Preparation method of resin for hemodialysis

Abstract

The invention discloses a preparation method of resin for hemodialysis. The preparation method comprises the following steps: immersing a polymethyl methacrylate porous resin film into a sodium hydroxide solution containing Tween-80 for pretreatment; then selecting hydroxyl polyethylene glycol to prepare a solution, adding a dibutyltin dilaurate catalyst and an antioxidant 1010, and carrying out infiltration reaction on the resin film; preparing a mixed solution containing citric acid, sodium citrate and titanium dioxide, and reacting the grafted resin film; and finally, washing and vacuum drying to obtain a finished product. The preparation method has the advantages that through detection, compared with the prior art, the anticoagulation time of the prepared resin film is prolonged by 30%-50%, the adsorption rate of common toxins is improved by 20%-30%, the adsorption rate of special toxins is remarkably improved, the biocompatibility is good, the cytotoxicity grade is 0-1 grade, the hemolysis rate is lower than 0.5%, the high-quality requirement of clinical hemodialysis can be effectively met, and the preparation method is suitable for industrial production. And a more reliable treatment scheme is provided for patients with end-stage kidney diseases.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, in particular to a method for preparing a resin for hemodialysis. Background Art

[0002] The kidney is an organ of vertebrates and part of the urinary system. It is responsible for filtering impurities from the blood, maintaining the balance of body fluids and electrolytes, and finally producing urine to be excreted from the body through the urethra. When there is a problem with the kidney, the blood in the body is prone to electrolyte imbalance due to renal insufficiency. At this time, extracorporeal circulation is needed to filter impurities in the blood. This treatment method is generally called dialysis.

[0003] End-stage renal disease (ESRD) poses a serious threat to patients' lives and health. As a key treatment, hemodialysis places extremely high demands on the performance of dialysis materials. Currently, polymer materials such as polymethyl methacrylate (PMMA) are widely used in hemodialysis membranes, but they have many drawbacks.

[0004] The surfaces of these materials differ significantly from human vascular endothelial cells, making them highly susceptible to protein adsorption, triggering the coagulation cascade. During hemodialysis, when blood comes into contact with the dialysis membrane, the hydrophobicity of the polymer surface and its lack of chemical structure similar to human tissue allow proteins such as fibrinogen and albumin to rapidly adsorb to the membrane surface. Studies have shown that within five minutes of contact, up to 10-15 μg of protein can be adsorbed per square centimeter of membrane surface. This adsorption process is not simply a physical attachment, but is accompanied by a change in protein conformation, leading to platelet activation. Activated platelets release a variety of bioactive substances, such as adenosine diphosphate (ADP) and thromboxane A2 (TXA2), which further induce platelet aggregation and platelet thrombus formation. Simultaneously, the adsorbed proteins initiate the coagulation cascade, activating a series of coagulation factors, such as factor XII and factor XI, ultimately leading to the formation of a fibrin clot. This not only leads to clogging of the membrane pores, thus obstructing the channel for material exchange during dialysis, but also significantly attenuates the membrane flux, reducing the dialyzer's efficiency in removing toxins from the body. Experimental data show that when using ordinary PMMA dialysis membranes for hemodialysis, the membrane flux decreases by approximately 35% after 2 hours of dialysis, and the creatinine clearance rate drops from the initial 70%-80% to 50%-60%. The decrease in membrane flux means that the efficiency of transmembrane transport of water and solutes during dialysis is reduced, and the decrease in creatinine clearance directly affects the removal of metabolic waste from the body. This indicates that the performance of ordinary PMMA dialysis membranes will gradually deteriorate during long-term use, making it difficult to continuously meet the dialysis needs of patients.

[0005] Furthermore, the issue of complement activation induced by polymer dialysis membranes cannot be ignored. The complement system is a crucial component of the human immune system. When blood comes into contact with the dialysis membrane, the foreign matter properties of the membrane surface activate the complement system. Studies have found that within 15-30 minutes after the start of hemodialysis, the concentration of the complement activation product C3a in the blood can increase 2-3 times. Activated complement produces various active fragments, such as C3a and C5a. These active fragments have potent biological effects, attracting immune cells such as neutrophils and monocytes to the dialysis membrane surface and triggering an inflammatory response. This inflammatory response not only causes local tissue damage but can also trigger a systemic inflammatory response syndrome, adversely affecting the patient's cardiovascular and respiratory systems, and increasing the risk of complications such as infection and cardiovascular disease. In long-term dialysis patients, the inflammatory response triggered by complement activation can lead to a variety of complications, including anemia, malnutrition, and cardiovascular disease, severely impacting their quality of life and survival. For example, a clinical study following 100 patients who used conventional dialysis membranes for a long time found that approximately 30% developed varying degrees of cardiovascular disease six months after dialysis, and their C-reactive protein (CRP) levels, a marker of inflammation, were significantly above the normal range. This suggests that the inflammatory response triggered by complement activation is closely linked to the development of cardiovascular disease in patients, and that this effect accumulates over the long-term dialysis process, posing a serious threat to patients' health.

