Degradable bio-based tissue adhesive material and preparation method and application thereof

Abstract

The present application provides a kind of degradable bio-based tissue adhesive material, which is formed by the one-step polymerization reaction of the light initiation of the complex of degradable amino acid end-capped bio-based supramolecular aqueous polyurethane, acrylic acid or its derivative and plasticizer, to form a transparent tissue adhesive material with double network structure.The adhesive material has the characteristics of instantaneous tissue adhesion, high bonding strength, high mechanical strength and plastic deformation capacity, and is suitable for biomedical fields such as rapid hemostasis of bleeding wounds, rapid closure of damaged wounds and repair of damaged soft tissues.The material also has biodegradability and excellent biocompatibility.In addition, compared with general tissue adhesive materials, the preparation process of the material is simple, the repetition rate is high, and the application range is wider.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of biomaterials, and particularly relates to a degradable bio-based tissue adhesive material and a preparation method and application thereof. BACKGROUND

[0002] Wound closure is crucial in surgical operations. Clinically, 60% of wounds are closed by suturing or stapling after surgery. Due to the fragility of soft tissue and local stress, mechanical closure can cause secondary injury, and the non-degradable suture or staple needs to be removed. Compared with traditional suture treatment, tissue adhesive material requires shorter treatment time and has better regeneration effect. In recent years, tissue adhesive material has achieved vigorous development and is widely used in different degrees of tissue injury repair due to its advantages of convenient operation, rapid sealing of damaged tissue and small damage to tissue. For severe tissue wounds or bleeding wounds, the adhesive material can be firmly attached to the tissue surface, keep the wound or wound site moist, and provide a good healing environment.

[0003] Traditional tissue adhesive materials include cyanoacrylate (Chinese patents CN113679876A and CN113599567A), fibrin (Chinese patent CN112843326A), polyethylene glycol (Chinese patent CN113350563A), and modified polysaccharides. Cyanoacrylate-based adhesives have excellent adhesive strength, but their exothermic polymerization, toxicity of degradation products, and residual unreacted monomers pose a great risk to tissues. Moreover, they have poor elasticity and cannot be used for adhesion of soft tissues with high mobility, such as joint skin. Fibrin or polysaccharide-based adhesives have weak mechanical properties and may break during use, with fragments entering the blood or tissues to cause blood vessel obstruction or formation of local lesions. In addition, the immunogenicity of fibrin may cause allergic reactions. Polyethylene glycol-based adhesives can absorb a large amount of tissue fluid or blood during use, leading to excessive swelling of the material itself and further damage to the damaged tissue. In recent years, tissue adhesive materials modified by functionalization with aldehyde groups (CHO), N-hydroxysuccinimide (NHS)-activated esters, or catechols have developed rapidly. They can adhere to tissues through interfacial crosslinking by interacting with functional groups on the tissue via their own active functional groups. However, these tissue adhesive materials often accumulate reaction heat or release low-molecular-weight compounds when they interact with tissues, causing harm to the human body, which greatly limits their application in tissue engineering. In addition, the degradability of these tissue adhesive materials during use and the biocompatibility of their degradation products are uncertain. Furthermore, the addition of metal ions or tannic acid (Chinese patents CN113941025A and CN113975451A) and other components to polymers to form adhesive hydrogels has strong adhesion to wet tissue surfaces, but the addition of these components affects the biocompatibility of the tissue adhesive material, which is not conducive to its use in clinical settings. The basic characteristics of an ideal tissue adhesive material should include strong adhesion, good biocompatibility, low cost, and a simple production and preparation process. However, to date, most available adhesive materials have limitations, and among the currently developed tissue adhesive materials, there are almost no materials that have strong adhesion to dry and wet tissue surfaces and excellent biocompatibility and the ability to promote wound healing. SUMMARY

[0004] The present application synthesizes a degradable aqueous polyurethane with excellent biocompatibility, which is compounded with an acrylic material and a plasticizer at room temperature to form a double-network composite tissue adhesive material with high adhesion, high strength, and high toughness through photo-initiated free radical polymerization, hydrogen bonding, and covalent bonding interactions.

[0005] One of the purposes of the present application is to provide a degradable bio-based tissue adhesive material comprising a polymer obtained by reaction of the following components:

[0006] (i) amino acid terminated bio-based supramolecular aqueous polyurethane;

[0007] (ii) at least one acrylic acid or its derivative;

[0008] (iii) at least one plasticizer.

