CN113292671A

CN113292671A - Polymer crosslinking agent containing phenylboronic acid group, biological adhesive prepared from polymer crosslinking agent, and preparation method and application of biological adhesive

Info

Publication number: CN113292671A
Application number: CN202110773090.8A
Authority: CN
Inventors: 刘吉; 薛羽; 张俊; 张加俊; 陈兴梅
Original assignee: Southern University of Science and Technology
Current assignee: Southern University of Science and Technology
Priority date: 2021-07-08
Filing date: 2021-07-08
Publication date: 2021-08-24
Anticipated expiration: 2041-07-08
Also published as: CN113292671B

Abstract

The invention provides a polymer crosslinking agent containing phenylboronic acid group, a biological adhesive prepared by the same, a preparation method and application thereof. The crosslinking agent is prepared from acrylic acid, monomers containing phenylboronic acid groups and other acrylic monomers or polymers containing hydroxyl or amino groups as raw materials, and can be used for the preparation of biological adhesives. The raw materials for the preparation of the biological adhesive include acrylic acid, acrylic acid-N-succinimidyl ester, macromolecular cross-linking agent containing phenylboronic acid group, polyol polymer, photoinitiator, acidity regulator and water. The crosslinking agent is mixed and reacted with acrylic acid and polyol polymers with succinimidyl ester groups, and the obtained bioadhesive has excellent comprehensive properties and can exhibit good adhesion and mechanical properties in a humid environment , and can be relatively easily debonded.

Description

Polymer crosslinking agent containing phenylboronic acid group, biological adhesive prepared from polymer crosslinking agent, and 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 capable of being detached, in particular to a polymeric cross-linking agent containing phenylboronic acid groups, a bioadhesive prepared from the polymeric cross-linking agent, a preparation method and application of the bioadhesive.

Background

Bioadhesives, including tissue adhesives, hemostats, and tissue sealants, are a biomedical material used to prevent tissue adhesion, hemostasis, and prevent air and body fluid leakage during surgery. In the aspects 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 convenient use, noninvasive closure, less pain, inhibition of body fluid leakage and additional injury brought by wound suturing and the like, meets the modern medical concept and high requirements on surgical operations, and has wide application prospects clinically. However, the bio-adhesives used in the current market, such as cycocyanoacrylates and fibrin adhesives, generally have the disadvantages of poor elasticity, poor moisture-resistant bonding performance, poor antibacterial and antiviral performance, and the like, and cannot meet the actual clinical requirements.

In addition, in more medical applications, the adhesive often needs to be removed after the wound or tissue has healed. Especially for fragile or important biological tissue sites, the adhesive must be removed without harming the body, thus placing higher demands on the bioadhesive debonding method. In general, the strong adhesive properties of adhesives are contradictory to the easy-to-understand adhesion. Strong adhesion is usually achieved by means of covalent bonds, physical interactions or a combination thereof. Covalent bonding, while having extremely high adhesion, is very difficult to break the adhesive and tissue surface chemical bonding; the strong adhesion of physical action makes it possible to achieve detackification, but requires solvent treatment before adhesion, and the treatment process is cumbersome and not environmentally friendly.

Some conventional adhesives are chemically modified to release adhesion under temperature (epoxy) or light (pressure sensitive adhesives), but such materials are generally biologically toxic and have little adhesion on wet surfaces.

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

Disclosure of Invention

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

In order 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, wherein the polymeric crosslinker has a structure represented by formula I:

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.

The R1 contains a phenylboronic acid group.

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

The R3

Wherein

Indicates the position of the group's attachment.

The side chain of the macromolecular cross-linking agent provided by the invention contains phenylboronic acid groups, and the phenylboronic acid groups have glucose responsiveness, so that the macromolecular cross-linking agent can be used for preparing a biological adhesive, and can overcome the contradiction between the adhesion performance and the de-adhesion performance of the biological adhesive.

As a preferred embodiment of the present invention, R is₁The R is₁Is composed of

Any one or a combination of at least two of them, wherein

Indicates the position of the group's attachment.

