A synthetic and method of preparation of a methacrylate catechol-based wet tissue-adhesive hydrogel that can be removed on demand

Abstract

The application discloses a preparation method of a methacrylate catechol wet-state tissue adhesive hydrogel which can be removed on demand, and comprises the following steps: S1, designing and synthesizing methacrylate catechols with different side groups; S2, uniformly mixing acrylic acid, water, chitosan quaternary ammonium salt, gelatin, catechol monomers, a crosslinking agent and an initiator at 50 DEG C, and obtaining the methacrylate catechol wet-state tissue adhesive hydrogel by ultraviolet light curing for 25 min under a nitrogen atmosphere; and S3, realizing on-demand removal of the wet-state tissue adhesion by using a biocompatible trigger liquid (urea or sodium chloride aqueous solution). The application has the advantages that: the application constructs an interpenetrating network by the synergistic effect of acrylic acid, catechol monomers and natural polymers, endows the hydrogel with the characteristics of toughness and fatigue resistance, and has good adhesion to various wet-state tissues and organs. Therefore, the adhesive hydrogel can adapt to wound closure of twisted tissues or dynamic organs and can be removed on demand.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of organic synthesis and the technical field of hydrogel preparation and application field, and particularly relates to synthesis of various novel catechols and a methacrylate catechol-based wet-state tissue adhesive hydrogel which is excellent in mechanical property and can be removed on demand. BACKGROUND

[0002] Tear and leakage of biological tissue wounds are the main causes of infection and death in general surgery, especially the wounds of internal organs of the organism (such as gastrointestinal tract, blood vessels, etc.), which are subjected to dynamic load accompanied by fluid flow. Generally, these challenging wounds are mechanically closed by suturing or stapling. However, such means will cause stress concentration around the wound, which is easy to cause tissue cracking and liquid leakage (blood or body fluid, etc.) in a dynamic environment. In the face of this problem, tissue adhesives can form intermolecular forces (hydrogen bonds, electrostatic interactions) or covalent bonds with the wet-state tissue interface to achieve adhesion and close the wound. At present, commercially available tissue adhesives include polyethylene glycol, fibrin glue, albumin-glutaraldehyde biological glue, cyanoacrylate, gelatin-resorcinol-formaldehyde, etc., which have good adhesion strength in dry environment. However, these tissue adhesives have problems such as poor wet-state / underwater adhesion, low cytotoxicity, and low mechanical strength. In addition, tissue adhesives with on-demand removability can avoid secondary damage that may occur when the patient removes the adhesive from the wound. Therefore, it is imperative to develop a tough tissue-selective wet / underwater adhesive hydrogel with good biocompatibility and on-demand removability.

[0003] Wet-state adhesion is of great significance to the gestation and development of life, and it is difficult to achieve strong wet-state adhesion because the combination of substrate and water forms a physical and chemical barrier, hindering the interaction between the adhesive and the substrate. In nature, mussels can firmly adhere to various wet substrates by the synergistic effect of positively charged lysine, catechol group and hydrophobic group in mussel protein. Undoubtedly, this provides inspiration for scholars to develop mussel-inspired adhesion materials, and the synthesis of biological tissue adhesives by catechol functionalized polymers has attracted much attention. However, the strategy of optimizing the adhesion performance from the molecular structure is still a major challenge. SUMMARY

[0004] In order to solve the problems existing in the above-mentioned technology, the purpose of the present application is to provide a synthesis method of novel catechols and a preparation method of methacrylate catechol-based wet-state tissue adhesive hydrogel which can be removed on demand. The prepared wet-state tissue adhesive hydrogel which is strong and can be removed on demand has good deformation recovery ability, biocompatibility and excellent wet-state tissue adhesion.

[0005] In order to achieve the above object, the present application adopts the following technical solutions:

[0006] The wet-state tissue adhesion hydrogel of the present application comprises the following steps:

[0007] S1. Inspired by the mussel adhesion chemistry, different side groups of methacrylate catechol are designed and synthesized, as follows:

[0008] ① 2-Aminoethyl methacrylate hydrochloride, 3,4-dihydroxyphenyl propionic acid, 4-dimethylaminopyridine and tetrahydrofuran are added to a round-bottom flask, followed by dropwise addition of N,N'-dicyclohexyl carbodiimide while stirring, and stirring at 25℃ for 5h. After the reaction is completed, saturated sodium bicarbonate aqueous solution is added, and the mixture is extracted 3-6 times with an organic solvent; the organic layer is dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue is purified by column chromatography to obtain a yellow viscous liquid, which is 2-(3-(3,4-dihydroxyphenyl) propionamido) ethyl methacrylate, named as DEM;

