CN105251038B - A kind of anti-infection soft tissue medical glue and preparation method thereof - Google Patents

Abstract

The invention provides an anti-infection soft tissue medical glue and a preparation method thereof, which are prepared from plant polyphenols, water-soluble polymers, aminoglycoside antibiotics and solvents. Among them, the catechol unit in the plant polyphenol can be hydrogen-bonded with the electron-donating group in the water-soluble polymer and electrostatically combined with the protonated aminoglycoside antibiotic in the physiological environment to obtain an anti-infective soft tissue medical glue. Compared with the existing technology, the medical adhesive has higher cohesiveness, better biocompatibility, and better hemostatic performance, and the pH value is different according to the amount of bacteria adhered to different parts of the material, and the responsive release Antibiotics have good durability, avoiding the problems of drug resistance and gradual release of antibiotics caused by long-term exposure to antibiotics. The preparation method of the anti-infection soft tissue medical glue is simple, low in cost and suitable for large-scale production. Experimental results show that the soft tissue medical glue has a cohesive force of 5.09N and a cohesive strength of 180kPa.

Description

A kind of anti-infection soft tissue medical glue and preparation method thereof

technical field

The invention relates to the field of medical devices, in particular to an anti-infection soft tissue medical glue and a preparation method thereof.

Background technique

There are 26 million to 90 million cutting injuries and more than 7 million trauma ruptures every year. In surgical operations, antibacterial and hemostasis are the basis, and for the repair of biological tissues, suture and tie are two basic operations. However, this traditional method of stitching and pricking is not only cumbersome and laborious, but also easily causes bleeding and new damage, which brings more pain to the patient. At present, medical glue can be used to replace or partly replace thread suture. Compared with suture thread, medical glue has many advantages: it can effectively stop bleeding, isolate air, avoid the damage of acupuncture to human tissue, easy to use, reduce operation time, and do not need to be removed. . An ideal medical adhesive should meet the following requirements: (1) non-toxic, non-carcinogenic, non-teratogenic and mutagenic; (2) good biocompatibility; (3) sterile and bacteriostatic; (4) ) can be used in a humid environment with blood and tissue fluid; (5) rapid adhesion can be achieved under normal temperature and pressure; (6) the adhesive strength and adhesion durability are good, and the adhesive part has certain elasticity and toughness; (8) Biodegradable; (9) The leached matter of degradation products does not affect healing and has no cytotoxicity; (9) According to the purpose of use, it can be quickly metabolized after completing the bonding mission.

Medical adhesives can be divided into soft tissue medical adhesives, hard tissue medical adhesives, and medical pressure-sensitive adhesives according to their uses; bonding wounds belongs to the category of soft tissue medical adhesives. The purpose of soft tissue bonding is to promote the natural healing of the tissue itself, so it usually only needs to maintain the bonding force for about one week, but the soft tissue medical adhesive must be able to bond quickly and coexist with fat and water.

Soft tissue medical glue widely used clinically at present is fibrin glue. The patent with the publication number CN02123757.3 discloses a highly coagulable fibrinogen glue, which is composed of fibrinogen, fibrinogen activity enhancing factor and a small amount of thrombin, and has the functions of highly effective hemostasis and wound healing promotion. Such adhesives have good biocompatibility and degradability, but have low adhesion and long setting time, which is not conducive to treatment, and there is also a risk of infection of blood-borne diseases.

Contents of the invention

In view of this, the object of the present invention is to provide an anti-infective soft tissue medical glue and a preparation method thereof. The anti-infective soft tissue medical glue provided by the present invention has high adhesion to wounds.

The invention provides an anti-infection soft tissue medical glue, which is prepared from plant polyphenols, water-soluble polymers, aminoglycoside antibiotics and solvents.

Preferably, the mass ratio of the plant polyphenols, water-soluble polymers and aminoglycoside antibiotics is 100:(5-80):(0.1-40).

Preferably, the plant polyphenol is selected from one or more of tannic acid, catechin, morin and gallol.

Preferably, the water-soluble polymer is selected from polyethylene glycol, polyoxyethylene-polyoxypropylene-polyoxyethylene, polyvinylpyrrolidone, chitosan, hyaluronic acid, sodium alginate, polyetheramine and branched One or more of polyethyleneimines.

Preferably, the aminoglycoside antibiotic is selected from one or more of gentamicin sulfate, tobramycin, polymyxin B, streptomycin, kanamycin and amikacin.

Preferably, the number average molecular weight of the water-soluble polymer is 1 kDa-40 kDa.

Preferably, the solvent is selected from one or more of water, physiological saline and phosphate buffered saline.

The present invention provides a preparation method of the anti-infective soft tissue medical glue described in the above technical solution, comprising the following steps:

The soft tissue medical glue is obtained by mixing plant polyphenols, water-soluble polymers, aminoglycoside antibiotics and solvents.

Preferably, the mixing temperature is 0-60°C; the mixing time is 0.005-12 hours.

Preferably, the mixture of plant polyphenols, water-soluble polymers, aminoglycoside antibiotics and solvents specifically includes:

Dissolving plant polyphenols, water-soluble polymers and aminoglycoside antibiotics in solvents respectively to obtain plant polyphenol solutions, water-soluble polymer solutions and aminoglycoside antibiotic solutions; plant polyphenol solutions, water-soluble polymer solutions Mix with aminoglycoside antibiotic solution.