[0009] In a more preferred embodiment,

[0010] The acrylic acid or its derivative is selected from at least one of acrylic acid, acrylamide, acrylate, preferably at least one of acrylic acid, acrylamide, isopropyl acrylamide, hydroxyethyl acrylate, hydroxyethyl methacrylate, hydroxypropyl acrylate;

[0011] The plasticizer is selected from at least one of sodium carboxymethyl cellulose, hydroxyethyl cellulose, polyamino acid, agar, polyvinyl alcohol, glycerol, methyl imidazole chloride salt;

[0012] The amino acid terminated bio-based supramolecular aqueous polyurethane comprises a modified polyurethane compound comprising a reaction product of:

[0013] (iv) at least one polyol;

[0014] (v) at least one isocyanate compound;

[0015] (vi) at least one polyhydroxy acid compound;

[0016] (vii) at least one cyclodextrin;

[0017] (viii) at least one amino acid;

[0018] The polyol is selected from at least one of polyester polyol, polyether polyol, polymeric polyol, natural vegetable oil, preferably at least one of polycaprolactone, polyglycolic acid, polyethylene glycol, polyvinyl alcohol, castor oil, soybean oil;

[0019] The isocyanate compound is selected from at least one of hexamethylene diisocyanate, toluene diisocyanate, diphenyl methane diisocyanate, isophorone diisocyanate, cyclohexane diisocyanate, triphenyl methane triisocyanate, p-phenylene diisocyanate, lysine diisocyanate;

[0020] The polyhydroxy acid compound is selected from at least one of dimethylol propionic acid, citric acid, tartaric acid, gallic acid, 3,4-dihydroxy benzoic acid;

[0021] The cyclodextrin is selected from at least one of a-cyclodextrin, b-cyclodextrin, g-cyclodextrin;

[0022] The amino acid is selected from at least one of proline, aspartic acid, arginine, lysine, glutamic acid, and serine.

[0023] The degradable biomaterial tissue adhesive material is prepared by compounding degradable supramolecular aqueous polyurethane with acrylic material and plasticizer, and through photoinitiated radical polymerization, hydrogen bond and covalent bond interaction, to form a double network composite structure adhesive material with high adhesion, high strength and high toughness.

[0024] The second object of the present application is to provide a preparation method of the degradable biomaterial tissue adhesive material, which comprises the following steps: mixing amino acid-terminated biomaterial supramolecular aqueous polyurethane, acrylic acid or its derivative, photoinitiator and plasticizer, and then performing light irradiation to obtain the degradable biomaterial tissue adhesive material.

[0025] Specifically, the preparation method comprises the following steps:

[0026] Step 1: heating and uniformly mixing polyol and isocyanate compound, then adding polyhydroxy acid compound, cyclodextrin and catalyst, and performing chain extension reaction, prepolymerization and neutralization reaction with neutralizing agent, and then adding amino acid solution to obtain amino acid-terminated biomaterial supramolecular aqueous polyurethane solution A;

[0027] Step 2: adding acrylic acid or its derivative into solution A to uniformly mix, and then standing and defoaming the mixed solution to obtain mixed solution B;

[0028] Step 3: adding plasticizer and photoinitiator into mixed solution B obtained in step 2, uniformly mixing through ultrasonic oscillation, and then performing light irradiation reaction to obtain the degradable biomaterial tissue adhesive material.

[0029] In a preferred specific embodiment of the present application, the degradable biomaterial tissue adhesive material can be prepared by the following steps:

[0030] Step 1, a certain amount of polyol is added to a flask, heated in an oil bath, and dissolved thoroughly. Isocyanate compound and a certain amount of catalyst are added to the polyol solution and mixed uniformly. Under the condition of nitrogen atmosphere, the supermolecular material component is added to the reaction system, and the mixture is heated to pre-polymerize. After pre-polymerization, the oil bath temperature is lowered, and the obtained pre-polymer capped with isocyanate groups (-NCO) is obtained. The viscosity of the pre-polymer is adjusted with an appropriate amount of organic solvent. Then a small amount of neutralizing agent is added for neutralization and to improve the solubility of the polymer. A certain amount of amino acid is dissolved in deionized water to prepare an amino acid solution with a certain concentration. The solution is added dropwise to the pre-polymer solution, and the stirring speed is increased to more than 1000 rpm. The mixture is stirred vigorously for 30-120 min to obtain an amino acid-capped bio-based supermolecular waterborne polyurethane. After standing and defoaming, the solution is recorded as solution A.

[0031] Step 2, a certain amount of acrylic compound is added to solution A at room temperature. The stirring speed is increased, and the mixture is mixed uniformly and reacted thoroughly to obtain solution B, which is stored in a cool and dark place.

[0032] Step 3, a certain amount of plasticizer and photoinitiator is added to solution B, which is continuously stirred at low speed in a closed incubator at room temperature and in the dark for 30-200 min until the solution is fully mixed and uniform. The mixed solution is irradiated with a fixed wavelength of light. After a certain period of time, the reactants in the solution react to form a viscous gel-like material.

[0033] In step 1 of the above preparation method:

[0034] The catalyst is selected from at least one of tertiary amines, organotin compounds, and organozinc compounds, preferably at least one of stannous octoate, triethylamine, triethylenediamine, N,N-dimethylcyclohexylamine, tetramethylbutanediamine, dibutyltin dilaurate, and zinc octoate;

[0035] The neutralizing agent is selected from at least one of triethylamine, ethylenediamine, and N,N-diethylmethylamine;

[0036] The concentration of the amino acid solution is 0.1-25 wt%, preferably 5-10 wt%.

[0037] In step 1 of the above preparation method, the temperature of the chain extension reaction is 65-95℃, and the reaction time is 1.5-3h; the temperature of the pre-polymerization reaction is 60-80℃, and the reaction time is 3-8h; the temperature of the neutralization reaction is 40-60℃.