[0006] To address these issues, existing technologies have developed an anticoagulant membrane material that grafts polyethylene glycol onto the surface of a PMMA porous resin membrane and cross-links it with sodium citrate. By introducing modified groups rich in hydroxyl and sodium carboxylate groups onto the membrane surface, this material significantly prolongs the anticoagulation time and improves biocompatibility. However, this existing technology still has significant drawbacks. During the grafting and cross-linking processes, the optimization of reaction conditions is limited, making it difficult to precisely control the microstructure of the resin membrane. Current reaction conditions make it difficult to achieve highly uniform grafting of polyethylene glycol onto the resin membrane surface. Some areas may be overgrafted while others may be undergrafted, resulting in uneven membrane surface properties. Experiments using scanning electron microscopy have revealed that the coverage of the polyethylene glycol-grafted areas on the surfaces of resin membranes prepared using existing technologies can vary by as much as 20%-30%. This microstructural variation can lead to unstable anticoagulant properties and inconsistent quality between batches. For example, in anticoagulation time testing, different batches of products produced using the same existing technology can experience fluctuations of up to 10-20 hours, increasing treatment uncertainty and risk in clinical applications. Furthermore, the degree and distribution of sodium citrate crosslinking during the crosslinking reaction are difficult to precisely control, hindering its full potential for anticoagulation and improved biocompatibility.

[0007] Furthermore, existing technologies lack in-depth research into the interaction mechanisms between resin membranes and various substances in the complex hemodialysis environment. Blood is a complex system containing not only blood cells, proteins, and coagulation factors, but also various metabolites and inflammatory mediators. The detailed interactions between the modified groups on the resin membrane surface and these complex components are currently unclear, making it difficult to further optimize the performance of the resin membrane based on these interactions. For example, existing resin membranes exhibit poor adsorption of certain specific uremic toxins, such as the medium- and large-molecular-weight toxin β2-microglobulin and advanced glycation end products (AGEs). Experimental testing has found that the adsorption rate of existing anticoagulant membrane materials for β2-microglobulin is only 20%-30%, and the adsorption rate for AGEs is even lower, at only 10%-15%. This indicates that existing technologies are unable to effectively remove these specific toxins and cannot meet patients' needs for comprehensive detoxification. Furthermore, due to a lack of understanding of the interaction mechanisms, it is difficult to specifically improve the preparation process to enhance the adsorption capacity of these toxins. In addition, during long-term dialysis, the interaction between the resin membrane and various substances in the blood may also lead to aging and performance degradation of the membrane material. However, existing technologies lack in-depth research on this and are unable to effectively predict and solve these problems, making it difficult to meet the growing high-quality needs of clinical hemodialysis. Summary of the Invention

[0008] In order to solve the above technical problems, the present invention provides a method for preparing a hemodialysis resin, aiming to break through the bottleneck of existing technologies, further optimize the anticoagulant properties and biocompatibility of the resin membrane, and significantly improve its adsorption capacity for toxins, so as to better meet the complex needs of clinical hemodialysis and provide patients with a more efficient and safe treatment plan. To achieve the above purpose, The present invention provides the following technical solutions: A method for preparing a hemodialysis resin, characterized in that it comprises the following steps: S1. Pretreatment: The polymethyl methacrylate porous resin membrane is immersed in an alkaline solution containing a surfactant for pretreatment. The surfactant is polyoxyethylene sorbitan fatty acid ester, i.e., Tween-80, and its mass fraction in the solution is 0.5%-1.5%. The alkaline solution is a sodium hydroxide solution with a mass fraction of 10%-12%. The pretreatment process lasts for 20-30 minutes at a temperature of 40-50°C to ensure that the surfactant can effectively reduce the interfacial tension between the solution and the resin membrane, so that the alkaline solution can evenly penetrate into the pores of the resin membrane, fully open the pore structure and increase the surface active sites. The porosity of the resin membrane after this pretreatment is significantly improved compared to that of the untreated membrane. The surface activity can be increased by 25%-35% before treatment, and the surface active sites are increased at the same time. When the mass fraction of Tween-80 is lower than 0.5%, the penetration effect of the solution on the pores of the resin membrane is significantly weakened, and the solution is difficult to fully open the pore structure. The pore opening degree is less than 60% of the ideal state; when it is higher than 1.5%, too many micelles will be formed on the surface of the resin membrane, hindering the subsequent grafting reaction from proceeding uniformly; when the temperature is lower than 40°C, the surfactant activity and the reaction rate of the alkaline solution decrease sharply. After 30 minutes of treatment, the opening degree of the resin membrane pores can only reach about 60% of the ideal state; when the temperature is higher than 50°C, the solution evaporates too quickly and is very likely to cause thermal deformation of the resin membrane, which is not conducive to subsequent processing.

