A high concentricity hemostatic gel plug and method of making same

Abstract

The application discloses a high-concentricity hemostatic gel plug and a preparation method thereof. In the application, a uniform hollow circular columnar skeleton is constructed through inorganic salt particle accumulation and saturated aqueous solution bridging technology, and the eccentric problem caused by the traditional curling process is fundamentally solved. The skeleton forming method utilizes the regular gap structure formed by the close arrangement of particles to provide an accurate template for the subsequent uniform filling of PEG solution. After solidification, the gel plug obtained by dissolving the inorganic salt has a high consistency in radial size, which ensures accurate matching of the channel shape when plugging the puncture channel and avoids the problem of loose plugging caused by eccentricity. Meanwhile, the entire preparation process is completed in a closed container, reducing the interference of the external environment on the forming precision, and the consistency between batches of products is significantly improved. The three-dimensional interpenetrating gap network formed in the preparation process greatly improves the blood absorption rate of the material.

Description

Technical Field

[0001] This invention belongs to the field of hemostatic medical device technology, specifically a high concentricity hemostatic gel plug and its preparation method. Background Technology

[0002] With the continuous improvement and development of interventional techniques, puncture site management, as the final step in surgery, especially the management of puncture site complications, has become an indispensable part. ExoSeal (Cordis), as an extravascular occlusion device, achieves hemostasis by placing an absorbable plug outside the vessel wall. It has a wide range of applications, causes no secondary damage to the vessel, significantly shortens the patient's time out of bed, and greatly reduces prolonged hospital stays, bed occupancy, workload, and additional financial burden on patients due to puncture complications. The MynxGrip occlusion system is used for patients undergoing diagnostic or interventional endovascular surgery to achieve hemostasis and immobilization time at the common femoral artery puncture site compared to manual pressure hemostasis. It has no serious closure-related complications at the major safety endpoint and has good safety, thus meeting the requirements of clinical application. The occlusion system requires the use of hemostatic gel plugs, which are biomaterial products used for hemostasis at the puncture site during medical procedures and are widely used in vascular puncture, catheter insertion, and interventional surgery. This product is typically made of natural or synthetic polymer materials and has good biocompatibility, hemostatic properties, and rapid coagulation ability. It can form a physical barrier at the puncture site to prevent blood leakage, while promoting platelet aggregation and activation of coagulation factors, thereby accelerating the hemostasis process.

[0003] However, existing gel plugs are made by rolling up sheet-like PEG sponges. In addition, the sponges are soft and tend to be somewhat off-center, which makes it impossible to properly block the puncture channel when sealing and stopping bleeding. Summary of the Invention

[0004] The purpose of this invention is to provide a high concentricity hemostatic gel plug and its preparation method in order to solve the problems mentioned above.

[0005] The technical solution adopted in this invention is as follows: a method for preparing a high concentricity hemostatic gel plug, the method comprising the following steps:

[0006] S1. Inorganic salt particles with a particle size of 0.1 mm to 1 mm are tightly packed into the receiving cavity of a solid container to obtain a ring-shaped columnar particle packing structure, wherein the receiving cavity of the solid container is ring-shaped and the top of the solid container has an opening communicating with the receiving cavity.

[0007] S2. Pour an inorganic salt saturated aqueous solution into the particle stacking structure in the solid container. After the inorganic salt saturated aqueous solution has seeped into the internal voids of the particle stacking structure, remove the inorganic salt saturated aqueous solution from the surface of the particle stacking structure exposed at the opening of the solid container. The inorganic salt saturated aqueous solution remaining in the internal voids of the particle stacking structure will link the inorganic salt particles in contact with it into a whole, resulting in a skeleton with internal voids.

[0008] S3. A PEG solution prepared by mixing multi-arm PEG, photoinitiator and organic solvent in a certain proportion is poured onto the skeleton. After the PEG solution completely fills the internal voids of the skeleton, the PEG solution on the surface of the skeleton exposed at the opening of the solid container is removed. The PEG solution retained in the skeleton is cured by photocuring to obtain a preform formed by the interweaving of inorganic salt skeleton and PEG solution cured product. The mass ratio of multi-arm PEG in the PEG solution is 10% to 30%, the mass ratio of organic solvent is 69% to 89%, and the balance is photoinitiator.

[0009] S4. Remove the preform from the solid container, soak it in water to dissolve the inorganic salt skeleton in the preform, wash it and freeze-dry it to obtain a hemostatic gel plug with high concentricity.

[0010] In a preferred embodiment, in step S1, water-soluble inorganic salt particles are selected as raw materials. The particle size must be strictly controlled within the range of 0.1 mm to 1 mm to ensure good flowability and stacking performance. The container cavity is designed as a smooth inner wall circular columnar structure, and the material is selected as glass or polytetrafluoroethylene with good chemical stability to avoid reaction with inorganic salt particles. The inner diameter and height of the container are determined according to the size of the target hemostatic gel plug, and the inner wall roundness error must be controlled within 0.1 mm to ensure the concentricity of the final product. The inorganic salt particles are slowly poured into the container cavity of the solid container, and the container is placed on a vibration table for vibration treatment. The vibration frequency is set to 80 Hz to 150 Hz, and the amplitude is controlled within 0.5 mm to 2 mm. The particles are naturally settled and tightly arranged under the action of gravity through vibration. The vibration duration is 10 min to 20 min until the particle stacking height no longer changes, forming a dense, non-porous circular columnar particle stacking structure.

