Biodegradable antibacterial medical adhesive and preparation method and application thereof

Abstract

The application relates to the technical field of medical adhesives, in particular to a biodegradable antibacterial medical adhesive as well as a preparation method and application thereof, which comprises the following components in mass fractions: 80-120 parts of polymerized monomers, 10-30 parts of gelatin, 1-10 parts of gallic acid, 5-20 parts of ethylenediamine, 1-20 parts of metal ions, 0.1-5 parts of ammonium persulfate and 1-10 parts of hyaluronic acid. The biodegradable antibacterial medical adhesive and the preparation method and application thereof are used, a degradable skeleton is constructed through the polymerized monomers, the gelatin and the hyaluronic acid, the gallic acid and the metal ions realize antibacterial and hemostatic synergy, the ethylenediamine strengthens crosslinking to improve mechanical properties, and the obtained medical adhesive has a high bacteriostatic rate and excellent biocompatibility.

Description

Technical Field

[0001] This invention relates to the field of medical adhesives, and in particular to a biodegradable antibacterial medical adhesive, its preparation method, and its application. Background Technology

[0002] Medical adhesives, as an important supplement or alternative to suturing techniques, play a crucial role in surgical procedures, wound closure, and hemostasis. An ideal medical adhesive should possess excellent tissue adhesion, good biocompatibility, biodegradability to match the tissue healing rate, and a certain degree of antibacterial ability to prevent postoperative infection.

[0003] Many existing adhesives struggle to simultaneously meet the multiple requirements of strong adhesion, controllable degradation, effective antibacterial properties, and good biocompatibility. For example, achieving antibacterial function through physical blending with antibiotics presents challenges such as drug burst release and drug resistance. Therefore, developing novel medical adhesives based on natural ingredients, achieving high-strength adhesion through multiple chemical cross-linking mechanisms, and possessing both intrinsic antibacterial activity and controllable biodegradability has become an urgent need in this field. Summary of the Invention

[0004] The purpose of this invention is to provide a biodegradable antibacterial medical adhesive, its preparation method and application. A biodegradable framework is constructed by polymerizing monomers, gelatin and hyaluronic acid, gallic acid and metal ions achieve synergistic antibacterial and hemostatic effects, and ethylenediamine strengthens crosslinking to improve mechanical properties. The resulting medical adhesive has a high antibacterial rate and excellent biocompatibility.

[0005] To achieve the above objectives, the present invention provides a biodegradable antibacterial medical adhesive comprising the following components by mass: 80-120 parts of polymeric monomer, 10-30 parts of gelatin, 1-10 parts of gallic acid, 5-20 parts of ethylenediamine, 1-20 parts of metal ions, 0.1-5 parts of ammonium persulfate, and 1-10 parts of hyaluronic acid.

[0006] Preferably, the metal ions include one or more of calcium ions, magnesium ions, zinc ions, iron ions, and silver ions.

[0007] Preferably, the polymerizing monomers include one or more of acrylic acid, hydroxyethyl acrylate, itaconic acid, fumaric acid, and hydroxyethyl methacrylate.

[0008] A method for preparing a biodegradable antibacterial medical adhesive, comprising the following steps: S1. Dissolve gelatin in deionized water and stir until completely dissolved to obtain a gelatin solution. Add hyaluronic acid and continue stirring to obtain a mixed solution. S2. Add the polymerizable monomer to the mixed solution obtained in S1, stir until homogeneous, heat, add ammonium persulfate and stir, lower the temperature and add gallic acid and continue stirring to obtain a mixed system. S3. Add metal ions to the mixture obtained in S2, and slowly add ethylenediamine dropwise while stirring to obtain the adhesive colloid. S4. Place the adhesive colloid obtained in S3 into a vacuum degassing machine to degas and sterilize it to obtain a medical adhesive, which should be stored in the dark and refrigerated.

[0009] Preferably, in S1, the stirring temperature is 40-50°C. The stirring speed is 300-500 rpm, and the stirring time is 10-60 min.

[0010] Preferably, in S2, the stirring speed is 400-800 rpm, the heating temperature is 50-60℃, and the cooling temperature is 25-40℃.

[0011] Preferably, in S3, the stirring temperature is 25-40°C. The stirring speed is 200-500 rpm, and the stirring time is 0.5-2 hours.

[0012] Preferably, in step S4, the vacuum degassing pressure is 0.08-0.2 MPa, and the degassing time is 5-30 min.

[0013] Preferably, in S4, sterilization is performed by filtration using a sterile filter membrane.

[0014] The aforementioned biodegradable antibacterial medical adhesive is used in medical materials for bonding bone tissue, bonding surgical incisions, and stopping bleeding from wounds.