The invention provides an anti-infection soft tissue medical glue, which is prepared from plant polyphenols, water-soluble polymers, aminoglycoside antibiotics and solvents. The raw materials for the preparation of the soft tissue medical glue provided by the present invention include plant polyphenols, water-soluble polymers and aminoglycoside antibiotics, wherein the catechol units in the plant polyphenols can respectively hydrogen bond with the electron-donating groups in the water-soluble polymers and Electrostatically combined with protonated aminoglycoside antibiotics in physiological environment to obtain anti-infection soft tissue medical glue. Compared with the existing technology, the soft tissue medical glue has higher cohesiveness, better biocompatibility, and better hemostatic performance, and the pH value will be different according to the amount of bacteria adhered to different parts of the material, and the responsiveness The release of antibiotics has better durability, avoiding the problems of drug resistance and gradual release of antibiotics caused by long-term exposure to antibiotics. Experimental results show that the anti-infection soft tissue medical glue provided by the invention has a cohesive force as high as 5.09N and a cohesive strength as high as 180kPa.

The preparation method provided by the invention is simple and convenient, has mild conditions, low cost and is suitable for large-scale production.

Description of drawings

Fig. 1 is the anti-infective soft tissue medical glue prepared in Example 1 of the present invention, the traditional Chinese medicine fibrin glue in Comparative Example 2 and the blood flow without any treatment in Comparative Example 3;

Fig. 2 is the laser scanning confocal microscope image of bacteria cultured for 24h in an environment where the surface pH value of the silicon wafer modified by the anti-infective soft tissue medical glue prepared in Example 1 of the present invention is 7.4;

Fig. 3 is the laser scanning confocal microscope image of bacteria cultured for 24 hours in an environment where the surface pH value of the silicon wafer modified by the anti-infective soft tissue medical glue prepared in Example 1 of the present invention is 5.5;

Fig. 4 is the laser scanning confocal microscope image of the bacteria cultured for 4 weeks in an environment where the surface pH value of the silicon wafer modified by the anti-infective soft tissue medical glue prepared in Example 1 of the present invention is 7.4;

Fig. 5 is the laser scanning confocal microscope image of the bacterial laser scanning confocal microscope for cultivating 24h under the environment of the silicon wafer surface pH value 7.4 modified by Chinese medical fibrin glue in Comparative Example 2 of the present invention;

Fig. 6 is the laser scanning confocal microscope image of the 24h bacterial laser scanning confocal microscope of the silicon wafer surface modified by Chinese medical fibrin glue in comparative example 2 of the present invention with a pH value of 5.5;

Fig. 7 is a laser scanning confocal microscope image of bacteria cultured for 4 weeks in an environment where the surface pH value of the silicon wafer modified with medical fibrin glue in Comparative Example 2 of the present invention is 7.4.

detailed description

The invention provides an anti-infection soft tissue medical glue, which is prepared from plant polyphenols, water-soluble polymers, aminoglycoside antibiotics and solvents.

The anti-infection soft tissue medical glue provided by the invention has high adhesion to wounds, good biocompatibility, excellent hemostatic performance, good anti-infection performance and strong durability.

The raw materials for the preparation of the anti-infective soft tissue medical glue provided by the present invention include plant polyphenols, which are preferably selected from one or more of tannic acid, catechin, morin and gallol, more preferably selected from One or more of tannic acid, catechin and morin. In the present invention, the plant polyphenols contain catechol units, and the catechol units can be hydrogen-bonded with electron-donating groups in water-soluble polymers and electrostatically combined with protonated antibiotics in physiological environments, making anti-infection Soft tissue medical glue has higher bonding strength, better biocompatibility, and better hemostatic performance.

The preparation raw material of the anti-infection soft tissue medical glue provided by the present invention comprises water-soluble polymer, and described water-soluble polymer is preferably selected from polyethylene glycol, polyoxyethylene-polyoxypropylene-polyoxyethylene, polyvinylpyrrolidone, chitosan One or more of sugar, hyaluronic acid, sodium alginate, polyetheramine and branched polyethyleneimine, more preferably selected from polyethylene glycol, polyethylene oxide-polyoxypropylene-polyoxyethylene, branched One or more of polyethyleneimine, polyetheramine, chitosan and sodium alginate. In the present invention, the number average molecular weight M _n of the water-soluble polymer is preferably 1 kDa-40 kDa, more preferably 2 kDa-30 kDa, most preferably 5 kDa-20 kDa. In the present invention, the mass ratio of the water-soluble polymer to the plant polyphenol is preferably 5:100-80:100, more preferably 10:100-70:100, and most preferably 20:100-60:100. In the present invention, there is no special limitation on the source of the water-soluble polymer, and the above-mentioned water-soluble polymer well-known to those skilled in the art can be used, such as commercially available products.

The raw materials for the preparation of the anti-infective soft tissue medical glue provided by the present invention include aminoglycoside antibiotics, the aminoglycoside antibiotics are antibiotics containing primary amino groups, and the aminoglycoside antibiotics are preferably selected from gentamicin sulfate, tobramycin One or more of polymyxin B, streptomycin, kanamycin and amikacin. In the present invention, the mass ratio of the antibiotic to the plant polyphenol is preferably 0.1:100-40:100, more preferably 0.5:100-30:100, and most preferably 1:100-20:100. In the present invention, there is no special limitation on the source of the aminoglycoside antibiotics, and the above-mentioned aminoglycoside antibiotics well-known to those skilled in the art can be used, such as commercially available products. In specific embodiments of the present invention, gentamicin sulfate and tobramycin produced by Bailingwei Technology Co., Ltd.; kanamycin sulfate produced by Aldrich Chemical Reagent Co., Ltd. of the United States can be used.

The raw materials for preparing the anti-infective soft tissue medical glue provided by the present invention include a solvent; the solvent preferably includes one or more of water, physiological saline and phosphate buffer solution. The present invention has no special limitation on the source of the above-mentioned solvent, and the above-mentioned solvent well-known to those skilled in the art can be used, for example, commercially available products can be used. In the present invention, the solvent can respectively dissolve plant polyphenols, water-soluble polymers and aminoglycoside antibiotics, and according to actual needs, it can be configured to a required concentration. In a specific embodiment of the present invention, the mass concentration of the plant polyphenol solution is preferably 0.001-5 g/mL, more preferably 0.01-4 g/mL, most preferably 0.05-3 g/mL; the water-soluble polymer solution The mass concentration of the aminoglycoside antibiotic solution is preferably 0.001～5g/mL, more preferably 0.01～4g/mL, most preferably 0.05～3g/mL; the mass concentration of the aminoglycoside antibiotic solution is preferably 0.001～5g/mL, more preferably 0.005-3 g/mL, most preferably 0.005-1 g/mL.

