A biodegradable strong medical adhesive and its preparation method and application
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- JIANGSU UNIV
- Filing Date
- 2026-04-22
- Publication Date
- 2026-05-29
Smart Images
Figure CN122097668A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of medical adhesives, and in particular to a biodegradable, high-strength medical adhesive, its preparation method, and its application. Background Technology
[0002] Traditional surgical sutures have significant limitations in clinical application. They require a high level of experience and skill from the operator, the suturing process is time-consuming, and they easily cause pain to the patient. Furthermore, after suturing, the sutures can easily lead to postoperative infection, tissue strain, and inflammatory reactions, requiring secondary suture removal after wound healing and often leaving noticeable scars. In contrast, bio-adhesives not only achieve effective wound closure but can also be functionalized to possess various bioactivities such as antioxidants and antibacterial agents, exhibiting superior overall performance.
[0003] However, current medical adhesive materials still generally suffer from problems such as insufficient adhesive strength, difficulty in controlling degradation behavior, and poor biocompatibility. In particular, they face challenges in balancing high-strength rapid adhesion with long-term stable adhesion, which limits their ability to provide continuous mechanical support during wound healing.
[0004] Silk fibroin, due to its unique molecular structure containing both hydrophobic and hydrophilic segments, exhibits excellent functional properties. The hydrophobic segments help to repel water molecules at the interface, maintain the integrity of the gel structure, and enhance cohesion, thereby improving instantaneous adhesion strength. The hydrophilic segments, on the other hand, facilitate the exposure of hydrophilic functional groups to the aqueous phase, allowing for the absorption and retention of water, thus providing a suitable environment for chemical reactions. Therefore, silk fibroin has significant advantages in high-strength initial adhesion and stable long-term bonding, while also possessing excellent biocompatibility and in vivo degradability.
[0005] Although silk fibroin possesses excellent mechanical and physicochemical properties, its limited number of adhesive functional groups restricts its adhesive ability and hinders its further application in medical adhesive materials. Notably, silk fibroin is composed of a variety of amino acids and has abundant side-group functional groups, providing diverse chemical modification sites and laying the foundation for its functionalization. Therefore, exploring novel chemical modification strategies using silk fibroin as a substrate to develop a biomedical adhesive that combines strong adhesion with controllable degradation has significant scientific value and application prospects. Summary of the Invention
[0006] The purpose of this invention is to provide a biodegradable, high-strength medical adhesive, its preparation method, and its application, thereby addressing the aforementioned problems in the background art. This invention designs a method for preparing a biodegradable, high-strength medical adhesive. Using silk fibroin as a substrate, leveraging its unique structural features and abundant modifiable amino acid sites, catechol and phenylboronic acid groups are successfully introduced through chemical modification. Through the borate ester bonds formed between the catechol and phenylboronic acid groups, a hydrogel with excellent tissue adhesion properties is successfully prepared.
[0007] To achieve the above objectives, the present invention provides the following technical solution: One of the technical solutions of the present invention is to provide a biodegradable medical adhesive, which contains catechol-modified silk fibroin and phenylboronic acid-modified silk fibroin.
[0008] The second technical solution of the present invention provides a method for preparing the above-mentioned biodegradable medical adhesive, comprising the following steps: (1) Mix silk fibroin and dicarboxylic anhydride in an organic solvent to carry out a nucleophilic addition reaction, and then dialyze in water to obtain an aqueous solution of carboxylated silk fibroin; (2) The carboxylated silk protein aqueous solution is mixed with an amide condensing agent and activated to obtain an activated carboxylated silk protein solution; (3) The activated carboxylated silk protein solution is mixed with a substance containing catechol groups and amino groups to carry out amidation reaction A to obtain catechol-modified silk protein solution; The activated carboxylated silk protein solution was mixed with a substance containing phenylboronic acid groups and amino groups to carry out amidation reaction B, thereby obtaining a phenylboronic acid modified silk protein solution. (4) The catechol-modified silk protein solution and the phenylboronic acid-modified silk protein solution are stored separately and then mixed for esterification reaction when needed to obtain the medical adhesive.