[0009] S2. Grafting reaction: Select polyethylene glycol with a hydroxyl value of 450-500 as the grafting raw material. Grafting reaction steps: Carefully select polyethylene glycol with a hydroxyl value of 450-500 as the grafting raw material, dissolve it in water, and strictly prepare it into a solution with a mass fraction of 35%-40%. At this concentration, the polyethylene glycol molecules maintain an appropriate distance, which can not only ensure sufficient grafting monomers to participate in the reaction, but also effectively avoid the agglomeration problem caused by excessive concentration. At the same time, 0.3%-0.6% dibutyltin dilaurate is added as a catalyst. This catalyst can significantly reduce the activation energy of the grafting reaction, so that the same grafting rate is achieved under the temperature condition of 45-50℃, and the reaction time is greatly shortened from 150-180min without catalyst to 60-90min. In addition, the addition of mass The antioxidant 1010 with a molar fraction of 0.1%-0.2% reacts preferentially with oxygen in the system during the grafting reaction, effectively preventing oxidation reaction between oxygen and polyethylene glycol or resin film, and avoiding degradation of the structure and performance of the grafted product. The pretreated and rinsed resin film is completely immersed in the grafting reaction solution and reacted at 45-50°C for 60-90 minutes to ensure that the polyethylene glycol forms a stable, uniform and high-strength chemical bond with the resin film surface. In an aerobic environment, the grafting reaction is carried out without adding antioxidants, and the tensile strength of the obtained product will be reduced by 15%-20%, and the anti-coagulation performance will also be significantly reduced.

[0010] S3. Cross-linking modification: prepare a mixed solution for cross-linking modification. In the mixed solution, the concentration of citric acid is strictly 150-180g / L, and the concentration of sodium citrate is fixed at 500-550g / L. These two components can accurately introduce rich sodium carboxylate groups on the surface of the resin film through cross-linking reaction, greatly enhancing the anti-coagulation performance. At the same time, nano titanium dioxide (TiO2) with a mass concentration of 0.5g / L-1g / L is added. The nano TiO2 has unique physical and chemical properties, and its particle size is accurately between 20-50nm. It can be highly evenly dispersed in the mixed solution and fully synergize with other ingredients. On the one hand, it significantly enhances the antibacterial properties of the resin film, ensuring that the antibacterial rate of common pathogens such as Escherichia coli and Staphylococcus aureus is stable at more than 90%. On the other hand, it has the ability to efficiently photocatalytically degrade some toxins under light conditions. In addition, during the cross-linking reaction process, nano TiO2 Deeply participate in the construction of the cross-linking network, finely optimize the microstructure of the resin film, immerse the resin film that has been grafted with polyethylene glycol and passed the test in the mixed solution, and react at a temperature of 85-90°C for 50-70 minutes. If the temperature is lower than 85°C, the cross-linking reaction is incomplete, and the anti-coagulation and mechanical properties of the resin film are limited, and the anti-coagulation time can only be extended by 10%-15%; if it is higher than 90°C, the solution is easy to volatilize, and the resin film is very likely to become brittle due to overheating, which seriously affects the use effect.

[0011] On the basis of the above scheme, the following technical solutions can also be adopted: After the pretreatment is completed, a rinsing step is also included: the pretreated resin film is rinsed with deionized water for at least 5 times until the pH value of the rinsing liquid is neutral, ensuring that the alkaline solution and other impurities remaining on the surface of the resin film are removed to provide a pure surface environment for the subsequent grafting reaction.

[0012] After the grafting reaction is completed, a testing step is also included: quality testing of the resin film after the grafting reaction, observing the coverage of the polyethylene glycol grafted area by scanning electron microscopy, requiring the coverage difference to be within 10%, and using tensile testing equipment to test the tensile strength of the grafted product, which should meet no less than 90% of the tensile strength of existing products of the same type. If the above-mentioned testing standards are not met, the parameters of the subsequent cross-linking modification step are adjusted to ensure the stability of product quality.

[0013] It also includes a post-processing step: taking out the cross-linked modified resin film from the mixed solution, first rinsing it with deionized water 3-5 times to remove the residual mixed solution components on the surface, and then placing it in a vacuum environment for drying at a drying temperature of 50-60°C and a drying time of 2-3 hours to ensure that the water content of the resin film is less than 5%, providing good conditions for subsequent packaging, storage and clinical use.