[0011] In a preferred embodiment, during step S1, it is necessary to ensure uniform particle distribution during the stacking process. This can be achieved by monitoring the levelness of the upper surface of the stacked structure using a level installed on the top of the container. If tilting occurs, the vibration direction needs to be adjusted or manual assistance is required for leveling. After stacking is completed, excess particles are scraped off along the edge of the container top opening using a straight scraper, so that the upper surface of the stacked structure is flush with the container opening and the surface remains flat and smooth. At this point, the density of the particle stacked structure needs to reach more than 85% of the loose packing density of inorganic salt particles, with uniform internal void distribution and a porosity controlled between 30% and 50%. This provides a uniform channel for the penetration and filling of the solution in subsequent steps, while ensuring the stability of the stacked structure and preventing collapse during subsequent operations.

[0012] In a preferred embodiment, in step S2, a saturated aqueous solution of the same type as the inorganic salt particles is prepared. The specific process is as follows: an appropriate amount of inorganic salt crystals are added to deionized water and stirred at a temperature of 60℃ to 80℃ until completely dissolved. Inorganic salt crystals are continued to be added until no more are dissolved, forming a supersaturated solution. The solution is then cooled to room temperature and allowed to stand for 2 to 4 hours to allow excess inorganic salt crystals to precipitate. After filtration, a clear saturated aqueous solution is obtained. The saturated aqueous solution is slowly added dropwise to the particle packing structure through a constant pressure dropping funnel. The dropping rate is controlled at 1 ml / min to 2 ml / min. During the dropping process, the funnel outlet is kept 1 cm to 2 cm away from the surface of the packing structure to avoid particle displacement caused by solution impact. The amount of solution added should just cover the upper surface of the packing structure. After the dropping is completed, the dropping is stopped and allowed to stand for 5 to 15 minutes to allow the solution to gradually penetrate into the internal voids of the packing structure under capillary action and gravity. At this time, it can be observed that the surface of the packing structure changes from dry to wet, and no liquid overflows.

[0013] In a preferred embodiment, in step S2, after the solution has completely penetrated, the solid container is tilted at a 45-degree angle to allow excess solution on the surface to flow out naturally. Then, clean absorbent paper is used to gently absorb the residual solution on the surface of the stacked structure, ensuring that the solution is retained only in the gaps. The container is then placed in a room temperature, well-ventilated environment for static drying, with the relative humidity controlled at 40%–60%, for 12–24 minutes. This allows the water in the saturated aqueous solution remaining in the gaps to evaporate slowly, and the solution gradually reaches a supersaturated state. Crystals precipitate at the contact points of the inorganic salt particles, forming crystal bridges that link adjacent particles together. During this process, drastic changes in ambient temperature must be avoided to prevent crystal growth from being too rapid and causing gap blockage. The final result is a circular columnar skeleton with retained original gaps and moderate mechanical strength. The compressive strength of the skeleton needs to reach 0.5 MPa–1 MPa to meet the structural stability requirements in subsequent operations.

[0014] In a preferred embodiment, in step S3, the multi-arm PEG is selected from derivatives with acrylate terminal groups, such as tetra-arm, hexa-arm, or octa-arm polyethylene glycol acrylate, with a molecular weight range of 5 kDa to 20 kDa, to ensure that the network structure formed after curing has good flexibility and biocompatibility; the photoinitiator is selected from 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylphenylacetone, with a mass percentage of 0.5% to 1% in the PEG solution, which can effectively initiate the polymerization reaction under ultraviolet or visible light irradiation; the organic solvent is selected from low-boiling-point, volatile ethanol or isopropanol, and the multi-arm PEG, photoinitiator, and organic solvent are mixed at a mass percentage of 10% to 30%, 0.5% to 1%, and 69% to 89%, respectively, and stirred at room temperature with a magnetic stirrer at a stirring speed of 300 r / min to 500 r / min. Stir at r / min for 20-30 minutes until a uniform, transparent, bubble-free PEG solution is formed. The viscosity of the solution needs to be controlled between 100 cP and 500 cP to ensure that it can fill the tiny gaps inside the skeleton smoothly.

[0015] In a preferred embodiment, in step S3, the prepared PEG solution is slowly added to the solid container using a pipette, adding it evenly from the inner edge of the container towards the center, avoiding direct impact on the skeleton surface. The amount of solution added should cover the upper surface of the skeleton by 1 mm to 2 mm. After addition, let it stand for 5 to 10 minutes to allow the solution to completely fill the internal voids of the skeleton under gravity and capillary action. If air bubbles are observed remaining in the voids during this process, they can be gently punctured with a fine needle to release the bubbles. After filling, use a clean glass scraper to scrape off the excess PEG solution from the exposed surface of the skeleton, making the surface smooth and free of droplets. Then, place the solid container under a UV curing lamp with a light source wavelength set to 365 nm to 405 nm and a light intensity controlled at 20 nm. The light intensity is mW / cm²~50mW / cm², and the irradiation time is adjusted according to the concentration of the PEG solution and the thickness of the skeleton, usually 2min~5min. This allows the multi-arm PEG in the solution to cross-link and solidify through the free radical polymerization reaction of the acrylate groups, forming a three-dimensional network structure that is tightly interwoven with the inorganic salt skeleton, resulting in a preform with a stable structure and a shape consistent with the container cavity.