[0038] In step 1 of the preparation method, an organic solvent is further added to adjust the viscosity of the prepolymer after the prepolymerization, wherein the organic solvent can be selected from water-miscible and volatile organic solvents, preferably the organic solvent is selected from at least one of acetone, dimethyl sulfoxide, dimethyl acetamide, tetrahydrofuran, and ethylenediamine. The viscosity of the prepolymer obtained after the prepolymerization in step 1 increases sharply, in order not to affect the subsequent reaction process, an organic solvent is added for dilution to reduce its viscosity, and the added organic solvent can make the prepolymer not form a block.

[0039] In step 2 of the preparation method, the mixing method can adopt the mechanical mixing method commonly used in the art, preferably the mixing temperature is 40-60°C and the mixing time is 1-2h. In step 2, a commonly used crosslinking agent such as N,N'-methylenebisacrylamide can also be added to accelerate the crosslinking reaction, and the addition amount is 0.1-1wt% of the acrylic acid or its derivative.

[0040] In step 3 of the preparation method:

[0041] The photoinitiator is not particularly limited and can be any water-soluble ultraviolet photoinitiator or blue light initiator commonly used in the art, for example, preferably selected from one of ultraviolet photoinitiator Irgacure 2959 (I2959), ultraviolet photoinitiator Darocur 1173 (1173), and blue light initiator phenyl-2,4,6-trimethylbenzoyl phosphonic acid lithium (LAP); the irradiation reaction time is 15-200min;

[0042] The biodegradable bio-based adhesive material obtained in step 3 also needs to be dialyzed to remove small molecular impurities to obtain a tissue adhesive material, and the dialysis treatment can be completed by using a commonly used dialysis separation treatment operation, preferably the dialysis treatment time is 24-72h.

[0043] The isocyanate compound is 100-270 parts, the polyhydroxy acid compound is 10-20 parts, the cyclodextrin is 1-15 parts, the catalyst is 0.05-2 parts, the neutralizing agent is 0.1-10 parts, the amino acid is 5-25 parts, the acrylic acid or its derivative is 30-100 parts, the plasticizer is 1-20 parts, and the photoinitiator is 0.1-5 parts, based on 100 parts by weight of the polyol; preferably, the isocyanate compound is 120-180 parts, the polyhydroxy acid compound is 10-15 parts, the cyclodextrin is 3-8 parts, the catalyst is 0.1-1 part, the neutralizing agent is 0.5-6 parts, the amino acid is 6-20 parts, the acrylic acid or its derivative is 40-80 parts, the plasticizer is 5-15 parts, and the photoinitiator is 0.5-2.5 parts, based on 100 parts by weight of the polyol.

[0044] The third object of the present application is to provide the above-mentioned degradable bio-based tissue adhesive material or the degradable bio-based tissue adhesive material prepared by the above-mentioned preparation method, which is applied to damaged tissue bonding, wound sealing, wound hemostasis and soft tissue repair.

[0045] In view of the limitations of the existing tissue adhesive materials, the present application selects an aqueous polyurethane with excellent biocompatibility, non-toxicity and controllable biodegradability. According to the structure adjustability of the polyurethane, by introducing a supramolecular adhesive component with multiple functional groups and an amino acid component, the material has strong tissue adhesion, cell compatibility and biodegradability. In order to improve the mechanical strength, plasticity and bonding strength of the tissue adhesive material, the present application combines acrylic materials, plasticizing materials and polyurethane to prepare the tissue adhesive material through covalent crosslinking and light-induced free radical polymerization. The acrylic material contains abundant carboxyl or amino groups, which can promote the formation of a crosslinked network structure in the composite material, improve the mechanical strength of the material, and also interact with the amino groups on the tissue to achieve strong tissue adhesion. At the same time, the use of plasticizers enables the obtained material to have high tensile properties and deformation ability, which can well fit any shaped tissue and meet the adhesion requirements of tissues of different parts and different shapes.

[0046] The present application has the following advantages:

[0047] 1. The present application introduces a supramolecular component with a large number of functional groups and an amino acid component to prepare an aqueous polyurethane with high dispersity, excellent biological safety and degradability. The aqueous polyurethane is combined with acrylic acid, acrylic ester or acrylamide material monomers, and a plasticizer is introduced to synthesize a composite material with a double network structure through hydrogen bonding, covalent bonding and light-induced free radical polymerization, which is used as a tissue adhesive material. The material is a transparent to light yellow gel with high biological safety and strong tissue adhesion, and is easy to use.

[0048] 2、The tissue adhesive material provided by the application has high tensile strength, 50-300 KPa, elongation at break, 100-400%, and bonding strength to animal tissue, 50-200 KPa, which is much higher than that of general gel adhesive material (10-50 KPa) and commercially available tissue adhesive fibrin glue (8.5 KPa). The tissue adhesive material can quickly realize tissue adhesion and can bear a larger tensile force (can bear the weight of 250 g metal or 300 g glass), has shorter tissue adhesion time, wider application range and higher bonding strength than cyanoacrylate adhesive material, and can realize rapid closure of a wound or a bleeding wound.

[0049] 3、The tissue adhesive material provided by the application can degrade after application, and the amino acid components released during the degradation process help to promote wound healing.