Preferably, said R is₂Is composed of

Any one or a combination of at least two of them, wherein

Indicates the position of the group's attachment.

Preferably, the polymeric crosslinker is poly (acrylic acid-co-vinylphenylboronic acid-co-methacrylic acid (ethyl isocyanate acrylate)) having a structure represented by formula II:

wherein x is an integer of 1 or more, y is an integer of zero or more, m is an integer of zero or more, and the number average molecular weight of the polymeric cross-linking 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 or 1000000 g/mol.

In a second aspect, the present invention provides a method for preparing the polymeric cross-linking agent according to the first aspect, the method comprising the following steps:

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

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

Preferably, the monomer containing a phenylboronic acid group includes any one 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, or a combination of at least two thereof.

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

Preferably, the feedstock 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 material I, the raw material II and the raw material III is (80-100): 10-20): 1, and may be, 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, and preferably 85:15: 1.

Preferably, the molar ratio of the raw material III to the modifying agent is 1 (1-1.2), and may be, for example, 1:1.05, 1:1.08, 1:1.1, 1:1.12, 1:1.15, 1:1.18, or the like.

Preferably, the polymerization reaction time is 3 to 5 hours, 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 raw material III is (0.5-0.8): 1, and may be, for example, 0.55:1, 0.6:1, 0.65:1, 0.7:1, or 0.75: 1.

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

In a third aspect, the present invention provides a bioadhesive that can be debonded, the bioadhesive comprising a polymeric crosslinker as described in the first aspect.

Preferably, the bioadhesive comprises: acrylic acid, N-succinimidyl acrylate, a polymeric crosslinker as described in the first aspect, a polyol polymer, a photoinitiator, an acidity regulator and water.

In the invention, the biological adhesive comprises acrylic acid with succinimide ester group, a crosslinking agent containing phenylboronic acid group and a polyalcohol polymer, wherein the acrylic acid with succinimide ester group is chemically bonded and adhered with the surface of biological tissue, and meanwhile, the acrylic polymer and the polyalcohol are chemically connected through a boric acid ester bond with glucose response; under the synergistic action of the succinimide ester group, the phenylboronic acid group and the polyalcohol, the obtained biological adhesive has excellent comprehensive performance, and can show good adhesion performance in a humid environment, mechanical performance matched with tissues, good biocompatibility and detackability.

Preferably, the preparation raw materials of the biological adhesive comprise the following components in parts by weight:

wherein, the weight portion of the acrylic acid can be 11, 12, 13, 14, 15, 16, 17, 18 or 19 parts, etc.; the weight portion of the acrylic acid-N-succinimide ester can be 1.2 portions, 1.4 portions, 1.5 portions, 1.6 portions or 1.8 portions, etc.; the weight portion of the cross-linking agent can be 2 portions, 3 portions, 4 portions or 4.5 portions, etc.; the polyol polymer may be present in 1 part, 1.5 parts, 2 parts, 2.5 parts, 3 parts, 3.5 parts, 4 parts, 4.5 parts, or the like; the weight portion of the photoinitiator can be 0.6 portion, 0.7 portion, 0.8 portion or 0.9 portion; the parts by weight of the acidity regulator can 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, or the like.

As a preferred technical solution of the present invention, the polyol polymer has various types, including synthetic polymers, such as polyvinyl alcohol, synthetic polymers containing side chains of dihydric alcohol or polyhydric alcohol, 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 of or a combination of at least two of alpha-ketoglutaric acid, alpha-hydroxyalkylphenone, or alpha-aminoalkylbenzophenone.

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

In a fourth aspect, the present invention also provides a method for preparing the biological adhesive according to the third aspect, the method comprising the steps of:

mixing the formula amount of acrylic acid, acrylic acid-N-succinimide ester, the cross-linking agent, the photoinitiator, the polyol polymer and the acidity regulator, carrying out photocrosslinking, and carrying out post-treatment to obtain the biological adhesive.

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

Preferably, the photo-crosslinking method comprises a uv curing method.