[0015] Therefore, the present invention employs the above-mentioned biodegradable antibacterial medical adhesive, its preparation method, and its application, with the following beneficial effects: 1. This invention constructs a biodegradable framework using polymer monomers, gelatin, and hyaluronic acid. Gallic acid and metal ions achieve synergistic antibacterial and hemostatic effects, while ethylenediamine enhances cross-linking and improves mechanical properties. The resulting medical adhesive has a high antibacterial rate, excellent biocompatibility, and a biodegradation cycle of about two weeks. 2. The preparation method provided by this invention does not require high temperature and high pressure conditions, making it suitable for large-scale production. It can be adapted to different application scenarios by adjusting the types of metal ions, covering multiple fields such as wound hemostasis, surgical incisions, and bone tissue repair.

[0016] The technical solution of the present invention will be further described in detail below through embodiments. Detailed Implementation

[0017] The present invention will be further described below with reference to embodiments. Unless otherwise defined, the technical or scientific terms used in this invention should have the ordinary meaning understood by one of ordinary skill in the art. The features mentioned above or in the specific examples mentioned in this invention can be combined arbitrarily, and these specific embodiments are only used to illustrate the invention and are not intended to limit the scope of the invention.

[0018] This invention provides a biodegradable antibacterial medical adhesive, comprising the following components by weight: 80-120 parts of polymeric monomers, 10-30 parts of gelatin, 1-10 parts of gallic acid, 5-20 parts of ethylenediamine, 1-20 parts of metal ions, 0.1-5 parts of ammonium persulfate, and 1-10 parts of hyaluronic acid. The polymeric monomers are polymerized via ammonium persulfate polymerization to form a polymer, which serves as the mechanical framework of the adhesive. The amino groups of gelatin react with the carboxyl groups of the polymer and the amino groups of ethylenediamine, while the hydroxyl groups of hyaluronic acid form hydrogen bonds with gallic acid, collectively contributing to biocompatibility and controllable degradation. The metal ions act as coordination centers, chelating with gallic acid to perform hemostatic, bone repair promoting, and antibacterial functions according to the application requirements.

[0019] In some embodiments of the present invention, the metal ions include one or more of calcium ions, magnesium ions, zinc ions, iron ions, and silver ions. Calcium ions (calcium chloride hexahydrate) exert a hemostatic effect and form a stable chelate with gallic acid, enhancing cross-linking strength. Magnesium ions (magnesium sulfate heptahydrate), as an osteoblast activity regulator, promote callus formation and hydroxyapatite deposition, suitable for bone tissue repair scenarios. Zinc ions have mild antibacterial properties and promote epithelial cell migration, suitable for chronic wounds. Iron ions' strong oxidizing properties disrupt bacterial cell membranes and form a blue-black chelate with gallic acid, suitable for infected wounds.

[0020] In some embodiments of the present invention, the polymeric monomers include one or more of acrylic acid, hydroxyethyl acrylate, itaconic acid, fumaric acid, and hydroxyethyl methacrylate. The polymeric monomers form the polymeric backbone of the adhesive through free radical polymerization, while simultaneously providing reactive groups such as carboxyl and hydroxyl groups to crosslink with gelatin, ethylenediamine, and metal ions, ultimately endowing the adhesive with mechanical strength, wet adhesion, biodegradability, and biocompatibility.

[0021] A method for preparing a biodegradable antibacterial medical adhesive, comprising the following steps: S1. Dissolve gelatin in deionized water and stir until completely dissolved to obtain a gelatin solution. Add hyaluronic acid and continue stirring to obtain a mixed solution. S2. Add the polymerizable monomer to the mixed solution obtained in S1, stir until homogeneous, heat, add ammonium persulfate and stir, lower the temperature and add gallic acid and continue stirring to obtain a mixed system. S3. Add metal ions to the mixture obtained in S2, and slowly add ethylenediamine dropwise while stirring to obtain the adhesive colloid. S4. Place the adhesive colloid obtained in S3 into a vacuum degassing machine to degas and sterilize it to obtain a medical adhesive, which should be stored in the dark and refrigerated.

[0022] In some embodiments of the present invention, in S1, the stirring temperature is 40-50°C. The stirring speed is 300-500 rpm, and the stirring time is 10-60 min. The temperature range is controlled to dissolve the gelatin to avoid its denaturation at high temperatures. Hyaluronic acid is added to swell and form a uniform natural polymer matrix, providing reaction sites for subsequent polymerization.