The present invention adopts plant polyphenols, water-soluble polymers and aminoglycoside antibiotics in a specific ratio, which can better play a synergistic effect and balance the effects of bonding, hemostasis and antibacterial, so that the bonding property is higher , better hemostatic effect, better anti-infection performance, longer duration, less adverse effects on blood and somatic cells, and better biocompatibility; moreover, the preparation is simple and convenient, the conditions are mild, the cost is low, and it is suitable for large-scale production .

The present invention provides a preparation method of the anti-infective soft tissue medical glue described in the above technical solution, comprising the following steps:

Mix plant polyphenols, water-soluble polymers, aminoglycoside antibiotics and solvents to obtain anti-infection soft tissue medical glue.

In the present invention, the mixing of the plant polyphenols, water-soluble polymers, aminoglycoside antibiotics and solvents preferably specifically includes:

Dissolving plant polyphenols, water-soluble polymers and aminoglycoside antibiotics in solvents respectively to obtain plant polyphenol solutions, water-soluble polymer solutions and aminoglycoside antibiotic solutions; plant polyphenol solutions, water-soluble polymer solutions Mix with aminoglycoside antibiotic solution.

In the present invention, the mass ratio of the plant polyphenols, water-soluble polymers and aminoglycoside antibiotics is preferably 100:(5-80):(0.1-40).

In the present invention, the types and sources of the plant polyphenols, water-soluble polymers, and aminoglycoside antibiotics are consistent with the types and sources of the plant polyphenols, water-soluble polymers, and aminoglycoside antibiotics described in the above technical scheme. This will not be repeated here.

In the present invention, the solvent preferably includes one or more of water, normal saline and phosphate buffer solution; the water is preferably ultrapure water; the mass concentration of the normal saline is preferably 0.85% to 0.9% . In the present invention, there is no special limitation on the source of the solvent, and the above-mentioned solvents well-known to those skilled in the art can be used.

In the present invention, preferably, the plant polyphenol, the water-soluble polymer and the aminoglycoside antibiotic are respectively dissolved in a solvent to obtain the plant polyphenol solution, the water-soluble polymer solution and the aminoglycoside antibiotic solution respectively. In the present invention, the dissolution time is preferably 0.005 to 12 hours, more preferably 0.01 to 8 hours, most preferably 0.02 to 6 hours; the dissolution temperature is preferably 0 to 60°C, more preferably 10 to 6 hours. 50°C, most preferably 20-45°C. In the present invention, the dissolution method preferably includes ultrasonication, stirring or standing. In the present invention, the dissolution of the plant polyphenols, water-soluble polymers and aminoglycoside antibiotics is preferably carried out under ultrasonic conditions. In the present invention, the solvents used for dissolving the plant polyphenols, water-soluble polymers and aminoglycoside antibiotics are preferably the same solvent. In a specific embodiment of the present invention, the mass concentration of the plant polyphenol solution is preferably 0.001-5 g/mL, more preferably 0.01-4 g/mL, most preferably 0.05-3 g/mL; the water-soluble polymer solution The mass concentration of the aminoglycoside antibiotic solution is preferably 0.001～5g/mL, more preferably 0.01～4g/mL, most preferably 0.05～3g/mL; the mass concentration of the aminoglycoside antibiotic solution is preferably 0.001～5g/mL, more preferably 0.005-3 g/mL, most preferably 0.005-1 g/mL.

After obtaining the plant polyphenol solution, the water-soluble polymer solution and the aminoglycoside antibiotic solution, the present invention mixes the plant polyphenol solution, the water-soluble polymer solution and the aminoglycoside antibiotic solution to obtain an anti-infection soft tissue medical glue. The present invention has no special restrictions on the mixing order of the plant polyphenol solution, the water-soluble polymer solution and the aminoglycoside antibiotic solution, and the present invention can simultaneously add the water-soluble polymer solution and the aminoglycoside antibiotic solution to the plant polyphenol solution ; It is also possible to mix the water-soluble polymer solution and the aminoglycoside antibiotic solution first, and then mix it with the plant polyphenol solution. In the present invention, the mixing time of the plant polyphenol solution, the water-soluble polymer solution and the aminoglycoside antibiotic solution is preferably 0.005-12 hours, more preferably 0.01-8 hours, most preferably 0.01-4 hours; The mixing temperature of the plant polyphenol solution, the water-soluble polymer solution and the aminoglycoside antibiotic solution is preferably 0-60°C, more preferably 10-50°C, and most preferably 20-45°C. In the present invention, the mixing method of the plant polyphenol solution, the water-soluble polymer solution and the aminoglycoside antibiotic solution includes ultrasonication, stirring or standing still. In the present invention, the mixing of the plant polyphenol solution, the water-soluble polymer solution and the aminoglycoside antibiotic solution is preferably carried out under the condition of stirring.

In the present invention, preferably, the plant polyphenol solution, the water-soluble polymer solution and the aminoglycoside antibiotic solution are uniformly mixed, centrifuged, and the upper solution is poured out to obtain the anti-infection soft tissue medical glue.

The preparation method of the anti-infective soft tissue medical glue provided by the present invention only needs to mix the plant polyphenol solution, the water-soluble polymer solution and the aminoglycoside antibiotic solution evenly to obtain the anti-infective soft tissue medical glue, the method is simple and easy to operate, and the cost is low .