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

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

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

(1) dissolving acrylic acid, vinyl benzene boric 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 acrylic acid, acrylic acid-N-succinimide ester, a high molecular crosslinking agent and a photoinitiator in formula amount in water to obtain a solution I, and dispersing and dissolving a polyalcohol polymer and an acidity regulator in formula amount in water to obtain a solution II;

and mixing the solution I and the solution II, pouring the mixture into a mold, curing the mixture under the irradiation of ultraviolet light, placing the mixture in air to volatilize the mixture, and soaking the mixture in a PBS (phosphate buffer solution) 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 an adhering step and a debonding step.

The adhering step includes: applying a 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 de-adhering comprises: and (3) coating a solution for debonding on the surface of the biological adhesive, and standing.

Preferably, the buffer comprises an aqueous PBS solution.

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

Preferably, the pressing time is 4-10 s, for example, 5s, 6s, 7s, 8s, or 9 s.

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

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

Preferably, the standing time is 8-15 s, for example, 9s, 10s, 11s, 12s, 13s or 14 s.

In a sixth aspect, the present invention also provides a use of the polymeric cross-linking agent according to the first aspect or the bioadhesive according to the third aspect in the preparation of biomedical materials.

The recitation of numerical ranges herein includes not only the above-recited values, but also any values between any of the above-recited numerical ranges not recited, and for brevity and clarity, is not intended to be exhaustive of the specific values encompassed within the range.

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

(1) the invention provides a polymeric cross-linking agent containing phenylboronic acid groups, which has glucose responsiveness and can help a biological adhesive to overcome the contradiction between the adhesive property and the debonding property of the biological adhesive;

(2) mixing the cross-linking agent with acrylic acid and polyalcohol polymers with succinimide ester groups, and chemically connecting the acrylic acid polymers and the polyalcohol polymers through a boric acid ester bond with glucose response through a photo-crosslinking curing reaction to prepare the obtained biological adhesive; the obtained biological adhesive contains a double-network structure constructed by acrylic polymer and polyalcohol polymer, can be chemically bonded and adhered to the surface of biological tissue, has strong adhesion effect and easy adhesion release effect, and has simple and convenient adhesion release method, mild and safe process and good biomedical prospect.

Drawings

FIG. 1 shows the nuclear magnetic spectrum of poly (acrylic acid-co-vinylbenzeneboronic acid-co-methacrylic acid (ethyl isocyanate acrylate)) as the macromolecular crosslinking agent prepared in example 1.

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

FIG. 3 is a graph comparing the bioadhesive PBAC/SA to porcine dermal tissue adhesion rheology curves before and after treatment with a 20 wt% glucose solution.

FIG. 4 is a graph comparing the 180 peel curves of bioadhesive PBAC/SA adhesion to porcine dermal tissue before and after treatment with a 20 wt% glucose solution.

FIG. 5 is a biocompatibility profile of bioadhesive PBAC/SA.

FIG. 6 is a comparison of the interfacial toughness of various bioadhesives and pigskin.

Detailed Description

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

Example 1

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

dissolving reaction raw materials of acrylic acid, 4-vinylbenzene boric acid, hydroxyethyl methacrylate and an initiator of azobisisobutyronitrile according to a molar ratio of 85:15:1:0.5 in 20mL of dry dimethyl sulfoxide (DMSO) solution;

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

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

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

the obtained reaction solution is settled in anhydrous ether and dried in vacuum to obtain a light yellow viscous substance, namely a macromolecular cross-linking agent poly (acrylic acid-co-vinylbenzeneboronic acid-co-methacrylic acid (ethyl isocyanate acrylate)), the chemical formula of which is shown in formula II, the number average molecular weight of which is 7031g/mol, and the nuclear magnetic resonance spectrum of which is shown in figure 1.

Example 2

This example provides a polymeric crosslinker with phenylboronic acid groups, which is prepared according to the following steps:

the reaction raw materials acrylic acid, 4-vinylbenzeneboronic acid, hydroxyethyl methacrylate and the initiator azobisisobutyronitrile were dissolved in a molar ratio of 80:10:1:0.5, and the remaining operations and treatment methods were the same as those in example 1.