[0009] Preferably, the dicarboxylic anhydride includes succinic anhydride, glutaric anhydride, or phthalic anhydride; the silk fibroin includes one or more of natural silk fibroin, recombinant silk fibroin, and regenerated silk fibroin; the mass ratio of the silk fibroin to the dicarboxylic anhydride is 1:0.1-10; the nucleophilic addition reaction is carried out at a temperature of 100-140°C for a time of 5 minutes to 72 hours.
[0010] Preferably, the amide condensing agent includes one or more of N-hydroxysuccinimide, carbodiimide compounds, urea hexafluorophosphate, phosphonium hexafluorophosphate, carbamate, and tetrahexylpyrophosphorous acid.
[0011] More preferably, the amide condensing agent is composed of N-hydroxysuccinimide and carbodiimide compounds; the carbodiimide compounds are 1-ethyl-(3-dimethylaminopropyl)carbodiimide and / or dicyclohexylcarbodiimide.
[0012] Preferably, the substance containing catechol groups and amino groups includes dopamine or a salt with dopamine as the parent nucleus; the mass ratio of carboxylated silk protein in the carboxylated silk protein aqueous solution to the substance containing catechol groups and amino groups is 1:0.1-0.6; and the duration of the amidation reaction A is 1-24 hours.
[0013] Preferably, the substance containing phenylboronic acid groups and amino groups includes 3-aminophenylboronic acid or a salt with 3-aminophenylboronic acid as the parent nucleus; the mass ratio of carboxylated silk protein in the carboxylated silk protein aqueous solution to the substance containing phenylboronic acid groups and amino groups is 1:1-10; and the duration of the amidation reaction B is 1-24 hours.
[0014] Preferably, in step (4), the mass ratio of catechol-modified silk fibroin to phenylboronic acid-modified silk fibroin is 1-3:1-3.
[0015] Preferably, the pH value of the esterification reaction is 7.
[0016] The third technical solution of the present invention is to provide an application of the above-mentioned biodegradable medical adhesive in the field of medical adhesive materials.
[0017] Preferably, the application is as a material used for adhesives of surgical incisions, bone tissues, or organs.
[0018] The beneficial technical effects of the present invention are as follows: This invention presents a method for preparing a biodegradable, high-strength medical adhesive. Using silk fibroin as a substrate, leveraging its unique structural features and abundant modifiable amino acid sites, catechol and phenylboronic acid groups were successfully introduced through chemical modification. The resulting borate ester bonds between the catechol and phenylboronic acid groups led to the successful preparation of a hydrogel with excellent tissue adhesion properties. This preparation strategy provides a new approach to the chemical modification of silk fibroin.
[0019] The resulting medical adhesive possesses excellent biocompatibility and biodegradability, achieving high-strength and rapid adhesion while maintaining long-term stable bonding, thus meeting the mechanical support requirements during the healing process of complex wounds. Furthermore, the adhesive has low raw material costs and a controllable preparation process, demonstrating promising clinical application prospects. Attached Figure Description
[0020] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.
[0021] Figure 1 This is a physical image of the carboxylated silk protein aqueous solution in step (1) of Example 1 of the present invention.
[0022] Figure 2 This is a physical image of the catechol-modified silk protein buffer salt solution in step (3) of Example 1 of the present invention.
[0023] Figure 3 This is a physical image of the phenylboronic acid-modified silk protein buffer salt solution in step (3) of Example 1 of the present invention.
[0024] Figure 4 This is a physical image of the medical adhesive used in step (4) of Embodiment 1 of the present invention.
[0025] Figure 5 This is a comparison of the 1H NMR spectra of carboxylated silk protein in aqueous solution, catechol-modified silk protein in buffered salt solution, and phenylboronic acid-modified silk protein in buffered salt solution in heavy water according to Example 1 of the present invention.
[0026] Figure 6 This is the in vitro degradation curve of the medical adhesive in step (4) of Embodiment 1 of the present invention.