The present invention tests the cohesive force and bonding strength of the anti-infective soft tissue medical glue. The test method is: fix pigskin with a diameter of 6 mm on the cylindrical fixture of the universal testing machine, and apply 3 mg of anti-infective soft tissue medical glue to two pieces. Between the front surface of the pigskin, after pulling the two pieces of pigskin back and forth for 10 times, press them with a force of 20N for 10 minutes, so that the bonding surfaces of the two pieces of pigskin are evenly in close contact, and then pull them apart at a speed of 1mm/min. , measured the cohesive force and cohesive strength of the anti-infective soft tissue medical glue, and repeated five times to get the average value.

The hemostatic effect of the anti-infection soft tissue medical glue of the present invention is tested. The test method is: puncture the liver of a male rat (30-35 g in weight), immediately take 10 mg of anti-infection soft tissue medical glue to the bleeding place, and weigh the quality of the bleeding within 30 seconds. , repeated five times to obtain the average value.

The present invention tests the bactericidal effect of the anti-infective soft tissue medical glue, and the test method is: take 10 mg of anti-infective soft tissue medical glue and evenly stick it on a silicon wafer (1cm×1.2cm), in 2 mL of LB with a bacterial concentration of 1×10 ⁶ cells/mL Cultivate at 37°C for 24 hours in the culture medium, the LB culture medium includes tryptone 10g/L, yeast extract 5g/L, sodium chloride 10g/L, then stained with LIVE/DEAD Bac Light Bacterial Viability Kit, laser scanning confocal Microscopic observation of the bactericidal effect of anti-infective soft tissue medical glue.

The invention provides an anti-infection soft tissue medical glue, which is prepared from plant polyphenols, water-soluble polymers, aminoglycoside antibiotics and solvents. The preparation raw materials of the anti-infective soft tissue medical glue provided by the present invention include plant polyphenols, water-soluble polymers and aminoglycoside antibiotics, wherein the catechol units in the plant polyphenols can hydrogen bond with the electron-donating groups in the water-soluble polymers respectively Combining and electrostatically combining with protonated aminoglycoside antibiotics in physiological environment to obtain anti-infection soft tissue medical glue. Compared with the existing technology, the soft tissue medical glue has higher bonding strength, better biocompatibility, and better hemostatic performance, and the pH value will be different according to the amount of bacteria adhered to different parts of the material, and the responsiveness Release antibiotics with good durability, avoiding the problems of drug resistance and gradual release of antibiotics caused by prolonged exposure of antibiotics. Experimental results show that the anti-infection soft tissue medical glue provided by the invention has a cohesive force as high as 5.09N and a cohesive strength as high as 180kPa.

The preparation method provided by the present invention only needs to mix the plant polyphenol solution, the water-soluble polymer solution and the aminoglycoside antibiotic solution evenly to obtain the anti-infection soft tissue medical glue. The preparation method is simple and convenient, the conditions are mild, and the cost is low. Mass production.

In order to further illustrate the present invention, an anti-infective soft tissue medical glue provided by the present invention and its preparation method are described in detail below in conjunction with examples, but they should not be construed as limiting the protection scope of the present invention.

Example 1

Add 5 g of tannic acid and 5 mL of ultrapure water to No. 1 beaker, and dissolve by ultrasonication at 30°C for 15 minutes to obtain 5 mL of 1 g/mL tannic acid aqueous solution. Add 5 g of polyethylene glycol with an M _n of 10 kDa and 5 mL of ultrapure water into the No. 2 beaker, and dissolve by ultrasonication at 30°C for 15 minutes to obtain 5 mL of a 1 g/mL polyethylene glycol aqueous solution. Add 0.5 g of gentamicin sulfate and 1 mL of ultrapure water to No. 3 beaker, and dissolve by ultrasonication at 30°C for 15 minutes to obtain 1 mL of 0.5 g/mL gentamicin sulfate aqueous solution.

Add 2.5mL of 1g/mL polyethylene glycol aqueous solution and 1mL of 0.5g/mL gentamicin sulfate aqueous solution into a beaker of 5mL 1g/mL tannic acid aqueous solution, stir well at 30°C, centrifuge, and pour out the upper layer solution , to obtain a soft tissue medical glue with anti-infection properties.

Fix the pigskin with a diameter of 6 mm on the cylindrical fixture of the universal testing machine, take 3 mg of the anti-infection soft tissue medical glue prepared in Example 1 and apply it between the front surfaces of the two pigskins, and pull the two pigskins back and forth for 10 After the second time, use 20N force to compress 10min, make the bonding surface of two pigskins even close contact; Then pull away with the speed of 1mm/min, measure the cohesive force and the anti-infection soft tissue medical glue that the present invention makes. Bond strength, repeated five times to get the average value, the results are shown in Table 1, Table 1 is the anti-infection soft tissue medical glue obtained in Examples 1-12 of the present invention, the tannic acid aqueous solution in Comparative Example 1 and the traditional Chinese medicine in Comparative Example 2 Adhesion test results of fibrin glue.

Table 1 The adhesion test results of the anti-infective soft tissue medical glue obtained in Examples 1-12 of the present invention, the tannic acid aqueous solution in Comparative Example 1, and the medical fibrin glue in Comparative Example 2

Example Adhesion (N) Bond strength (kPa) Example 1 4.01 142 Example 2 5.09 180 Example 3 1.89 67 Example 4 3.93 139 Example 5 3.25 115 Example 6 2.37 84 Example 7 1.61 57 Example 8 1.95 69 Example 9 3.31 117 Example 10 3.00 106 Example 11 3.90 138 Example 12 3.36 119 Comparative example 1 1.27 45 Comparative example 2 1.98 70

As can be seen from Table 1, the cohesive strength of the tannic acid solution in Comparative Example 1 is lower, far lower than the anti-infection soft tissue medical glue provided by the present invention, and the cohesive strength of the Chinese medical fibrin glue in Comparative Example 2 is also lower , and after adjusting the ratio, the cohesive force of the anti-infective soft tissue medical glue provided by the present invention is as high as 5.09N, and the cohesive strength is as high as 180kPa.