[0014] In the cross-linking modification step, the nano-titanium dioxide particle size is between 20-50nm, which can be evenly dispersed in the mixed solution, fully contacting and synergistically acting with other components, so that the resin film has an antibacterial rate of more than 90% against common pathogens such as Escherichia coli and Staphylococcus aureus, and can photocatalytically degrade some toxins under light conditions.

[0015] The coverage difference of the polyethylene glycol grafted area on the resin membrane surface is reduced by at least 50% compared with the existing technology. The anticoagulation performance of different batches of products is extremely stable. The anticoagulation time fluctuation range of the same batch of products is within 5 hours. The anticoagulation time can be improved by an average of 35%-50% compared with the existing technology of grafting polyethylene glycol on the surface of PMMA porous resin membrane and cross-linking sodium citrate. In addition, during long-term hemodialysis, the decline in anticoagulation performance is reduced by at least 30% compared with the existing technology.

[0016] Compared with the existing technology of grafting polyethylene glycol on the surface of PMMA porous resin membrane and cross-linking sodium citrate, the adsorption rate of common toxins such as creatinine and urea nitrogen is increased by 20%-30%. Compared with the existing technology, the adsorption rate of specific uremic toxins such as β2-microglobulin and advanced glycation end products (AGEs) is increased by at least 10% and 15% respectively. In addition, during long-term use, the decline in the adsorption capacity of toxins is reduced by at least 20% compared with the existing technology.

[0017] The resin membrane has excellent biocompatibility and has been rigorously evaluated through cytotoxicity and hemolysis tests. The cytotoxicity level is stably maintained at 0-1, and the hemolysis rate is less than 0.5%. This can minimize adverse reactions in patients during dialysis, significantly improving treatment comfort. Moreover, in a long-term blood contact environment, the degree of biocompatibility degradation is reduced by at least 25% compared to existing technologies.

[0018] During long-term use, the resin membrane has significantly lower aging and performance degradation of the membrane material caused by interaction with various substances in the blood compared with the existing technology, and the membrane flux attenuation rate is reduced by at least 20% compared with the existing technology. It can fully meet the growing high-quality demand for clinical hemodialysis and provide patients with end-stage renal disease with a more reliable and efficient dialysis treatment plan.

[0019] In the pretreatment step, the mass fraction of Tween-80 is 1%, the mass fraction of the sodium hydroxide solution is 10%, the treatment temperature is 45° C., and the treatment time is 25 minutes.

[0020] The hydroxyl value of the polyethylene glycol is 480, the mass fraction of the solution is 35%, the mass fraction of the catalyst dibutyltin dilaurate is 0.3%, the mass fraction of the antioxidant 1010 is 0.1%, the grafting reaction temperature is 45° C., and the reaction time is 90 min.

[0021] The mixed solution has a citric acid concentration of 150 g / L, a sodium citrate concentration of 500 g / L, a nano-titanium dioxide mass concentration of 0.5 g / L, a cross-linking reaction temperature of 85° C., and a reaction time of 70 min.

[0022] The beneficial effects of the present invention are: Improved anticoagulant performance: Through precise optimization of pretreatment and grafting reaction conditions, polyethylene glycol can be more evenly and firmly grafted onto the resin membrane surface. During the cross-linking reaction, the synergistic effect of nano-titanium dioxide increases the effective exposure of sodium carboxylate groups, resulting in a 30%-50% increase in anticoagulation time compared to existing technologies. This means that during hemodialysis, the resin membrane prepared using this invention can significantly reduce the risk of thrombosis and improve the safety and stability of dialysis treatment.

[0023] Enhanced biocompatibility: The rational use of surfactants and antioxidants effectively minimizes damage to the resin membrane structure during the reaction. The surfactant gently treats the resin membrane surface during pretreatment, while the antioxidant protects the membrane's structural integrity during the grafting reaction. Furthermore, the antibacterial properties of nano-titanium dioxide reduce the risk of infection during dialysis. This combined effect further enhances biocompatibility, reduces adverse reactions during dialysis, and improves treatment comfort.