[0016] In a preferred embodiment, in step S4, when removing the preform from the solid container, the edges of the preform should be gently held with tweezers to avoid squeezing and damaging the internal structure. If the preform is slightly adhered to the inner wall of the container, the container can be placed in a water bath at 40°C to 50°C for 1 to 2 minutes to separate the preform from the container using the principle of thermal expansion and contraction. The removed preform should be immediately placed in a beaker containing deionized water, with the amount of water being 10 to 20 times the volume of the preform. The soaking temperature should be controlled at room temperature. The deionized water should be replaced every 6 to 8 hours during the soaking process to accelerate the dissolution of the inorganic salt skeleton. The total soaking time is 24 to 48 hours until the conductivity of the soaking solution is basically the same as that of the deionized water, confirming that the inorganic salt has been completely dissolved.

[0017] In a preferred embodiment, in step S3, after dissolution, the remaining PEG-cured product is rinsed 3 to 5 times with deionized water. Each rinse involves gently brushing the product surface with a soft brush to remove residual inorganic salt crystals and unreacted small molecules. Each rinse lasts 5 to 10 minutes. The cleaned product is then placed in the sample tray of a freeze dryer, spread evenly, and pre-frozen at -40°C for 2 to 4 hours to completely freeze the water in the product into ice crystals. The vacuum system is then activated, reducing the vacuum level to 1 to 5 Pa. The temperature during the sublimation drying stage is controlled at -20°C to -10°C, and the drying time is 24 to 36 hours, until the product weight no longer changes and the moisture content drops below 5%. The resulting hemostatic gel plug is cylindrical with high concentricity and an interconnected porous structure with a porosity of 60% to 80%. It exhibits good mechanical properties and meets the requirements for clinical hemostasis applications.

[0018] The present invention also provides a high concentricity hemostatic gel plug, which is prepared by the above-described method for preparing a high concentricity hemostatic gel plug.

[0019] In summary, due to the adoption of the above technical solution, the beneficial effects of the present invention are:

[0020] 1. This invention utilizes an innovative inorganic salt particle stacking and saturated aqueous solution bridging technique to construct a uniformly structured, hollowed-out circular columnar skeleton, fundamentally solving the eccentricity problem caused by traditional curling processes. This skeleton forming method leverages the regular void structure formed by the close arrangement of particles to provide a precise template for the subsequent uniform filling of the PEG solution. After curing, the gel plug obtained by dissolving and removing the inorganic salts has highly consistent radial dimensions, ensuring precise matching of the channel shape during puncture channel sealing and avoiding incomplete sealing due to eccentricity. Simultaneously, the entire preparation process is completed in a sealed container, reducing the interference of the external environment on the molding accuracy and significantly improving batch-to-batch consistency.

[0021] 2. In this invention, the three-dimensional interconnected porous network formed during the preparation process greatly enhances the material's blood absorption rate, enabling rapid absorption of wound exudate and the formation of a stable blood clot. The multi-arm PEG cross-linked structure provides suitable mechanical strength to maintain the sealing effect. The material slowly degrades in vivo through ester bond hydrolysis, and the degradation products are naturally metabolized by the body, avoiding the risk of secondary surgical removal. Furthermore, strictly controlled process parameters in each step ensure the stability of product quality. The comprehensive quality control system, from raw material selection to final freeze-drying, demonstrates reliable safety and effectiveness in clinical applications for this gel plug. Attached Figure Description

[0022] Figure 1 This is a schematic diagram illustrating the process principle of the present invention. 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 the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0024] Reference Figure 1 A method for preparing a high-concentricity hemostatic gel plug, the method comprising the following steps:

[0025] S1. Inorganic salt particles with a particle size of 0.1 mm to 1 mm are tightly packed into the receiving cavity of a solid container to obtain a ring-shaped columnar particle packing structure, wherein the receiving cavity of the solid container is ring-shaped and the top of the solid container has an opening communicating with the receiving cavity.

[0026] S2. Pour an inorganic salt saturated aqueous solution into the particle stacking structure in the solid container. After the inorganic salt saturated aqueous solution has seeped into the internal voids of the particle stacking structure, remove the inorganic salt saturated aqueous solution from the surface of the particle stacking structure exposed at the opening of the solid container. The inorganic salt saturated aqueous solution remaining in the internal voids of the particle stacking structure will link the inorganic salt particles in contact with it into a whole, resulting in a skeleton with internal voids.

[0027] S3. A PEG solution prepared by mixing multi-arm PEG, photoinitiator and organic solvent in a certain proportion is poured onto the skeleton. After the PEG solution completely fills the internal voids of the skeleton, the PEG solution on the surface of the skeleton exposed at the opening of the solid container is removed. The PEG solution retained in the skeleton is cured by photocuring to obtain a preform formed by the interweaving of inorganic salt skeleton and PEG solution cured product. The mass ratio of multi-arm PEG in the PEG solution is 10% to 30%, the mass ratio of organic solvent is 69% to 89%, and the balance is photoinitiator.

[0028] S4. Remove the preform from the solid container, soak it in water to dissolve the inorganic salt skeleton in the preform, wash it and freeze-dry it to obtain a hemostatic gel plug with high concentricity.