[0009] ② 2-Aminoethyl methacrylate hydrochloride, 3,4-dihydroxyphenyl acetic acid, 4-dimethylaminopyridine and tetrahydrofuran are added to a round-bottom flask, followed by dropwise addition of N,N'-dicyclohexyl carbodiimide while stirring, and stirring at 25℃ for 5h. After the reaction is completed, saturated sodium bicarbonate aqueous solution is added, and the mixture is extracted 3-6 times with an organic solvent; the organic layer is dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue is purified by column chromatography to obtain a yellow viscous liquid, which is 2-(2-(3,4-dihydroxyphenyl) acetylamino) ethyl methacrylate, named as AEM;

[0010] ③ Glycidyl methacrylate, 3,4-dihydroxyphenyl propionic acid, tetrabutylammonium bromide and acetonitrile are added to a round-bottom flask, and stirred at 80℃ for 12h under nitrogen atmosphere. After the reaction is completed, 5% potassium carbonate aqueous solution is added to the mixture, and the mixture is extracted 3-6 times with an organic solvent; the organic layer is dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue is purified by column chromatography to obtain a yellow viscous liquid, which is 3-((3-(3,4-dihydroxyphenyl) propionyl) oxy)-2-hydroxypropyl methacrylate and 2-((3-(3,4-dihydroxyphenyl) propionyl) oxy)-3-hydroxypropyl methacrylate, named as DHM;

[0011] The molar ratio of 3,4-dihydroxyphenyl propionic acid (or 3,4-dihydroxyphenyl acetic acid), 2-aminoethyl methacrylate hydrochloride, 4-dimethylaminopyridine and N,N'-dicyclohexyl carbodiimide is 1:1-2:0.01-0.1:1-2;

[0012] The molar ratio of the 3,4-dihydroxyphenylpropionic acid, glycidyl methacrylate and tetrabutylammonium bromide is 1:1-1.5:0.1-0.4;

[0013] The mass ratio of the 3,4-dihydroxyphenylpropionic acid and tetrahydrofuran is 1:10-20;

[0014] The mass ratio of the 3,4-dihydroxyphenylpropionic acid and acetonitrile is 1:5-15;

[0015] The organic solvent is dichloromethane, ethyl acetate;

[0016] The column chromatography liquid is dichloromethane, ethyl acetate or petroleum ether;

[0017] The synthesis route (chemical equation) of the different side group methacrylate catechol monomer of the application is as follows:

[0018]

[0019] S2. 5 g of acrylic acid, 3.5 mL of deionized water, 0-0.225 g of chitosan quaternary ammonium salt, 0-0.075 g of gelatin, 0.000001-0.01 g of crosslinking agent and 0.004-0.007 g of photoinitiator were stirred and mixed at 50°C, and then were cured under UV light for 25 min in a nitrogen atmosphere to obtain the wet-state tissue-adhesive hydrogel; 5 g of acrylic acid, 3.5 mL of deionized water, 0-0.225 g of chitosan quaternary ammonium salt, 0-0.075 g of gelatin, DEM, 0.000001-0.01 g of crosslinking agent and 0.004-0.007 g of photoinitiator were stirred and mixed at 50°C, and then were cured under UV light for 25 min in a nitrogen atmosphere to obtain the methacrylate catechol-based wet-state tissue-adhesive hydrogel PADQG; 5 g of acrylic acid, 3.5 mL of deionized water, 0-0.225 g of chitosan quaternary ammonium salt, 0-0.075 g of gelatin, 0-0.075 g of AEM, 0.000001-0.01 g of N,N-methylenebisacrylamide crosslinking agent and 0.004-0.007 g of 2,4,6-trimethylbenzoyl-diphenylphosphine oxide photoinitiator were stirred and mixed at 50°C, and then were cured under UV light for 25 min in a nitrogen atmosphere to obtain the methacrylate catechol-based wet-state tissue-adhesive hydrogel PAEQG; 5 g of acrylic acid, 3.5 mL of deionized water, 0-0.225 g of chitosan quaternary ammonium salt, 0-0.075 g of gelatin, 0-0.075 g of DHM, 0.000001-0.01 g of N,N-methylenebisacrylamide crosslinking agent and 0.004-0.007 g of 2,4,6-trimethylbenzoyl-diphenylphosphine oxide photoinitiator were stirred and mixed at 50°C, and then were cured under UV light for 25 min in a nitrogen atmosphere to obtain the methacrylate catechol-based wet-state tissue-adhesive hydrogel PAHQG; 5 g of acrylic acid, 3.5 mL of deionized water, 0-0.225 g of chitosan quaternary ammonium salt, 0-0.075 g of gelatin, 0-0.075 g of urushiol (UH), 0.000001-0.01 g of N,N-methylenebisacrylamide crosslinking agent and 0.004-0.007 g of 2,4,6-trimethylbenzoyl-diphenylphosphine oxide photoinitiator were stirred and mixed at 50°C, and then were cured under UV light for 25 min in a nitrogen atmosphere to obtain the methacrylate catechol-based wet-state tissue-adhesive hydrogel PAUQG; the mass of the catechol monomer is greater than or equal to 0 and less than or equal to 0.075 g;

[0020] S3. The wet-state tissue adhesion is removed on demand by using a urea or sodium chloride aqueous solution.

