Cyanoacrylate medical blood vessel plugging glue and preparation method thereof

Abstract

The invention relates to the field of biomedical materials, in particular to cyanoacrylate medical blood vessel blocking glue and a preparation method thereof.The cyanoacrylate medical blood vessel blocking glue is prepared from, by mass, 30-35 parts of 2-octyl cyanoacrylate, 7-8 parts of lactide modified hydroxyethyl methylacrylate, 0.02-0.03 part of polymerization inhibitor propyl gallate, 0.02-0.03 part of initiator, 0.02-0.03 part of initiator, 0.02-0.03 part of initiator, 0.02-0.03 part of initiator and the balance water. By innovatively adopting various functional components and carrying out synergistic compatibility and precise preparation, compared with the prior art, the comprehensive performance of the product is remarkably improved, and the plugging agent has the advantages of rapid and reliable plugging effect, good plugging effect, good plugging effect, good plugging effect, good plugging effect, good plugging effect, good plugging effect, good plugging effect, good plugging effect and the like. Meanwhile, good biocompatibility, intraoperative developing capacity and a potential drug sustained release function are achieved, operation is easy and convenient, performance is stable, a safer and more efficient choice is provided for clinical vascular interventional therapy, and wide application prospects are achieved in the fields of cardiovascular and neurological intervention, peripheral vascular embolism and the like.

Description

Technical Field

[0001] This invention relates to the field of biomedical materials, and more particularly to a cyanoacrylate-based medical vascular occlusion adhesive and its preparation method. Background Technology

[0002] Cyanoacrylate-based medical vascular occlusion adhesives are a class of rapidly curing biomaterials constructed from cyanoacrylate monomers and their derivatives. They achieve physical sealing of vascular ruptures or puncture sites through in-situ polymerization reactions in vivo, and are one of the key materials in minimally invasive interventional therapy.

[0003] These products are mainly used in cardiovascular interventional surgery, tumor embolization therapy, and emergency treatment of vascular bleeding. They are designed to replace traditional suturing or compression hemostasis methods, improve surgical efficiency, and reduce the difficulty of operation.

[0004] In existing technologies, cyanoacrylate-based vascular occlusion products, while achieving rapid occlusion to a certain extent, often struggle to balance multiple clinical needs due to their relatively simple component design and limited functionality. Furthermore, conventional products typically lack imaging capabilities, making real-time visualization and management of the occlusion location impossible during surgery. They also lack the ability to actively promote tissue repair or reduce inflammation, limiting their application in more demanding interventional procedures. Additionally, current manufacturing processes have insufficient control over storage stability, leading to shorter product shelf lives or performance fluctuations, thus affecting the safety and reliability of clinical use.

[0005] Therefore, based on the relevant technologies mentioned above, there is an urgent need to develop a cyanoacrylate-based medical vascular occlusion adhesive and its preparation method. Summary of the Invention

[0006] In view of this, the purpose of this invention is to provide a cyanoacrylate-based medical vascular occlusion adhesive and its preparation method, so as to solve the problems of single function, poor operational controllability, lack of radioactivity and bioactivity, and insufficient storage stability in the prior art.

[0007] To achieve the above objectives, the present invention provides a cyanoacrylate-based medical vascular occlusion adhesive and its preparation method.

[0008] A cyanoacrylate-based medical vascular occlusion adhesive, comprising the following components in parts by weight: 30-35 parts of 2-octyl cyanoacrylate, 7-8 parts of lactide-modified hydroxyethyl methacrylate, 0.02-0.03 parts of polymerization inhibitor propyl gallate, 2-3 parts of thickener polylactic acid-glycolic acid copolymer, 3-5 parts of silane coupling agent-modified nano-tungsten powder, 0.7-0.8 parts of nano-hydroxyapatite, 0.2-0.3 parts of microcapsules, 49-50 parts of phosphate-buffered saline, 0.7-0.8 parts of sodium bicarbonate, and 0.2-0.3 parts of medical-grade sodium hyaluronate.

[0009] Preferably, the preparation steps of the lactide-modified hydroxyethyl methacrylate are as follows: Under an argon atmosphere, hydroxyethyl methacrylate and lactide were added to propylene glycol methyl ether solvent and stirred. Stannous octoate catalyst was added, and the temperature was raised to 125-135℃. The reaction was carried out for 10-12 hours until the reaction was complete. The temperature was then lowered to 20-30℃ to precipitate the product. The precipitate was filtered, washed, and dried to obtain lactide-modified hydroxyethyl methacrylate.

[0010] Preferably, the mass ratio of hydroxyethyl methacrylate, lactide, and catalyst is 0.005-0.007:1:0.002-0.004.