[0029] In step S1, water-soluble inorganic salt particles are selected as raw materials. The particle size must be strictly controlled within the range of 0.1 mm to 1 mm to ensure that the particles have good flowability and packing properties. The inorganic salt particles are selected from one or more of sodium chloride (NaCl), sodium carbonate (Na2CO3), sodium bicarbonate (NaHCO3), potassium chloride (KCl), potassium sulfate (K2SO4), magnesium chloride (MgCl2), calcium chloride (CaCl2), and potassium dihydrogen phosphate (KH2PO4). The container for the solid product is designed as a smooth, cylindrical ring structure made of chemically stable glass or polytetrafluoroethylene to avoid reaction with inorganic salt particles. The inner diameter and height of the container are determined according to the size of the target hemostatic gel plug, and the roundness error of the inner wall must be controlled within 0.1 mm to ensure the concentricity of the final product. Inorganic salt particles are slowly poured into the container of the solid product, and the container is placed on a vibration table for vibration treatment. The vibration frequency is set to 80 Hz to 150 Hz, and the amplitude is controlled to 0.5 mm to 2 mm. Vibration causes the particles to settle naturally and arrange themselves tightly under the action of gravity. The vibration duration is 10 min to 20 min until the particle accumulation height no longer changes, forming a dense, non-porous, cylindrical granular particle accumulation structure.

[0030] In step S1, during the stacking process, it is necessary to ensure that the particles are evenly distributed. This can be achieved by installing a level on the top of the container to monitor the levelness of the upper surface of the stacked structure. If tilting occurs, the vibration direction needs to be adjusted or manual assistance is required to level it. After stacking is completed, use a straight scraper to scrape off excess particles along the edge of the opening at the top of the container, so that the upper surface of the stacked structure is flush with the container opening and the surface remains flat and smooth. At this time, the density of the particle stacked structure needs to reach more than 85% of the loose packing density of inorganic salt particles, with uniform internal void distribution and a porosity controlled between 30% and 50%. This provides a uniform channel for the penetration and filling of the solution in subsequent steps, while ensuring the stability of the stacked structure and preventing collapse during subsequent operations.

[0031] In step S2, a saturated aqueous solution of the same type as the inorganic salt particles is prepared. The specific process is as follows: an appropriate amount of inorganic salt crystals are added to deionized water and stirred at 60℃~80℃ until completely dissolved. Inorganic salt crystals are added until no more are dissolved, forming a supersaturated solution. The solution is then cooled to room temperature and allowed to stand for 2h~4h to allow excess inorganic salt crystals to precipitate. After filtration, a clear saturated aqueous solution is obtained. The saturated aqueous solution is slowly added dropwise to the particle packing structure through a constant pressure dropping funnel at a dropping rate of 1ml / min~2ml / min. During the dropping process, the funnel outlet is kept 1cm~2cm away from the surface of the packing structure to avoid particle displacement caused by solution impact. The amount of solution added should just cover the upper surface of the packing structure. After the dropping is completed, the dropping is stopped and allowed to stand for 5min~15min to allow the solution to gradually penetrate into the internal pores of the packing structure under capillary action and gravity. At this time, it can be observed that the surface of the packing structure changes from dry to wet, and no liquid overflows.

[0032] In step S2, after the solution has completely penetrated, the solid container is tilted at a 45-degree angle to allow excess solution on the surface to flow out naturally. Then, clean absorbent paper is used to gently absorb the remaining solution on the surface of the stacked structure, ensuring that the solution is retained only in the pores. The container is then placed in a room temperature, well-ventilated environment for static drying, with the relative humidity controlled at 40%–60%, for 12–24 minutes. This allows the water in the saturated aqueous solution remaining in the pores to evaporate slowly, and the solution gradually reaches a supersaturated state. Crystals precipitate at the contact points of the inorganic salt particles, forming crystal bridges that link adjacent particles together. During this process, drastic changes in ambient temperature must be avoided to prevent the crystals from growing too quickly and causing the pores to become blocked. The final result is a circular columnar skeleton with moderate mechanical strength and retained internal pores. The compressive strength of the skeleton needs to reach 0.5 MPa–1 MPa to meet the structural stability requirements in subsequent operations.

[0033] In step S3, the multi-arm PEG is selected from derivatives with acrylate terminal groups, such as tetra-arm, hexa-arm, or octa-arm polyethylene glycol acrylate, with a molecular weight range of 5 kDa to 20 kDa, to ensure that the network structure formed after curing has good flexibility and biocompatibility; the photoinitiator is selected from 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylphenylacetone, with a mass percentage of 0.5% to 1% in the PEG solution, which can effectively initiate the polymerization reaction under ultraviolet or visible light irradiation; the organic solvent is selected from low-boiling-point, volatile ethanol or isopropanol. The multi-arm PEG, photoinitiator, and organic solvent are mixed at a mass percentage of 10% to 30%, 0.5% to 1%, and 69% to 89%, respectively, and stirred at room temperature with a magnetic stirrer at a stirring speed of 300 r / min to 500 r / min. Stir at r / min for 20-30 minutes until a uniform, transparent, bubble-free PEG solution is formed. The viscosity of the solution needs to be controlled between 100 cP and 500 cP to ensure that it can fill the tiny gaps inside the skeleton smoothly.