The liver of the male rat (30-35g in weight) was punctured, and 10 mg of the anti-infective soft tissue medical glue prepared in Example 1 was immediately taken and stuck to the bleeding place, and the quality of bleeding within 30 seconds was weighed to obtain the anti-infective soft tissue medical glue prepared by the present invention. Repeat five times to get the average value, the results are as shown in Figure 1, Figure 1 is the anti-infection soft tissue medical glue prepared in the embodiment of the present invention 1, comparative example 2 Chinese medical fibrin glue and comparative example 3 without any Processed blood flow. It can be seen from Fig. 1 that the hemostatic effect of the traditional Chinese medical fibrin glue in Comparative Example 2 is poor, and the amount of bleeding is large, while the anti-infective soft tissue medical glue provided by the present invention has an excellent hemostatic effect.

Take 10 mg of the anti-infective soft tissue medical glue prepared in Example 1 and evenly stick it on a silicon chip (1cm×1.2cm), culture it in 2mL of LB culture solution with a bacterial concentration of 1×10 ⁶ cells/mL and a pH value of 7.4 at 37°C for 24h Afterwards, it was stained with LIVE/DEAD BacLight Bacterial Viability Kit, and the bactericidal effect of the anti-infective soft tissue medical glue cultured for 24 hours in an environment with a pH value of 7.4 was observed under a laser scanning confocal microscope. The results were repeated five times. The results are shown in Figure 2. Laser scanning confocal microscopic image of bacteria cultured for 24 hours on the silicon wafer surface modified with anti-infective soft tissue medical glue prepared in Example 1 of the present invention with a pH value of 7.4. Adjust the pH value of the LB culture medium to 5.5, incubate in 2 mL of LB culture liquid with a bacterial concentration of 1×10 ⁶ cells/mL and a pH value of 5.5 at 37°C for 24 hours, observe the bactericidal effect of the anti-infective soft tissue medical glue in a weakly acidic environment, The results were repeated five times, and the results are shown in Figure 3, which is a laser scanning confocal microscope image of bacteria cultured for 24 hours in an environment with a pH value of 5.5 on the surface of silicon wafers modified with anti-infective soft tissue medical glue prepared in Example 1 of the present invention. After culturing at 37°C for 4 weeks in 2 mL of LB medium (pH 7.4) with a bacterial concentration of 1×10 ⁶ cells/mL, the long-term bactericidal effect of the anti-infective soft tissue medical glue was observed and repeated five times. The results are shown in Figure 4 4 is a confocal laser scanning microscope image of bacteria cultured for 4 weeks in an environment with a pH value of 7.4 on the surface of silicon wafers modified with anti-infective soft tissue medical glue prepared in Example 1 of the present invention. It can be seen from Figures 2 to 4 that the anti-infective soft tissue medical glue provided by the present invention will respond to different pH values caused by the amount of bacteria adhered to different positions of the material, and release antibiotics in a responsive manner, which has high-efficiency anti-infection performance and durability Well, avoiding the problem of long-term exposure to antibiotics to produce resistance and gradual release.

Example 2

Add 5g of tannic acid and 5mL of ultrapure water to No. 1 beaker, and dissolve by ultrasonication at 30°C for 15 minutes to obtain 5mL of 1g/mL tannic acid aqueous solution; add 5g of polyetheramine and 5mL of ultrapure water to No. Dissolve to obtain 5 mL of 1 g/mL polyetheramine aqueous solution; add 0.05 g of gentamicin sulfate and 1 mL of ultrapure water to No. 3 beaker, and dissolve by ultrasonication at 30°C for 15 minutes to obtain 1 mL of 0.05 g/mL gentamicin sulfate aqueous solution.

Add 2.5mL of 1g/mL polyetheramine aqueous solution and 1mL of 0.05g/mL gentamycin sulfate aqueous solution into a beaker of 5mL of 1g/mL tannic acid aqueous solution, stir well at 30°C, centrifuge, pour out the upper layer solution, A soft tissue medical glue with anti-infection properties is obtained.

According to the method in Example 1, the present invention tested the cohesive force and cohesive strength of the anti-infective soft tissue medical glue obtained in Example 2, and the results are shown in Table 1.

Example 3

Add 5 g of tannic acid and 5 mL of ultrapure water to No. ₁ beaker, and dissolve by ultrasonication at 25 ° C for 20 minutes to obtain 5 mL of 1 g/mL tannic acid aqueous solution; 5mL, ultrasonically dissolved at 25°C for 20min to obtain 5mL of 1g/mL polyethylene glycol aqueous solution; add 0.5g of gentamycin sulfate and 1mL of ultrapure water to No. Ampicillin aqueous solution 1mL.

Add 4mL of 1g/mL polyethylene glycol aqueous solution and 1mL of 0.5g/mL gentamycin sulfate aqueous solution into a beaker of 5mL 1g/mL tannic acid aqueous solution, stir well at 25°C, centrifuge, pour out the upper layer solution, A soft tissue medical glue with anti-infection properties is obtained.

According to the method in Example 1, the present invention tested the cohesive force and cohesive strength of the anti-infective soft tissue medical glue obtained in Example 3, and the results are shown in Table 1.

