylate and azo-bis-isobutyronitrile as initiator are dissolved according to the molar ratio of 100:20:1:0.8, and the rest operation and treatment method are the same as those of the example 1.

Comparative example 1

This comparative example provides a crosslinker, whose preparation differs from example 1 in that: the reaction raw materials do not contain 4-vinylphenylboronic acid; the molar ratio of acrylic acid, hydroxyethyl methacrylate and initiator azobisisobutyronitrile was 100:1:0.5, the remainder of the procedure and treatment was as in example 1.

Application example 1

The application example provides a polyacrylic acid-sodium alginate (PBAc/SA) double-network biological adhesive, which is prepared from the following raw materials:

the preparation method comprises the following steps:

dissolving acrylic acid, acrylic acid-N-succinimide, a cross-linking agent, a photoinitiator and acetic acid solution in 5mL deionized water, uniformly mixing and removing bubbles;

dissolving a polyol polymer in 5mL of deionized water to remove bubbles;

mixing the two solutions, slowly pouring into a mold, sealing in an ultraviolet curing box, reacting for 30min, volatilizing the solvent, vacuum drying, and soaking in PBS aqueous solution with pH of 7.4 for 1min to obtain the biological adhesive with high adhesive property;

the adhesion and de-adhesion process of the bioadhesive comprises:

coating PBS aqueous solution (2 mL) on the surface of pigskin with a wound of 5mm, cutting a bioadhesive material with the length and width of 10mm multiplied by 0.1mm, adhering the bioadhesive material on the surface of the wound, and pressing for 5s to realize the adhesion and sealing of the bioadhesive to biological tissues;

and (3) coating 1mL of glucose solution with the mass fraction of 5wt% on the bonding area, and waiting for 10s to easily lift the bioadhesive.

Application example 2

This example provides a polyacrylic acid-polyvinyl alcohol (PBAc/PVA) dual network bioadhesive differing from application example 1 only in that 0.1g sodium alginate in application example 1 was replaced with 0.1g polyvinyl alcohol; the rest of the operation and processing method are consistent with the application example 1.

Application example 3

This example provides a polyacrylic acid-chitosan (PBAc/CTS) double-network bioadhesive, which differs from application example 1 only in that 0.1g sodium alginate in application example 1 was replaced with 0.1g chitosan; the rest of the operation and processing method are consistent with the application example 1.

Application example 4

This example provides a polyacrylic acid-hydroxyethyl cellulose (PBAc/HEC) dual network bioadhesive differing from application example 1 only in that 0.1g sodium alginate in application example 1 was replaced with 0.1g hydroxyethyl cellulose; the rest of the operation and processing method are consistent with the application example 1.

Application example 5

This example provides a polyacrylic acid-hyaluronic acid (PBAc/HA) dual-network bioadhesive differing from application example 1 only in that 0.1g sodium alginate in application example 1 was replaced with 0.1g hyaluronic acid; the rest of the operation and processing method are consistent with the application example 1.

Application example 6

The application example provides a polyacrylic acid-sodium alginate double-network biological adhesive, which is different from application example 1 only in that the crosslinking agent is replaced by the crosslinking agent prepared in example 2; the rest of the operation and processing method are consistent with the application example 1.

Application example 7

The application example provides a polyacrylic acid-sodium alginate double-network biological adhesive, which is different from application example 1 only in that the crosslinking agent is replaced by the crosslinking agent prepared in example 3; the rest of the operation and processing method are consistent with the application example 1.

Comparative example 1 was used

This comparative example provides a bioadhesive whose raw material for production differs from that of application example 1 in that the crosslinking agent produced in example 1 is not contained in the raw material for production, while the amount of acrylic acid is increased to 2.3g; the rest of the operation and processing method are consistent with the application example 1.

Comparative example 2 was used

This comparative example provides a bioadhesive whose raw material for preparation differs from that of application example 1 in that the crosslinking agent prepared in example 1 is replaced with an acrylic acid-N-succinimidyl ester of equal mass in the raw material for preparation; the rest of the operation and processing method are consistent with the application example 1.

Comparative example 3 was used

This comparative example provides a bioadhesive whose raw material for preparation is different from that of application example 1 in that the crosslinking agent prepared in example 1 is replaced with the crosslinking agent prepared in comparative example 1; the rest of the operation and processing method are consistent with the application example 1.

Comparative example 4 was used

This comparative example provides a bioadhesive whose raw material for production differs from that of application example 1 in that it does not contain acrylic acid-N-succinimidyl ester, while the amount of acrylic acid is increased to 2.1g; the rest of the operation and processing method are consistent with the application example 1.

