Polyphenol-containing medical adhesive and preparation method thereof

Abstract

The invention discloses a preparation method of a polyphenol-containing medical adhesive. The preparation method comprises the following steps: respectively preparing a gelatin solution, a gallic acid solution and a tea polyphenol solution; mixing the gelatin solution and the gallic acid solution, and reacting at 40-60 DEG C for 6-12 hours to obtain a modified gelatin solution; mixing the tea polyphenol solution with the modified gelatin solution, adding an alkaline solution to adjust the pH value to 6.5-8.0, and uniformly mixing to obtain a mixed solution; the mixed solution is aged at 20-40 DEG C, water generated in the aging process is removed, and the polyphenol-containing medical adhesive is obtained. According to the preparation method of the polyphenol-containing medical adhesive, a gelatin protein molecular chain is used as a framework material, gallic acid is introduced into the protein molecular chain, tea polyphenol is used as a main chain cross-linking agent, the polyphenol-containing medical adhesive is prepared, a phenolic hydroxyl group can penetrate through a water boundary layer on the surface of a base material to form an adhesive bond with the base material, and the medical adhesive has the advantages that the water boundary layer can penetrate through the water boundary layer; good wet adhesion is shown on tissues.

Description

Technical Field

[0001] The invention belongs to the technical field of medical adhesives, and in particular relates to a method for preparing a polyphenol-containing medical adhesive and the medical adhesive prepared by the preparation method. Background Art

[0002] Gelatin is derived from collagen in animal bones, connective tissues and skin. It has good biodegradability, biocompatibility and bioactivity, and is widely used in the field of medical adhesives. However, single-component gelatin is easily soluble in water, has poor mechanical properties, and is easily affected by external factors, which seriously hinders its application. Therefore, gelatin is often modified by certain methods to meet the needs of practical applications.

[0003] The reason why mussels in the ocean can adhere to rocks with high strength under harsh conditions of complete wetness is that the proteins secreted by mussels contain a large amount of 3,4-dihydroxyphenylalanine. 3,4-dihydroxyphenylalanine is an amino acid present in mussel adhesive proteins. It has been proven to be able to penetrate the water boundary layer and form adhesive bonds with the substrate. However, it is expensive and not economically effective. Gallic acid is mainly derived from plants such as Rheum palmatum and Eucalyptus globulus. It is cheap and has a polyphenol structure similar to 3,4-dihydroxyphenylalanine. Therefore, using gallic acid as a substitute for 3,4-dihydroxyphenylalanine has become the inspiration for the design of medical adhesives. Tea polyphenols are mainly derived from various teas. They have anti-inflammatory, bactericidal, and antioxidant effects. They are non-toxic and beneficial biological cross-linkers. The abundant phenolic hydroxyl groups in the structure can cross-link with protein molecular chains by hydrogen bonds, thereby increasing the network space density of protein medical adhesives.

[0004] For example, patent CN113368312B discloses a method for preparing a biodegradable self-adhesive hydrogel and its application. Gelatin is modified with methacrylic anhydride, and then dialyzed and freeze-dried to obtain methacrylic anhydride gelatin; secondly, tea polyphenols are dissolved in pure water, the solution is adjusted to alkaline, and stirred for a period of time to obtain a tea polyphenol prepolymer solution; finally, the methacrylic anhydride gelatin is dissolved in deionized water. The tea polyphenol prepolymer solution is added to the methacrylic anhydride gelatin solution, and then a degradable self-adhesive adhesive is obtained by free radical polymerization. The adhesive prepared by this method has weak adhesion and is easy to fall off from the tissue surface. In addition, the gelatin needs to be modified with methacrylic anhydride, and complex operations such as dialysis and freeze-drying are required, which is not economical.

[0005] For example, patent application CN114762737A discloses a high-strength gelatin hydrogel and its preparation method and application. At 30-45°C, the gelatin hydrogel to be enhanced is immersed in a tea polyphenol solution to obtain a high-strength gelatin hydrogel. Compared with the original hydrogel, the high-strength gelatin hydrogel based on gelatin has significantly improved tensile / compressive strength, Young's modulus, elongation at break and fracture toughness. The hydrogel prepared by this method enhances the mechanical strength of the gelatin itself, but there is still a problem of weak adhesion to the wet tissue surface.

[0006] The disclosure of the above background technology content is only used to assist in understanding the inventive concept and technical solution of the present invention. It does not necessarily belong to the prior art of this patent application. In the absence of clear evidence that the above content has been disclosed before the filing date of this patent application, the above background technology should not be used to evaluate the novelty and creativity of the present application. Summary of the invention

[0007] In view of this, in order to overcome the defects of the prior art, the object of the present invention is to provide a medical adhesive containing polyphenols, which can form an adhesive bond with a substrate during bonding and exhibit good wet adhesion to tissues.