[0050] 4、The application adopts light-induced irradiation reaction molding, which has the advantages of high efficiency, rapidness, high repeatability, high sample transparency and excellent sample performance. BRIEF DESCRIPTION OF DRAWINGS

[0051] Fig. 1 A schematic diagram of the bonding effect of the tissue adhesive material obtained in Example 1;

[0052] Fig. 2 A tensile property test diagram of the tissue adhesive material obtained in Example 1;

[0053] Fig. 3 A schematic diagram of the adhesion effect of the tissue adhesive material obtained in Example 1 (the glass three-necked flask is 300 g). DETAILED DESCRIPTION

[0054] The application will be described in detail below with reference to specific examples. It is necessary to point out that the following examples are only used to further illustrate the application and cannot be understood as limiting the protection scope of the application. Some non-essential improvements and adjustments of the application made by those skilled in the art according to the content of the application still fall within the protection scope of the application.

[0055] The test instruments and test conditions used in the examples are as follows:

[0056] 1. Mechanical strength test method

[0057] According to the method in the national standard GB / T1040.3-2006, the tensile properties of the samples were tested by a mechanical testing machine, and each sample was tested 3 times to take the average value. The tensile rate was 1 mm / s, and the tensile sample size was 10 cm x 1 cm x 0.5 cm.

[0058] 2. Bonding strength test method

[0059] The adhesion of the tissue adhesive material sample to different material surfaces, including animal tissue, glass, metal sheet, etc. is tested. Two pieces of substrate material with a length of 25 mm and a width of 10 mm are selected, and a tissue adhesive material sample (1 cm x 1 cm) is adhered between the two pieces of material. The resulting combined sample is subjected to a tensile stress-strain curve test to measure the ultimate tensile force (F) during stretching. The bonding strength (O) is obtained from the maximum tensile force (F) and the adhering area (S) of the tissue adhesive material by the formula O = F / S.

[0060] 3. Adhesion effect characterization method

[0061] The material is cut into a 1 cm x 1 cm piece and adhered to glassware of different weights to observe the adhesion strength. The material is adhered to different shaped substrate materials and human joint parts to observe the adhesion effect.

[0062] 4. Degradation performance test

[0063] (1) Preparation of phosphate buffer solution

[0064] Weigh 0.27 g of potassium dihydrogen phosphate (KH2PO4), 1.42 g of sodium phosphate dibasic (Na2HPO4), 8.00 g of sodium chloride (NaCl), and 0.20 g of potassium chloride (KCl), add 800 mL of deionized water, stir well to dissolve, then add hydrochloric acid to adjust the pH to 7.4, and dilute to 1 L to prepare the phosphate buffer solution (PBS), which is used as the buffer solution for the degradation experiment. During the degradation process, the PBS solution is replaced every certain time interval to effectively ensure the stability of the degradation environment.

[0065] (2) Degradation performance evaluation

[0066] The tissue adhesive material is prepared into a strip sample (3 cm x 1 cm x 0.5 cm) and dried to constant weight in a 40°C vacuum drying oven. The initial mass of the sample is recorded as W0. The prepared sample is placed in a reagent bottle containing PBS solution, and the degradation is observed every certain time (t) to calculate the mass loss rate during the degradation process. The mass loss rate during the degradation process is calculated by the formula:

[0067] Mass loss rate (%) = (W t -W0) / W0*100%

[0068] Sources of raw materials used in the examples:

[0069] The compounds used in the examples are either commercially available or prepared according to the methods disclosed in the prior art.

[0070] Example 1

[0071] Step 1, 20 g of polyethylene glycol 400 was added to a three-necked flask, heated at 95 °C for 80 min in an oil bath, and stirred at low speed for 2 h to fully dissolve. 26.7 g of isophorone diisocyanate and 0.02 g of stannous octoate were added to the stirred mixture. 2 g of dimethylol propionic acid and 1.2 g of α-cyclodextrin were added to the reactor under the condition of 80 °C and nitrogen, and the mixture was allowed to react for 2 h to undergo prepolymerization. After the prepolymerization, the temperature was lowered to 45 °C, and 30 ml of acetone was added to adjust the viscosity of the prepolymer. 0.8 g of triethylamine was added to neutralize the excess dimethylol propionic acid. 12 g of deionized water was taken, lysine was added, and a 9 wt% lysine solution was prepared, which was added dropwise to the prepolymer solution. The solution was stirred vigorously at a speed of 1200 rpm for 1.5 h to obtain an aqueous polyurethane solution.

[0072] Step 2, 16 g of acrylic acid and 0.02 g of N,N'-methylenebisacrylamide were added to the aqueous polyurethane solution at 20 °C. The speed was increased, the mixture was mixed uniformly, and reacted for 1 h. The mixture was defoamed by ultrasonic oscillation and stored in a cool, dark place.

[0073] Step 3, 1.5 g of sodium carboxymethyl cellulose and 150 mg of I2959 were added to the mixture, and the mixture was continuously stirred at low speed in a sealed incubator at room temperature and in the dark for 180 min until the components in the solution were fully mixed and uniform. The mixed solution was irradiated with an external 365 nm, 15 W power ultraviolet light for 1 h to obtain a transparent gel material.