Performance test 1

The following performance tests were performed on the bioadhesives provided in application examples 1 to 7 and application comparative examples 1 to 4:

(1) The stress strain curve test method comprises the following steps: the hydrogel bioadhesive was prepared into a rectangular shape of 20mm length, 5mm width and 1mm thickness using a mold, and the stress strain curve of the hydrogel was tested using a tensile machine.

(2) The rheological curve test method comprises the following steps: the hydrogel bioadhesive was prepared into a disc shape with a diameter of 20mm and a height of 1mm using a mold, and the change in storage modulus and loss modulus of the hydrogel with stress was measured using a rheometer.

(3) The toughness test of the bonding interface between the biological adhesive and the pigskin comprises the following steps: in the present invention, three control experiments were tested, pigskin-pigskin, pigskin-backing and pigskin-backing treated with glucose solution, respectively. Firstly, treating the surface of pigskin by using PBS solution, then firmly adhering the pigskin to the pigskin or the back lining by using a biological adhesive, finally testing the adhesive interface toughness, and simultaneously spraying glucose solution on the surface of the back lining to test the interface toughness.

Wherein the stress-strain curves of the bioadhesive PBAc/SA prepared in application example 1 before and after treatment with a 20wt% glucose solution are shown in FIG. 2;

the rheological curves of the treated pigskin tissue after adhesion with the 20wt% glucose solution are shown in FIG. 3, and the values of G '/G' are significantly smaller after the glucose solution treatment.

The 180 ° peel test results before and after treatment with 20wt% dextrose solution are shown in fig. 4;

from the above results, it is clear that the stress of the bioadhesive PBAc/SA is significantly reduced after the treatment with the glucose solution, that is, the adsorption force between the bioadhesive and the adhesive surface is reduced after the treatment with the glucose solution, thereby achieving the effect of releasing the adhesion.

Likewise, the stress of application examples 2 to 7 was significantly reduced after glucose treatment, and the specific data are shown in Table 1 below:

TABLE 1

From the above table, the use of the macromolecular crosslinking agent provided by the invention can obviously improve the mechanical and adhesive properties of the hydrogel biological adhesive.

Performance test 2

The biocompatibility test method comprises the following steps: the cells used in the invention are NIH3T3 type, the cells are grown in 24 pore plates, and the testing method is consistent with the international standard biocompatibility testing mode.

The results of the test of the bioadhesive PBAc/SA prepared in application example 1 are shown in FIG. 5, and it is understood from the graph that the cell viability obtained by the test on days 1, 3 and 5 after the treatment with the bioadhesive was less different from that of the blank group, and the cell viability was about 85%.

The results of the biocompatibility test of the application examples and the application comparative examples are shown in the following table 2, wherein the cell viability is the cell viability after the first day of treatment, based on 100% of the control group;

TABLE 2

Sample of	Cell viability (%)	Sample of	Cell viability (%)
				Application example 1	81.4	Comparative example 1 was used	80.2
Application example 2	83.5	Comparative example 2 was used	80.9
				Application example 3	81.9	Comparative example 3 was used	81.1
Application example 4	80.8	Comparative example 4 was used	81.9
				Application example 5	82.7
Application example 6	81.6
				Application example 7	82.8

As can be seen from the above table, the bioadhesive provided in the present invention has good biosafety.

Performance test 3

The different bioadhesives and pigskin adhesive interface toughness test patterns were consistent with the method used in performance test 1. The results of the interfacial toughness tests of the PBAc/SA provided in application example 1, the PBAc/CTS provided in application example 3, the PBAc/HEC provided in application example 4 and the PBAc/HA provided in application example 5 are shown in FIG. 6, and it is understood that the toughness of the obtained adhesive interface is significantly reduced after the treatment with a glucose solution regardless of the polyol polymer used.

In summary, the crosslinking agent provided by the invention can realize rapid and stable adhesion with tissues, but the adhesion performance is reduced rapidly after the treatment by glucose solution.

The applicant declares that the above is only a specific embodiment of the present invention, but the scope of the present invention is not limited thereto, and it should be apparent to those skilled in the art that any changes or substitutions that are easily conceivable within the technical scope of the present invention disclosed by the present invention fall within the scope of the present invention and the disclosure.

Claims

1. A bioadhesive, characterized in that it comprises: acrylic acid, acrylic acid-N-succinimidyl ester, a high molecular cross-linking agent, a polyalcohol polymer, a photoinitiator, an acidity regulator and water;

the macromolecular crosslinking agent has a structure shown in a formula II:

wherein x is an integer greater than or equal to 1, y is an integer greater than or equal to zero, m is an integer greater than zero, and the number average molecular weight of the polymeric cross-linking agent is 600-1000000 g/mol.