[0008] In order to achieve the above object, the present invention adopts the following technical solutions:

[0009] A method for preparing a medical adhesive containing polyphenols comprises the following steps:

[0010] Prepare gelatin solution, gallic acid solution and tea polyphenol solution respectively;

[0011] The gelatin solution and the gallic acid solution are mixed and reacted at 40 to 60° C. for 6 to 12 hours to obtain a modified gelatin solution;

[0012] The tea polyphenol solution and the modified gelatin solution are mixed, an alkaline solution is added to adjust the pH value to 6.5-8.0, and the mixture is mixed evenly to obtain a mixed solution;

[0013] The mixed solution is aged at 20-40° C., and water produced during the aging process is removed to obtain the polyphenol-containing medical adhesive.

[0014] The present invention uses gallic acid to modify the gelatin protein molecular chain, dissociate the interaction between some gelatin protein molecular chains, reduce the cross-linking density, and expose more hydrophobic structures of the protein molecular chain to combine with gallic acid to improve wet adhesion. Then, tea polyphenols and functional groups on the protein molecular chain (such as -NH 2 , -COOH, -SH) reacts through hydrogen bonding to form an adhesive. The reactivity of polyphenols is used to make tissue adhesives have functional properties such as antibacterial, anti-inflammatory, and antioxidant.

[0015] According to some preferred embodiments of the present invention, the concentration of the gelatin solution is 10% to 20%.

[0016] According to some preferred embodiments of the present invention, the concentration of the gallic acid solution is 1% to 3%.

[0017] According to some preferred embodiments of the present invention, the concentration of the tea polyphenol solution is 5% to 20%.

[0018] According to some preferred embodiments of the present invention, the gelatin solution is prepared by the following method: mixing solid gelatin particles with deionized water, heating to 40-60° C., so that the solid gelatin particles are completely dissolved in the deionized water, and obtaining a gelatin solution with a concentration of 10% to 20%.

[0019] According to some preferred embodiments of the present invention, the gallic acid solution is prepared by the following method: mixing gallic acid with deionized water at 40-60° C. to completely dissolve the gallic acid in the deionized water to obtain a gallic acid solution with a concentration of 1% to 3%.

[0020] According to some preferred embodiments of the present invention, when preparing the modified gelatin solution, the volume ratio of the gelatin solution to the gallic acid solution is 1:0.5-1.

[0021] According to some preferred embodiments of the present invention, the tea polyphenol solution is prepared by the following method: at room temperature, tea polyphenol is dissolved in deionized water at 30-50° C. to prepare a tea polyphenol solution with a concentration of 5% to 20%.

[0022] According to some preferred embodiments of the present invention, the alkaline solution is a 0.1-1 mol / L sodium hydroxide solution. The system is adjusted to a pH value of 6.5-8.0 to promote the reaction and avoid the acidity of gallic acid causing the reaction to be difficult to proceed.

[0023] According to some preferred embodiments of the present invention, the aging time is 2-20 hours. During the aging process, the system will shrink and drain water, and the generated water will be removed to obtain a medical adhesive containing polyphenols.

[0024] According to some preferred embodiments of the present invention, the gelatin is medical gelatin with a molecular weight of 50,000-200,000.

[0025] In some embodiments of the present invention, the preparation method of the medical adhesive containing polyphenols, using gelatin as raw material, comprises the following steps:

[0026] Step 1: Prepare gelatin solution

[0027] The solid gelatin particles are mixed with deionized water, and heated and stirred to completely dissolve the solid gelatin particles in the deionized water to prepare a gelatin solution. The gelatin is medical gelatin with a molecular weight of 50,000 to 200,000.

[0028] Specifically, the solid gelatin particles are mixed with deionized water, and heated to 40-60° C. to completely dissolve the solid gelatin particles in the deionized water to obtain a gelatin solution with a concentration of 10%-20%.

[0029] Step 2: Prepare Gallic Acid Solution

[0030] Dissolve gallic acid powder in hot water and stir to prepare gallic acid solution.

[0031] Specifically, gallic acid is dissolved in deionized water at 40-60° C., and the mixture is stirred to completely dissolve the gallic acid in the deionized water to prepare a gallic acid solution with a concentration of 1% to 3%.

[0032] Step 3: Prepare modified gelatin solution

[0033] Add the gallic acid solution obtained in step 2 to the gelatin solution obtained in step 1, and heat and stir.

[0034] Specifically, the gallic acid solution is added to the gelatin solution at a volume ratio of 1:0.5-1, the water bath temperature is controlled at 40-60°C, and the reaction is stirred for 6-12 hours to obtain a modified gelatin solution. In other embodiments, the gelatin solution can also be added to the gallic acid solution, as long as the two are mixed.

[0035] Step 4: Prepare tea polyphenols solution

[0036] The tea polyphenol powder is dissolved in 30-50° C. deionized water, and stirred to prepare a tea polyphenol solution with a concentration of 5% to 20%.

[0037] Step 5: Prepare the medical adhesive

[0038] Add the tea polyphenol solution obtained in step 4 to the modified gelatin solution obtained in step 3, stir and mix thoroughly, then add an alkaline solution to adjust the pH value to 6.5-8.0, mix well, and obtain a mixed solution;

[0039] The mixed solution is aged in a water bath at 20-40° C. for 2-20 hours to remove water eliminated during the aging process, and a polyphenol-containing medical adhesive is obtained through hydrogen bond interaction between tea polyphenols and protein chains.