[0027] Figure 7 This is a cytotoxicity test diagram of the medical adhesive in step (4) of Embodiment 1 of the present invention. Detailed Implementation
[0028] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention. It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the present invention.
[0029] Furthermore, regarding the numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Any stated value or intermediate value within a stated range, as well as each smaller range between any other stated value or intermediate value within said range, are also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.
[0030] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. It should be noted that any aspects of this invention not described in detail are conventional practices in the art and are not the focus of this invention.
[0031] The terms “comprising,” “including,” “having,” “containing,” etc., used in this invention are all open-ended terms, meaning that they include but are not limited to.
[0032] This invention discloses a method for preparing a biodegradable medical adhesive, comprising the following steps: (1) Mix silk fibroin and dicarboxylic anhydride in an organic solvent to carry out a nucleophilic addition reaction, and then dialyze in water to obtain an aqueous solution of carboxylated silk fibroin; (2) The carboxylated silk protein aqueous solution is mixed with an amide condensing agent and activated to obtain an activated carboxylated silk protein solution; (3) The activated carboxylated silk protein solution is mixed with a substance containing catechol groups and amino (-NH2) to carry out amidation reaction A to obtain catechol-modified silk protein solution; The activated carboxylated silk protein solution was mixed with a substance containing phenylboronic acid groups and amino groups to carry out amidation reaction B, thereby obtaining a phenylboronic acid modified silk protein solution. (4) The catechol-modified silk protein solution and the phenylboronic acid-modified silk protein solution are stored separately and then mixed when needed. Sodium hydroxide solution is added dropwise to the solution until the pH value is 6-8 (preferably 7) to carry out esterification reaction and form hydrogel to obtain the medical adhesive.
[0033] Furthermore, the silk fibroin refers to materials based on silk fibroin, including one or more of natural silk fibroin, recombinant silk fibroin, and regenerated silk fibroin with different molecular weights.
[0034] Furthermore, the method for preparing the silk fibroin includes the following steps: Add silkworm cocoons to an aqueous solution of sodium carbonate / sodium bicarbonate, heat to boiling, and stir for 30-60 minutes to obtain degummed silk. Wash the silk 3-5 times in water and then dry it at 60°C to obtain the silk protein.
[0035] Further, the organic solvent includes, but is not limited to, N,N-dimethylformamide, dimethyl sulfoxide, dimethylacetamide, or methylpyrrolidone. Even further, the organic solvent is N,N-dimethylformamide.
[0036] Further, the dicarboxylic anhydride includes, but is not limited to, succinic anhydride, glutaric anhydride, or phthalic anhydride. Even further, the dicarboxylic anhydride is succinic anhydride.
[0037] Furthermore, the mass ratio of the silk fibroin to the dicarboxylic anhydride is 1:0.1-10, preferably 1:2.
[0038] Furthermore, the reaction temperature of the nucleophilic addition reaction is 100-140℃, preferably 100℃, and the reaction time is 5 minutes to 72 hours, preferably 2 hours.
[0039] Further, the amide condensing agent includes a catalyst capable of activating the carboxyl group to undergo an amidation reaction with an amino group. Even further, the amide condensing agent includes one or more of N-hydroxysuccinimide, carbodiimide compounds, urea hexafluorophosphate, phosphonium hexafluorophosphate, carbamate, and tetrahexylpyrophosphorous acid. Even further, the carbodiimide compound is 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC) and / or dicyclohexylcarbodiimide.
[0040] Further, the substance containing both catechol and amino groups is a compound whose molecular structure contains both catechol structural units and amino units. Even further, the substance containing both catechol and amino groups includes dopamine or a salt with dopamine as its core; preferably, the salt with dopamine as its core is dopamine hydrochloride.
[0041] Furthermore, the mass ratio of carboxylated silk protein to substances containing catechol groups and amino groups in the carboxylated silk protein aqueous solution is 1:0.1-0.6, preferably 1:0.2.