2. The bioadhesive of claim 1, wherein the method of preparing the polymeric crosslinker comprises the steps of:

wherein, the raw material I is acrylic acid, the raw material II is 4-vinylphenylboronic acid, and the raw material III is hydroxyethyl methacrylate.

3. The releasable adhesive of claim 2, wherein the initiator comprises azobisisobutyronitrile.

4. The bioadhesive of claim 2, wherein the molar ratio of raw material I, raw material II and raw material III is from (80 to 100): (10 to 20): 1.

5. The bioadhesive of claim 4, wherein the molar ratio of raw material I, raw material II and raw material III is 85:15:1.

6. The bioadhesive of claim 2, wherein the molar ratio of the starting material III to the modifying agent is 1 (1-1.2).

7. The bioadhesive of claim 2, wherein the polymerization time is from 3 to 5 hours.

8. The bioadhesive of claim 2, wherein the molar ratio of initiator to starting material III is from (0.5 to 0.8): 1.

9. The bioadhesive of claim 3, wherein the molar ratio of azobisisobutyronitrile to hydroxyethyl methacrylate is from (0.5 to 0.8): 1.

10. The bioadhesive of claim 1, wherein the bioadhesive is prepared from the following raw materials in parts by weight:

11. the bioadhesive of claim 1, wherein the polyol polymer comprises any one or a combination of at least two of polyvinyl alcohol, polyvinyl alcohol copolymer, sodium alginate, chitosan, cellulose, hydroxyethyl cellulose, gelatin, carrageenan, agar, or hyaluronic acid.

12. The bioadhesive of claim 1, wherein the photoinitiator comprises any one or a combination of at least two of α -ketoglutarate, α -hydroxyalkylphenone, or α -aminoalkylphenone.

13. The bioadhesive of claim 1, wherein the acidity regulator comprises any one or a combination of at least two of acetic acid, lactic acid, or hydrochloric acid.

14. A method of preparing a bioadhesive according to any one of claims 1 to 13, comprising the steps of:

mixing the formula amount of acrylic acid, acrylic acid-N-succinimidyl ester, a high molecular cross-linking agent, a photoinitiator, a polyalcohol polymer and an acidity regulator, photo-crosslinking, and performing post-treatment to obtain the biological adhesive.

15. The method of claim 14, wherein the solvent used in the mixing comprises water.

16. The method of claim 14, wherein the photo-crosslinking method comprises uv curing.

17. The method of claim 14, wherein the photocrosslinking temperature is 18 to 30 ℃.

18. The method of claim 17, wherein the photocrosslinking temperature is 25 ℃.

19. The method of claim 14, wherein the photocrosslinking is for a period of 0.5 to 1 hour.

20. The method of claim 14, wherein the post-treatment comprises immersing the photo-crosslinked material in an aqueous solution of PBS.

21. The preparation method according to claim 14, characterized in that the preparation method comprises the steps of:

(1) Dissolving acrylic acid, vinylphenylboronic acid and hydroxyethyl methacrylate in a dimethyl sulfoxide solvent, adding an initiator azodiisobutyronitrile, reacting for 3-5 h, and then adding isocyanate ethyl acrylate for modification to obtain a cross-linking agent;

(2) Dissolving formula amount of acrylic acid, acrylic acid-N-succinimidyl ester, a cross-linking agent and a photoinitiator in water to obtain a solution I, and dispersing and dissolving formula amount of polyol polymer and an acidity regulator in water to obtain a solution II;

22. A method of using the bioadhesive of any one of claims 1-13, wherein said method of use comprises a adhering step and a de-adhering step;

the adhering step includes: coating buffer solution on the surface of biological tissue, adhering the biological adhesive on the surface of the biological tissue, and pressing;

the step of deadhesing comprises: and (3) coating a debonding solution on the surface of the biological adhesive, and standing.

23. The method of use of claim 22, wherein the buffer comprises an aqueous PBS solution.

24. The method of claim 23, wherein the aqueous PBS solution has a pH of 7.2 to 7.6.

25. The method of claim 23, wherein the pressing is for a period of 4 to 10 seconds.

26. The method of use according to claim 23, wherein the debonding solution comprises any one or a combination of at least two of a glucose solution, a fructose solution, a sucrose solution, a maltose solution, or glycerol.

27. Use according to claim 23, characterized in that the mass concentration of the debonding solution is between 5 and 30wt%.

28. The method of claim 23, wherein the time of resting is 8-15 s.

29. Use of a bioadhesive according to any one of claims 1-13 for the preparation of biomedical materials.