[0040] The present invention also provides another medical adhesive containing polyphenols prepared by the preparation method as described above. The medical adhesive only highlights its medical value. In fact, the adhesive prepared by the present invention has good adhesion to various substrates (rubber, glass, plastic, steel, etc.), and the medical adhesive does not limit the use scenario of the adhesive of the present invention.

[0041] The principle of the present invention is: with gelatin protein molecular chain as the skeleton, gallic acid binds to -NH on the gelatin protein chain through hydrogen bonding, static electricity, addition, and π-π stacking. 2 , -COOH, -SH and other active groups, further opening the structure of collagen and exposing more active groups and hydrophobic segments. After the interaction between gallic acid and gelatin, an adhesion-modified gelatin molecular chain is obtained, and the phenolic hydroxyl groups contained in it will participate in the adhesion to the substrate. Then tea polyphenols are introduced into the gelatin solution modified with gallic acid. At this time, tea polyphenols and gelatin molecular chains are mainly bound to each other through hydrogen bonds and hydrophobic effects. The phenolic hydroxyl structure in the tea polyphenol molecule will hydrogen bond with the amino acid residues on the protein (such as tyrosine, lysine, histidine and other amino acid residues containing hydrogen bond acceptors or donors on the surface of the protein). At the same time, the benzene ring structure in tea polyphenols will interact with the hydrophobic region of the protein to form a hydrophobic effect, which promotes the formation of a stable bond between tea polyphenols and protein molecular chains.

[0042] The reason why marine mussels can adhere to the surface of various wet substrates is that the adhesive proteins they secrete are rich in DOPA (3,4-dihydroxyphenylalanine). The phenolic hydroxyl structure of DOPA can break through the water layer and form strong covalent or non-covalent bonds with the wet substrate. Gallic acid and tea polyphenols have very similar structures to DOPA. The hydroxyl groups in gallic acid can form strong hydrogen bonds with N, O, etc., and can also form strong hydrogen bonds with various metals (Fe 3+ , Ca 2+ The benzene ring can form a cation-π interaction with the matrix cation, or form a π-π stacking with other aromatic rings. Polyphenols contain a large number of aromatic rings, which are hydrophobic. When they come into contact with wet tissue, they can remove the water layer from the adhesion interface through the hydrophobic effect. At this time, the phenolic hydroxyl groups exposed on the outside of the aromatic rings will interact with the functional groups on the tissue (such as -NH 2 , -COOH, -SH) to form covalent bonds / intermolecular forces, thereby achieving efficient adhesion. In addition, the structure of pyrogallol in tea polyphenols is easily oxidized to a quinone structure, which can react with the active groups on the substrate to form stronger covalent cross-links and improve adhesion strength.

[0043] In addition, the adhesive can also produce strong adhesion with other substrates. The cellulose and lignin in the wood chips carry a large number of active functional groups such as phenolic hydroxyl groups and carboxyl groups, which can form strong hydrogen bonds, π-π stacking, and electrostatic attraction with the adhesive; a large number of silanol groups and metal oxides on the glass surface can produce strong hydrogen bonds and metal coordination with the catechol units of the adhesive; a small amount of metal oxides on the iron plate surface form metal coordination with the adhesive; phenolic hydroxyl groups form π-π stacking and weak hydrogen bonding with the plastic surface. These effects make the adhesive in the present invention widely used and not limited to the medical field.

[0044] Due to the adoption of the above technical scheme, the present invention has the following advantages compared with the prior art: the preparation method of the polyphenol-containing adhesive of the present invention uses gelatin protein molecular chains as the skeleton material, introduces gallic acid into the protein molecular chains, and then uses tea polyphenols as the main chain cross-linking agent to prepare a polyphenol-containing medical adhesive, which can utilize phenolic hydroxyl groups to penetrate the water boundary layer on the surface of the substrate to form an adhesive bond with the substrate and exhibits good wet adhesion to the tissue; at the same time, the polyphenols present in the adhesive have anti-inflammatory, antibacterial, antioxidant and other properties, and play an important role in promoting hemostasis and wound healing. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the following briefly introduces the drawings required for use in the description of the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative work.

[0046] Figure 1 A photo of the medical adhesive prepared in Example 2 of the present invention;

[0047] Figure 2 These are photos of the adhesion effects of the medical adhesive prepared in Example 2 of the present invention on different substrates;

[0048] Figure 3 This is a bar graph of the adhesion test of the medical adhesive prepared in Example 2 of the present invention on pig skin under different aqueous solution environments;

[0049] Figure 4 This is a photo of a rat wound being repaired using the medical adhesive prepared in Example 2 of the present invention;

[0050] Figure 5 It is a bar graph comparing the adhesion test of the medical adhesive prepared in Example 2 of the present invention, the adhesive containing only tea polyphenols prepared in Comparative Example 1, and the adhesive containing only gallic acid prepared in Comparative Example 2. DETAILED DESCRIPTION

[0051] In order to enable those skilled in the art to better understand the technical solution of the present invention, the technical solution in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work should fall within the scope of protection of the present invention.