[0034] In step S3, the prepared PEG solution is slowly added to the solid container through a pipette, evenly from the inner edge of the container wall towards the center, avoiding direct impact on the skeleton surface. The amount of solution added should cover the upper surface of the skeleton by 1 mm to 2 mm. After addition, let it stand for 5 min to 10 min to allow the solution to completely fill the internal gaps of the skeleton under gravity and capillary action. If air bubbles are observed in the gaps during this period, they can be gently punctured with a fine needle to release the air bubbles. After filling, use a clean glass scraper to scrape off the excess PEG solution on the exposed surface of the skeleton to make the surface smooth and free of droplets. Then, place the solid container under a UV curing lamp with the light source wavelength set to 365 nm to 405 nm and the light intensity controlled at 20 mW / cm² to 50 mW / cm². The irradiation time is adjusted according to the concentration of the PEG solution and the thickness of the skeleton, usually 2 min to 5 min. This allows the multi-arm PEG in the solution to cross-link and solidify through the free radical polymerization reaction of the acrylate groups, forming a three-dimensional network structure that is tightly interwoven with the inorganic salt skeleton, resulting in a preform with a stable structure and a shape consistent with the container cavity.

[0035] In step S4, when removing the preform from the solid container, the edges of the preform should be gently held with tweezers to avoid squeezing and damaging the internal structure. If the preform is slightly adhered to the inner wall of the container, the container can be placed in a water bath at 40℃~50℃ for 1min~2min to separate the preform from the container using the principle of thermal expansion and contraction. Immediately after removal, the preform should be placed in a beaker containing deionized water, with the water volume being 10 to 20 times the volume of the preform. The soaking temperature should be controlled at room temperature. The deionized water should be replaced every 6h~8h during the soaking process to accelerate the dissolution of the inorganic salt skeleton. The total soaking time is 24h~48h until the conductivity of the soaking solution is basically the same as that of the deionized water, confirming that the inorganic salt has been completely dissolved.

[0036] In step S3, after dissolution, the remaining PEG-cured product is rinsed 3 to 5 times with deionized water. During each rinse, the product surface is gently brushed with a soft brush to remove residual inorganic salt crystals and unreacted small molecules. Each rinse lasts 5 to 10 minutes. The cleaned product is placed in the sample tray of a freeze dryer, spread evenly, and pre-frozen at -40°C for 2 to 4 hours to completely freeze the water in the product into ice crystals. Then, the vacuum system is activated, and the vacuum level is reduced to 1 Pa to 5 Pa. The temperature of the sublimation drying stage is controlled at -20°C to -10°C, and the drying time is 24 to 36 hours until the product weight no longer changes and the moisture content drops below 5%. The final hemostatic gel plug is cylindrical with high concentricity and an interconnected porous structure with a porosity of 60% to 80%. It has good mechanical properties and can meet the needs of clinical hemostasis applications.

[0037] Example 1

[0038] Select sodium chloride particles with a particle size of 0.1 mm to 0.5 mm. The raw materials are accurately weighed according to the following parts by weight: 10 parts of four-arm PEG (molecular weight 10 kDa), 89 parts of organic solvent (ethanol), and 1 part of photoinitiator (2-hydroxy-4'-(2-hydroxyethoxy)-2-methylphenylacetone). Figure 1 The method shown in the diagram for preparing high concentricity hemostatic gel plugs yields concentricity hemostatic gel plugs.

[0039] Example 2

[0040] Sodium carbonate particles with a particle size of 0.6 mm to 1 mm were selected. The raw materials were accurately weighed according to the following parts by weight: 30 parts of six-arm PEG (molecular weight 5 kDa), 67.5 parts of organic solvent (isopropanol), and 2.5 parts of photoinitiator (2-hydroxy-4'-(2-hydroxyethoxy)-2-methylphenylacetone). Figure 1 The method shown in the diagram for preparing high concentricity hemostatic gel plugs yields concentricity hemostatic gel plugs.

[0041] Example 3

[0042] Sodium chloride particles with a particle size of 0.1 mm to 0.3 mm were selected. The raw materials were accurately weighed according to the following parts by weight: 20 parts of six-arm PEG (molecular weight 8 kDa), 79.99 parts of organic solvent (ethanol), and 0.01 parts of photoinitiator (2-hydroxy-4'-(2-hydroxyethoxy)-2-methylphenylacetone). Figure 1 The method shown in the diagram for preparing high concentricity hemostatic gel plugs yields concentricity hemostatic gel plugs.

[0043] Example 4

[0044] Sodium bicarbonate particles with a particle size of 0.2 mm to 0.5 mm were selected. The raw materials were accurately weighed according to the following parts by weight: 16 parts of octagonal PEG (molecular weight 20 kDa), 83.9 parts of organic solvent (ethanol), and 0.1 parts of photoinitiator (2-hydroxy-4'-(2-hydroxyethoxy)-2-methylphenylacetone). Figure 1 The method shown in the diagram for preparing high concentricity hemostatic gel plugs yields concentricity hemostatic gel plugs.

[0045] Example 5

[0046] Select calcium chloride particles with a particle size of 0.1 mm to 0.7 mm. The raw materials are accurately weighed according to the following parts by weight: 12 parts of four-arm PEG (molecular weight 15 kDa), 85 parts of organic solvent (ethanol), and 3 parts of photoinitiator (2-hydroxy-4'-(2-hydroxyethoxy)-2-methylphenylacetone). Figure 1 The method shown in the diagram for preparing high concentricity hemostatic gel plugs yields concentricity hemostatic gel plugs.

[0047] Example 6

[0048] Sodium carbonate particles with a particle size of 0.5 mm to 1 mm were selected. The raw materials were accurately weighed according to the following parts by weight: 18 parts of six-arm PEG (molecular weight 10 kDa), 81 parts of organic solvent (isopropanol), and 1 part of photoinitiator (2-hydroxy-4'-(2-hydroxyethoxy)-2-methylphenylacetone). Figure 1 The method shown in the diagram for preparing high concentricity hemostatic gel plugs yields concentricity hemostatic gel plugs.