[0023] In some embodiments of the present invention, in step S2, the stirring speed is 400-800 rpm and the heating temperature is 50-60°C. Lower the temperature to 25-40 degrees Celsius. Controlling the reaction conditions initiates the polymerization of monomers to form polymer chains; the temperature is then lowered to 25-40°C. Gallic acid was then added to prevent the high temperature from damaging the phenolic hydroxyl structure.

[0024] In some embodiments of the present invention, in step S3, the stirring temperature is 25-40°C. The stirring speed is 200-500 rpm, and the stirring time is 0.5-2 hours. Metal ions are added to form coordination crosslinks with gallic acid, and ethylenediamine is added slowly dropwise to avoid excessive local alkalinity that could denature the gelatin. Covalent crosslinks are formed through an amidation reaction, constructing a coordination-covalent dual network.

[0025] In some embodiments of the present invention, in step S4, the vacuum degassing pressure is 0.08-0.2 MPa, and the degassing time is 5-30 min. The purpose of vacuum degassing is to remove air bubbles to prevent the formation of voids during adhesion.

[0026] In some embodiments of the present invention, in S4, sterilization is performed by using a sterile filter membrane for filtration, and the sterilization operation ensures that medical sterility standards are met.

[0027] The aforementioned biodegradable antibacterial medical adhesive is used in medical materials for bonding bone tissue, bonding surgical incisions, and stopping bleeding from wounds.

[0028] Example 1 S1. Dissolve 10 parts of gelatin in deionized water, stirring at 400 rpm. Stir for 20 minutes until completely dissolved to obtain a gelatin solution. Add 1 part of hyaluronic acid and continue stirring for 20 minutes to obtain a mixed solution.

[0029] S2. Add 80 parts of acrylic acid to the mixed solution obtained in S1, stir at 500 rpm, and heat to 55°C after stirring until homogeneous. Add 1 part ammonium persulfate and stir, then lower the temperature to 30°C. Then add 1 part gallic acid and continue stirring to obtain a mixed system.

[0030] S3. Add 1 part of metal ions (calcium ions and zinc ions mixed in a 1:1 mass ratio) to the mixed system obtained in S2, and slowly add 5 parts of ethylenediamine dropwise while stirring at 30°C. The stirring speed was 400 rpm and the stirring time was 1 hour. The adhesive colloid was obtained by adding and stirring at the same time.

[0031] S4. Place the adhesive colloid obtained in S3 into a vacuum degassing machine for degassing. The vacuum degassing pressure is 0.1 MPa and the degassing time is 20 min. Filter the colloid through a 0.22 μm sterile filter membrane for sterilization. After sterilization, the medical adhesive is obtained and stored in a cool, dark place.

[0032] Example 2 S1. Dissolve 30 parts of gelatin in deionized water, stirring at 400 rpm. Stir for 20 minutes until completely dissolved to obtain a gelatin solution. Add 10 parts of hyaluronic acid and continue stirring for 20 minutes to obtain a mixed solution.

[0033] S2. Add 120 parts of hydroxyethyl acrylate to the mixed solution obtained in S1, stir at 500 rpm, and heat to 55°C after stirring until homogeneous. Add 2 parts ammonium persulfate and stir, then lower the temperature to 30°C. Then add 2 parts gallic acid and continue stirring to obtain a mixed system.

[0034] S3. Add 20 parts of metal ions (iron ions) to the mixture obtained in S2, and slowly add 20 parts of ethylenediamine dropwise while stirring at 30°C. The stirring speed was 400 rpm and the stirring time was 1 hour. The adhesive colloid was obtained by adding and stirring at the same time.

[0035] S4. Place the adhesive colloid obtained in S3 into a vacuum degassing machine for degassing. The vacuum degassing pressure is 0.1 MPa and the degassing time is 20 min. Filter the colloid through a 0.22 μm sterile filter membrane for sterilization. After sterilization, the medical adhesive is obtained and stored in a cool, dark place.

[0036] Example 3 S1. Dissolve 20 parts of gelatin in deionized water, stirring at 400 rpm. Stir for 20 minutes until completely dissolved to obtain a gelatin solution. Add 3 parts of hyaluronic acid and continue stirring for 20 minutes to obtain a mixed solution.

[0037] S2. Add 100 parts itaconic acid to the mixed solution obtained in S1, stir at 500 rpm, and heat to 55°C after stirring until homogeneous. Add 1 part ammonium persulfate and stir, then lower the temperature to 30°C. Then add 3 parts gallic acid and continue stirring to obtain a mixed system.

[0038] S3. Add 15 parts of metal ions (calcium ions and magnesium ions mixed in a mass ratio of 1.5:1) to the mixed system obtained in S2, and slowly add 10 parts of ethylenediamine dropwise while stirring at 30°C. The stirring speed was 400 rpm and the stirring time was 1 hour. The adhesive colloid was obtained by adding and stirring at the same time.