[0052] The mechanism of the adhesive in the present invention combining with various substrates mainly includes two aspects: chemical and physical: physically, the softness and elasticity of the adhesive enable it to quickly adapt to the morphology of various substrate surfaces and form a tight bond with the surface. At the same time, the hydroxyl and phenolic hydroxyl groups contained in the outer layer of the adhesive make it hydrophilic and can form stable hydrogen bond crosslinks with the substrate surface. Chemically, the hydroxyl and phenolic hydroxyl groups of gallic acid and tea polyphenols and the quinone groups formed by oxidation can react with functional groups such as carboxyl and amino groups on the substrate surface to form corresponding chemical bonds such as esterification, amidation, and condensation. These bonds can further enhance the interaction between the adhesive and the substrate surface, thereby providing a stronger adsorption, bonding and stabilizing effect between the adhesive and the substrate.

[0053] After the polyphenols and gelatin protein molecular chains are combined, the hydroxyl groups, phenolic hydroxyl groups, oxidized quinone groups, etc. in the polyphenols are combined with the carboxyl groups and amino groups in the protein through hydrogen bonds, ionic bonds, van der Waals forces, condensation, etc., so that the charge distribution on the surface of the adhesive is uniform, forming a stable structure. This structural stability can prevent water molecules in body fluids from entering the interior of the adhesive, making it difficult to decompose the adhesive in a short period of time. In addition, after the polyphenols are combined with gelatin protein, they can also prevent the protein from being degraded by enzymes in the body to a certain extent. The enzymes in the cells will recognize the amino acid sequence on the protein and degrade it, but the structure and stability of the adhesive can protect the gelatin protein to a certain extent.

[0054] The medical adhesive prepared by the present invention solves the shortcomings of the prior art adhesives such as low tissue adhesion and toxic crosslinking agents. At the same time, the gallic acid in the adhesive has multiple biological activities such as anti-inflammatory, anti-oxidation and anti-free radical, and the tea polyphenols as a crosslinking agent are non-toxic and harmless and have antibacterial effects. It is suitable for medical use. The preparation method of the present invention has simple process, high economic benefits, is environmentally friendly, and has good tissue adhesion, biocompatibility, and hemostasis.

[0055] Specifically, the preparation method of the polyphenol-containing medical adhesive of the present invention uses gelatin as a raw material and comprises the following steps:

[0056] Step 1: Prepare gelatin solution

[0057] The solid gelatin particles are mixed with deionized water and heated to 40-60°C to completely dissolve the solid gelatin particles in the deionized water to obtain a gelatin solution with a concentration of 10%-20%. The gelatin is medical gelatin with a molecular weight of 50,000-200,000.

[0058] Step 2: Prepare Gallic Acid Solution

[0059] Dissolve gallic acid in deionized water at 40-60° C., stir and mix to make the gallic acid completely dissolved in the deionized water, and prepare a gallic acid solution with a concentration of 1% to 3%.

[0060] Step 3: Prepare modified gelatin solution

[0061] Add gallic acid solution to the gelatin solution at a volume ratio of 1:0.5-1, control the temperature in a water bath to 40-60° C., stir and react for 6-12 hours to obtain a modified gelatin solution.

[0062] Step 4: Prepare tea polyphenols solution

[0063] The tea polyphenol powder is dissolved in deionized water at 30-50° C., and stirred to prepare a tea polyphenol solution with a concentration of 5%-20%.

[0064] Step 5: Prepare the medical adhesive

[0065] Add the tea polyphenol solution obtained in step 4 to the modified gelatin solution obtained in step 3, stir and mix thoroughly, then add 0.1-1 mol / L sodium hydroxide solution, adjust the pH value to 6.5-8.0, mix well, and obtain a mixed solution.

[0066] The mixed solution is aged in a water bath at 20-40° C. for 2-20 hours to remove water discharged during the aging process, and a polyphenol-containing medical adhesive is obtained through hydrogen bond interaction between tea polyphenols and protein chains.

[0067] Example 1

[0068] The preparation method of the polyphenol-containing medical adhesive of this embodiment comprises the following steps:

[0069] 1) Dissolve 1 g of solid gelatin particles in 9 mL of deionized water at 40°C. The concentration of the gelatin solution is 10%.

[0070] 2) Dissolve 0.1 g of gallic acid powder in 9.9 mL of 40° C. deionized water and stir to prepare a 1% gallic acid solution;

[0071] 3) adding the 1% gallic acid solution obtained in step 2) to the 10% gelatin solution obtained in step 1) at 40° C., heating and stirring for 6 hours to obtain a modified gelatin solution;

[0072] 4) Dissolve 0.4 g of tea polyphenol powder in 3.6 mL of 40° C. deionized water, and the concentration of the tea polyphenol solution is 10%;

[0073] 5) adding the tea polyphenol solution obtained in step 4) to the modified gelatin solution obtained in step 3), stirring thoroughly, adding 0.5 mol / L sodium hydroxide solution to adjust the pH value to 7, and mixing well to obtain a mixed solution;

[0074] 6) Aging the mixed solution in a water bath at 30° C. for 10 h, removing water discharged during the aging process, and obtaining a medical adhesive containing polyphenols.

[0075] Example 2

[0076] The preparation method of the polyphenol-containing medical adhesive of this embodiment comprises the following steps:

[0077] 1) Dissolve 2 g of solid gelatin particles in 8 mL of deionized water at 50°C. The concentration of the gelatin solution is 20%.