Example 3

the reaction raw materials acrylic acid, 4-vinylbenzeneboronic acid, hydroxyethyl methacrylate and the initiator azobisisobutyronitrile were dissolved in a molar ratio of 100:20:1:0.8, and the remaining operations and treatment methods were the same as those in example 1.

Comparative example 1

This comparative example provides a crosslinking agent whose preparation differs from example 1 in that: 4-vinyl benzene boric acid is not contained in the reaction raw materials; the molar ratio of acrylic acid, hydroxyethyl methacrylate and the initiator azobisisobutyronitrile was 100:1:0.5, and the remaining operations and processing methods were consistent with 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 an acetic acid solution in 5mL of deionized water, uniformly mixing and defoaming;

dissolving a polyalcohol polymer in 5mL of deionized water, and removing bubbles;

mixing the two solutions, slowly pouring into a mold, sealing, carrying out closed reaction in an ultraviolet curing box for 30min, volatilizing the solvent, carrying out vacuum drying, and soaking in a PBS (phosphate buffer solution) aqueous solution with the pH of 7.4 for 1min to obtain the biological adhesive with high adhesion;

the process of adhering and detaching the biological adhesive comprises the following steps:

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

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

Application example 2

This example provides a polyacrylic acid-polyvinyl alcohol (PBAc/PVA) double-network bioadhesive, which differs from application example 1 only in that 0.1g of sodium alginate in application example 1 is replaced with 0.1g of polyvinyl alcohol; the remaining operations and processing methods were consistent with application example 1.

Application example 3

The embodiment provides a polyacrylic acid-chitosan (PBAC/CTS) double-network biological adhesive, which is different from the application example 1 only in that 0.1g of sodium alginate in the application example 1 is replaced by 0.1g of chitosan; the remaining operations and processing methods were consistent with application example 1.

Application example 4

This example provides a polyacrylic acid-hydroxyethyl cellulose (PBAc/HEC) dual network bioadhesive, which differs from application example 1 only in that 0.1g of sodium alginate in application example 1 is replaced with 0.1g of hydroxyethyl cellulose; the remaining operations and processing methods were consistent with application example 1.

Application example 5

This example provides a polyacrylic acid-hyaluronic acid (PBAc/HA) dual-network bioadhesive, which differs from application example 1 only in that 0.1g of sodium alginate in application example 1 is replaced with 0.1g of hyaluronic acid; the remaining operations and processing methods were consistent with application example 1.

Application example 6

The application example provides a polyacrylic acid-sodium alginate double-network biological adhesive, which is different from the application example 1 only in that the cross-linking agent is replaced by the cross-linking agent prepared in the example 2; the remaining operations and processing methods were consistent with application example 1.

Application example 7

The application example provides a polyacrylic acid-sodium alginate double-network biological adhesive, which is different from the application example 1 only in that the cross-linking agent is replaced by the cross-linking agent prepared in the example 3; the remaining operations and processing methods were consistent with application example 1.

Application comparative example 1

This comparative example provides a bioadhesive whose preparation starting materials are different from application example 1 in that the crosslinking agent prepared in example 1 is not contained in the preparation starting materials, while the amount of acrylic acid used is increased to 2.3 g; the remaining operations and processing methods were consistent with application example 1.

Comparative application example 2

This comparative example provides a bioadhesive whose preparation starting materials are different from application example 1 in that the crosslinking agent prepared in example 1 is replaced with an equal mass of N-succinimidyl acrylate; the remaining operations and processing methods were consistent with application example 1.

Comparative application example 3

This comparative example provides a bioadhesive whose preparation starting materials are different from application example 1 in that the crosslinking agent prepared in example 1 is replaced with the crosslinking agent prepared in comparative example 1; the remaining operations and processing methods were consistent with application example 1.

Application comparative example 4

This comparative example provides a bioadhesive whose preparation raw materials are different from application example 1 in that the preparation raw materials do not contain N-succinimidyl acrylate, while the amount of acrylic acid used is increased to 2.1 g; the remaining operations and processing methods were consistent with application example 1.