[0049] Example 7

[0050] Sodium carbonate particles with a particle size of 0.3 mm to 0.9 mm were selected. The raw materials were accurately weighed according to the following parts by weight: 28 parts of six-arm PEG (molecular weight 15 kDa), 71.5 parts of organic solvent (isopropanol), and 0.5 parts of photoinitiator (2-hydroxy-4'-(2-hydroxyethoxy)-2-methylphenylacetone). Figure 1 The method shown in the diagram for preparing high concentricity hemostatic gel plugs yields concentricity hemostatic gel plugs.

[0051] Example 8

[0052] Sodium bicarbonate particles with a particle size of 0.2 mm to 0.8 mm were selected. The raw materials were accurately weighed according to the following parts by weight: 25 parts of octagonal PEG (molecular weight 10 kDa), 74.5 parts of organic solvent (isopropanol), and 0.5 parts of photoinitiator (2-hydroxy-4'-(2-hydroxyethoxy)-2-methylphenylacetone). Figure 1 The method shown in the diagram for preparing high concentricity hemostatic gel plugs yields concentricity hemostatic gel plugs.

[0053] Comparative Example 1: Traditional freeze-drying method

[0054] Raw material composition: 25 parts of 4-arm PEG (molecular weight 8000, molar ratio of terminal ester bond to double bond 1:1), 1.5 parts of gelatin (molecular weight 80kDa), and 73.5 parts of deionized water (free of sodium chloride particles, chitosan microspheres, nano hydroxyapatite, etc.).

[0055] Preparation steps: S1 Add 4-arm PEG and gelatin to deionized water and stir at 60°C until completely dissolved; S2 Pour the solution into a mold and freeze at -20°C for 12 hours; S3 Vacuum dry (-50°C, 0.01Pa) for 24 hours to obtain a blood-absorbing sponge. Roll the blood-absorbing sponge into a columnar shape to obtain a columnar blood-absorbing sponge.

[0056] Comparative Example 2: Traditional freeze-drying method:

[0057] Raw material composition: 40 parts of 8-arm PEG (molecular weight 8000, molar ratio of terminal ester bond to double bond 1:1), 2 parts of gelatin (molecular weight 80kDa), and 58 parts of deionized water (free of sodium chloride particles, chitosan microspheres, nano hydroxyapatite, etc.).

[0058] Preparation steps: S1 Add 8-arm PEG and gelatin to deionized water and stir at 60°C until completely dissolved; S2 Pour the solution into a mold and freeze at -20°C for 12 hours; S3 Vacuum dry (-50°C, 0.01Pa) for 24 hours to obtain a blood-absorbing sponge. Roll the blood-absorbing sponge into a columnar shape to obtain a columnar blood-absorbing sponge.

[0059] From the gel plugs and sponges obtained in the examples and comparative examples, gel plugs and sponges with the same wall thickness and length were cut as samples, and the following experiments were conducted to test the blood absorption and hemostasis performance of each sample.

[0060] Experiment 1: Take 80mL of fresh rabbit blood and inject it into a 200mL beaker. Completely immerse the gel stopper in the blood. Use a stopwatch to record the time from contact with the blood until there is no obvious liquid adsorption on the surface of the gel stopper and the weight no longer increases. This is the time required for the blood to be absorbed to saturation.

[0061] Experiment 2: A 10F (approximately 3.3mm) outer diameter simulated occlusion device was used to create a wound in the wall of the porcine carotid artery, with a depth of 2 / 3 of the vessel wall thickness. The gel plug was aligned with the center of the wound and pressed down to ensure complete coverage. A stopwatch was started to observe the bleeding until it completely stopped and there was no re-bleeding within 30 seconds. The time from the start of pressing to the cessation of bleeding was recorded as the hemostasis time.

[0062] The experimental results of each embodiment and comparative example are shown in the table below:

[0063] Example 1 20 120 Example 2 9 85 Example 3 22.5 163 Example 4 18 114 Example 5 15 102 Example 6 8.5 72 Example 7 10.5 93 Example 8 12 100 Comparative Example 1 60 300 Comparative Example 2 72 380

[0064] Therefore, the blood absorption speed of Examples 1-8 is significantly better than that of Comparative Examples 1 and 2. Traditional freeze-drying methods generally result in closed and non-connected pores in hemostatic sponges, leading to slow blood penetration and a longer time required to reach saturation. This invention utilizes inorganic salt particles and a saturated aqueous solution to construct a perforated framework. Because the framework is interconnected, a roughly uniform and interconnected pore structure is formed in the PEG solidified material left after dissolving the inorganic salts, significantly increasing the blood penetration speed in the hemostatic gel. Comparing Examples 1-8, larger inorganic salt particle sizes correspond to larger pore sizes in the gel plug, resulting in less time to reach saturation and faster blood penetration into the sponge.

[0065] In terms of the time required to seal the wound, Examples 1-8 are significantly shorter than Comparative Examples 1 and 2, achieving hemostasis more quickly. This is due, on one hand, to the interconnected and uniform pores of the gel plugs in Examples 1-8, which allow for rapid blood absorption; and on the other hand, to the high concentricity between the gel plugs and the wound and the guidewire of the sealing device, eliminating any eccentricity issues during wound sealing and ensuring proper sealing of the puncture channel, reducing or preventing blood leakage from the side, resulting in shorter hemostasis time and better hemostatic effect.