[0078] 2) Dissolve 0.2 g of gallic acid powder in 9.8 mL of 50°C hot water and stir to prepare a 2% gallic acid solution;

[0079] 3) adding the 20% gelatin solution obtained in step 1) to the 2% gallic acid solution obtained in step 2) at 50° C. and continuing stirring for 12 hours to obtain a modified gelatin solution;

[0080] 4) Dissolve 0.8 g of tea polyphenol powder in 3.2 mL of 50° C. deionized water, and the concentration of the tea polyphenol solution is 20%;

[0081] 5) adding the tea polyphenol solution obtained in step 4) to the modified gelatin solution obtained in step 3), stirring thoroughly, adding 1 mol / L sodium hydroxide solution to adjust the pH value to 8.0, and mixing well to obtain a mixed solution;

[0082] 6) Aging the mixed solution in a water bath at 35° C. for 7 h, removing water discharged during the aging process, and obtaining a medical adhesive containing polyphenols.

[0083] Figure 1 The bonding morphology photograph of the polyphenol-containing medical adhesive prepared in this example shows that a very sticky structure is formed. Figure 2 The following are photos of the adhesion effects of the polyphenol-containing medical adhesive prepared in this example on different substrates. Figure 2 It can be seen that the medical adhesive prepared in this example has strong adhesion to biological tissues such as pig skin, pig liver, and pig heart, and also exhibits good adhesion to common rubber, plastic, glass, steel, and the like in life.

[0084] Figure 3 The following is a bar graph of the adhesion test of the polyphenol-containing medical adhesive prepared in this example in different aqueous solutions. The specific method is to apply the adhesive between two 1cm×2cm pig skins (the coating area is 1cm×1cm), press with fingers for 10s, then put the pig skins into different solutions (water, DMEM, PBS, acid solution, alkali solution), and let it stand in a constant temperature box (37°C) for 1h. Then, the adhesion of the adhesive to the pig skin under different solution treatments is tested with a universal strong material tester. The results are as follows: Figure 3 shown.

[0085] Figure 4 The photographs of the polyphenol-containing medical adhesive prepared in this example repairing the wound of a rat show that the adhesive remained adhered without falling off or swelling during the experiment, and ultimately the wound healed without a trace.

[0086] Example 3

[0087] The preparation method of the polyphenol-containing medical adhesive of this embodiment comprises the following steps:

[0088] 1) Dissolve 1.5 g of solid gelatin particles in 8.5 mL of deionized water at 60°C. The concentration of the gelatin solution is 15%.

[0089] 2) Dissolve 0.3 g of gallic acid powder in 9.7 mL of 60°C hot water and stir to prepare a 2% gallic acid solution;

[0090] 3) adding the 3% gallic acid solution obtained in step 2) to the 15% gelatin solution obtained in step 1) at 60° C., heating and stirring for 12 h to obtain a modified gelatin solution;

[0091] 4) Dissolve 0.8 g of tea polyphenol powder in 3.2 mL of 50° C. deionized water, and the concentration of the tea polyphenol solution is 20%;

[0092] 5) adding the tea polyphenol solution obtained in step 4) to the modified gelatin solution obtained in step 3), stirring thoroughly, adding 0.8 mol / L sodium hydroxide solution to adjust the pH value to 7.5, mixing well, and obtaining a mixed solution;

[0093] 6) Aging the mixed solution in a water bath at 40° C. for 5 h, removing water discharged during the aging process, and obtaining a medical adhesive containing polyphenols.

[0094] Example 4

[0095] The preparation method of the polyphenol-containing medical adhesive of this embodiment comprises the following steps:

[0096] 1) Dissolve 1.5 g of solid gelatin particles in 8.5 mL of deionized water at 50°C. The concentration of the gelatin solution is 15%.

[0097] 2) Dissolve 0.2 g of gallic acid powder in 9.8 mL of 50°C hot water and stir to prepare a 2% gallic acid solution;

[0098] 3) adding the 2% gallic acid solution obtained in step 2) to the 15% gelatin solution obtained in step 1) at 50° C., heating and stirring for 8 h to obtain a modified gelatin solution;

[0099] 4) Dissolve 0.4 g of tea polyphenol powder in 3.6 mL of 30° C. deionized water, and the concentration of the tea polyphenol solution is 10%;

[0100] 5) adding the tea polyphenol solution obtained in step 4) to the modified gelatin solution obtained in step 3), stirring thoroughly, adding 0.2 mol / L sodium hydroxide solution to adjust the pH value to 6.8, and mixing well to obtain a mixed solution;

[0101] 6) Aging the mixed solution in a water bath at 25° C. for 15 h, removing water discharged during the aging process, and obtaining a medical adhesive containing polyphenols.

[0102] Example 5

[0103] The preparation method of the polyphenol-containing medical adhesive of this embodiment comprises the following steps:

[0104] 1) Dissolve 1.5 g of solid gelatin particles in 8.5 mL of deionized water at 50°C. The concentration of the gelatin solution is 15%.