Example 4

Add 1 g of tannic acid and 1 mL of ultrapure water to No. 1 beaker, and ultrasonically dissolve at 45 ° C for 15 minutes to obtain 1 mL of 1 g/mL tannic acid aqueous solution; add 1 g of polyethylene glycol with M _n of 20 kDa to No. 2mL, ultrasonically dissolved at 50°C for 30min to obtain 2mL of 0.5g/mL polyethylene glycol aqueous solution; add 0.1g polymyxin B and 0.1mL of ultrapure water to No. 3 beaker, and ultrasonically dissolve at 45°C for 15min to obtain 1g/mL Colistin B aqueous solution 0.1 mL.

Add 1.2mL of 0.5g/mL polyethylene glycol aqueous solution and 0.01mL of 1g/mL polymyxin B aqueous solution into a beaker of 1mL of 1g/mL tannic acid aqueous solution, stir well at 45°C, centrifuge, pour the upper layer solution A soft tissue medical glue with anti-infection properties was obtained.

According to the method in Example 1, the present invention tested the cohesive force and cohesive strength of the anti-infective soft tissue medical glue obtained in Example 4, and the results are shown in Table 1.

Example 5

Add 5 g of tannic acid and 5 mL of ultrapure water to No. 1 beaker, and dissolve it by ultrasonication at 30 ° C for 15 minutes to obtain 5 mL of 1 g/mL tannic acid aqueous solution; add 2 g of polyethylene glycol with _Mn of 40 kDa to No. 4mL, 30°C ultrasonic for 15min, to obtain 4mL of 0.5g/mL polyethylene glycol aqueous solution; add 1g of polymyxin B, 1mL of ultrapure water, 30°C for 15min, to obtain 1g/mL polymyxa Sodium B aqueous solution 1mL.

Add 3mL 0.5g/mL polyethylene glycol aqueous solution and 1mL 1g/mL polymyxin B aqueous solution into a beaker of 5mL 1g/mL tannic acid aqueous solution, stir well at 30°C, centrifuge, and pour out the upper layer solution , to obtain a soft tissue medical glue with anti-infection properties.

According to the method in Example 1, the present invention tested the cohesive force and cohesive strength of the soft tissue medical glue obtained in Example 5, and the results are shown in Table 1.

Example 6

Add 5 g of catechin, 1 mL of ultrapure water to No. 1 beaker, and dissolve by ultrasonication at 45 ° C for 30 min to obtain 1 mL of 5 g/mL catechin aqueous solution; add 5 g of polyetheramine and 1 mL of ultra pure water to No. 2 beaker, and stir at 45 ° C for 12 h Dissolve to obtain 1 mL of 5 g/mL polyetheramine aqueous solution; add 1 g of tobramycin and 1 mL of ultrapure water to a No. 3 beaker, and dissolve by ultrasonication at 45°C for 30 minutes to obtain 1 mL of 1 g/mL tobramycin aqueous solution.

Add 0.4mL of 5g/mL polyetheramine aqueous solution and 1mL of 1g/mL tobramycin aqueous solution into a beaker of 1mL of 5g/mL catechin aqueous solution, and stir evenly at 45°C to obtain a soft tissue medical glue with anti-infection properties.

According to the method in Example 1, the present invention tested the cohesive force and cohesive strength of the soft tissue medical glue obtained in Example 6, and the results are shown in Table 1.

Example 7

Add 5g of morin, 2mL of ultrapure water into No. 1 beaker, and dissolve by ultrasonication at 60°C for 20 minutes to obtain 2mL of 2.5g/mL morin aqueous solution; add 5g of polyvinylpyrrolidone, 2mL of ultrapure water into No. 2 beaker, stir at 60°C for 6h , to obtain 2.5 g/mL polyvinylpyrrolidone aqueous solution 2 mL; add 5 mg polymyxin B and 1 mL ultrapure water to No. 3 beaker, and dissolve by ultrasonication at 60 ° C for 5 minutes to obtain 1 mL 0.005 g/mL polymyxin B aqueous solution.

Add 0.1mL of 2.5g/mL polyvinylpyrrolidone aqueous solution and 1mL of 0.005g/mL polymyxin B aqueous solution into a beaker of 2mL 2.5g/mL morin aqueous solution, and stir evenly at 60°C to obtain anti-infective Soft tissue medical glue.

According to the method in Example 1, the present invention tested the cohesive force and cohesive strength of the soft tissue medical glue obtained in Example 7, and the results are shown in Table 1.

Example 8

Add 4g of gallol, 1mL of normal saline to No. 1 beaker, and dissolve by ultrasonication at 20°C for 30 minutes to obtain 1mL of 4g/mL gallol solution; add 2g of branched polyethyleneimine, 1mL of normal saline to No. , to obtain 1 mL of 2 g/mL branched polyethyleneimine solution; add 2 g of streptomycin and 1 mL of normal saline to No. 3 beaker, and dissolve by ultrasonication at 20°C for 30 min to obtain 1 mL of 2 g/mL streptomycin solution.

Add 0.4mL 2g/mL branched polyethyleneimine solution and 0.8mL 2g/mL streptomycin solution into a beaker of 1mL 4g/mL gallol solution, and ultrasonically mix at 20°C to obtain soft tissue with anti-infection properties medical glue.

According to the method in Example 1, the present invention tested the cohesive force and cohesive strength of the soft tissue medical glue obtained in Example 8, and the results are shown in Table 1.

Example 9

Add 5g of tannic acid and 5mL of phosphate buffer to No. 1 beaker, and dissolve by ultrasonication for 15 minutes at 30°C to obtain 5mL of 1g/mL tannic acid solution; add 2g of hyaluronic acid and 2mL of phosphate buffer to No. Dissolve by ultrasonication for 15 minutes to obtain 2 mL of 1 g/mL hyaluronic acid solution; add 0.005 g of kanamycin and 5 mL of phosphate buffer to No. 3 beaker, and dissolve by ultrasonication for 15 min at 30°C to obtain 5 mL of 0.001 g/mL kanamycin solution.