[0021] As a preferred embodiment, the molar ratio of 3,4-dihydroxyphenylpropionic acid (or 3,4-dihydroxyphenylacetic acid), 2-aminoethyl methacrylate hydrochloride, 4-dimethylaminopyridine and N,N'-dicycloethylcarbodiimide in step S1 is 1:1.3:0.05:1.5.

[0022] As a preferred embodiment, the molar ratio of 3,4-dihydroxyphenylpropionic acid, glycidyl methacrylate and tetrabutylammonium bromide in step S1 is 1:1.1:0.2.

[0023] As a preferred embodiment, the mass ratio of 3,4-dihydroxyphenylpropionic acid to tetrahydrofuran in step S1 is 1:16.

[0024] As a preferred embodiment, the mass ratio of 3,4-dihydroxyphenylpropionic acid to acetonitrile in step S1 is 1:10.

[0025] As a preferred embodiment, the organic solvent in step S1 is ethyl acetate.

[0026] As a preferred embodiment, the column chromatography solvent in step S1 is ethyl acetate and petroleum ether (volume ratio of 1:5 to 1:1).

[0027] As a preferred embodiment, the masses of chitosan quaternary ammonium salt, gelatin, catechol monomer (DEM or AEM or DHM or urushiol (UH)), N,N-methylenebisacrylamide and 2,4,6-trimethylbenzoyl-diphenylphosphine oxide in step S2 are 0.15 g, 0.05 g, 0.05 g, 0.01 g and 0.005 g, respectively.

[0028] Insufficient amounts of chitosan quaternary ammonium salt, gelatin, and N,N-methylenebisacrylamide will cause the hydrogel to become brittle, while excessive amounts will result in high rigidity; insufficient amounts of 2,4,6-trimethylbenzoyl-diphenylphosphine oxide will prevent polymerization, while excessive amounts will cause explosive polymerization.

[0029] As a preferred embodiment, the triggering liquid in step S3 is a 5% urea aqueous solution or a 0.9% sodium chloride aqueous solution.

[0030] A methacrylate-based catechol monomer prepared by the aforementioned method and a methacrylate-based wet tissue adhesion hydrogel that can be removed as needed.

[0031] UV curing has advantages such as ease of use, short time, high light transmittance, and safe operation. Under UV light (365nm) radiation, the outer electrons of the photoinitiator hop, generating active centers in a very short time. These centers then interact with the unsaturated groups of the monomers in the prepolymer solution, and as the chain grows, the system cross-links to form a film.

[0032] Compared with the prior art, the present application has the following outstanding advantages:

[0033] 1. The present application first synthesizes a methyl methacrylate catechol monomer, which retains the adhesion of the catechol group and is easily soluble in an acrylic acid / water solution system, and the prepared hydrogel has high light transmittance. The present technology has simple post-processing and is more suitable for industrialization.

[0034] 2. The synergistic effect of the poly-cation, poly-anion, hydrophobic chain and catechol group in the prepared methyl methacrylate catechol wet-state tissue adhesive hydrogel endows the hydrogel with strong mechanical properties and excellent wet-state tissue adhesion capacity, and the hydrogel is suitable for wound closure of various tissue torsion or dynamic organs.

[0035] 3. The prepared methyl methacrylate catechol wet-state tissue adhesive hydrogel can be debonded by a biocompatible trigger liquid, precise adhesion can be achieved and the pain of patients can be reduced. BRIEF DESCRIPTION OF DRAWINGS

[0036] Other features, objects and advantages of the present application will become more apparent from the following detailed description of non-limiting embodiments with reference to the following drawings:

[0037] Figure 1 NMR spectrum of the novel methyl methacrylate catechol monomer synthesized in Example 1 in the present application.

[0038] Figure 2 Statistics of (a) tensile stress, (b) tensile strain, (c) toughness and (d) interfacial toughness of wet-state pig skin adhesion of the wet-state tissue adhesive hydrogel obtained in Example 2 in the present application.

[0039] Figure 3 Statistics of tensile stress-strain of the methyl methacrylate catechol wet-state tissue adhesive hydrogel obtained in Examples 3-6 in the present application.

[0040] Figure 4 Statistics of tensile fracture toughness of the methyl methacrylate catechol wet-state tissue adhesive hydrogel obtained in Examples 3-6 in the present application.

[0041] Figure 5 Peeling curve of the methyl methacrylate catechol wet-state tissue adhesive hydrogel obtained in Examples 3-6 in the present application on wet-state pig skin.

[0042] Figure 6 Statistics of adhesion strength of the methyl methacrylate catechol wet-state tissue adhesive hydrogel obtained in Example 5 on various wet-state tissue organs.

[0043] Figure 7Peeling curves for debonding experiments of the methacrylate catechol-based wet tissue-adhesive hydrogel obtained in Example 5.

[0044] Figure 8 Statistics of wet tissue-adhesive hydrogels made from different pendant catechol monomers for the toughness of the adhesive interface with wet porcine skin.