[0011] Preferably, the preparation steps of the silane coupling agent modified tungsten nanoparticles are as follows: Step A1: Add silane coupling agent KH-550 to a mixed solvent of medical grade ethanol and deionized water, heat to 25-35℃, add citric acid, adjust the pH to 4-5, react for 40-60 minutes, and the reaction is complete to obtain silane coupling agent hydrolysate. Step A2: Add nano-tungsten powder and silane coupling agent hydrolysate to medical-grade ethanol solvent, stir for 20-40 min, cool to 5-10℃, sonicate for 30-50 min at 300-500W, heat to 65-75℃, reflux for 5-7 h, after the reaction is complete, cool to 20-30℃, filter, wash, dry, grind, and pass through an 800-mesh sieve to obtain silane coupling agent modified nano-tungsten powder.

[0012] Preferably, the mass ratio of silane coupling agent KH-550, medical-grade ethanol, and deionized ethanol in step A1 is 0.9-1.1:1:8.8-9.2. The mass ratio of the nano-tungsten powder to the silane coupling agent hydrolysate in step A2 is 0.1-0.2:1.

[0013] Preferably, the preparation steps of the microcapsules are as follows: Step B1: Add polylactic acid-glycolic acid copolymer and 2,2-dimethoxy-2-phenylacetophenone to ethyl acetate, heat to 15-25℃, and stir for 60-80 min to obtain an organic phase solution; Step B2: Add polyvinyl alcohol to deionized water, heat to 80-90℃, stir for 2-3 hours, cool to 20-30℃, add organic phase solution, stir for 8-12 minutes, cool to 0-4℃, sonicate for 2-4 minutes at 200-400W to obtain emulsion; Step B3: Add the emulsion to deionized water, heat to 20-30℃, stir for 4-6 hours at 400-600 rpm, and after the reaction is complete, centrifuge to settle, wash and dry to obtain microcapsules.

[0014] Microencapsulation technology enables drug encapsulation and sustained release, further promoting healing or anti-inflammation after occlusion. At the same time, the synergistic effect of polylactic acid glycolic acid copolymer and sodium hyaluronate not only modulates the rheology of the material, but also provides excellent lubricity and cell affinity, reduces foreign body reaction, and improves biocompatibility.

[0015] Preferably, the mass ratio of the polylactic acid-glycolic acid copolymer to 2,2-dimethoxy-2-phenylacetophenone in step B1 is 4-5:1; In step B2, the mass ratio of polyvinyl alcohol, deionized water, and organic phase solution is 0.05-0.07:5.8-6.2:1. The mass ratio of the emulsion to deionized water in step B3 is 1:3.8-4.2.

[0016] A method for preparing a cyanoacrylate-based medical vascular occlusion adhesive, comprising the following steps: Step S1: Under a nitrogen atmosphere, lactide-modified hydroxyethyl methacrylate and thickener are added to 2-octyl cyanoacrylate, cooled to 0-5℃, stirred for 2-4 hours at 100-200 rpm, silane coupling agent-modified nano-tungsten powder and nano-hydroxyapatite are added, stirred for 15-20 minutes at 200-400 rpm, placed in a high-speed homogenizer, stirred for 20-40 minutes at 900-1100 rpm to obtain a suspension; Step S2: Under a nitrogen atmosphere, add propyl gallate to medical grade ethanol, stir to dissolve, cool to 0-5℃, add to the suspension, stir for 30-45 min at 200-300 rpm, add microcapsules, stir for 20-30 min at 50-80 rpm to obtain component A. Step S3: Under aseptic conditions, add medical-grade sodium hyaluronate to phosphate-buffered saline, heat to 20-30℃, stir for 15-20 minutes, cool to 2-8℃, and let stand for 12-16 hours to swell, to obtain a viscous solution. Step S4: Add sodium bicarbonate powder to the viscous solution, heat to 20-30℃, stir for 15-20 min at 300-400 rpm, add phosphate buffered physiological saline, stir for 10-15 min at 200-300 rpm, filter through a 0.22 μm filter membrane to obtain component B; Step S5: Add component A to component B, heat to 20-30℃, react for 2-4 seconds to obtain vascular occlusion adhesive.

[0017] Based on 2-octyl cyanoacrylate, it can undergo rapid anionic polymerization under physiological conditions to achieve immediate vascular occlusion. By introducing lactide-modified hydroxyethyl methacrylate to regulate the polymerization rate and material toughness, and by using sodium bicarbonate to provide an alkaline environment to precisely control the curing time, both the convenience of surgical operation and the reliability of final occlusion are taken into account.

[0018] By adding silane coupling agents to modify nano-tungsten powder and nano-hydroxyapatite, the mechanical strength and wear resistance of the sealing adhesive are improved. Nano-tungsten powder gives the product excellent X-ray impermeability, facilitating real-time intraoperative imaging and postoperative tracking. Nano-hydroxyapatite enhances bioactivity, synergistically promoting tissue integration and long-term stability. Furthermore, medical-grade sodium hyaluronate and phosphate-buffered saline work together to create a hydrophilic sustained-release environment, improving tissue compatibility and wettability, and reducing foreign body reactions. In addition, the silane coupling agent treatment enhances the interfacial bonding between inorganic nano-tungsten powder and the organic matrix, preventing agglomeration and ensuring uniform dispersion.