[0074] Step 4, the prepared transparent gel material was dialyzed in distilled water at 30 °C for 48 h to remove small molecular impurities and obtain a tissue adhesive material.

[0075] Example 2

[0076] Step 1, 18 g of polyethylene glycol 400 and 1.5 g of polyvinyl alcohol were added to a three-necked flask, heated at 95 °C for 120 min in an oil bath, and stirred at low speed for 2 h to make the mixture uniform. 25.3 g of hexamethylene diisocyanate and 0.02 g of stannous octoate were added to the stirred mixture. 2.5 g of citric acid and 0.8 g of α-cyclodextrin were added to the reaction system under the condition of 80 °C and nitrogen, and the mixture was stirred uniformly and continuously reacted for 3 h to undergo prepolymerization. After the prepolymerization, the temperature was lowered to 50 °C, 20 ml of acetone was added to adjust the viscosity of the prepolymer, and 0.15 g of triethylamine was added to adjust the pH of the mixture. 12 g of deionized water was taken, serine was added, and a 10 wt% amino acid solution was prepared, which was added dropwise to the prepolymer solution. The solution was stirred vigorously at a speed of 1000 rpm for 1 h to obtain an amino acid modified aqueous polyurethane solution.

[0077] Step 2, 14 g of acrylic acid and 0.02 g of N,N'-methylenebisacrylamide were added to the aqueous polyurethane solution at 20°C. The speed was increased, mixed uniformly, reacted for 1 h, defoamed by ultrasonic oscillation to obtain a mixed solution, and stored in a cool, dark place.

[0078] Step 3, 1.2 g of polyglutamic acid and 140 mg of I2959 were added to the mixed solution, and continuously stirred at low speed in a closed incubator at room temperature and in the dark for 200 min until the components in the solution were fully mixed and uniform. The mixed solution was irradiated with an external 365 nm, 40 W ultraviolet light for 90 min to obtain a transparent gel material.

[0079] Step 4, the prepared transparent gel material was dialyzed in distilled water at 30°C for 48 h to remove small molecular impurities to obtain a tissue adhesive material.

[0080] Example 3

[0081] Step 1, 10 g of castor oil and 3 g of polyethylene glycol 400 were added to a three-necked flask, which was placed in an oil bath and heated at 95°C for 120 min, and stirred at low speed for 2 h to make the mixture uniform. 18.25 g of diphenylmethane diisocyanate and 0.11 g of triethylenediamine were added and mixed uniformly. 0.9 g of β-cyclodextrin and 2 g of citric acid were added to the stirred mixture under nitrogen at 80°C, stirred uniformly and continuously reacted for 2 h to make the mixture undergo prepolymerization to form a prepolymer. Then cooled to 50°C, then added 0.2 g of triethylamine to adjust the pH of the solution and improve the solubility of the polymer. 10 ml of dimethyl sulfoxide was added to adjust the viscosity of the prepolymer. 20 g of deionized water was taken, and a mixture of lysine and proline (mass ratio of lysine to proline was 4:1) was added to prepare an amino acid solution with a mass fraction of 10 wt%, which was added dropwise to the prepolymer solution, the speed was increased to above 1000 rpm, and the mixture was stirred vigorously for 60 min to obtain an amino acid modified aqueous polyurethane solution.

[0082] Step 2, 1 g of polyvinyl alcohol was added to the aqueous polyurethane solution at 75°C, and reacted for 1 h. The temperature was lowered to 20°C, 12 g of acrylamide, 0.02 g of N,N'-methylenebisacrylamide, 8 g of deionized water and 144 mg of LAP blue light initiator were added, stirred at low speed for 30 min, mixed uniformly, and reacted for 1 h in a closed incubator at room temperature and in the dark. A mixed solution was obtained by ultrasonic oscillation defoaming, and stored in a cool, dark place.

[0083] Step 3, the mixed solution was irradiated with an external 365 nm, 15 W ultraviolet light for 20 min to obtain a light yellow gel material.

[0084] Step 4: The prepared light yellow gel material was dialyzed in distilled water at 30°C for 48 h to remove small molecule impurities, and a tissue adhesive material was obtained.

[0085] Example 4

[0086] Step 1: 18 g of polyethylene glycol 800, 27.2 g of isophorone diisocyanate, and 0.02 g of stannous octoate were added to a three-necked flask, which was placed in an oil bath and heated at 95°C for 80 min, and the mixture was stirred at low speed for 2 h to make it uniform. 1.2 g of α-cyclodextrin and 2 g of dimethylol propionic acid were added to the stirred mixture at 80°C under nitrogen for 2 h to make the mixture undergo a prepolymerization reaction. After the prepolymerization reaction, the mixture was cooled to 45°C, and 30 ml of acetone was added to adjust the viscosity of the prepolymer. 0.8 g of triethylamine was added to neutralize the excess dimethylol propionic acid. 16 g of deionized water was taken, and lysine was added to make a 9 wt% amino acid solution, which was added dropwise to the prepolymer solution, and the mixture was stirred at 1200 rpm for 1.5 h to obtain an aqueous polyurethane solution.