[0045] Figure 9 Statistics of the tensile fracture toughness of methacrylate catechol-based wet tissue-adhesive hydrogels with different water contents. DETAILED DESCRIPTION

[0046] The application will be described in greater detail with reference to the specific embodiments illustrated in the drawings. The following examples are provided to further assist those skilled in the art in understanding the application, but are not intended to limit the scope of the application in any way. It should be noted that, for those skilled in the art, several modifications and improvements can be made without departing from the concept of the application. These all fall within the scope of the present application. Example 1

[0047] Synthesis of 2-(3-(3,4-dihydroxyphenyl)propionamido)ethyl methacrylate

[0048] 2-Aminoethyl methacrylate hydrochloride (6.5 mmol), 3,4-dihydroxyphenylpropionic acid (5 mmol), 4-dimethylaminopyridine (0.25 mmol) and tetrahydrofuran (25 mL) were added to a round-bottom flask, followed by dropwise addition of N,N'-dicyclohexyl carbodiimide (7.5 mmol) while stirring. The reaction was stirred at 25°C for 5 h. After the reaction was completed, saturated aqueous sodium bicarbonate solution was added, and extraction was performed 3-6 times with ethyl acetate; the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography, and concentrated to obtain a yellow viscous liquid, which was 2-(3-(3,4-dihydroxyphenyl)propionamido)ethyl methacrylate, designated as DEM in the present application. The nuclear magnetic resonance spectrum is shown in Figure 1 .

[0049] Synthesis of 2-(2-(3,4-dihydroxyphenyl)acetamido)ethyl methacrylate

[0050] A round bottom flask was charged with 2-aminoethyl methacrylate hydrochloride (6.5 mmol), 3,4-dihydroxyphenyl acetic acid (5 mmol), 4-dimethylamino pyridine (0.25 mmol) and tetrahydrofuran (25 mL), followed by dropwise addition of N,N'-dicyclohexyl carbodiimide (7.5 mmol) with stirring. The reaction was stirred at 25 °C for 5 h. After the reaction was completed, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate for 3-6 times. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography, and concentrated to give a yellow viscous liquid, which was methyl 2-(2-(3,4-dihydroxyphenyl)acetamido)ethyl methacrylate, named as AEM in the present application. The nuclear magnetic resonance spectrum is shown in Figure 1 .

[0051] Synthesis of methyl 3-((3-(3,4-dihydroxyphenyl)propionyl)oxy)-2-hydroxypropyl methacrylate and methyl 2-((3-(3,4-dihydroxyphenyl)propionyl)oxy)-3-hydroxypropyl methacrylate

[0052] A round bottom flask was charged with glycidyl methacrylate (7.5 mmol), 3,4-dihydroxyphenyl propionic acid (5 mmol), tetrabutylammonium bromide (1 mmol) and acetonitrile (20 mL), and stirred at 80 °C for 12 h under nitrogen atmosphere. After the reaction was completed, the mixture was added to 5% potassium carbonate aqueous solution, and extracted with organic solvent for 3-6 times. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography, and concentrated to give a yellow viscous liquid, which was methyl 3-((3-(3,4-dihydroxyphenyl)propionyl)oxy)-2-hydroxypropyl methacrylate and methyl 2-((3-(3,4-dihydroxyphenyl)propionyl)oxy)-3-hydroxypropyl methacrylate, named as DHM in the present application. The nuclear magnetic resonance spectrum is shown in Figure 1 . Example 2

[0053] Preparation of a series of wet tissue adhesive hydrogels of different mass fractions of chitosan quaternary ammonium salt and gelatin

[0054] A round bottom flask was charged with 5 g of acrylic acid, 3.5 mL of deionized water, chitosan quaternary ammonium salt (equivalent to 0%, 1.5%, 3.0%, 4.5% of the mass fraction of acrylic acid), gelatin (equivalent to 0%, 0.5%, 1.0%, 1.5% of the mass fraction of acrylic acid), 0.01 g of N,N-methylene bisacrylamide crosslinking agent and 0.005 g of 2,4,6-trimethylbenzoyl-diphenyl phosphine oxide photoinitiator, and stirred at 50 °C until uniform. The mixture was then ultraviolet light cured for 25 min under a nitrogen atmosphere. The orthogonal experiment obtained the wet tissue adhesive hydrogel. The tensile strength, strain, fracture toughness and adhesive interfacial toughness to wet pigskin of the wet tissue adhesive hydrogel are shown in Table 1.Figure 2 . Example 3

[0055] Preparation of methacrylate catechol-based wet tissue-adhesive hydrogel containing 0.0% (mass fraction, the same below) of catechol monomer (DEM) / acrylic acid (AA)