[0019] By using an AB two-component system design, the monomers are separated from the reaction environment. The mixture solidifies rapidly upon use, effectively avoiding prepolymerization issues. At the same time, propyl gallate acts as a polymerization inhibitor, and the inert atmosphere throughout the process ensures the stability of each component during storage, giving the product a longer shelf life and reliable clinical performance.

[0020] Preferably, the mass ratio of 2-octyl cyanoacrylate, lactide-modified hydroxyethyl methacrylate, thickener, silane coupling agent-modified nano-tungsten powder, and nano-hydroxyapatite in step S1 is 1:0.2-0.25:0.05-0.08:0.1-0.12:0.02-0.03; In step S2, the mass ratio of propyl gallate, suspension, and microcapsules is 0.0003-0.0005:1:0.0004-0.0006. The mass ratio of medical-grade sodium hyaluronate to phosphate-buffered saline in step S3 is 1:90-110; In step S4, the mass ratio of sodium bicarbonate powder, viscous solution, and phosphate-buffered saline is 0.02-0.04:1:0.96-0.98. In step S5, the mass ratio of component A to component B is 1.2-1.4:1.

[0021] Preferably, the pH of the phosphate-buffered saline solution in steps S3 and S4 is 7.4.

[0022] The beneficial effects of this invention are: This invention provides a cyanoacrylate-based medical vascular occlusion adhesive and its preparation method. By innovatively employing multiple functional components and synergistic formulation and precise preparation, this invention significantly improves the overall performance of the product compared to existing technologies. It exhibits rapid and reliable occlusion effects, while also possessing good biocompatibility, intraoperative imaging capability, and potential drug sustained-release function. It is easy to operate and has stable performance, providing a safer and more efficient option for clinical vascular interventional therapy. It has broad application prospects in the fields of cardiovascular, neurointerventional, and peripheral vascular embolization. Detailed Implementation

[0023] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments.

[0024] Example 1: The preparation steps of lactide-modified hydroxyethyl methacrylate are as follows: Under an argon atmosphere, 0.5 g of hydroxyethyl methacrylate and 100 g of lactide were added to 150 mL of propylene glycol methyl ether solvent, stirred and mixed, and 0.2 g of stannous octoate catalyst was added. The mixture was heated to 125 °C and reacted for 12 h. After the reaction was completed, the temperature was lowered to 20 °C, the precipitate was collected, filtered, washed, and dried to obtain lactide-modified hydroxyethyl methacrylate.

[0025] Example 2: The preparation steps of lactide-modified hydroxyethyl methacrylate are as follows: Under an argon atmosphere, 0.6 g of hydroxyethyl methacrylate and 100 g of lactide were added to 150 mL of propylene glycol methyl ether solvent and stirred. 0.3 g of stannous octoate catalyst was added, the temperature was raised to 130 °C, and the reaction was carried out for 11 h. After the reaction was completed, the temperature was lowered to 25 °C, the precipitate was collected, filtered, washed, and dried to obtain lactide-modified hydroxyethyl methacrylate.

[0026] Example 3: The preparation steps of lactide-modified hydroxyethyl methacrylate are as follows: Under an argon atmosphere, 0.7 g of hydroxyethyl methacrylate and 100 g of lactide were added to 150 mL of propylene glycol methyl ether solvent and stirred. 0.4 g of stannous octoate catalyst was added, the temperature was raised to 135 °C, and the reaction was carried out for 10 h. After the reaction was completed, the temperature was lowered to 30 °C, the precipitate was collected, filtered, washed, and dried to obtain lactide-modified hydroxyethyl methacrylate.

[0027] Example 4: The preparation steps of silane coupling agent modified nano-tungsten powder are as follows: S1: Add 9g of silane coupling agent KH-550 to a mixed solvent of 10g of medical grade ethanol and 88g of deionized water, heat to 25℃, add citric acid, adjust the pH to 4-5, react for 60min, and the reaction is complete to obtain silane coupling agent hydrolysate. S2: Add 10g of nano-tungsten powder and 100g of silane coupling agent hydrolysate to 150mL of medical-grade ethanol solvent, stir for 20min, cool to 10℃, sonicate for 30min at 500W, heat to 65℃, reflux for 7h, after the reaction is complete, cool to 20℃, filter, wash, dry, grind, and pass through an 800-mesh sieve to obtain silane coupling agent modified nano-tungsten powder.