[0024] Improved Toxin Adsorption: The introduction of nano-titanium dioxide imparts the resin membrane with the ability to photocatalytically degrade toxins, synergizing with its existing adsorption function. Experiments have shown that the adsorption rate of common toxins such as creatinine and urea nitrogen is 20%-30% higher than existing technologies. This enables the dialyzer to more effectively remove toxins from the patient's body, enhancing the effectiveness of dialysis treatment and improving the patient's health. DETAILED DESCRIPTION

[0025] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0026] The present invention relates to a method for preparing a hemodialysis resin, comprising pretreatment, grafting reaction and cross-linking modification, specifically comprising: Preprocessing steps: A polymethyl methacrylate porous resin membrane is pretreated by immersing it in an alkaline solution containing a specific surfactant. Polyoxyethylene sorbitan fatty acid ester (Tween-80) is selected as the surfactant due to its excellent emulsifying and dispersing properties, effectively reducing the interfacial tension between the solution and the resin membrane. Extensive experimental screening determined that a mass fraction of 0.5%-1.5% in the solution is optimal. For example, a mass fraction below 0.5% significantly weakens the solution's penetration into the resin membrane's pores, making it difficult to fully open the pore structure. A mass fraction above 1.5% may result in excessive micelle formation on the membrane surface, hindering the uniformity of the subsequent grafting reaction. A 10%-12% mass fraction of sodium hydroxide solution is used as the alkaline solution. This concentration range ensures moderate etching of the resin membrane surface, increasing active sites, while preventing excessive corrosion that could damage the membrane structure. The pretreatment process lasts for 20-30 minutes at a precisely controlled temperature of 40-50°C. Research data shows that below 40°C, the activity of the surfactant and the reaction rate of the alkaline solution decrease significantly. After 30 minutes of treatment, the degree of opening of the resin membrane pores can only reach about 60% of the ideal state; when the temperature is above 50°C, the volatilization of the solution intensifies and it is easy to cause thermal deformation of the resin membrane, which is also not conducive to subsequent processing. In this step, the surfactant can reduce the surface tension of the solution, allowing the alkaline solution to penetrate more evenly into the pores of the resin membrane, effectively opening the pore structure and increasing the surface active sites. Experimental tests have found that after pretreatment, the porosity of the resin membrane can be increased by 25%-35% compared to before treatment. These active sites provide more reaction sites for the subsequent grafting reaction, which is beneficial to improving the efficiency and uniformity of the grafting reaction.

[0027] Rinse step: Rinse the pretreated resin membrane with deionized water for at least 5 times until the pH value of the rinse solution is neutral, ensuring that the alkaline solution and other impurities remaining on the surface of the resin membrane are removed, providing a pure surface environment for the subsequent grafting reaction.

[0028] Grafting reaction steps: Carefully selected polyethylene glycol with a hydroxyl value of 450-500 is used as the grafting raw material. Polyethylene glycol in this hydroxyl value range exhibits moderate reactivity and good hydrophilicity, enabling stable and uniform chemical bonding with the resin membrane surface. The polyethylene glycol is dissolved in water to create a 35%-40% by weight solution. At this concentration, the spacing between polyethylene glycol molecules is optimal, ensuring sufficient grafting monomers for the reaction while preventing agglomeration that would otherwise occur at high concentrations. Simultaneously, 0.3%-0.6% dibutyltin dilaurate is added as a catalyst, effectively lowering the activation energy of the grafting reaction and accelerating the reaction. For example, without a catalyst, the grafting reaction at 45-50°C takes 150-180 minutes to achieve the same grafting rate. However, with the addition of an appropriate amount of catalyst, the reaction time can be shortened to 60-90 minutes. In addition, antioxidant 1010 is added at a mass fraction of 0.1%-0.2%. This is because during the grafting reaction, oxygen in the system readily undergoes oxidation reactions with the polyethylene glycol or resin film, leading to changes in the structure and properties of the grafted product. Experiments have shown that when the grafting reaction is carried out in an aerobic environment without the addition of an antioxidant, the tensile strength of the resulting product decreases by 15%-20%, and its anticoagulant properties also decrease. Antioxidant 1010 preferentially reacts with oxygen, protecting the polyethylene glycol and resin film, ensuring that the grafting reaction proceeds as intended, thereby guaranteeing the stability and quality of the grafted product. The pretreated resin film is completely immersed in the grafting reaction solution and reacted at a temperature of 45-50°C for 60-90 minutes. This temperature range ensures the activity of the polyethylene glycol while avoiding side reactions caused by excessively high temperatures.

[0029] Testing steps: Perform quality testing on the resin film after the grafting reaction. Observe the coverage of the polyethylene glycol grafted area using a scanning electron microscope. The coverage difference is required to be within 10%. Use tensile testing equipment to test the tensile strength of the grafted product. It should meet no less than 90% of the tensile strength of existing products of the same type. If the above testing standards are not met, adjust the parameters of the subsequent cross-linking modification step to ensure the stability of product quality.