[0056] 5 g of acrylic acid, 3.5 mL of deionized water, 0.15 g of chitosan quaternary ammonium salt, 0.05 g of gelatin, 0.01 g of N,N-methylene bisacrylamide and 0.005 g of 2,4,6-trimethylbenzoyl-diphenylphosphine oxide were stirred and mixed at 50°C, and then cured under UV light for 25 min under a nitrogen atmosphere to obtain the on-demand removable methacrylate catechol-based wet tissue-adhesive hydrogel (without DEM), which was recorded as PAD0Q3G1. The tensile strength-strain of PAD0Q3G1 is shown in Figure 3 , the fracture toughness is shown in Figure 4 , and the adhesive interfacial toughness to wet porcine skin is shown in Figure 5 . Example 4

[0057] Preparation of methacrylate catechol-based wet tissue-adhesive hydrogel containing 0.5% of DEM / AA

[0058] 5 g of acrylic acid, 3.5 mL of deionized water, 0.15 g of chitosan quaternary ammonium salt, 0.05 g of gelatin, 0.025 g of DEM prepared in Example 1, 0.01 g of N,N-methylene bisacrylamide and 0.005 g of 2,4,6-trimethylbenzoyl-diphenylphosphine oxide were stirred and mixed at 50°C, and then cured under UV light for 25 min under a nitrogen atmosphere to obtain the on-demand removable methacrylate catechol-based wet tissue-adhesive hydrogel, which was recorded as PAD 0.5 Q3G1. The tensile strength-strain of PAD Figure 3 , the fracture toughness is shown in Figure 4 , and the adhesive interfacial toughness to wet porcine skin is shown in Figure 5 . Example 5

[0059] Preparation of methacrylate catechol-based wet tissue-adhesive hydrogel containing 1.0% of DEM / AA

[0060] 5 g of acrylic acid, 3.5 mL of deionized water, 0.15 g of chitosan quaternary ammonium salt, 0.05 g of gelatin, 0.05 g of DEM prepared in Example 1, 0.01 g of N,N-methylenebisacrylamide, and 0.005 g of 2,4,6-trimethylbenzoyl-diphenylphosphine oxide were stirred and mixed at 50 °C, and cured under nitrogen atmosphere with ultraviolet light for 25 min to obtain the removable methacrylate catechol wet tissue adhesion hydrogel, denoted as PAD1Q3G1. Its tensile strength-strain profile is shown in [reference needed]. Figure 3 Fracture toughness see Figure 4 The adhesion interface toughness of wet pigskin is shown in the figure. Figure 5 . Example 6

[0061] Preparation of methacrylate-catechin-based wet tissue adhesion hydrogels containing 1.5% DEM / AA.

[0062] 5 g of acrylic acid, 3.5 mL of deionized water, 0.15 g of chitosan quaternary ammonium salt, 0.05 g of gelatin, 0.075 g of DEM prepared in Example 1, 0.01 g of N,N-methylenebisacrylamide, and 0.005 g of 2,4,6-trimethylbenzoyl-diphenylphosphine oxide were stirred and mixed at 50 °C and cured under nitrogen atmosphere with ultraviolet light for 25 min to obtain the removable methacrylate catechol wet tissue adhesion hydrogel, denoted as PAD. 1.5 Q3G1. Its tensile strength-strain profile is shown in [reference needed]. Figure 3 Fracture toughness see Figure 4 The adhesion interface toughness of wet pigskin is shown in the figure. Figure 5 . Example 7

[0063] The PAD1Q3G1 hydrogel prepared in Example 5 was used to conduct wound closure experiments on various tissues or organs (fresh pig skin, liver, heart, kidney, and stomach). PAD1Q3G1 hydrogel samples (20 mm long, 10 mm wide, and 0.6 mm thick) with PET film were symmetrically overlapped between two identical wet tissue samples (50 mm long and 20 mm wide). The samples were placed in a sealed container at 37°C for 20 minutes before testing. Adhesion strength is shown in [the table below]. Figure 6 . Example 8

[0064] The PAD1Q3G1 hydrogel prepared in Example 5 was selected to carry out the debonding experiment. The PAD1Q3G1 hydrogel sample (60 mm in length, 10 mm in width, and 0.6 mm in thickness) with PET film was adhered to the surface of fresh wet pigskin (50 mm in length, 20 mm in width), and then placed in a closed container at 37°C for 20 min. Then, 5% urea aqueous solution or 0.9% NaCl aqueous solution was added to the interface, and then the 90° peeling test was carried out. The change of adhesion performance is shown in Figure 7 . Example 9

[0065] The PAD1Q3G1 hydrogel prepared in Example 5 was selected to carry out the wound closure experiment. The rats with a body weight of 220-250 g were randomly selected, and then 0.7 mL of 2wt% sodium pentobarbital solution was injected into the abdominal cavity. Then, the epithelial tissue of the abdomen was cut by a surgical scissors to expose the liver of the rat, and a wound with a length of 10 mm, a width of 0.4 mm, and a depth of 5 mm was made on the liver of the rat. Then, the PAD1Q3G1 hydrogel with a length of 20 mm and a width of 20 mm was adhered, and after 3 min, the bleeding stopped and the hydrogel was firmly adhered to the surface of the liver. Further, the rats with a body weight of 220-250 g were randomly selected, and then 0.7 mL of 2wt% sodium pentobarbital solution was injected into the abdominal cavity. Then, the epithelial tissue of the hind leg was cut by a surgical knife to expose the femoral artery and vein of the rat, and the femoral artery was cut and bled. Then, the PAD1Q3G1 hydrogel with a length of 20 mm and a width of 20 mm was adhered, and the results were the same as described above. At the end of the experiment, the rats were euthanized. The experimental study qualitatively indicated that the hydrogel had excellent wound closure ability.