[0066] This invention utilizes an innovative inorganic salt particle stacking and saturated aqueous solution bridging technique to construct a uniformly structured, hollowed-out circular ring-shaped framework, ultimately producing a hemostatic gel plug with a circular ring-shaped structure. This fundamentally solves the eccentricity problem caused by traditional rolling processes. This framework molding method uses the regular void structure formed by the close arrangement of particles to provide a precise template for the subsequent uniform filling of the PEG solution. After curing, the gel plug obtained by dissolving and removing inorganic salts has highly consistent radial dimensions, ensuring precise matching of the channel shape during puncture closure and avoiding incomplete sealing due to eccentricity. Simultaneously, the entire preparation process is completed in a sealed container, reducing the interference of the external environment on the molding accuracy and significantly improving batch-to-batch consistency.

[0067] The three-dimensional interconnected porous network formed during the preparation process of this invention greatly enhances the blood absorption rate of the material, enabling it to rapidly absorb wound exudate and form a stable blood clot. The multi-armed PEG cross-linked structure provides suitable mechanical strength to maintain the sealing effect. The material slowly degrades in vivo through ester bond hydrolysis, and the degradation products are naturally metabolized by the body, avoiding the risk of secondary surgical removal. Furthermore, strictly controlled process parameters in each step ensure the stability of product quality. The comprehensive quality control system, from raw material selection to final freeze-drying, demonstrates reliable safety and effectiveness in clinical applications for this gel plug.

[0068] This embodiment provides a high-concentricity hemostatic gel plug, prepared using the aforementioned method. This gel plug can be used in conjunction with an occluder. The guidewire of the occluder can directly pass through the hollow channel inside the annular cylindrical gel plug. The gel plug is compressed within the occluder. When it is necessary to seal the vascular puncture channel, the occluder releases the gel plug into the puncture channel. The gel plug absorbs blood, expands, and seals the puncture channel, achieving rapid hemostasis. The guidewire is then withdrawn.

[0069] It should be noted that, in this document, relational terms such as "first" and "second" are used merely to distinguish one entity or operation from another, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Furthermore, the term "comprising" or any other variations thereof is intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Without further limitations, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes said element.

[0070] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing a high-concentricity hemostatic gel plug, characterized in that, The method includes the following steps: S1. Inorganic salt particles with a particle size of 0.1 mm to 1 mm are tightly packed into the receiving cavity of a solid container to obtain a ring-shaped columnar particle packing structure, wherein the receiving cavity of the solid container is ring-shaped and the top of the solid container has an opening communicating with the receiving cavity. S2. Pour an inorganic salt saturated aqueous solution into the particle stacking structure in the solid container. After the inorganic salt saturated aqueous solution has seeped into the internal voids of the particle stacking structure, remove the inorganic salt saturated aqueous solution from the surface of the particle stacking structure exposed at the opening of the solid container. The inorganic salt saturated aqueous solution remaining in the internal voids of the particle stacking structure will link the inorganic salt particles in contact with it into a whole, resulting in a skeleton with internal voids. The inorganic salt saturated aqueous solution is a saturated aqueous solution prepared using inorganic salt particles of the same type as those in step S1. The specific process is as follows: an appropriate amount of inorganic salt crystals are added to deionized water and stirred at a temperature of 60℃~80℃ until completely dissolved. Inorganic salt crystals are added until no more are dissolved, forming a supersaturated solution. The solution is then cooled to room temperature and allowed to stand for 2h~4h to allow excess inorganic salt crystals to precipitate. After filtration, a clear saturated aqueous solution is obtained. The step of pouring an inorganic salt saturated aqueous solution into a particle-packed structure in a solid container includes: slowly adding the saturated aqueous solution to the particle-packed structure through a constant-pressure dropping funnel, with the dropping rate controlled at 1 ml / min to 2 ml / min, and keeping the funnel outlet 1 cm to 2 cm away from the surface of the packing structure during the dropping process; the amount of solution added should be just enough to cover the upper surface of the packing structure, and after the dropping is completed, let it stand for 5 min to 15 min. S3. A PEG solution prepared by mixing multi-arm PEG, photoinitiator, and organic solvent in a certain proportion is poured onto the skeleton. After the PEG solution completely fills the internal voids of the skeleton, the PEG solution exposed on the surface of the skeleton at the opening of the solid container is removed. The PEG solution retained in the skeleton is cured by photocuring to obtain a preform formed by the interweaving of inorganic salt skeleton and PEG solution cured product. The PEG solution contains 10% to 30% multi-arm PEG by mass, 69% to 89% organic solvent by mass, and the remainder is photoinitiator. The multi-arm PEG is selected from derivatives with acrylate terminal groups, including tetra-arm, hexa-arm, or octa-arm polyethylene glycol acrylate, with a molecular weight range of 5kDa to 20kDa. S4. Remove the preform from the solid container, soak it in water to dissolve the inorganic salt skeleton in the preform, clean it and freeze-dry it to obtain a hemostatic gel plug with high concentricity.