[0105] 2) Dissolve 0.1 g of gallic acid powder in 9.9 mL of 50°C hot water and stir to prepare a 1% gallic acid solution;

[0106] 3) adding the 2% gallic acid solution obtained in step 2) to the 15% gelatin solution obtained in step 1) at 50° C., heating and stirring for 12 h to obtain a modified gelatin solution;

[0107] 4) Dissolve 0.4 g of tea polyphenol powder in 3.6 mL of 30° C. deionized water, and the concentration of the tea polyphenol solution is 10%;

[0108] 5) adding the tea polyphenol solution obtained in step 4) to the modified gelatin solution obtained in step 3), stirring thoroughly, adding 0.1 mol / L sodium hydroxide solution to adjust the pH value to 6.5, mixing well, and obtaining a mixed solution;

[0109] 6) Aging the mixed solution in a water bath at 35° C. for 4 hours, removing water discharged during the aging process, and obtaining a medical adhesive containing polyphenols.

[0110] Example 6

[0111] The preparation method of the polyphenol-containing medical adhesive of this embodiment comprises the following steps:

[0112] 1) Dissolve 2 g of solid gelatin particles in 8 mL of deionized water at 50°C. The concentration of the gelatin solution is 20%.

[0113] 2) Dissolve 0.3 g of gallic acid powder in 9.7 mL of 50°C hot water and stir to prepare a 3% gallic acid solution;

[0114] 3) adding the 3% gallic acid solution obtained in step 2) to the 20% gelatin solution obtained in step 1) at 50° C., heating and stirring for 12 h to obtain a modified gelatin solution;

[0115] 4) Dissolve 0.4 g of tea polyphenol powder in 3.6 mL of 30° C. deionized water, and the concentration of the tea polyphenol solution is 10%;

[0116] 5) adding the tea polyphenol solution obtained in step 4) to the modified gelatin solution obtained in step 3), stirring thoroughly, adding 0.7 mol / L sodium hydroxide solution to adjust the pH value to 7.8, and mixing well to obtain a mixed solution;

[0117] 6) Aging the mixed solution in a water bath at 30° C. for 14 h, removing water discharged during the aging process, and obtaining a medical adhesive containing polyphenols.

[0118] Example 7

[0119] The preparation method of the polyphenol-containing medical adhesive of this embodiment comprises the following steps:

[0120] 1) Dissolve 1.5 g of solid gelatin particles in 8.5 mL of deionized water at 40°C. The concentration of the gelatin solution is 15%.

[0121] 2) Dissolve 0.3 g of gallic acid powder in 9.7 mL of 40°C hot water and stir to prepare a 3% gallic acid solution;

[0122] 3) adding the 3% gallic acid solution obtained in step 2) to the 15% gelatin solution obtained in step 1) at 40° C., heating and stirring for 12 h to obtain a modified gelatin solution;

[0123] 4) Dissolve 0.4 g of tea polyphenol powder in 3.6 mL of 30° C. deionized water, and the concentration of the tea polyphenol solution is 10%;

[0124] 5) adding the tea polyphenol solution obtained in step 4) to the modified gelatin solution obtained in step 3), stirring thoroughly, adding 1 mol / L sodium hydroxide solution to adjust the pH value to 8.0, and mixing well to obtain a mixed solution;

[0125] 6) Aging the mixed solution in a water bath at 30° C. for 6 h, removing water discharged during the aging process, and obtaining a medical adhesive containing polyphenols.

[0126] Example 8

[0127] The preparation method of the polyphenol-containing medical adhesive of this embodiment comprises the following steps:

[0128] 1) Dissolve 2 g of solid gelatin particles in 8 mL of deionized water at 40°C. The concentration of the gelatin solution is 20%.

[0129] 2) Dissolve 0.2 g of gallic acid powder in 9.8 mL of 40°C hot water and stir to prepare a 2% gallic acid solution;

[0130] 3) adding the 2% gallic acid solution obtained in step 2) to the 20% gelatin solution obtained in step 1) at 40° C., heating and stirring for 12 h to obtain a modified gelatin solution;

[0131] 4) Dissolve 0.4 g of tea polyphenol powder in 3.6 mL of 30° C. deionized water, and the concentration of the tea polyphenol solution is 10%;

[0132] 5) adding the tea polyphenol solution obtained in step 4) to the modified gelatin solution obtained in step 3), stirring thoroughly, adding 0.6 mol / L sodium hydroxide solution to adjust the pH value to 7.2, and mixing well to obtain a mixed solution;

[0133] 6) Aging the mixed solution in a water bath at 26° C. for 10 h, removing water discharged during the aging process, and obtaining a medical adhesive containing polyphenols.

[0134] Example 9

[0135] The preparation method of the polyphenol-containing medical adhesive of this embodiment comprises the following steps:

[0136] 1) Dissolve 1 g of solid gelatin particles in 9 mL of deionized water at 60°C. The concentration of the gelatin solution is 10%.