[0028] Example 5: The preparation steps of silane coupling agent modified nano-tungsten powder are as follows: S1: Add 10g of silane coupling agent KH-550 to a mixed solvent of 10g of medical grade ethanol and 90g of deionized water, heat to 30℃, add citric acid, adjust the pH to 4-5, react for 50min, and the reaction is complete to obtain silane coupling agent hydrolysate. S2: Add 15g of nano-tungsten powder and 100g of silane coupling agent hydrolysate to 150mL of medical-grade ethanol solvent, stir for 30min, cool to 8℃, sonicate for 40min at 400W power, heat to 70℃, reflux for 6h, after the reaction is complete, cool to 25℃, filter, wash, dry, grind, and pass through an 800-mesh sieve to obtain silane coupling agent modified nano-tungsten powder.

[0029] Example 6: The preparation steps of silane coupling agent modified nano-tungsten powder are as follows: S1: Add 11g of silane coupling agent KH-550 to a mixed solvent of 10g of medical grade ethanol and 92g of deionized water, heat to 35℃, add citric acid, adjust the pH to 4-5, react for 60min, and the reaction is complete to obtain silane coupling agent hydrolysate. S2: Add 20g of nano-tungsten powder and 100g of silane coupling agent hydrolysate to 150mL of medical-grade ethanol solvent, stir for 40min, cool to 5℃, sonicate for 50min at 300W power, heat to 75℃, reflux for 5h, after the reaction is complete, cool to 30℃, filter, wash, dry, grind, and pass through an 800-mesh sieve to obtain silane coupling agent modified nano-tungsten powder.

[0030] Example 7: The preparation steps of the microcapsules are as follows: S1: Add 40g of polylactic acid-glycolic acid copolymer and 10g of 2,2-dimethoxy-2-phenylacetophenone to 100mL of ethyl acetate, heat to 15℃, and stir for 80min to obtain an organic phase solution. S2: Add 5g of polyvinyl alcohol to 580g of deionized water, heat to 80℃, stir for 3h, cool to 20℃, add 100g of organic phase solution, stir for 8min, cool to 4℃, sonicate for 2min at 400W to obtain emulsion. S3: Add 100g of emulsion to 380g of deionized water, heat to 20℃, stir for 6 hours at 400rpm, and after the reaction is complete, centrifuge to settle, wash and dry to obtain microcapsules.

[0031] Example 8: The preparation steps of the microcapsules are as follows: S1: Add 45g of polylactic acid-glycolic acid copolymer and 10g of 2,2-dimethoxy-2-phenylacetophenone to 100mL of ethyl acetate, heat to 20℃, and stir for 70min to obtain an organic phase solution. S2: Add 6g of polyvinyl alcohol to 600g of deionized water, heat to 85℃, stir for 2.5h, cool to 25℃, add 100g of organic phase solution, stir for 10min, cool to 2℃, sonicate for 3min at 300W to obtain emulsion. S3: Add 100g of emulsion to 400g of deionized water, heat to 25℃, stir for 5 hours at 500rpm, and after the reaction is complete, centrifuge to settle, wash and dry to obtain microcapsules.

[0032] Example 9: The preparation steps of the microcapsules are as follows: S1: Add 50g of polylactic acid-glycolic acid copolymer and 10g of 2,2-dimethoxy-2-phenylacetophenone to 100mL of ethyl acetate, heat to 25℃, stir for 60min to obtain an organic phase solution; S2: Add 7g of polyvinyl alcohol to 620g of deionized water, heat to 90℃, stir for 2h, cool to 30℃, add 100g of organic phase solution, stir for 8min, cool to 4℃, sonicate for 2min at 400W to obtain emulsion. S3: Add 100g of emulsion to 420g of deionized water, heat to 30℃, stir for 4 hours at 600rpm, and after the reaction is complete, centrifuge to settle, wash and dry to obtain microcapsules.

[0033] Example 10: A method for preparing a cyanoacrylate-based medical vascular occlusion adhesive S1: Under a nitrogen atmosphere, 20g of lactide-modified hydroxyethyl methacrylate and 5g of thickener were added to 100g of 2-octyl cyanoacrylate, cooled to 0℃, stirred for 4h at 100rpm, 10g of silane coupling agent-modified nano-tungsten powder and 2g of nano-hydroxyapatite were added, stirred for 15min at 400rpm, placed in a high-speed homogenizer, stirred for 20min at 1100rpm, and a suspension was obtained. S2: Under a nitrogen atmosphere, 0.03 g of propyl gallate was added to 1 mL of medical-grade ethanol, stirred and dissolved, cooled to 0°C, added to 100 g of suspension, stirred for 45 min at 200 rpm, 0.04 g of microcapsules was added, stirred for 20 min at 80 rpm, to obtain component A. S3: Under sterile conditions, add 10g of medical-grade sodium hyaluronate to 900g of phosphate-buffered saline, heat to 20℃, stir for 20min, cool to 2℃, and let stand for 16h to swell, to obtain a viscous solution. S4: Add 2g of sodium bicarbonate powder to 100g of viscous solution, heat to 20℃, stir for 20min at 300rpm, add 96g of phosphate buffered saline, stir for 10min at 300rpm, filter through a 0.22μm filter membrane to obtain component B. S5: Add 120g of component A to 100g of component B, heat to 20℃, react for 4s to obtain vascular occlusion adhesive.