[0042] Furthermore, the duration of the amidation reaction A is 1-24 hours, preferably 24 hours.
[0043] Further, the substance containing phenylboronic acid groups and amino groups is a compound whose molecular structure simultaneously contains catechol structural units and amino units. Even further, the substance containing phenylboronic acid groups and amino groups includes 3-aminophenylboronic acid or a salt with 3-aminophenylboronic acid as the parent nucleus; preferably, the salt with 3-aminophenylboronic acid as the parent nucleus is a 3-aminophenylboronic acid salt.
[0044] Furthermore, the mass ratio of carboxylated silk protein to substances containing phenylboronic acid groups and amino groups in the carboxylated silk protein aqueous solution is 1:1-10, preferably 1:5.
[0045] Furthermore, the duration of the amidation reaction B is 1-24 hours, preferably 24 hours.
[0046] Furthermore, the catechol-modified silk protein solution and the phenylboronic acid-modified silk protein solution in step (4) must be dialyzed before use.
[0047] Further, in step (4), the mass ratio of the catechol-modified silk protein to the phenylboronic acid-modified silk protein is 1-3:1-3.
[0048] The reaction formula for the esterification reaction of the present invention is as follows:
[0049] Furthermore, the preparation method includes the following steps: (1) Dissolve the degummed and dried silk protein in 1-butyl-3-methylimidazolium chloride, add an organic solvent to the resulting mixed solution, and then add dicarboxylic anhydride under nitrogen protection to carry out a nucleophilic addition reaction to obtain a carboxylated silk protein solution. Then add sodium hydroxide solution dropwise until the solution pH is 7. Dialyze the resulting solution with water, and then dry and concentrate to obtain a high concentration of carboxylated silk protein aqueous solution. (2) The carboxylated silk protein aqueous solution is mixed with N-hydroxysuccinimide (NHS) and carbodiimide compounds, and citric acid or sodium citrate is added dropwise to adjust the pH of the solution to 6 to carry out the activation reaction to obtain an activated carboxylated silk protein solution. (3) The activated carboxylated silk protein solution is mixed with a substance containing catechol groups and amino groups to carry out amidation reaction A to obtain catechol-modified silk protein solution; The activated carboxylated silk protein solution was mixed with a substance containing phenylboronic acid groups and amino groups to carry out amidation reaction B, thereby obtaining a phenylboronic acid modified silk protein solution. (4) The catechol-modified silk protein solution and the phenylboronic acid-modified silk protein solution are stored separately and then mixed when needed. Sodium hydroxide solution is added dropwise to the solution until the pH value is 7, and an esterification reaction is carried out to form a hydrogel to obtain the medical adhesive.
[0050] 1-Butyl-3-methylimidazole chloride is part of the solvent and is used before the subsequently added solvent.
[0051] Furthermore, the mass ratio of the silk fibroin to 1-butyl-3-methylimidazole chloride is 1:5-8, preferably 1:6.5.
[0052] Furthermore, the ratio of the silk protein to the organic solvent is 1g:12-30mL, preferably 1g:15mL.
[0053] Furthermore, the temperature at which the solution is dissolved in 1-butyl-3-methylimidazole chloride is 100-140°C, preferably 120°C.
[0054] Furthermore, prior to the addition of dicarboxylic anhydride, the solution system is subjected to a deoxygenation treatment. The purpose of this deoxygenation treatment is to prevent the subsequently added dicarboxylic anhydride from being oxidized.
[0055] Furthermore, the concentration of the sodium hydroxide solution is 1-5M.
[0056] Furthermore, the mass ratio of carboxylated silk protein to N-hydroxysuccinimide in the carboxylated silk protein aqueous solution is 1:0.1-0.5, preferably 1:0.35.
[0057] Furthermore, the mass ratio of carboxylated silk protein to carbodiimide compounds in the carboxylated silk protein aqueous solution is 1:0.1-1, preferably 1:0.42.
[0058] N-hydroxysuccinimide and carbodiimide compounds need to be added simultaneously as catalysts for this stage.