[0030] Cross-linking modification steps: A special mixed solution was prepared for cross-linking modification. The concentration of citric acid in the mixed solution was 150-180 g / L, and sodium citrate was 500-550 g / L. These two components, through cross-linking reactions, introduce abundant sodium carboxylate groups onto the resin film surface, enhancing its anticoagulant properties. Nano-titanium dioxide (TiO2) was also added at a concentration of 0.5 g / L-1 g / L. Nano-TiO2 possesses unique physical and chemical properties. Its particle size, typically between 20 and 50 nm, allows for uniform dispersion in the mixed solution, allowing for full contact and synergistic interaction with the other components. Furthermore, it not only enhances the antibacterial properties of the resin film, achieving an inhibition rate of over 90% against common pathogens such as Escherichia coli and Staphylococcus aureus, but also photocatalytically degrades some toxins under illumination. During the cross-linking reaction, nano-TiO2 interacts with citric acid, sodium citrate, and polyethylene glycol, participating in the construction of a cross-linked network, optimizing the resin film's microstructure and further enhancing its overall performance. The resin film grafted with polyethylene glycol was immersed in the mixed solution and reacted at 85-90°C for 50-70 minutes. Experiments have found that at temperatures below 85°C, the cross-linking reaction is incomplete, resulting in limited improvements in the anticoagulant and mechanical properties of the resin film. For example, the anticoagulation time can only be extended by 10%-15%. Above 90°C, the solution is volatile, and the resin film may become brittle due to overheating, affecting its performance.

[0031] Post-processing steps: Remove the cross-linked modified resin film from the mixed solution, rinse it with deionized water 3-5 times to remove the residual mixed solution components on the surface, and then place it in a vacuum environment for drying at a temperature of 50-60°C and a drying time of 2-3 hours to ensure that the moisture content of the resin film is less than 5%, providing good conditions for subsequent packaging, storage and clinical use.

[0032] For detailed description, the following uses specific parameters to explain: Example 1

[0033] A 10% sodium hydroxide solution containing 1% Tween-80 was prepared, and the polymethyl methacrylate porous resin membrane was completely immersed in it. It was then treated in a constant temperature water bath at 45°C for 15 min, 25 min, and 35 min, respectively, to explore the effects of different pretreatment times.

[0034] When the treatment time was 15 minutes, the surfactant and alkaline solution failed to fully penetrate the resin membrane pores due to the short treatment time, resulting in limited pore opening. Testing showed that the resin membrane porosity increased by only approximately 15%. During the subsequent grafting reaction, insufficient active sites resulted in a polyethylene glycol grafting rate of only 25%, and the grafting uniformity was poor, with grafting density varying by as much as 15% across different regions of the membrane surface. In the final dialysis performance test, the adsorption rate for creatinine was 50%, the adsorption rate for urea nitrogen was 55%, and the anticoagulation time was 75 hours.

[0035] When the standard 25-minute treatment is performed, a circulating water bath is used to ensure that the solution temperature is uniform and stable to avoid local overheating or overcooling that may affect the treatment effect. A high-precision timer is used to precisely control the treatment time to ensure that the surfactant and alkaline solution fully act on the resin membrane. After the treatment, the resin membrane is repeatedly rinsed with deionized water for 8 times until the rinse liquid is neutral, thereby obtaining a pretreated resin membrane. During this process, the temperature and time are controlled to ensure that the surfactant and alkaline solution fully act on the resin membrane, opening up the pore structure and increasing the surface active sites. Testing has shown that the porosity of the pretreated resin membrane reaches 40%, a 30% increase compared to the untreated state, providing a good foundation for the subsequent grafting reaction.

[0036] Extending the treatment time to 35 minutes further increased the pore opening, reaching a porosity of 45%. However, prolonged exposure to an alkaline environment caused slight corrosion to the resin membrane surface, compromising its structural integrity. During the subsequent grafting reaction, the polyethylene glycol grafting rate increased to 38%, but due to damage to the membrane surface microstructure, the grafting uniformity deteriorated, with grafting density varying by 10% across different regions. Regarding dialysis performance, the creatinine adsorption rate was 62%, the urea nitrogen adsorption rate was 67%, and the anticoagulation time was 85 hours. However, the membrane's mechanical properties declined, with the tensile strength decreasing by approximately 8%.

[0037] Overall, a 25-minute pretreatment time ensures the structural integrity of the resin membrane while maximally optimizing the pore structure, creating favorable conditions for subsequent reactions and achieving optimal dialysis results. Subsequent grafting and cross-linking steps are as described above: Polyethylene glycol with a hydroxyl number of 480 was accurately weighed to obtain a dialysis resin membrane. Example 2

[0038] The polymethyl methacrylate porous resin membrane was placed in a 12% sodium hydroxide solution containing 0.5% Tween-80 and treated at 40°C for 20 minutes, 30 minutes and 40 minutes respectively for comparative study.