[0066] Figure 1 The DEM synthesized in Example 1 of the present application was confirmed by the chemical shift of different groups to prove the successful synthesis of the monomer. Figure 2 The tensile stress, strain, toughness, and interface toughness of the wet tissue-adhesive hydrogel obtained in Example 2 of the present application were statistically analyzed. The figure shows that an appropriate amount of chitosan quaternary ammonium salt and gelatin helps to improve the mechanical properties and wet adhesion properties of the hydrogel. Figure 3 The tensile stress-strain statistics of the methacrylate catechol-based wet tissue-adhesive hydrogel obtained in Examples 3-6 of the present application are shown in the figure. With the change of the content of DEM, the tensile strength and strain also change constantly. When the content of DEM / AA is 1%, the hydrogel has the best tensile strain of 515.49±25.64%. Figure 4 The tensile fracture toughness statistics of the methacrylate catechol-based wet tissue-adhesive hydrogel obtained in Examples 3-6 of the present application are shown in the figure. It can be seen from the figure that the content of DEM / AA of 1% has a significant effect on the fracture toughness of the hydrogel. The fracture toughness of all the hydrogels is 3.93 MJ / m3 The above is because DEM plays a cross-linking role in the system, and too high DEM content forms too many physical cross-linking points, causing stress concentration, thereby damaging the extensibility of the hydrogel. Figure 5 The peel curves of the methacrylate catechol-based wet tissue-adhesive hydrogel obtained in Example 3-6 of the present application to wet pigskin; as the DEM content changes, the adhesive capacity also changes constantly.

[0067] When the DEM / AA is 1%, the hydrogel has the best adhesive capacity of 1193.22±93.03 N / m. Figure 6 The statistics of the adhesive strength of the methacrylate catechol-based wet tissue-adhesive hydrogel obtained in Example 5 of the present application to various wet tissue organs; the PAD1Q3G1 hydrogel has good adhesive capacity to fresh wet pigskin, liver, heart, kidney and stomach, and exhibits adhesive differences due to different tissue surface roughness; the liver and kidney are broken during the test process because their own strength is less than the adhesive strength of the PAD1Q3G1 hydrogel, and the corresponding data cannot be measured. Figure 7 The peel curves of the methacrylate catechol-based wet tissue-adhesive hydrogel obtained in Example 5 of the present application to wet pigskin; after treatment with a 5% urea aqueous solution, the wet tissue-adhesive capacity of the PAD1Q3G1 hydrogel decreases to 214.92±24.27 N / m, due to the destruction of the interfacial hydrogen bond by the solution; and by destroying the interfacial electrostatic action through a 0.9% sodium chloride aqueous solution, the wet tissue-adhesive capacity of the PAD1Q3G1 hydrogel decreases to 346.88±46.18 N / m; therefore, the biocompatible trigger liquid can effectively achieve on-demand removal.

[0068] Comparative Example 1

[0069] The difference between this comparative example and Example 1 is only that 4-dimethylaminopyridine and / or N,N'-dicyclohexyl carbodiimide are not added. Under the same experimental conditions, the yield of the catechol monomer synthesized in Example 1 is greatly reduced.

[0070] Comparative Example 2

[0071] The difference between this comparative example and Example 5 is only that DEM is replaced with the same mass of AEM (or DHM or urushiol UH) to prepare PAE1Q3G1 or PAH1Q3G1 or PAU1Q3G1 hydrogel. Due to the influence of the polarity of different side groups on the oxidation degree of the catechol group, different adhesive properties to wet pigskin are exhibited (such as Figure 8 ), among which the PAD1Q3G1 hydrogel exhibits the best adhesive strength to wet pigskin.

[0072] Comparative Example 3

[0073] The difference between this comparative example and Example 5 is only that the deionized water is 5.3 mL.

[0074] Comparative Example 4

[0075] The difference between this comparative example and Example 5 is only that the deionized water is 7.9 mL.

[0076] Under the same experimental conditions, tensile tests were performed on Example 5 (40 wt% water content in the system) and Comparative Examples 3 and 4 (50 wt% and 60 wt% water content in the system, respectively), and the results are shown in Table 1. Figure 9 As shown in Table 1, with the increase of water content, the fracture toughness of the hydrogel decreases from 3.93 ± 0.26 MJ / m 3 to 2.37 ± 0.39 MJ / m 3 , which is attributed to the fact that water molecules destroy the physical crosslinking points inside the hydrogel network, resulting in a decrease in strength.