Add 2mL of 1g/mL hyaluronic acid solution and 5mL of 0.001g/mL kanamycin solution into a beaker of 5mL of 1g/mL tannic acid solution, stir and mix evenly at 30°C, and after centrifugation, pour out the upper layer solution to obtain Soft tissue medical glue with anti-infective properties.

According to the method in Example 1, the present invention tested the cohesive force and cohesive strength of the soft tissue medical glue obtained in Example 9, and the results are shown in Table 1.

Example 10

Add 0.5g of catechin and 1mL of ultrapure water to No. 1 beaker, and dissolve it by ultrasonication at 0°C for 30 minutes to obtain 1mL of 0.5g/mL catechin aqueous solution; add 0.5g of chitosan and 1mL of ultrapure water to No. 2 beaker, Dissolve by ultrasonication at ℃ for 30 minutes to obtain 1 mL of 0.5 g/mL chitosan aqueous solution; add 0.1 g of amikacin and 1 mL of ultrapure water to No. .

Add 0.1mL 0.5g/mL chitosan aqueous solution and 0.15mL 0.1g/mL amikacin aqueous solution to a beaker of 1mL 0.5g/mL catechin aqueous solution, and stir evenly at 0°C to obtain anti-infective Soft tissue medical glue.

According to the method in Example 1, the present invention tested the cohesive force and cohesive strength of the soft tissue medical glue obtained in Example 10, and the results are shown in Table 1.

Example 11

Add 5 g of tannic acid and 2.5 mL of ultrapure water to No. 1 beaker, and dissolve by ultrasonication at 60 ° C for 15 minutes to obtain 2.5 mL of 2 g/mL tannic acid aqueous solution; add 2.5 mL of polyoxyethylene-polyoxypropylene-polyoxyethylene to No. g, 2.5mL of ultrapure water, ultrasonically dissolved at 60°C for 15min to obtain 2.5mL of 1g/mL polyoxyethylene-polyoxypropylene-polyoxyethylene aqueous solution; add 0.5g of tobramycin to No. 3 beaker, 1mL of ultrapure water, Dissolve by ultrasonication at 30°C for 15 minutes to obtain 1 mL of 0.5 g/mL tobramycin aqueous solution.

Add 2.5mL of 1g/mL polyoxyethylene-polyoxypropylene-polyoxyethylene aqueous solution and 1mL of 0.5g/mL tobramycin aqueous solution into a beaker of 2.5mL 2g/mL tannic acid aqueous solution, stir well at 60°C, After centrifugation, pour out the upper layer solution to obtain soft tissue medical glue with anti-infection properties.

According to the method in Example 1, the present invention tested the cohesive force and cohesive strength of the soft tissue medical glue obtained in Example 11, and the results are shown in Table 1.

Example 12

Add 5g of tannic acid and 2.5mL of ultrapure water to No. 1 beaker, and dissolve by ultrasonication at 50°C for 20 minutes to obtain 2.5mL of 2g/mL tannic acid aqueous solution; add 2g of sodium alginate and 2mL of ultrapure water to No. 2 beaker, Dissolve by ultrasonication for 20 minutes to obtain 2 mL of 1 g/mL sodium alginate aqueous solution; add 0.5 g of tobramycin and 0.5 mL of ultrapure water to No. 3 beaker, and dissolve by ultrasonication for 15 minutes at 30°C to obtain 0.5 mL of 1 g/mL tobramycin aqueous solution.

Add 2mL of 1g/mL sodium alginate aqueous solution and 0.5mL of 1g/mL tobramycin aqueous solution into a beaker of 2.5mL 2g/mL tannic acid aqueous solution, stir well at 50°C, centrifuge, pour out the upper layer solution, A soft tissue medical glue with anti-infection properties is obtained.

According to the method in Example 1, the present invention tested the cohesive force and cohesive strength of the soft tissue medical glue obtained in Example 12, and the results are shown in Table 1.

Comparative example 1

Add 5 g of tannic acid and 5 mL of ultrapure water to No. 1 beaker, and dissolve by ultrasonication at 30°C for 15 minutes to obtain 5 mL of 1 g/mL tannic acid aqueous solution.

Fix the pigskin with a diameter of 6mm on the cylindrical fixture of the universal testing machine, take 3 mg of tannic acid aqueous solution and apply it between the front surfaces of the two pigskins, pull the two pigskins back and forth for 10 times, and then press them tightly 10min, so that the adhesive surfaces of the two pigskins are evenly in close contact; then pull them apart at a speed of 1mm/min, measure the adhesive force and adhesive strength of the tannic acid aqueous solution, and repeat five times to get the average value. The results are shown in Table 1. Table 1 shows the adhesion test results of the anti-infective soft tissue medical glue obtained in Examples 1-12 of the present invention, the tannic acid aqueous solution in Comparative Example 1, and the Chinese medical fibrin glue in Comparative Example 2.

Comparative example 2

Fix the pigskin with a diameter of 6mm on the cylindrical fixture of the universal testing machine, take 3mg of medical fibrin glue (from Hangzhou Puji Medical Technology Development Co., Ltd.) and apply it between the front surfaces of the two pigskins After pulling apart and bonding 10 times, press with 20N force for 10 minutes, so that the bonded surfaces of the two pigskins are evenly in close contact; then pull them apart at a speed of 1mm/min, and measure the bonding force and strength of the medical fibrin glue. Bond strength, repeated five times to take the average value, the results are shown in Table 1.

The liver of the male rat (30-35 g in weight) was punctured, and 10 mg of medical fibrin glue (from Hangzhou Puji Medical Technology Development Co., Ltd.) was immediately stuck to the bleeding site, and the mass of the bleeding within 30 s was weighed to obtain the medical fibrin glue. Hemostatic effect, repeated five times to get the average value, the results are as shown in Figure 1, Figure 1 is the anti-infection soft tissue medical glue prepared in Example 1 of the present invention, the traditional Chinese medicine fibrin glue in Comparative Example 2 and Comparative Example 3 without any treatment blood flow.