[0039] S4. Place the adhesive colloid obtained in S3 into a vacuum degassing machine for degassing. The vacuum degassing pressure is 0.1 MPa and the degassing time is 20 min. Filter the colloid through a 0.22 μm sterile filter membrane for sterilization. After sterilization, the medical adhesive is obtained and stored in a cool, dark place.

[0040] Example 4 S1. Dissolve 25 parts of gelatin in deionized water, stirring at 400 rpm. Stir for 20 minutes until completely dissolved to obtain a gelatin solution. Add 5 parts of hyaluronic acid and continue stirring for 20 minutes to obtain a mixed solution.

[0041] S2. Add 120 parts of fumaric acid to the mixed solution obtained in S1, stir at 500 rpm, and heat to 55°C after stirring until homogeneous. Add 1 part ammonium persulfate and stir, then lower the temperature to 30°C. Then add 5 parts gallic acid and continue stirring to obtain a mixed system.

[0042] S3. Add 18 parts of metal ions (magnesium ions) to the mixture obtained in S2, and slowly add 12 parts of ethylenediamine dropwise while stirring at 30°C. The stirring speed was 400 rpm and the stirring time was 1 hour. The adhesive colloid was obtained by adding and stirring at the same time.

[0043] S4. Place the adhesive colloid obtained in S3 into a vacuum degassing machine for degassing. The vacuum degassing pressure is 0.1 MPa and the degassing time is 20 min. Filter the colloid through a 0.22 μm sterile filter membrane for sterilization. After sterilization, the medical adhesive is obtained and stored in a cool, dark place.

[0044] Example 5 S1. Dissolve 30 parts of gelatin in deionized water, stirring at 400 rpm. Stir for 20 minutes until completely dissolved to obtain a gelatin solution. Add 8 parts of hyaluronic acid and continue stirring for 20 minutes to obtain a mixed solution.

[0045] S2. Add 120 parts of hydroxyethyl methacrylate to the mixed solution obtained in S1, stir at 500 rpm, and heat to 55°C after stirring until homogeneous. Add 1.5 parts of ammonium persulfate and stir, then lower the temperature to 30°C. Then add 8 parts gallic acid and continue stirring to obtain a mixed system.

[0046] S3. Add 20 parts of metal ions (calcium ions, zinc ions, and iron ions mixed in a mass ratio of 1:1:1) to the mixed system obtained in S2, and slowly add 15 parts of ethylenediamine dropwise while stirring at 30°C. The stirring speed was 400 rpm and the stirring time was 1 hour. The adhesive colloid was obtained by adding and stirring at the same time.

[0047] S4. Place the adhesive colloid obtained in S3 into a vacuum degassing machine for degassing. The vacuum degassing pressure is 0.1 MPa and the degassing time is 20 min. Filter the colloid through a 0.22 μm sterile filter membrane for sterilization. After sterilization, the medical adhesive is obtained and stored in a cool, dark place.

[0048] Comparative Example 1 S1. Dissolve 20 parts of gelatin in deionized water, stirring at 400 rpm. Stir for 20 minutes until completely dissolved to obtain a gelatin solution. Add 3 parts of hyaluronic acid and continue stirring for 20 minutes to obtain a mixed solution.

[0049] S2. Add 100 parts of acrylic acid to the mixed solution obtained in S1, stir at 500 rpm, stir until homogeneous, and then heat to 55°C. Add 1 part ammonium persulfate and stir to obtain a mixed system.

[0050] S3. Slowly add 10 parts of ethylenediamine dropwise to the mixture obtained in S2, while stirring at 30°C. The stirring speed was 400 rpm and the stirring time was 1 hour. The adhesive colloid was obtained by adding and stirring at the same time.

[0051] S4. Place the adhesive colloid obtained in S3 into a vacuum degassing machine for degassing. The vacuum degassing pressure is 0.1 MPa and the degassing time is 20 min. Filter the colloid through a 0.22 μm sterile filter membrane for sterilization. After sterilization, the medical adhesive is obtained and stored in a cool, dark place.

[0052] Test case The medical adhesives obtained in Examples 1-5 and Comparative Example 1 were subjected to the following performance tests, and the results are shown in Table 1.

[0053] The pH of the adhesive colloid was directly measured using a pH meter (25). ); In a simulated body fluid (PBS, pH 7.4) at 37°C, the time from contact with the adhesive to loss of fluidity was recorded. According to ASTM D3359, test the force (in N / cm) when the adhesive peels off the tissue surface. Apply the adhesive to PBS (37) Soak in water and periodically measure the weight change before and after swelling. Calculate the swelling rate (%) = (weight after swelling - initial weight) / initial weight × 100%.