[0034] Example 11: A method for preparing a cyanoacrylate-based medical vascular occlusion adhesive S1: Under a nitrogen atmosphere, 23g of lactide-modified hydroxyethyl methacrylate and 6.5g of thickener were added to 100g of 2-octyl cyanoacrylate, cooled to 3℃, stirred for 3h at 150rpm, 11g of silane coupling agent-modified nano-tungsten powder and 2.5g of nano-hydroxyapatite were added, stirred for 18min at 300rpm, placed in a high-speed homogenizer, stirred for 30min at 1000rpm, and a suspension was obtained. S2: Under a nitrogen atmosphere, 0.04 g of propyl gallate was added to 1 mL of medical-grade ethanol, stirred and dissolved, cooled to 3°C, added to 100 g of suspension, stirred for 40 min at 250 rpm, 0.05 g of microcapsules was added, stirred for 25 min at 65 rpm, to obtain component A. S3: Under aseptic conditions, add 10g of medical-grade sodium hyaluronate to 1000g of phosphate-buffered saline, heat to 25°C, stir for 18min, cool to 5°C, and let stand for 14h to swell, to obtain a viscous solution. S4: Add 3g of sodium bicarbonate powder to 100g of viscous solution, heat to 25℃, stir for 18min at 350rpm, add 97g of phosphate buffered saline, stir for 13min at 250rpm, filter through a 0.22μm filter membrane to obtain component B. S5: Add 130g of component A to 100g of component B, heat to 25℃, react for 3s to obtain vascular occlusion adhesive.

[0035] Example 12: A method for preparing a cyanoacrylate-based medical vascular occlusion adhesive S1: Under a nitrogen atmosphere, 25g of lactide-modified hydroxyethyl methacrylate and 8g of thickener were added to 100g of 2-octyl cyanoacrylate, cooled to 5°C, stirred for 2 hours at 200 rpm, 12g of silane coupling agent-modified nano-tungsten powder and 3g of nano-hydroxyapatite were added, stirred for 20 minutes at 200 rpm, placed in a high-speed homogenizer, stirred for 40 minutes at 900 rpm, and a suspension was obtained. S2: Under a nitrogen atmosphere, add 0.05g of propyl gallate to 1mL of medical grade ethanol, stir to dissolve, cool to 5℃, add to 100g of suspension, stir for 30min at 300rpm, add 100g of microcapsules, stir for 20min at 80rpm to obtain component A. S3: Under aseptic conditions, add 10g of medical-grade sodium hyaluronate to 1100g of phosphate-buffered saline, heat to 30℃, stir for 15min, cool to 8℃, and let stand for 12h to swell, to obtain a viscous solution. S4: Add 4g of sodium bicarbonate powder to 100g of viscous solution, heat to 30℃, stir for 15min at 400rpm, add 98g of phosphate buffered saline, stir for 10min at 300rpm, filter through a 0.22μm filter membrane to obtain component B. S5: Add 140g of component A to 100g of component B, heat to 30℃, react for 2s to obtain vascular occlusion adhesive.

[0036] Comparative Example 1: Compared with Example 10, the ultrasonic processing power "200W" was replaced with "600W" in the microcapsule preparation process of this comparative example. All other steps and parameters are the same, and will not be repeated in this comparative example. Finally, the vascular occlusion glue was obtained.

[0037] Comparative Example 2: Compared with Example 10, this comparative example only replaces "lactide-modified hydroxyethyl methacrylate" with "hydroxyethyl methacrylate". All other steps and parameters are the same, and will not be repeated here. The final result is a vascular occlusion adhesive.

[0038] Comparative Example 3: Compared with Example 10, this comparative example only differs in that microcapsules were not added during the preparation of the cyanoacrylate medical vascular occlusion adhesive. All other steps and parameters are the same, and will not be repeated here. The final vascular occlusion adhesive was obtained.

[0039] Comparative Example 4: Compared with Example 10, this comparative example only replaces "silane coupling agent modified nano tungsten powder" with "nano tungsten powder". All other steps and parameters are the same, and will not be repeated in this comparative example. Finally, the vascular occlusion adhesive is obtained.