Take 10 mg of medical fibrin glue (from Hangzhou Puji Medical Technology Development Co., Ltd.) and evenly stick it on a silicon wafer (1cm×1.2cm), in 2mL of LB culture solution with a bacterial concentration of 1×10 ⁶ cells/mL and a pH value of 7.4 After culturing at 37°C for 24 hours, stain with LIVE/DEAD Bac Light Bacterial Viability Kit, observe the bactericidal effect of medical fibrin glue cultured for 24 hours under the environment of pH value 7.4 with laser scanning confocal microscope, repeat five times, the results are shown in Figure 5 5 is a laser scanning confocal microscope image of bacteria cultured for 24 hours in an environment where the surface pH value of the silicon wafer modified with medical fibrin glue in Comparative Example 2 of the present invention is 7.4. Adjust the pH value of the LB culture medium to 5.5, incubate in 2 mL of LB culture liquid with a bacterial concentration of 1×10 ⁶ cells/mL and a pH value of 5.5 at 37°C for 24 hours, observe the bactericidal effect of medical fibrin glue in a weakly acidic environment, and repeat Five times, the results are shown in Figure 6, Figure 6 is a laser scanning confocal microscope image of bacteria cultured for 24 hours in an environment of 5.5 on the surface of silicon wafers modified with medical fibrin glue in Comparative Example 2 of the present invention. After culturing in 2 mL of LB culture medium (pH value 7.4) with a bacterial concentration of 1×10 ⁶ cells/mL at 37°C for 4 weeks, the long-term bactericidal effect of medical fibrin glue was observed and repeated five times. The results are shown in Figure 7. Fig. 7 is a confocal laser scanning microscope image of bacteria cultured for 4 weeks on the surface of a silicon wafer modified with medical fibrin glue in Comparative Example 2 of the present invention with a pH of 7.4. It can be seen from Figures 5 to 7 that, compared with the anti-infection soft tissue medical glue prepared by the present invention, medical fibrin glue has almost no bactericidal property, and a large number of living bacteria grow on the surface.

Comparative example 3

The liver of male rats (30-35 g in weight) was punctured without any treatment, and the mass of bleeding within 30 seconds was weighed to obtain the blood flow without any treatment. The average value was obtained after five repetitions. The results are shown in Figure 1.

It can be seen from the above examples that the present invention provides an anti-infective soft tissue medical glue prepared from plant polyphenols, water-soluble polymers, aminoglycoside antibiotics and solvents. The preparation raw materials of the anti-infective soft tissue medical glue provided by the present invention include plant polyphenols, water-soluble polymers and aminoglycoside antibiotics, wherein the catechol units in the plant polyphenols can hydrogen bond with the electron-donating groups in the water-soluble polymers respectively Combining and electrostatically combining with protonated aminoglycoside antibiotics in physiological environment to obtain anti-infection soft tissue medical glue. Compared with the existing technology, the soft tissue medical glue has higher cohesiveness, better biocompatibility, and better hemostatic performance, and the pH value will be different according to the amount of bacteria adhered to different parts of the material, and the responsiveness The release of antibiotics has better durability, avoiding the problems of drug resistance and gradual release of antibiotics caused by long-term exposure to antibiotics. Experimental results show that the anti-infection soft tissue medical glue provided by the invention has a cohesive force as high as 5.09N and a cohesive strength as high as 180kPa.

The preparation method provided by the invention is simple and convenient, has mild conditions, low cost and is suitable for large-scale production.

The above is only a preferred embodiment of the present invention, and it should be pointed out that for those of ordinary skill in the art, some improvements and modifications can be made without departing from the principle of the present invention. It should be regarded as the protection scope of the present invention.

Claims (5)

1. A kind of 1. anti-infective soft tissue medical adhesive, by plant polyphenol, water-soluble polymer, aminoglycoside antibiotics and solvent system It is standby to obtain；

   The mass ratio of the plant polyphenol, water-soluble polymer and aminoglycoside antibiotics is 100:(5~80):(0.1~ 40)；

   The plant polyphenol includes the one or more in tannic acid, catechin, morin and pyrogallol；The water-soluble poly Compound includes polyethylene glycol, polyethylene glycol oxide-PPOX-polyethylene glycol oxide, polyvinylpyrrolidone, chitosan, transparent One or more in matter acid, sodium alginate, polyetheramine and branched polyethylene imine；The aminoglycoside antibiotics includes sulphur One or more in sour gentamicin, TOB, polymyxin B, streptomysin, kanamycins and amikacin；It is described molten One or more of the agent in water, physiological saline and phosphate buffer solution.
2. 2. anti-infective soft tissue medical adhesive according to claim 1, it is characterised in that the number of the water-soluble polymer is equal Molecular weight is 1kDa~40kDa.
3. 3. the preparation method of anti-infective soft tissue medical adhesive, comprises the following steps described in a kind of claim 1~2 any one：

   Plant polyphenol, water-soluble polymer, aminoglycoside antibiotics and solvent are mixed, it is medical to obtain anti-infective soft tissue Glue.
4. 4. preparation method according to claim 3, it is characterised in that the temperature of the mixing is 0~60 DEG C；The mixing Time be 0.005~12 hour.
5. 5. preparation method according to claim 3, it is characterised in that the plant polyphenol, water-soluble polymer, amino sugar Tobramycin antibiotic and solvent mixing specifically include：

   Plant polyphenol, water-soluble polymer and aminoglycoside antibiotics are dissolved in a solvent respectively, it is more to respectively obtain plant Phenol solution, water-soluble polymer solution and Aminoglycoside solutions；By plant polyphenol solution, water-soluble polymer solution Mixed with Aminoglycoside solutions.