[0087] Step 2: 8 g of hydroxyethyl methacrylate and 0.01 g of N,N'-methylene bisacrylamide were added to the aqueous polyurethane solution at 20°C. The speed was increased, and the mixture was mixed uniformly and reacted for 1 h. The mixture was defoamed by ultrasonic oscillation and stored in a cool, dark place.

[0088] Step 3: 2 g of glycerol and 120 mg of Darocur 1173 were added to the mixture, which was placed in a sealed incubator and continuously stirred at low speed in the dark at room temperature for 180 min until the components in the solution were fully mixed and uniform. The mixed solution was irradiated with an external 330 nm, 50 W power ultraviolet light for 30 min to obtain a transparent gel material.

[0089] Step 4: The prepared transparent gel material was dialyzed in distilled water at 30°C for 48 h to remove small molecule impurities, and a tissue adhesive material was obtained.

[0090] Comparative Example 1

[0091] Step 1, 20 g of polyethylene glycol 400 was added to a three-necked flask, which was placed in an oil bath at 95 °C and heated for 80 min with low speed stirring for 2 h. 26.7 g of isophorone diisocyanate and 0.02 g of stannous octoate were added to the solution, which was reacted at 80 °C under nitrogen for 2 h to make the mixture pre-polymerize. After pre-polymerization, the temperature was lowered to 70 °C, 1.2 g of α-cyclodextrin and 2 g of dimethylol propionic acid were added to the reactor, and the reaction was continued for 2 h. Then the temperature was lowered to 45 °C, and 30 ml of acetone was added to adjust the viscosity of the pre-polymer. 0.85 g of triethylamine was added to neutralize the excess dimethylol propionic acid. 15 g of deionized water was taken, lysine was added, and a 9 wt% amino acid solution was prepared, which was added dropwise to the pre-polymer solution, and stirred at 1200 rpm for 1.5 h to obtain an aqueous polyurethane solution.

[0092] Step 2, 16 g of acrylic acid and 0.02 g of N,N'-methylene bisacrylamide were added to the aqueous polyurethane solution at 20 °C. The speed was increased, the mixture was mixed uniformly, and reacted for 1 h. The mixture was obtained by ultrasonic oscillation defoaming, and was stored in a cool, dark place.

[0093] Step 3, 150 mg of I2959 was added to the mixture, which was placed in a sealed incubator and continuously stirred at low speed at room temperature in the dark for 180 min until the components in the solution were fully mixed and uniform. The mixed solution was irradiated with an external 365 nm, 15 W power ultraviolet light for 1 h to obtain a transparent gel material.

[0094] Step 4, the prepared transparent gel material was placed in distilled water at 30 °C and dialyzed for 48 h to remove small molecular impurities to obtain a tissue adhesive material.

[0095] Comparative Example 2

[0096] Step 1, 20 g of polyethylene glycol 400 was added to a three-necked flask, which was placed in an oil bath at 95 °C and heated for 80 min with low speed stirring for 2 h. 26.7 g of isophorone diisocyanate and 0.02 g of stannous octoate were added to the solution, which was reacted at 80 °C under nitrogen for 2 h, and the temperature was lowered to 70 °C. 2 g of 1,4-butanediol was added to the reactor, and the reaction was continued for 2 h to generate a pre-polymer. Then the temperature was lowered to 45 °C, and 10 ml of acetone was added to adjust the viscosity of the pre-polymer. 12 g of deionized water was taken, lysine was added, and a 9 wt% amino acid solution was prepared, which was added dropwise to the pre-polymer solution, and stirred at 1000 rpm for 1 h to obtain an aqueous polyurethane solution.

[0097] Step 2, 16 g of acrylic acid and 0.02 g of N,N'-methylene bisacrylamide were added to the aqueous polyurethane solution at 20 °C. The speed was increased, the mixture was mixed uniformly, and reacted for 1 h. The mixture was obtained by ultrasonic oscillation defoaming, and was stored in a cool, dark place.

[0098] Step 3, 1.5 g of sodium carboxymethyl cellulose and 150 mg of I2959 were added to the mixed solution, which was placed in a closed incubator at room temperature and continuously stirred at low speed for 100 min in the dark until the components in the solution were fully mixed and uniform. The mixed solution was irradiated with an external 365 nm, 15 W power ultraviolet light for 1 h to obtain a transparent gel material.

[0099] Step 4, the prepared transparent gel material was dialyzed in distilled water at 30°C for 48 h to remove small molecular impurities to obtain a tissue adhesive material.

[0100] Comparative Example 3

[0101] Step 1, 20 g of polyethylene glycol 400 was added to a three-necked flask, which was placed in an oil bath and heated at 95°C for 80 min and stirred at low speed for 2 h. 26.7 g of isophorone diisocyanate and 0.02 g of stannous octoate were added to the solution, which was reacted at 80°C under nitrogen for 2 h to cause the mixture to undergo prepolymerization. After the prepolymerization, the temperature was lowered to 70°C, 1.2 g of α-cyclodextrin and 2 g of dimethylol propionic acid were added to the reactor, and the reaction was continued for 2 h. Then it was cooled to 45°C, 30 ml of acetone was added to adjust the viscosity of the prepolymer. 0.85 g of triethylamine was added to neutralize the excess dimethylol propionic acid. 15 g of deionized water was taken, lysine was added to make a 9 wt% amino acid solution, which was added dropwise to the prepolymer solution, and stirred at 1200 rpm for 1.5 h to obtain an aqueous polyurethane solution.