[0059] Furthermore, after the activation reaction, the process also includes a deoxygenation treatment of the solution system. The purpose of this deoxygenation treatment is to prevent the oxidation of subsequently added substances containing catechol groups and amino groups, or substances containing phenylboronic acid groups and amino groups.
[0060] Unless otherwise specified, "room temperature" in this invention refers to 10-30°C.
[0061] All raw materials used in the following embodiments and comparative examples of the present invention are commercially available products.
[0062] Example 1 A method for preparing a biodegradable medical adhesive, comprising the following steps: (1) Dissolve 1g of degummed and dried silk fibroin (the type and source of which is mulberry silkworm cocoon) in 6.5g of 1-butyl-3-methylimidazole chloride, heat to 120℃ and react for 4 hours, then add 15mL of N,N-dimethylformamide to the resulting mixed solution, continue heating and stirring until the solute is completely dissolved, then add 2g of succinic anhydride under nitrogen protection and carry out nucleophilic addition reaction (react at 100℃ for 2 hours) to obtain carboxylated silk fibroin solution, then add 3M sodium hydroxide solution dropwise until the solution pH is 7, dialyze the resulting solution with water, and then concentrate to obtain a high concentration of carboxylated silk fibroin aqueous solution (concentration of 20mg / mL).
[0063] (2) At room temperature, N-hydroxysuccinimide (350 mg) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide (420 mg) were added to 100 mL of carboxylated silk protein aqueous solution. The pH of the solution was adjusted to 6 by adding 0.1 M citric acid aqueous solution. The activation reaction was carried out for 1.5 hours to obtain activated carboxylated silk protein solution.
[0064] (3) Add dopamine hydrochloride (400 mg) to the activated carboxylated silk protein solution and carry out amidation reaction for 24 hours. Then dialyze at room temperature for two days in a citric acid / sodium citrate buffer solution with pH=5.2, changing the dialysate every 12 hours during the period. Then dry and concentrate the solution to obtain a 100 mg / mL catechol-modified silk protein buffer solution.
[0065] Repeat step (2) to prepare an activated carboxylated silk protein solution with the same parameters. Then, add 3-aminophenylboronic acid (10g) to the activated carboxylated silk protein solution and carry out an amidation reaction for 24 hours. Then, dialyze the solution at room temperature for two days in a citric acid / sodium citrate buffer solution with a pH of 5.2, changing the dialysate every 12 hours. Then, dry and concentrate the solution to obtain a 100mg / mL phenylboronic acid modified silk protein buffer solution.
[0066] (4) The catechol-modified silk protein buffer solution and the phenylboronic acid-modified silk protein buffer solution are mixed at a volume ratio of 2:1 to obtain a mixture, and 3M sodium hydroxide solution is added dropwise to the mixture until the pH value of the solution is 7 to obtain a medical adhesive.
[0067] Figure 1 This is a physical image of the carboxylated silk protein aqueous solution in step (1) of Example 1 of the present invention.
[0068] Figure 2 This is a physical image of the catechol-modified silk protein buffer salt solution in step (3) of Example 1 of the present invention.
[0069] Figure 3 This is a physical image of the phenylboronic acid-modified silk protein buffer salt solution in step (3) of Example 1 of the present invention.
[0070] Figure 4 This is a physical image of the medical adhesive used in step (4) of Embodiment 1 of the present invention. Figure 4 As can be seen, the medical adhesive obtained after mixing the solutions is gel-like.
[0071] Example 2 The only difference from Example 1 is that the volume ratio in step (4) is changed from 2:1 to 1:1.
[0072] Example 3 The only difference from Example 1 is that the volume ratio in step (4) is changed from 2:1 to 1:2.
[0073] Comparative Example 1 The only difference from Example 1 is that the pH value in step (4) is changed from 7 to 6.
[0074] Comparative Example 2 The only difference from Comparative Example 1 is that the volume ratio in step (4) is changed from 2:1 to 1:1.