[0137] 2) Dissolve 0.3 g of gallic acid powder in 9.7 mL of 60°C hot water and stir to prepare a 3% gallic acid solution;

[0138] 3) adding the 3% gallic acid solution obtained in step 2) to the 20% gelatin solution obtained in step 1) at 60° C., heating and stirring for 8 h to obtain a modified gelatin solution;

[0139] 4) Dissolve 0.4 g of tea polyphenol powder in 3.6 mL of 30° C. deionized water, and the concentration of the tea polyphenol solution is 10%;

[0140] 5) adding the tea polyphenol solution obtained in step 4) to the modified gelatin solution obtained in step 3), stirring thoroughly, adding 0.3 mol / L sodium hydroxide solution to adjust the pH value to 7.0, and mixing well to obtain a mixed solution;

[0141] 6) Aging the mixed solution in a water bath at 30° C. for 6 h, removing water discharged during the aging process, and obtaining a medical adhesive containing polyphenols.

[0142] Example 10

[0143] The preparation method of the polyphenol-containing medical adhesive of this embodiment comprises the following steps:

[0144] 1) Dissolve 2 g of solid gelatin particles in 8 mL of deionized water at 60°C to a gelatin solution concentration of 20%;

[0145] 2) Dissolve 0.2 g of gallic acid powder in 9.8 mL of 60°C hot water and stir to prepare a 2% gallic acid solution;

[0146] 3) adding the 3% gallic acid solution obtained in step 2) to the 15% gelatin solution obtained in step 1) at 50° C., heating and stirring for 8 h to obtain a modified gelatin solution;

[0147] 4) Dissolve 0.4 g of tea polyphenol powder in 3.6 mL of 30° C. deionized water, and the concentration of the tea polyphenol solution is 10%;

[0148] 5) adding the tea polyphenol solution obtained in step 4) to the modified gelatin solution obtained in step 3), stirring thoroughly, adding 1 mol / L sodium hydroxide solution to adjust the pH value to 8.2, and mixing well to obtain a mixed solution;

[0149] 6) Aging the mixed solution in a water bath at 35° C. for 5 h, removing water discharged during the aging process, and obtaining a medical adhesive containing polyphenols.

[0150] Embodiment 11

[0151] The preparation method of the polyphenol-containing medical adhesive of this embodiment comprises the following steps:

[0152] 1) Dissolve 1.5 g of solid gelatin particles in 8.5 mL of deionized water at 60°C. The concentration of the gelatin solution is 15%.

[0153] 2) Dissolve 0.3 g of gallic acid powder in 9.7 mL of 60°C hot water and stir to prepare a 3% gallic acid solution;

[0154] 3) adding the 3% gallic acid solution obtained in step 2) to the 15% gelatin solution obtained in step 1) at 60° C., heating and stirring for 12 h to obtain a modified gelatin solution;

[0155] 4) Dissolve 0.8 g of tea polyphenol powder in 3.2 mL of 40° C. deionized water, and the concentration of the tea polyphenol solution is 20%;

[0156] 5) adding the tea polyphenol solution obtained in step 4) to the modified gelatin solution obtained in step 3), stirring thoroughly, adding 0.5 mol / L sodium hydroxide solution to adjust the pH value to 7.5, mixing well, and obtaining a mixed solution;

[0157] 6) Aging the mixed solution in a water bath at 35° C. for 6 h, removing water discharged during the aging process, and obtaining a medical adhesive containing polyphenols.

[0158] Example 12

[0159] The preparation method of the polyphenol-containing medical adhesive of this embodiment comprises the following steps:

[0160] 1) Dissolve 1 g of solid gelatin particles in 9 mL of deionized water at 50°C. The concentration of the gelatin solution is 10%.

[0161] 2) Dissolve 0.1 g of gallic acid powder in 9.9 mL of 50°C hot water and stir to prepare a 1% gallic acid solution;

[0162] 3) adding the 3% gallic acid solution obtained in step 2) to the 15% gelatin solution obtained in step 1) at 50° C., heating and stirring for 8 h to obtain a modified gelatin solution;

[0163] 4) Dissolve 0.8 g of tea polyphenol powder in 3.2 mL of 40° C. deionized water, and the concentration of the tea polyphenol solution is 20%;

[0164] 5) adding the tea polyphenol solution obtained in step 4) to the modified gelatin solution obtained in step 3), stirring thoroughly, adding 0.3 mol / L sodium hydroxide solution to adjust the pH value to 6.5, mixing well, and obtaining a mixed solution;

[0165] 6) Aging the mixed solution in a water bath at 30° C. for 6 h, removing water discharged during the aging process, and obtaining a medical adhesive containing polyphenols.

[0166] Comparative Example 1 Gelatin adhesive containing tea polyphenols

[0167] The preparation method of the adhesive of this comparative example comprises the following steps:

[0168] 1) Dissolve 2 g of solid gelatin particles in 8 mL of deionized water at 50°C. The concentration of the gelatin solution is 20%.

[0169] 2) Dissolve 0.8 g of tea polyphenol powder in 3.2 mL of 40° C. deionized water, and the concentration of the tea polyphenol solution is 20%;

[0170] 3) adding the tea polyphenol solution obtained in step 2) to the gelatin solution obtained in step 1), and stirring thoroughly to obtain a gelatin adhesive containing only tea polyphenols.