[0054] Table 1. Performance data of Chinese medicine adhesives in Examples 1-5 and comparative examples.

[0055] The medical adhesives obtained in Examples 1-5 and Comparative Example 1 were subjected to the following bioperformance tests, and the results are shown in Table 2.

[0056] L929 fibroblasts or human umbilical vein endothelial cells (HUVECs) were used to determine the adhesive extract (37) using the MTT assay. Cell viability (%) after 24 hours; The adhesive was soaked in PBS, and the extract was periodically taken to test the antibacterial rate and record the duration of antibacterial performance. In simulated body fluids (PBS, pH 7.4, 37) In the experiment, the weight loss rate (%) of the adhesive was measured periodically after two weeks = (initial weight - weight after degradation) / initial weight × 100%.

[0057] Table 2, Bioperformance data of traditional Chinese medicine adhesives in Examples 1-5 and Comparative Example 1

[0058] As shown in Tables 1 and 2, the medical adhesives obtained in Examples 1-5 exhibited superior antibacterial rates and cell viability compared to the medical adhesive in Comparative Example 1, indicating that the presence of gallic acid and metal ions significantly enhanced the antibacterial properties of the medical adhesives. Furthermore, the medical adhesives in Examples 1-5 demonstrated excellent biodegradability and were non-cytotoxic.

[0059] Therefore, the present invention adopts the above-mentioned biodegradable antibacterial medical adhesive and its preparation method and application. By constructing a biodegradable framework through polymer monomers, gelatin and hyaluronic acid, gallic acid and metal ions achieve synergistic antibacterial and hemostatic effects, and ethylenediamine strengthens cross-linking to improve mechanical properties. The resulting medical adhesive has a high antibacterial rate and excellent biocompatibility.

[0060] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can still be made to the technical solutions of the present invention, and these modifications or equivalent substitutions cannot cause the modified technical solutions to deviate from the spirit and scope of the technical solutions of the present invention.

Claims

1. A biodegradable antibacterial medical adhesive, characterized in that: The product comprises the following components by mass: 80-120 parts of polymeric monomer, 10-30 parts of gelatin, 8 parts of gallic acid, 5-20 parts of ethylenediamine, 1-20 parts of metal ions, 1.5 parts of ammonium persulfate, and 1-10 parts of hyaluronic acid. Metal ions include one or more of the following: calcium ions, magnesium ions, zinc ions, iron ions, and silver ions. The polymeric monomers include one or more of acrylic acid, hydroxyethyl acrylate, itaconic acid, fumaric acid, and hydroxyethyl methacrylate; the preparation method of the above-mentioned biodegradable antibacterial medical adhesive includes the following steps: S1. Dissolve gelatin in deionized water and stir until completely dissolved to obtain a gelatin solution. Add hyaluronic acid and continue stirring to obtain a mixed solution. S2. Add the polymerizable monomer to the mixed solution obtained in S1, stir until homogeneous, heat, add ammonium persulfate and stir, lower the temperature and add gallic acid and continue stirring to obtain a mixed system. In S2, the stirring speed is 400-800 rpm, the heating temperature is 50-60℃, and the cooling temperature is 25-40℃. S3. Add metal ions to the mixture obtained in S2, and slowly add ethylenediamine dropwise while stirring to obtain the adhesive colloid. S4. Place the adhesive colloid obtained in S3 into a vacuum degassing machine to degas and sterilize it to obtain a medical adhesive, which should be stored in the dark and refrigerated.

2. The biodegradable antibacterial medical adhesive according to claim 1, characterized in that: In S1, the stirring temperature is 40-50℃, the stirring speed is 300-500rpm, and the stirring time is 10-60min.

3. The biodegradable antibacterial medical adhesive according to claim 1, characterized in that: In S3, the stirring temperature is 25-40℃, the stirring speed is 200-500rpm, and the stirring time is 0.5-2h.

4. The biodegradable antibacterial medical adhesive according to claim 1, characterized in that: In S4, the vacuum degassing pressure is 0.08-0.2 MPa, and the degassing time is 5-30 min.

5. The biodegradable antibacterial medical adhesive according to claim 1, characterized in that: In S4, sterilization is achieved by using sterile filter membranes for filtration.

6. The application of a biodegradable antibacterial medical adhesive, characterized in that: The biodegradable antibacterial medical adhesive according to any one of claims 1-5 is used in medical materials for bonding bone tissue, bonding surgical incisions, and stopping bleeding from wounds.

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