[0075] Comparative Example 3 The only difference from Comparative Example 1 is that the volume ratio in step (4) is changed from 2:1 to 1:2.
[0076] Comparative Example 4 The only difference from Example 1 is that the pH value in step (4) is changed from 7 to 8.
[0077] Comparative Example 5 The only difference from Comparative Example 4 is that the volume ratio in step (4) is changed from 2:1 to 1:1.
[0078] Comparative Example 6 The only difference from Comparative Example 4 is that the volume ratio in step (4) is changed from 2:1 to 1:2.
[0079] Test Example 1 Performance testing Performance testing was conducted using fresh pigskin as the bonding substrate: Overlap shear strength: According to the relevant records in industry standard YY / T 0729.1-2009 "Test Methods for Adhesive Properties of Tissue Adhesives Part 1: Overlap - Shear Tensile Capacity", the lap shear strength of the medical adhesives obtained in Examples 1, 2, and 3, and Comparative Examples 1, 2, 3, 4, 5, and 6 were tested. The test results are shown in Table 1.
[0080]
[0081] As shown in Table 1 above, the volume ratio of catechol-modified silk protein buffered salt solution and phenylboronic acid-modified silk protein buffered salt solution and the solution pH value are important factors affecting medical adhesives. The reason is that the mixing ratio affects the crosslinking density of borate ester bonds, and the pH value also affects the formation of borate ester bonds, thereby affecting the crosslinking strength.
[0082] As can be seen from Examples 2, 2, and 5, the adhesive strength of the adhesive first increases and then decreases as the pH value increases. This may be because the increase in pH value helps to form borate ester bonds, but the silk protein itself is damaged in an alkaline environment, thus the adhesive strength decreases.
[0083] Considering the combined volume ratio of the two solutions and the effect of pH on the adhesive strength, experiments have verified that the preferred method is to mix catechol-modified silk protein buffer solution and phenylboronic acid-modified silk protein buffer solution in a volume ratio of 1:1, and adjust the pH to 7.
[0084] In conjunction with Examples 2, 2, and 5, the adhesives formed by catechol-modified silk fibroin and phenylboronic acid-modified silk fibroin still exhibit high adhesive strength in acidic or alkaline environments, making them suitable for various tissue environments in the human body.
[0085] Test Example 2 Figure 5 This is a comparison of the 1H NMR spectra of carboxylated silk protein in aqueous solution, catechol-modified silk protein in buffered salt solution, and phenylboronic acid-modified silk protein in buffered salt solution in heavy water according to Example 1 of the present invention.
[0086] The determination of 1H NMR data for carboxylated silk fibroin in the aqueous solution of carboxylated silk fibroin in Example 1 is a key characterization for determining the successful carboxylation of silk fibroin. The test results are as follows: Figure 5 As shown in the figure, the peak at 2.5 nm in the 1H NMR spectrum confirms the successful carboxylation of silk fibroin.
[0087] Test Example 3 The determination of the proton NMR spectrum of the catechol-modified silk fibroin in the buffered saline solution in Example 1 is a key characterization for determining the successful catechol modification of silk fibroin. The test results are as follows: Figure 5 As shown in the figure, the discontinuous peak at 2.5 and the shift of the peak at 6.5-7 confirm that silk fibroin successfully modified catechol.
[0088] Test Example 4 The 1H NMR data of the phenylboronic acid-modified silk fibroin in Example 1 is a key characterization for determining the successful modification of silk fibroin by phenylboronic acid. The test results are as follows: Figure 5 As shown in the figure, the discontinuous peak at 2.5 and the shift of the peak at 6.5-7 confirm that silk fibroin was successfully modified with phenylboronic acid.
[0089] Test Example 5 The sample from Example 1 was placed in an aqueous solution of 10 U / mL α-chymotrypsin at 37°C to test the in vitro degradation of the sample.
[0090] Figure 6 This is the in vitro degradation curve of the medical adhesive in step (4) of Embodiment 1 of the present invention.