[0102] Step 2, 16 g of acrylic acid was added to the aqueous polyurethane solution at 20°C. The speed was increased and the mixture was mixed and reacted for 1 h, then defoamed by ultrasonic vibration to obtain a mixed solution, which was stored in a cool and dark place.

[0103] Step 3, 90 mg of ammonium persulfate was added to the mixed solution under a nitrogen atmosphere and mixed uniformly. The temperature was raised to 65°C and the reaction was continued for 7 h to obtain a gel material.

[0104] Step 4, the prepared gel material was dialyzed in distilled water at 30°C for 48 h to remove small molecular impurities.

[0105] Adhesive material test

[0106] The test results of tensile strength, elongation at break and adhesive strength of the tissue adhesive materials prepared in Examples 1-4 and Comparative Examples 1-3 are shown in Table 1.

[0107] Table 1. Test results of tissue adhesive materials prepared in Examples 1-4 and Comparative Examples 1-3

[0108]

[0109] As can be seen from the data in Table 1, the tissue adhesive materials prepared in Examples 1-4 of this invention have excellent tensile strength and better overall performance. The tissue adhesive material obtained in Comparative Example 1 has lower tensile strength and elongation at break, and poorer plasticity; the tissue adhesive material obtained in Comparative Example 2 has lower bonding strength and limited adhesion; and the tissue adhesive material obtained in Comparative Example 3 has obvious defects and cannot meet the requirements for use. Furthermore, from the attached... Figs. 1-3 As can be seen, the tissue adhesive material provided by this invention can firmly adhere to any curved surface, exhibits strong adhesion to tissue, achieves rapid tissue adhesion, and can withstand significant tensile forces, enabling rapid closure of damaged wounds or bleeding wounds and soft tissue repair. This tissue adhesive material possesses instantaneous tissue adhesion characteristics, high adhesive strength, high mechanical strength, and plastic deformation capability, making it suitable for biomedical fields such as rapid hemostasis of bleeding wounds, rapid closure of damaged wounds, and repair of damaged soft tissues. The material also exhibits biodegradability and excellent biocompatibility.

Claims

1. A degradable bio-based tissue adhesive material, comprising a polymer obtained by reaction of: (i) an amino acid-terminated bio-based supramolecular aqueous polyurethane; (ii) at least one acrylic acid or derivative thereof; (iii) at least one plasticizer; wherein the amino acid-terminated bio-based supramolecular aqueous polyurethane comprises a modified polyurethane compound comprising a reaction product of: (iv) at least one polyol selected from at least one of a polyester polyol, a polyether polyol, a natural vegetable oil; (v) at least one isocyanate compound selected from at least one of hexamethylene diisocyanate, toluene diisocyanate, diphenylmethane diisocyanate, isophorone diisocyanate, cyclohexane diisocyanate, triphenylmethane triisocyanate, p-phenylene diisocyanate, lysine diisocyanate; (vi) at least one polyhydroxy acid compound selected from at least one of dimethylol propionic acid, citric acid, tartaric acid, gallic acid, 3,4-dihydroxybenzoic acid; (vii) at least one cyclodextrin selected from at least one of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin; (viii) at least one amino acid selected from at least one of proline, aspartic acid, arginine, lysine, glutamic acid, serine. 2.The amino acid-terminated bio-based supramolecular aqueous polyurethane is prepared by the following steps: adding the polyol into a flask, heating in an oil bath, dissolving thoroughly, adding the isocyanate compound and the catalyst into the polyol solution and mixing uniformly, adding the polyhydroxy acid compound and the cyclodextrin into the reaction system under a nitrogen atmosphere, heating and reacting to make the mixture pre-polymerize, lowering the oil bath temperature after the pre-polymerization, adjusting the viscosity of the obtained isocyanate-terminated prepolymer with an organic solvent, adding the neutralizing agent to neutralize, dissolving the amino acid in deionized water to prepare an amino acid solution, adding the amino acid solution drop by drop into the prepolymer solution, increasing the rotation speed to above 1000 rpm, and stirring vigorously for 30-120 min; the catalyst is selected from at least one of tertiary amines, organic tin compounds, and organic zinc compounds; the neutralizing agent is selected from at least one of triethylamine, ethylenediamine, and N,N-diethylmethylamine; the concentration of the amino acid solution is 0.1-25 wt%; the temperature of the chain extension reaction is 65-95℃, and the reaction time is 1.5-3 h; the temperature of the pre-polymerization reaction is 60-80℃, and the reaction time is 3-8 h; the temperature of the neutralization reaction is 40-60℃; and the organic solvent is selected from at least one of acetone, dimethyl sulfoxide, dimethylacetamide, tetrahydrofuran, and ethylenediamine. ​ ​ wherein ​ ​ ​ ​ ​ ​ ​ The isocyanate compound is 100-270 parts, the polyhydroxy acid compound is 10-20 parts, the cyclodextrin is 1-15 parts, the catalyst is 0.05-2 parts, the neutralizing agent is 0.1-10 parts, the amino acid is 5-25 parts, the acrylic acid or its derivative is 30-100 parts, and the plasticizer is 1-20 parts, all based on 100 parts by weight of the polyol.