[0171] Comparative Example 2: Gelatin adhesive containing only gallic acid

[0172] The preparation method of the adhesive of this comparative example comprises the following steps:

[0173] 1) Dissolve 2 g of solid gelatin particles in 8 mL of deionized water at 50°C. The concentration of the gelatin solution is 20%.

[0174] 2) Dissolve 0.2 g of gallic acid powder in 9.8 mL of 50°C hot water and stir to prepare a 2% gallic acid solution;

[0175] 3) Adding the 2% gallic acid solution obtained in step 2) to the 20% gelatin solution obtained in step 1) at 50° C., heating and stirring for 12 hours, to obtain a gelatin adhesive containing only gallic acid.

[0176] Figure 5 The following are the adhesion test graphs of the medical adhesive prepared in Example 2, the gelatin adhesive containing only tea polyphenols prepared in Comparative Example 1, and the gelatin adhesive containing only gallic acid prepared in Comparative Example 2. Figure 5 It can be seen that the gelatin adhesive containing only tea polyphenols or the gelatin adhesive containing only gallic acid prepared in the comparative example has a weak adhesion to pig skin, which is significantly lower than the adhesive containing polyphenols prepared in the example.

[0177] The present invention designs a gelatin-gallic acid-tea polyphenol adhesive, which solves the problems of weak adhesion, single function, and complicated synthesis conditions of protein medical adhesives. Specifically, the preparation method of the polyphenol-containing adhesive of the present invention uses gelatin protein molecular chains as the skeleton material, introduces gallic acid into the protein molecular chains, and then uses tea polyphenols as the main chain crosslinking agent to prepare a medical adhesive containing polyphenols. The preparation steps are as follows: first, solid gelatin particles and gallic acid powder are dissolved in deionized water respectively; second, gallic acid solution is added to the gelatin solution, and the modified gelatin solution modified by gallic acid is obtained after sufficient stirring and reaction; finally, tea polyphenol powder is dissolved in deionized water to obtain a tea polyphenol solution, and the tea polyphenol solution is added to the modified gelatin solution, and the pH is adjusted, aged, and dehydrated to obtain a polyphenol-containing adhesive. The present invention introduces gallic acid into the gelatin molecular chain, and reacts with -NH on the gelatin protein chain through hydrogen bonding, static electricity, addition, and π-π stacking. 2 , -COOH, -SH and other active groups, thereby changing the adhesive properties of gelatin. Tea polyphenols will react quickly with the modified gelatin molecular chain to form an adhesive. The polyphenol-containing medical adhesive prepared by the present invention utilizes phenolic hydroxyl groups to penetrate the water boundary layer on the surface of the substrate to form an adhesive bond with the substrate, exhibits good wet adhesion to the tissue, does not cause pollution to the environment, has good biocompatibility, degradability, and wound repairability. At the same time, the polyphenols present in the adhesive have anti-inflammatory, antibacterial, antioxidant and other properties, and have an important role in promoting hemostasis and wound healing.

[0178] The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with this technology to understand the contents of the present invention and implement them accordingly. They cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.

[0179] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

Claims

1. A method for preparing a medical adhesive containing polyphenols, characterized in that: The steps include: Prepare gelatin solution, gallic acid solution and tea polyphenol solution respectively; The gelatin solution and the gallic acid solution are mixed and reacted at 40 to 60° C. for 6 to 12 hours to obtain a modified gelatin solution; The tea polyphenol solution and the modified gelatin solution are mixed, an alkaline solution is added to adjust the pH value to 6.5-8.0, and the mixture is mixed evenly to obtain a mixed solution; The mixed solution is aged at 20-40° C., and water produced during the aging process is removed to obtain the polyphenol-containing medical adhesive.

2. The preparation method according to claim 1, characterized in that: The concentration of the gelatin solution is 10% to 20%; the concentration of the gallic acid solution is 1% to 3%; and the concentration of the tea polyphenol solution is 5% to 20%.

3. The preparation method according to claim 1, characterized in that: The gelatin solution is prepared by the following method: gelatin is mixed with deionized water, heated to 40-60° C., the gelatin is completely dissolved in the deionized water, and a gelatin solution with a concentration of 10%-20% is obtained.

4. The preparation method according to claim 1, characterized in that: The gallic acid solution is prepared by the following method: mixing gallic acid with deionized water at 40-60° C. to completely dissolve the gallic acid in the deionized water to obtain a gallic acid solution with a concentration of 1%-3%.

5. The preparation method according to claim 1, characterized in that: When preparing the modified gelatin solution, the volume ratio of the gelatin solution to the gallic acid solution is 1:0.5-1.

6. The preparation method according to claim 1, characterized in that: The tea polyphenol solution is prepared by the following method: at room temperature, tea polyphenol is dissolved in deionized water at 30-50° C. to prepare a tea polyphenol solution with a concentration of 5% to 20%.

7. The preparation method according to claim 1, characterized in that: The alkaline solution is a 0.1-1 mol / L sodium hydroxide solution.

8. The preparation method according to claim 1, characterized in that: The aging time is 2-20h.

9. The preparation method according to any one of claims 1 to 8, characterized in that: The gelatin is medical gelatin with a molecular weight of 50,000 to 200,000.

10. A medical adhesive containing polyphenols prepared by the preparation method according to any one of claims 1 to 9.

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