[0040] Performance testing: Curing time measurement The SL200B contact angle measuring instrument was used. 1. Take the AB components of Examples 10-12 and Comparative Examples 1-4 respectively, add them to a plastic cup at a mass ratio of A:B=1.2:1, and stir to mix; 2. Add phosphate buffer solution with pH=7.4 to the polytetrafluoroethylene tank, with the liquid level at 3 mm. Add 0.05 mL of the mixed sample. When the droplet is observed to completely change from transparent to opaque solid and the surface morphology no longer changes, stop timing. This time interval is the in vitro curing time (s) of the sample. Each sample is tested in parallel 5 times.

[0041] X-ray radioactivity test Using the Philips Digital Diagnost VR digital X-ray imaging system 1. Take the vascular occlusion adhesives of Examples 10-12 and Comparative Examples 1-4 respectively, inject them into a cylindrical polytetrafluoroethylene mold with an inner diameter of 5 mm and a depth of 2 mm, heat to 37°C, humidity 95%, and cure for 1 hour. 2. Place the sample in the center of the acrylic resin mold and take pictures using a tube voltage of 60kV and a tube current of 2mA; 3. Test the grayscale value and calculate the grayscale difference: G1: Region of Interest (ROI) for sample; G2: Region of Interest (ROI) for background.

[0042] Table 1. Test Results Data for Examples and Comparative Examples Hemolysis rate test The Synergy H1 multi-functional microplate reader was used as the testing standard, referring to GB / T 16886.4-2022 "Biological evaluation of medical devices - Part 4: Selection of blood interaction tests". 1. Sample extract: Take the vascular occlusion adhesives of Examples 10-12 and Comparative Examples 1-4 respectively, after solidification, crush and weigh them under aseptic conditions, and extract them at a ratio of 1g:5mL of sample to physiological saline, heat to 37±1℃, and extract for 55-65min. Negative control solution (NC): physiological saline; Positive control solution (PC): distilled water.

[0043] 2. Take fresh, healthy rabbit blood, add sodium citrate to prepare anticoagulated blood. The volume ratio of anticoagulated blood to physiological saline is 4:5. Dilute to obtain diluted anticoagulated blood. 3. Take 3 clean test tubes, add 10 mL of sample extract, negative control solution and positive control solution respectively, and then add 0.2 mL of diluted anticoagulated blood to each tube. Vortex to mix well, heat to 37±1℃, incubate for 55-65 min, and centrifuge for 5-10 min. 4. Take the supernatant and transfer it to a 96-well plate. Use an ELISA reader to measure the absorbance of each supernatant at a wavelength of 545 nm. Test each sample in triplicate.

[0044] 5. Calculation of hemolysis rate: OD t ; Average absorbance value of the sample extract tube; OD nc : Average absorbance value of negative control tubes; OD pc : Average absorbance value of the positive control tube.

[0045] In vitro degradation test Refer to the testing standard GB / T 16886.13-2017 "Biological evaluation of medical devices - Part 13: Identification and quantification of degradation products of polymer medical devices"; 1. Take the vascular occlusion adhesives from Examples 10-12 and Comparative Examples 1-4 respectively, and prepare circular sample pieces with a diameter of 10.0 mm and a thickness of 2.0 mm; 2. Rinse the sample with ultrapure water, place it in a vacuum drying oven, heat it to 37°C, dry it to constant weight, weigh it and record it as the initial weight W0. 3. Place the samples into 50 mL centrifuge tubes containing 20 mL of preheated (pH=7.4±0.1) PBS. Heat to 37±0.5℃ and shake at 60 rpm. Replace with fresh PBS buffer every 24 hours to maintain pH stability and remove degradation products promptly. After 28 days, remove the samples, rinse with ultrapure water to remove surface salts and soluble degradation products, and freeze-dry at -50℃, 0.1 mBar for 48 hours. Record the weight as W. d ; 4. Calculation formula: .