Performance test 1

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

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

(2) And (3) testing a rheological curve, wherein the testing method comprises the following steps: the hydrogel biological binder is prepared into a disc shape with the diameter of 20mm and the height of 1mm by using a mould, and then the storage modulus and the loss modulus of the hydrogel are tested according to the change of stress by using a rheometer.

(3) The toughness of the bonding interface of the biological adhesive and the pigskin is tested by the following method: in the present invention, three sets of control experiments were tested, pigskin-pigskin, pigskin-backing and pigskin-backing treated with glucose solution. Firstly, the surface of the pigskin is treated by PBS solution, then the pigskin is firmly adhered with the pigskin or the back lining by using biological adhesive, finally the adhesion interface toughness is tested, and simultaneously, the glucose solution is sprayed on the surface of the back lining to test the interface toughness.

Wherein, the PBAC/SA of the bio-adhesive prepared in application example 1 is shown in FIG. 2 before and after treatment with 20 wt% glucose solution;

the rheological curve of the sample adhered to the pigskin tissue before and after treatment with a 20 wt% glucose solution is shown in FIG. 3, and it can be seen that the value of G '/G' is significantly reduced after treatment with a glucose solution.

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

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

Similarly, 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 cross-linking agent provided by the invention can significantly improve the mechanical and adhesion 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 a 24-well plate, and the test method is consistent with the international standard biological compatibility test mode.

The results of the test using the bio-adhesive PBAc/SA prepared in example 1 are shown in fig. 5, and it can be seen that the cell viability measured on

days

1, 3 and 5 after the treatment using the bio-adhesive is less than that of the blank control group, and the cell viability is about 85%.

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

TABLE 2

Sample (I)	Cell viability (%)	Sample (I)	Cell viability (%)
				Application example 1	81.4	Application comparative example 1	80.2
Application example 2	83.5	Comparative application example 2	80.9
				Application example 3	81.9	Comparative application example 3	81.1
Application example 4	80.8	Application comparative example 4	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 specific test method of the toughness test chart of the bonding interface of different biological adhesives and pigskins is consistent with the method used in the performance test 1. The results of the interfacial toughness test of PBAc/SA provided in application example 1, PBAc/CTS provided in application example 3, PBAc/HEC provided in application example 4, and PBAc/HA provided in application example 5 are shown in fig. 6, and it can be seen from the graph that regardless of the polyol polymer, the toughness of the resulting adhesive interface is significantly reduced after the treatment with the glucose solution.

In conclusion, the present invention provides a cross-linking agent that can achieve fast and robust adhesion to tissue, but the adhesion performance is rapidly reduced after treatment with a glucose solution.

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

Claims

1. a macromolecular crosslinking agent containing phenylboronic acid group, is characterized in that, described macromolecular crosslinking agent has the structure shown in formula I:

Among them, 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 R ₁ contains a phenylboronic acid group;

The R ₂ contains any one group or a combination of at least two of the carboxyl group, ester group or acid chloride;

The _R3 is

in

Indicates the access position of the group.

2. The polymer crosslinking agent according to claim 1, wherein the R ₁ is

any one or a combination of at least two, wherein

Indicates the access position of the group;

Preferably, the R ₂ is

any one or a combination of at least two, wherein

Indicates the access position of the group;

Preferably, the polymer crosslinking agent has the structure shown in 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 or equal to zero, and the number average molecular weight of the polymer crosslinking agent is 600-1,000,000 g/mol.