2. The method for preparing a high concentricity hemostatic gel plug as described in claim 1, characterized in that: In step S1, water-soluble inorganic salt particles are selected as raw materials, and the particle size is controlled within the range of 0.1 to 1 mm. The cavity of the solid container is designed as a smooth inner wall circular columnar structure, and the material is selected as glass or polytetrafluoroethylene with good chemical stability. The inner diameter and height of the solid container are determined according to the size of the target hemostatic gel plug, and the inner wall roundness error is within 0.1 mm. In step S1, inorganic salt particles are slowly poured into the container cavity of the solid container, and the container is placed on a vibration table for vibration treatment. The vibration frequency is set to 80 Hz to 150 Hz, the amplitude is controlled at 0.5 mm to 2 mm, and the vibration duration is 10 min to 20 min.

3. The method for preparing a high concentricity hemostatic gel plug as described in claim 1, characterized in that: In step S1, during the stacking process, the levelness of the upper surface of the particle stacking structure is monitored by installing a level on the top of the solid container. If tilting occurs, the vibration direction needs to be adjusted or manual assistance is required to level it. After the accumulation is completed, use a flat scraper to scrape off the excess particles along the edge of the top opening of the container, so that the upper surface of the accumulation structure is flush with the container opening and the surface is flat and smooth; the density of the particle accumulation structure reaches more than 85% of the loose accumulation density of inorganic salt particles, the internal voids are evenly distributed, and the porosity is controlled between 30% and 50%.

4. The method for preparing a high concentricity hemostatic gel plug as described in claim 1, characterized in that: In step S2, after the solution has completely penetrated, tilt the solid container at 45° to allow excess solution on the surface to flow out naturally. Then, gently absorb the remaining solution on the surface of the stacked structure with clean absorbent paper or non-woven fabric to ensure that the solution is retained only in the gaps. Place the container in a room temperature, ventilated environment for static drying, with the relative humidity controlled at 40% to 60%, for 12 to 24 hours. This allows the water in the saturated aqueous solution remaining in the gaps to evaporate slowly, and the solution gradually reaches a supersaturated state. Crystals precipitate at the contact points of the inorganic salt particles, forming crystal bridges that link adjacent particles together.

5. The method for preparing a high concentricity hemostatic gel plug as described in claim 1, characterized in that: In step S3, the photoinitiator is 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylphenylacetone, which accounts for 0.5% to 1% of the PEG solution by mass and can effectively initiate the polymerization reaction under ultraviolet light. The organic solvent is low-boiling-point, volatile ethanol or isopropanol. The multi-arm PEG, photoinitiator and organic solvent are mixed and stirred with a magnetic stirrer at room temperature at a speed of 300 r / min to 500 r / min for 20 min to 30 min until a uniform, transparent, bubble-free PEG solution is formed. The viscosity of the solution needs to be controlled between 100 cP and 500 cP.

6. The method for preparing a high concentricity hemostatic gel plug as described in claim 1, characterized in that: In step S3, the prepared PEG solution is slowly added to the solid container through a pipette, evenly from the inner edge of the container wall towards the center, avoiding direct impact on the skeleton surface. The amount of solution added should cover the upper surface of the skeleton by 1 mm to 2 mm. After addition, let it stand for 5 min to 10 min to allow the solution to completely fill the internal voids of the skeleton under gravity and capillary action. After filling, use a clean glass scraper to scrape off the excess PEG solution on the exposed surface of the skeleton to make the surface smooth and free of droplets. Then, place the solid container under a UV curing lamp with the light source wavelength set to 365 nm to 405 nm, the light intensity controlled at 20 mW / cm² to 50 mW / cm², and the light exposure time at 2 min to 5 min. This allows the multi-arm PEG in the solution to cross-link and solidify through the free radical polymerization reaction of the acrylate groups, forming a three-dimensional network structure that is tightly interwoven with the inorganic salt skeleton, resulting in a preform with a stable structure and a shape consistent with the container cavity.

7. The method for preparing a high concentricity hemostatic gel plug as described in claim 1, characterized in that: In step S4, the preform is removed from the solid container. The removed preform is placed in a beaker containing deionized water, with the amount of water being 10 to 20 times the volume of the preform. The soaking temperature is controlled at room temperature. During the soaking process, the deionized water is replaced every 6 to 8 hours to accelerate the dissolution of the inorganic salt skeleton. The total soaking time is 24 to 48 hours until the conductivity of the soaking solution is basically the same as that of the deionized water, as confirmed by a conductivity meter, indicating that the inorganic salt has been completely dissolved.

8. The method for preparing a high concentricity hemostatic gel plug as described in claim 1, characterized in that: In step S4, after dissolution, the remaining PEG-cured product is rinsed 3 to 5 times with deionized water. Each time, the product surface is gently brushed with a soft brush to remove residual inorganic salt crystals and unreacted small molecules. Each rinse lasts 5 to 10 minutes. The cleaned product is placed in the sample tray of a freeze dryer, spread evenly, and pre-frozen at -40°C for 2 to 4 hours to completely freeze the water in the product into ice crystals. Then, the vacuum system is activated, and the vacuum level is reduced to 1 Pa to 5 Pa. The temperature of the sublimation drying stage is controlled at -20°C to -10°C, and the drying time is 24 to 36 hours until the product weight no longer changes and the moisture content drops below 5%. The final hemostatic gel plug is cylindrical with high concentricity and an interconnected porous structure with a porosity of 60% to 80%.

9. A high concentricity hemostatic gel plug, characterized in that, It was prepared using the method described in any one of claims 1-8 for preparing high concentricity hemostatic gel plugs.

Images