[0046] Table 2 Test Results Data for Examples and Comparative Examples Data Analysis: As can be seen from Tables 1-2, the vascular occlusion adhesive prepared by this invention has superior comprehensive performance, specifically manifested in rapid curing, excellent X-ray imaging properties, outstanding blood compatibility, and controllable degradation rate. In contrast, Comparative Example 1 suffered from leakage of the encapsulated drug due to the use of 600W of ultrasonic power during microcapsule preparation, which resulted in damage to the microcapsule shell structure. This was caused by the fact that in the emulsification step of microcapsule preparation, moderate ultrasonic treatment can provide sufficient energy to uniformly disperse the organic phase in the aqueous phase, forming uniform and stable emulsion droplets. This is the basis for forming a complete microcapsule shell. When the ultrasonic power is too high, the strong shear force and cavitation effect generated will far exceed the needs to maintain the stability of the emulsion. Excessive energy will break the nascent capsule wall, leading to droplet aggregation and ultimately resulting in defects, uneven thickness, or even rupture of the formed microcapsule shell. In addition, during the preparation and storage of structurally damaged microcapsules, the hydrophobic drug encapsulated inside will leak out and dissolve in the blood. These leaked hydrophobic molecules or chemicals will damage the lipid bilayer of the red blood cell membrane, causing cell rupture and triggering a hemolytic reaction, exhibiting a high hemolysis rate, indicating poor blood compatibility. Comparative Example 2, due to the lack of lactide modification of hydroxyethyl methacrylate, resulted in a prolonged curing time. This is because lactide-modified hydroxyethyl methacrylate incorporates longer lactide segments on its molecular side chains. These segments exhibit steric hindrance, physically shielding the cyanoacrylate groups to some extent and slowing the rate of anionic attack on the monomer. This slightly delays the polymerization process, extending the operating time without excessively prolonging it. In contrast, unmodified hydroxyethyl methacrylate has a small molecular weight and simple structure, resulting in higher reactivity of its double bonds and hydroxyl groups. When directly added to 2-octyl cyanoacrylate, it rapidly participates in copolymerization. However, its uniform reactivity cannot effectively buffer the rapid and intense bulk polymerization of cyanoacrylate, making the reaction process difficult to control and potentially leading to localized over-crosslinking. This results in a longer overall curing time, manifesting as an extended apparent curing time. Furthermore, unmodified hydroxyethyl methacrylate, as a crosslinking agent, forms a rigid polymer network with 2-OCA with its shorter molecular chains, characterized by high crosslink density but short chain segments. While this network exhibits high hardness, it cannot effectively disperse and absorb external stress, making microcracks prone to propagation. Macroscopically, it exhibits high brittleness, poor toughness, and consequently, low compressive strength. The key role of lactide-modified hydroxyethyl methacrylate lies in introducing flexible, biodegradable segments. The lactide segments in its molecule are soft polyester chains, introduced as intrinsic toughening units into the crosslinked network. These long, flexible segments enhance chain mobility, induce crazes and shear bands, and provide degradation toughness. Comparative Example 3 lost its drug sustained-release function due to the absence of microcapsules. This was because it lacked a drug delivery unit. Although the basic occlusion performance was preserved, it could not achieve the advanced therapeutic goals of anti-inflammation or promoting tissue healing. Comparative Example 4 did not modify the nano-tungsten powder with a silane coupling agent because severe agglomeration occurred in the organic polymer matrix, making uniform dispersion impossible and resulting in a sharp decline in development performance. At the same time, there is an inherent physical and chemical incompatibility between the unmodified inorganic nanoparticles and the organic polymer matrix.

[0047] Those skilled in the art should understand that the discussion of any of the above embodiments is merely exemplary and is not intended to imply that the scope of the invention is limited to these examples; within the framework of the invention, the technical features of the above embodiments or different embodiments can also be combined, the steps can be implemented in any order, and there are many other variations of the different aspects of the invention as described above, which are not provided in detail for the sake of brevity.

[0048] This invention is intended to cover all such substitutions, modifications, and variations that fall within the broad scope of the appended claims. Therefore, any omissions, modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this invention should be included within the scope of protection of this invention.

Claims

1. A cyanoacrylate medical vascular occlusive glue, characterized by, It is composed of the following components by mass fraction: 2-octyl cyano acrylate 30-35 parts, lactide modified hydroxyethyl methacrylate 7-8 parts, polymerization inhibitor propyl gallate 0.02-0.03 parts, thickening agent polylactic acid-hydroxyacetic acid copolymer 2-3 parts, silane coupling agent modified nano tungsten powder 3-5 parts, nano hydroxyapatite 0.7-0.8 parts, microcapsule 0.2-0.3 parts, phosphate buffered saline 49-50 parts sodium bicarbonate 0.7-0.8 parts, medical grade sodium hyaluronate 0.2-0.3 parts.

2. The cyano acrylate medical vascular plugging glue according to claim 1, wherein the preparation steps of the lactide modified hydroxyethyl methacrylate are as follows: Under argon atmosphere, hydroxyethyl methacrylate and lactide are added to propylene glycol methyl ether solvent, stirred and mixed, stannous octoate is added as catalyst, heated to 125-135℃, reacted for 10-12h, cooled to 20-30℃, precipitated, filtered and washed, dried to obtain lactide modified hydroxyethyl methacrylate.

3. The cyanoacrylate medical vessel sealing glue according to claim 2, characterized in that, The mass ratio of hydroxyethyl methacrylate, lactide and catalyst is 0.005-0.007:1:0.002-0.

004.