[0091] Test Example 6 The test conditions were as follows: The medical adhesive (cylindrical sample) from step (4) of Example 1 of this invention was immersed in 20 mL of PBS solution with pH=7.4 containing 10 U / mL α-chymotrypsin, and placed in a constant temperature environment of 37°C, and continuously shaken at a rate of 80 rpm. At each predetermined time point, the adhesive sample was freeze-dried and weighed.
[0092] The residual rate is calculated using the following formula: Residual rate = Wt / Wo × 100%, where W0 and Wt represent the initial dry weight of the adhesive and the remaining weight of the freeze-dried adhesive after degradation at different time points, respectively.
[0093] Figure 7 This is a cytotoxicity test diagram of the medical adhesive in step (4) of Embodiment 1 of the present invention.
[0094] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.
Claims
1. A biodegradable medical adhesive, characterized in that, It contains catechol-modified silk protein and phenylboronic acid-modified silk protein.
2. A method for preparing the biodegradable medical adhesive according to claim 1, characterized in that, Includes the following steps: (1) Mix silk fibroin and dicarboxylic anhydride in an organic solvent to carry out a nucleophilic addition reaction, and then dialyze in water to obtain an aqueous solution of carboxylated silk fibroin; (2) The carboxylated silk protein aqueous solution is mixed with an amide condensing agent and activated to obtain an activated carboxylated silk protein solution; (3) The activated carboxylated silk protein solution is mixed with a substance containing catechol groups and amino groups to carry out amidation reaction A to obtain catechol-modified silk protein solution; The activated carboxylated silk protein solution was mixed with a substance containing phenylboronic acid groups and amino groups to carry out amidation reaction B, thereby obtaining a phenylboronic acid modified silk protein solution. (4) The catechol-modified silk protein solution and the phenylboronic acid-modified silk protein solution are stored separately and then mixed for esterification reaction when needed to obtain the medical adhesive.
3. The preparation method according to claim 2, characterized in that, The dicarboxylic anhydride includes succinic anhydride, glutaric anhydride, or phthalic anhydride; the silk fibroin includes one or more of natural silk fibroin, recombinant silk fibroin, and regenerated silk fibroin; the mass ratio of the silk fibroin to the dicarboxylic anhydride is 1:0.1-10; the nucleophilic addition reaction is carried out at a temperature of 100-140°C for a time of 5 minutes to 72 hours.
4. The preparation method according to claim 2, characterized in that, The amide condensing agent includes one or more of N-hydroxysuccinimide, carbodiimide compounds, urea hexafluorophosphate, phosphonium hexafluorophosphate, carbamate, and tetrahexylpyrophosphorous acid.
5. The preparation method according to claim 4, characterized in that, The amide condensing agent is composed of N-hydroxysuccinimide and carbodiimide compounds; the carbodiimide compounds are 1-ethyl-(3-dimethylaminopropyl)carbodiimide and / or dicyclohexylcarbodiimide.
6. The preparation method according to claim 2, characterized in that, The substance containing catechol groups and amino groups includes dopamine or a salt with dopamine as the parent nucleus; the mass ratio of carboxylated silk protein in the carboxylated silk protein aqueous solution to the substance containing catechol groups and amino groups is 1:0.1-0.6; the duration of the amidation reaction A is 1-24 hours.
7. The preparation method according to claim 2, characterized in that, The substance containing phenylboronic acid groups and amino groups includes 3-aminophenylboronic acid or a salt with 3-aminophenylboronic acid as the parent nucleus; the mass ratio of carboxylated silk protein in the carboxylated silk protein aqueous solution to the substance containing phenylboronic acid groups and amino groups is 1:1-10; the duration of the amidation reaction B is 1-24 hours.
8. The preparation method according to claim 2, characterized in that, In step (4), the mass ratio of catechol-modified silk fibroin to phenylboronic acid-modified silk fibroin is 1-3:1-3.
9. The preparation method according to claim 2, characterized in that, The pH value of the esterification reaction is 7.
10. The application of the biodegradable medical adhesive of claim 1 in the field of medical adhesive materials.