2. The tissue adhesive material of claim 1, wherein, the acrylic acid or its derivative is selected from at least one of an acrylic acid, an acrylamide, an acrylate, and / or, the plasticizer is selected from at least one of sodium carboxymethyl cellulose, hydroxyethyl cellulose, a polyamino acid, agar, polyvinyl alcohol, glycerol, and methyl imidazole chloride.

3. The tissue adhesive material of claim 2, wherein, the acrylic acid or its derivative is selected from at least one of an acrylic acid, an acrylamide, an isopropyl acrylamide, a hydroxyethyl acrylate, a hydroxyethyl methacrylate, and a hydroxypropyl acrylate.

4. The tissue adhesive material of claim 1, wherein, the polyol is selected from at least one of polycaprolactone, polyglycolic acid, polyethylene glycol, polyvinyl alcohol, castor oil, and soybean oil.

5. A method of preparing the degradable bio-based tissue adhesive material of any one of claims 1-4, comprising the steps of: mixing components including an amino acid-terminated bio-based supramolecular aqueous polyurethane, an acrylic acid or its derivative, a photoinitiator, and a plasticizer, and then performing a photoirradiation reaction to obtain the degradable bio-based tissue adhesive material.

6. The production method according to claim 5, wherein The method of preparing the degradable bio-based tissue adhesive material specifically comprises the following steps: Step 1: uniformly mixing a polyol and an isocyanate compound, then adding a polyhydroxy acid compound, a cyclodextrin, and a catalyst, and then performing a chain extension reaction, a prepolymerization reaction, and a neutralization reaction with a neutralizing agent, and then adding an amino acid solution to obtain an amino acid-terminated bio-based supramolecular aqueous polyurethane solution A; Step 2: uniformly mixing an acrylic acid or its derivative with the solution A, and then standing the mixture to remove bubbles to obtain a mixed solution B; Step 3: adding a plasticizer and a photoinitiator to the mixed solution B, uniformly mixing the mixture by ultrasonic oscillation, and then performing a photoirradiation reaction to obtain the degradable bio-based tissue adhesive material.

7. The production method according to claim 6, characterized by, In Step 1: the catalyst is selected from at least one of a tertiary amine, an organotin, and an organozinc; and / or, the neutralizing agent is selected from at least one of triethylamine, ethylenediamine, and N,N-diethylmethylamine; and / or, the concentration of the amino acid solution is 0.1-25 wt%; and / or, the temperature of the chain extension reaction is 65-95°C, and the reaction time is 1.5-3 h; and / or, the temperature of the prepolymerization reaction is 60-80°C, and the reaction time is 3-8 h; and / or, the temperature of the neutralization reaction is 40-60°C; and / or, an organic solvent is further added after the prepolymerization reaction to adjust the viscosity of the prepolymer.

8. The preparation method according to claim 7, characterized in that, In Step 1: The catalyst is at least one selected from triethylamine, triethylenediamine, N, N-dimethylcyclohexylamine, tetramethylbutanediamine, stannous octoate, dibutyltin dilaurate, zinc octoate; and / or, The concentration of the amino acid solution is 5-10 wt%; and / or, The organic solvent is at least one selected from acetone, dimethyl sulfoxide, dimethylacetamide, tetrahydrofuran, ethylenediamine.

9. The preparation method according to claim 6, characterized in that, In step 2: The mixing temperature in step 2 is 40-60°C, and the mixing time is 1-2 h.

10. The method of claim 6, wherein, In step 3: The photoinitiator is selected from water-soluble ultraviolet photoinitiators or blue light initiators; and / or, The time of the light irradiation reaction is 15-200 min; and / or, The degradable bio-based adhesive material obtained in step 3 needs to be dialyzed.

11. The method of claim 10, wherein, In step 3: The dialysis treatment time is 24-72 h.

12. The preparation method of claim 6, wherein, The isocyanic acid compound is 100-270 parts, the polyhydroxy acid compound is 10-20 parts, the cyclodextrin is 1-15 parts, the catalyst is 0.05-2 parts, the neutralizing agent is 0.1-10 parts, the amino acid is 5-25 parts, the acrylic acid or its derivative is 30-100 parts, the plasticizer is 1-20 parts, and the photoinitiator is 0.1-5 parts, based on 100 parts by weight of the polyol.

13. The preparation method of claim 12, wherein, The isocyanic acid compound is 120-180 parts, the polyhydroxy acid compound is 10-15 parts, the cyclodextrin is 3-8 parts, the catalyst is 0.1-1 part, the neutralizing agent is 0.5-6 parts, the amino acid is 6-20 parts, the acrylic acid or its derivative is 40-80 parts, the plasticizer is 5-15 parts, and the photoinitiator is 0.5-2.5 parts, based on 100 parts by weight of the polyol.

14. The degradable bio-based tissue adhesive material of any one of claims 1-4 or obtained by the preparation method of any one of claims 5-13, which is applied to damaged tissue bonding, wound sealing, wound hemostasis, and soft tissue repair.

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