[0039] After 20 minutes of treatment, solution penetration was poor, the resin membrane porosity increased to 25%, and active sites were limited. The polyethylene glycol grafting rate after the grafting reaction was 28%, with poor surface uniformity and a 12% variation in graft density across different regions. During dialysis testing, creatinine adsorption was 48%, urea nitrogen adsorption was 52%, and anticoagulation time was 78 hours.

[0040] The standard 30-minute treatment was performed in a constant temperature and humidity chamber to ensure temperature and humidity stability and reduce external interference with the pretreatment process. After treatment, the resin membrane was rinsed with a large amount of deionized water (at least 1000 ml) until clean, obtaining a pretreated resin membrane. In this step, a lower surfactant concentration, higher alkali concentration, and longer treatment time were used to explore the effects of different pretreatment conditions on the performance of the resin membrane. Testing showed that the porosity of the resin membrane increased to 35% under this pretreatment method, providing a certain amount of active sites for subsequent reactions.

[0041] After 40 minutes of treatment, the resin membrane's pores became excessively open, reaching a porosity of 42%, and slight surface swelling occurred, affecting the uniformity of subsequent reactions. The polyethylene glycol grafting rate was 34%, with average grafting uniformity and a 9% variation in grafting density between different regions. Dialysis performance was demonstrated by a creatinine adsorption rate of 60%, a urea nitrogen adsorption rate of 64%, and an anticoagulation time of 82 hours. Similarly, the membrane's mechanical properties declined slightly, with tensile strength decreasing by approximately 6%.

[0042] It can be seen that the pretreatment time of 30 minutes is most suitable under the specific conditions of this embodiment. The subsequent grafting and cross-linking steps are as described above: polyethylene glycol with a hydroxyl value of 450 is weighed to obtain a resin membrane for dialysis.

[0043] A dialysis resin membrane was prepared using a conventional process involving grafting polyethylene glycol onto the surface of a PMMA porous resin membrane and cross-linking it with sodium citrate. This was used as a comparative reference to clearly demonstrate the advantages of the present invention's preparation method. Various performance indicators were tested under the same testing conditions, demonstrating a stark contrast to those of Examples 1 and 2. Example 3

[0044] Prepare a 10% sodium hydroxide solution containing 1% Tween-80, completely immerse the polymethyl methacrylate porous resin membrane in it, and treat it in a constant temperature water bath at 35℃, 45℃ and 55℃ for 25 minutes respectively to explore the differences brought about by different pretreatment temperatures.

[0045] When the temperature was set at 35°C, the low temperature inhibited the activity of the surfactant and the reaction rate of the alkaline solution. The solution's penetration into the resin membrane pores was poor, and testing showed that the resin membrane porosity only increased by approximately 20%. During the subsequent grafting reaction, the relatively small number of active sites resulted in a polyethylene glycol grafting rate of only 28%, and the grafting uniformity was poor, with the grafting density varying by 12% across different regions of the membrane surface. In the final dialysis performance test, the adsorption rate for creatinine was 52%, the adsorption rate for urea nitrogen was 57%, and the anticoagulation time was 78 hours.

[0046] At a standard temperature of 45°C, a circulating water bath device is used to ensure that the solution temperature is uniform and stable to avoid local overheating or overcooling that affects the treatment effect. A high-precision timer is used to accurately control the treatment time to ensure that the surfactant and alkaline solution fully act on the resin membrane. After the treatment, the resin membrane is repeatedly rinsed with deionized water for no less than 5 times until the rinse liquid is neutral to obtain a pretreated resin membrane. In this process, by controlling the temperature and time, it is ensured that the surfactant and alkaline solution fully act on the resin membrane, open the pore structure and increase the surface active sites. After testing, the porosity of the pretreated resin membrane reached 40%, which is 30% higher than that before treatment, providing a good foundation for the subsequent grafting reaction.

[0047] If the temperature is raised to 55°C, the volatilization of the solution will intensify, which will not only cause fluctuations in the solution concentration and affect the treatment effect, but also easily cause thermal deformation of the resin membrane. At this time, although the porosity of the resin membrane can be increased to 45%, obvious wrinkles appear on the surface and the structural integrity is damaged. In the subsequent grafting reaction, the polyethylene glycol grafting rate reached 36%, but the grafting uniformity deteriorated, and the difference in grafting density in different areas was 10%. In terms of dialysis performance, the creatinine adsorption rate was 60%, the urea nitrogen adsorption rate was 65%, and the anticoagulation time was 82h. At the same time, the mechanical properties of the membrane decreased significantly, and the tensile strength decreased by about 10%.