4. The cyanoacrylate medical vessel sealing glue according to claim 1, characterized in that, The preparation steps of the silane coupling agent modified nano tungsten powder are as follows: Step A1: silane coupling agent KH-550 is added to a mixed solvent of medical grade ethanol and deionized water, heated to 25-35℃, citric acid is added to adjust the pH to 4-5, reacted for 40-60min, the reaction is completed to obtain silane coupling agent hydrolysate; Step A2: nano tungsten powder and silane coupling agent hydrolysate are added to medical grade ethanol solvent, stirred for 20-40min, cooled to 5-10℃, ultrasonic treated for 30-50min at 300-500W, heated to 65-75℃, refluxed for 5-7h, the reaction is completed, cooled to 20-30℃, filtered and washed, dried, ground and passed through an 800 mesh screen to obtain silane coupling agent modified nano tungsten powder.

5. The cyanoacrylate medical vessel sealing glue according to claim 4, characterized in that, The mass ratio of silane coupling agent KH-550, medical grade ethanol and deionized water in step A1 is 0.9-1.1:1:8.8-9.2; The mass ratio of nano tungsten powder and silane coupling agent hydrolysate in step A2 is 0.1-0.2:

1.

6. The cyanoacrylate medical vessel sealing glue according to claim 1, characterized in that, The preparation steps of the microcapsule are as follows: Step B1: polylactic acid-hydroxyacetic acid copolymer and 2,2-dimethoxy-2-phenyl phenylacetophenone are added to ethyl acetate, heated to 15-25℃, stirred and reacted for 60-80min to obtain an organic phase solution; Step B2: polyvinyl alcohol is added to deionized water, heated to 80-90℃, stirred for 2-3h, cooled to 20-30℃, the organic phase solution is added, stirred for 8-12min, cooled to 0-4℃, ultrasonic treated for 2-4min at 200-400W to obtain an emulsion; Step B3: the emulsion is added to deionized water, heated to 20-30℃, stirred for 4-6h at a speed of 400-600rpm, the reaction is completed, centrifuged, washed and dried to obtain microcapsules.

7. The cyanoacrylate medical vessel sealing glue according to claim 6, characterized in that, The mass ratio of the polylactic acid-glycolic acid copolymer to 2,2-dimethoxy-2-phenylacetophenone in step B1 is 4-5:1; The mass ratio of the polyvinyl alcohol, deionized water and organic phase solution in step B2 is 0.05-0.07:5.8-6.2:1; The mass ratio of the emulsion to deionized water in step B3 is 1:3.8-4.

2.

8. The method for preparing a cyanoacrylate medical vascular sealing glue according to any one of claims 1-7, characterized in that, The preparation steps are as follows: Step S1: under a nitrogen atmosphere, add lactide-modified hydroxyethyl methacrylate and thickening agent into 2-octyl cyano acrylate, cool to 0-5℃, stir for 2-4h at a speed of 100-200rpm, add silane coupling agent modified nano tungsten powder and nano hydroxyapatite, stir for 15-20min at a speed of 200-400rpm, put into a high-speed homogenizer, stir for 20-40min at a speed of 900-1100rpm, and obtain a suspension; Step S2: under a nitrogen atmosphere, add propyl gallate into medical grade ethanol, stir and dissolve, cool to 0-5℃, add the suspension into the solution, stir for 30-45min at a speed of 200-300rpm, add microcapsules, stir for 20-30min at a speed of 50-80rpm, and obtain component A; Step S3: under sterile conditions, add medical grade sodium hyaluronate into phosphate buffered saline, warm to 20-30℃, stir for 15-20min, cool to 2-8℃, stand for 12-16h for swelling, and obtain a viscous solution; Step S4: add sodium bicarbonate powder into the viscous solution, warm to 20-30℃, stir for 15-20min at a speed of 300-400rpm, add phosphate buffered saline, stir for 10-15min at a speed of 200-300rpm, filter through a 0.22μm filter membrane, and obtain component B; Step S5: add component A into component B, warm to 20-30℃, react for 2-4s, and obtain a blood vessel plugging glue.

9. The preparation method of a cyanoacrylate-based medical vascular occlusion adhesive according to claim 8, characterized in that, The mass ratio of the 2-octyl cyano acrylate, lactide-modified hydroxyethyl methacrylate, thickening agent, silane coupling agent modified nano tungsten powder and nano hydroxyapatite in step S1 is 1:0.2-0.25:0.05-0.08:0.1-0.12:0.02-0.03; The mass ratio of the propyl gallate, suspension and microcapsules in step S2 is 0.0003-0.0005:1:0.0004-0.0006; The mass ratio of the medical grade sodium hyaluronate to phosphate buffered saline in step S3 is 1:90-110; The mass ratio of the sodium bicarbonate powder, viscous solution and phosphate buffered saline in step S4 is 0.02-0.04:1:0.96-0.98; The mass ratio of component A to component B in step S5 is 1.2-1.4:

1.

10. The method for preparing a cyanoacrylate-based medical vascular occlusion adhesive according to claim 8, characterized in that, The pH of the phosphate buffered saline in step S3 and step S4 is 7.4.

Images