3. a preparation method of polymer crosslinking agent as claimed in claim 1 or 2, is characterized in that, described preparation method comprises the steps:

Dissolving raw material I, raw material II and raw material III, adding an initiator to generate a polymerization reaction, and then adding a modifier for modification to obtain the polymer crosslinking agent;

Wherein, raw material I is acrylic acid, raw material II is a monomer containing a phenylboronic acid group, and raw material III is acrylamide and/or acrylate containing hydroxyl and/or amino groups;

Preferably, the monomer containing a phenylboronic acid group includes 2-vinylbenzeneboronic acid, 3-vinylbenzeneboronic acid, 4-vinylbenzeneboronic acid, 2-(2-carboxyvinyl)benzeneboronic acid, 3-(2-carboxylate) any one or a combination of at least two of vinyl) benzene boronic acid or 4-(2-carboxyvinyl) benzene boronic 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 material I, the raw material II and the raw material III is (80-100):(10-20):1, preferably 85:15:1;

Preferably, the molar ratio of the raw material III and the modifier is 1:(1～1.2);

Preferably, the time of the polymerization reaction is 3-5h;

Preferably, the molar ratio of the initiator to the raw material III is (0.5-0.8):1;

Preferably, the molar ratio of the azobisisobutyronitrile to hydroxyethyl methacrylate is (0.5-0.8):1.

4. A debonding bioadhesive, wherein the bioadhesive comprises the polymer cross-linking agent according to claim 1 or 2;

Preferably, the bioadhesive comprises: acrylic acid, acrylic acid-N-succinimidyl ester, polymer crosslinking agent according to claim 1 or 2, polyol polymer, photoinitiator, acidity regulator and water;

Preferably, the raw materials for the preparation of the bioadhesive include in parts by weight:

5. The bioadhesive according to claim 4, wherein the polyol polymer comprises polyvinyl alcohol, polyvinyl alcohol copolymer, sodium alginate, chitosan, chitosan, cellulose, Any one or a combination of at least two of hydroxyethylcellulose, gelatin, carrageenan, agar or hyaluronic acid;

Preferably, the photoinitiator comprises any one or a combination of at least two of α-ketoglutaric acid, α-hydroxyalkylphenone or α-aminoalkylphenone;

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

6. a preparation method of bioadhesive as claimed in claim 4 or 5, is characterized in that, described preparation method comprises the steps:

Mix the formula amount of acrylic acid, acrylic acid-N-succinimidyl ester, polymer crosslinking agent as claimed in claim 1 or 2, photoinitiator, polyol polymer and acidity regulator, photocrosslinking, and then The bioadhesive is obtained after post-processing.

7. preparation method according to claim 6, is characterized in that, the solvent used when described mixing comprises water;

Preferably, the method of photocrosslinking includes ultraviolet light curing method;

Preferably, the temperature of the photocrosslinking is 18-30°C, preferably 25°C;

Preferably, the photo-crosslinking time is 0.5h～1h;

Preferably, the post-processing operation includes soaking the photocrosslinked material in a PBS aqueous solution.

8. preparation method according to claim 6 or 7, is characterized in that, described preparation method comprises the steps:

(1) Dissolve acrylic acid, vinylbenzene boric acid and hydroxyethyl methacrylate in dimethyl sulfoxide solvent, add initiator azobisisobutyronitrile, react for 3-5h, and then add isocyanate ethyl acrylate for modification, to obtain a cross-linking agent;

(2) acrylic acid, acrylic acid-N-succinimidyl ester, crosslinking agent and photoinitiator of formula amount are dissolved in water to obtain solution I, and the polyol polymer and acidity regulator of formula amount are dispersed and dissolved in water to obtain solution II;

Then, the solution I and the solution II were mixed, poured into a mold, cured under ultraviolet light irradiation, placed in the air to dry, and then soaked in a PBS aqueous solution to obtain the biological adhesive.

9. A method of using the bioadhesive according to claim 4 or 5, characterized in that, the method of using comprises a step of adhering and de-adhering;

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

The debonding step includes: coating a debonding solution on the surface of the bioadhesive, and leaving it to stand;

Preferably, the buffer comprises aqueous PBS;

Preferably, the pH value of the PBS aqueous solution is 7.2-7.6;

Preferably, the pressing time is 4-10s;

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

Preferably, the mass concentration of the debonding solution is 5-30 wt%;

Preferably, the standing time is 8-15s.

10. The application of the polymer crosslinking agent according to claim 1 or 2 or the bioadhesive according to claim 4 or 5 in the preparation of biomedical materials.