[0077] The specific embodiments of the present application are described above. It should be understood that the present application is not limited to the specific embodiments described above, and various modifications or changes can be made by those skilled in the art within the scope of the claims, which do not affect the essential content of the present application.

Claims

1. A method for preparing a wet-state tissue adhesive hydrogel of methacrylate catechol, which can be removed on demand, comprising the following steps: S1. Designing and synthesizing methacrylate catechols with different side groups, the specific steps being as follows: ① Synthesizing 2-(3-(3,4-dihydroxyphenyl)propionamido)ethyl methacrylate DEM: adding 2-aminoethyl methacrylate hydrochloride, 3,4-dihydroxyphenylpropionic acid, 4-dimethylaminopyridine and tetrahydrofuran into a round-bottom flask, then adding N,N'-dicyclohexyl carbodiimide dropwise while stirring, stirring at 25°C for 5 h; after the reaction is completed, adding saturated sodium bicarbonate aqueous solution, and extracting 3-6 times with an organic solvent; drying the organic layer with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, purifying the residue by column chromatography, and concentrating to obtain a yellow viscous liquid, which is 2-(3-(3,4-dihydroxyphenyl)propionamido)ethyl methacrylate DEM; ② Synthesizing 2-(2-(3,4-dihydroxyphenyl)acetamido)ethyl methacrylate AEM: adding 2-aminoethyl methacrylate hydrochloride, 3,4-dihydroxyphenylacetic acid, 4-dimethylaminopyridine and tetrahydrofuran into a round-bottom flask, then adding N,N'-dicyclohexyl carbodiimide dropwise while stirring, stirring at 25°C for 5 h; after the reaction is completed, adding saturated sodium bicarbonate aqueous solution, and extracting 3-6 times with an organic solvent; drying the organic layer with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, purifying the residue by column chromatography, and concentrating to obtain a yellow viscous liquid, which is 2-(2-(3,4-dihydroxyphenyl)acetamido)ethyl methacrylate AEM; ③ Synthesizing 3-((3-(3,4-dihydroxyphenyl)propionyl)oxy)-2-hydroxypropyl methacrylate and 2-((3-(3,4-dihydroxyphenyl)propionyl)oxy)-3-hydroxypropyl methacrylate DHM: adding glycidyl methacrylate, 3,4-dihydroxyphenylpropionic acid, tetrabutylammonium bromide and acetonitrile into a round-bottom flask, stirring at 80°C for 12 h under a nitrogen atmosphere; after the reaction is completed, adding a 5% potassium carbonate aqueous solution, and extracting 3-6 times with an organic solvent; drying the organic layer with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, purifying the residue by column chromatography, and concentrating to obtain a yellow viscous liquid, which is 3-((3-(3,4-dihydroxyphenyl)propionyl)oxy)-2-hydroxypropyl methacrylate and 2-((3-(3,4-dihydroxyphenyl)propionyl)oxy)-3-hydroxypropyl methacrylate DHM; The molar ratio of 3,4-dihydroxyphenylpropionic acid (or 3,4-dihydroxyphenylacetic acid), 2-aminoethyl methacrylate hydrochloride, 4-dimethylaminopyridine and N,N'-dicyclohexyl carbodiimide is 1:1-2:0.01-0.1:1-2; The molar ratio of 3,4-dihydroxyphenylpropionic acid, glycidyl methacrylate and tetrabutylammonium bromide is 1:1-1.5:0.1-0.4; The mass ratio of 3,4-dihydroxyphenylpropionic acid and tetrahydrofuran is 1:10-20; The mass ratio of the 3,4-dihydroxyphenylpropionic acid to acetonitrile is 1:5-15; The organic solvent is dichloromethane, ethyl acetate or toluene; The column chromatography uses dichloromethane, ethyl acetate or petroleum ether as the chromatography liquid; The column chromatography uses dichloromethane, ethyl acetate or petroleum ether as the chromatography liquid; S2. 5 g of acrylic acid, 3.5 mL of deionized water, 0-0.225 g of chitosan quaternary ammonium salt, 0-0.075 g of gelatin, 0.000001-0.01 g of N, N-methylene bisacrylamide crosslinking agent and 0.004-0.007 g of 2, 4, 6-trimethylbenzoyl-diphenyl phosphine oxide photoinitiator were stirred and mixed uniformly at 50°C, and then cured under ultraviolet light for 25 min in a nitrogen atmosphere to obtain a base hydrogel; 5 g of acrylic acid, 3.5 mL of deionized water, 0-0.225 g of chitosan quaternary ammonium salt, 0-0.075 g of gelatin, 0.000001-0.075 g of DEM, 0.000001-0.01 g of N, N-methylene bisacrylamide crosslinking agent and 0.004-0.007 g of 2, 4, 6-trimethylbenzoyl-diphenyl phosphine oxide photoinitiator were stirred and mixed uniformly at 50°C, and then cured under ultraviolet light for 25 min in a nitrogen atmosphere to obtain the methacrylate catechol wet-state tissue adhesive hydrogel PADQG; or 5 g of acrylic acid, 3.5 mL of deionized water, 0-0.225 g of chitosan quaternary ammonium salt, 0-0.075 g of gelatin, 0.000001-0.075 g of AEM, 0.000001-0.01 g of N, N-methylene bisacrylamide crosslinking agent and 0.004-0.007 g of 2, 4, 6-trimethylbenzoyl-diphenyl phosphine oxide photoinitiator were stirred and mixed uniformly at 50°C, and then cured under ultraviolet light for 25 min in a nitrogen atmosphere to obtain the methacrylate catechol wet-state tissue adhesive hydrogel PAEQG; or 5 g of acrylic acid, 3.5 mL of deionized water, 0-0.225 g of chitosan quaternary ammonium salt, 0-0.075 g of gelatin, 0.000001-0.075 g of DHM, 0.000001-0.01 g of N, N-methylene bisacrylamide crosslinking agent and 0.004-0.007 g of 2, 4, 6-trimethylbenzoyl-diphenyl phosphine oxide photoinitiator were stirred and mixed uniformly at 50°C, and then cured under ultraviolet light for 25 min in a nitrogen atmosphere to obtain the methacrylate catechol wet-state tissue adhesive hydrogel PAHQG; or 5 g of acrylic acid, 3.5 mL of deionized water, 0-0.225 g of chitosan quaternary ammonium salt, 0-0.075 g of gelatin, 0.000001-0.075 g of urushiol (UH), 0.000001-0.01 g of N, N-methylene bisacrylamide crosslinking agent and 0.004-0.007 g of 2, 4, 6-trimethylbenzoyl-diphenyl phosphine oxide photoinitiator were stirred and mixed uniformly at 50°C, and then cured under ultraviolet light for 25 min in a nitrogen atmosphere to obtain the methacrylate catechol wet-state tissue adhesive hydrogel PAUQG; The plurality of methacrylate catechol wet-state tissue adhesive hydrogels are prepared by introducing different single catechol monomers into a base hydrogel; S3. Realizing on-demand removal of wet tissue adhesion of methacrylate catechol-based wet tissue-adhesive hydrogel by using biocompatible trigger solution.

2. A process for the preparation of a wet tissue adhesive methylacrylate catechol-based hydrogel according to claim 1, characterized in that: The molar ratio of 3,4-dihydroxyphenylpropionic acid or 3,4-dihydroxyphenylacetic acid, 2-aminoethyl methacrylate hydrochloride, 4-dimethylaminopyridine and N,N'-dicyclohexyl carbodiimide in step S1 is 1:1.3:0.05:1.

5.

3. A process for the preparation of a wet tissue adhesive methylacrylate catechol-based hydrogel according to claim 1, characterized in that: The molar ratio of 3,4-dihydroxyphenylpropionic acid, glycidyl methacrylate and tetrabutylammonium bromide in step S1 is 1:1.1:0.

2.

4. A process for the preparation of a wet tissue adhesive methylacrylate catechol-based hydrogel according to claim 1, characterized in that: The mass ratio of 3,4-dihydroxyphenylpropionic acid and tetrahydrofuran in step S1 is 1:

16.

5. A process for the preparation of a wet tissue adhesive hydrogel of methylacrylate catechol-based according to claim 1, characterized by the fact that: The mass ratio of 3,4-dihydroxyphenylpropionic acid and acetonitrile in step S1 is 1:

10.

6. A process for the preparation of a wet tissue adhesive methylacrylate catechol-based hydrogel according to claim 1, characterized in that: The organic solvent in step S1 is ethyl acetate.

7. A process for the preparation of a wet tissue adhesive hydrogel of methylacrylate catechol-based according to claim 1, characterized by the fact that: The eluent of column chromatography in step S1 is ethyl acetate and petroleum ether, and the volume ratio is 1:5 to 1:

1.

8. A process for the preparation of a wet tissue adhesive hydrogel of methylacrylate catechol-based according to claim 1, characterized by the fact that: The mass of chitosan quaternary ammonium salt, gelatin, DEM or AEM or DHM or urushiol (UH), N,N-methylene bisacrylamide and 2,4,6-trimethylbenzoyl-diphenylphosphine oxide in step S2 is 0.15 g, 0.05 g, 0.05 g, 0.01 g, 0.005 g, respectively.

9. A process for the preparation of a wet tissue adhesive hydrogel of methylacrylate catechol-based according to claim 1, characterized by the fact that: The biocompatible trigger solution in step S3 is 5% urea aqueous solution or 0.9% sodium chloride aqueous solution.

10. The methacrylate catechol monomer and on-demand removable methacrylate catechol-based wet tissue-adhesive hydrogel obtained by the preparation method of any one of claims 1 to 9.

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