[0048] Comprehensive comparison shows that the pretreatment temperature of 45°C performs best in terms of balanced pore structure optimization, membrane structure stability and subsequent reaction activity. The subsequent grafting and cross-linking steps are the same as those in Example 1. Description: Polyethylene glycol with a hydroxyl value of 480 is accurately weighed to obtain a dialysis resin membrane. Example 4

[0049] The polymethyl methacrylate porous resin membrane was placed in a 12% sodium hydroxide solution containing 0.5% Tween-80 and treated at 30℃, 40℃ and 50℃ for 30 minutes respectively to study the temperature effect.

[0050] When treated at 30°C, the reaction system exhibited low activity, with the resin membrane porosity increasing to only 22% and few active sites. The grafting reaction resulted in a 26% polyethylene glycol grafting rate, poor surface uniformity, and a 15% variation in graft density across different regions. During dialysis testing, the creatinine adsorption rate was 45%, the urea nitrogen adsorption rate was 48%, and the anticoagulation time was 75 hours.

[0051] The treatment was carried out at a standard 40°C temperature and humidity chamber to ensure temperature and humidity stability and reduce external interference with the pretreatment process. After treatment, the resin membrane was rinsed with a large amount of deionized water (at least 1000ml) until it was clean, obtaining a pretreated resin membrane. In this step, a lower surfactant concentration, a higher alkali concentration, and a longer treatment time were used to explore the effects of different pretreatment conditions on the performance of the resin membrane. Testing showed that the porosity of the resin membrane increased to 35% under this pretreatment method, providing a certain active site foundation for subsequent reactions.

[0052] When the temperature rose to 50°C, solution volatilization and thermal deformation became prominent, and the resin membrane pores became excessively open and swollen, resulting in a porosity of 40%. The polyethylene glycol grafting rate was 32%, with average grafting uniformity and a 10% variation in grafting density between different regions. Dialysis performance was demonstrated by a creatinine adsorption rate of 58%, a urea nitrogen adsorption rate of 62%, and an anticoagulation time of 80 hours. The membrane's mechanical properties declined, with tensile strength decreasing by approximately 8%.

[0053] It can be seen that the pretreatment time at 40° C. is most suitable under the specific conditions of this embodiment, and the subsequent grafting and cross-linking steps remain unchanged: polyethylene glycol with a hydroxyl value of 450 is weighed to obtain a resin membrane for dialysis.

[0054] A dialysis resin membrane was prepared using a conventional process involving grafting polyethylene glycol onto the surface of a PMMA porous resin membrane and cross-linking sodium citrate. This was used as a comparative reference to clearly demonstrate the advantages of the present invention's preparation method. Under identical testing conditions, various performance indicators were evaluated, demonstrating a clear comparison with those of Examples 3 and 4.

[0055] Performance testing Anticoagulant performance testing: A static anticoagulation test (Lee-White method) was used. The specific procedure was as follows: Under sterile conditions, fresh blood was collected from healthy volunteers and placed in contact with the resin membranes prepared in Example 1, Example 2, and the prior art. The blood samples were then placed in a constant temperature environment at 37°C. Blood coagulation was observed at regular intervals, and the time at which coagulation began, known as the anticoagulation time, was recorded. The experimental results showed that the anticoagulation time for Example 1 was 90.5 hours, and for Example 2 was 88.3 hours, while the anticoagulation time for the prior art was only 73.8 hours. Compared with the prior art, the anticoagulation times for Examples 1 and 2 were significantly extended by 16.7 hours and 14.5 hours, respectively. This demonstrates that the resin membranes prepared in this invention exhibit superior performance in inhibiting blood coagulation, effectively reducing the risk of thrombosis during dialysis and providing a safer dialysis treatment environment for patients.

[0056] Toxin Adsorption Capacity Testing: To simulate the human blood environment, simulated blood solutions containing a certain concentration of creatinine and urea nitrogen were prepared. The resin membranes prepared in Example 1, Example 2, and the prior art were placed in the simulated blood solutions and reacted at 37°C with constant temperature and oscillation for a specified time. After the reaction, the residual concentrations of creatinine and urea nitrogen in the solutions were determined using high-performance liquid chromatography, and the adsorption rates of creatinine and urea nitrogen by the resin membranes were calculated. Experimental data showed that Example 1 had a creatinine adsorption rate of 65% and a urea nitrogen adsorption rate of 70%; Example 2 had a creatinine adsorption rate of 62% and a urea nitrogen adsorption rate of 68%; the prior art had a creatinine adsorption rate of 45% and a urea nitrogen adsorption rate of 50%. The adsorption rates of Examples 1 and 2 for creatinine improved by 20 percentage points and 17 percentage points, respectively, compared to the prior art, and for urea nitrogen improved by 20 percentage points and 18 percentage points, respectively. This fully demonstrates that the resin membrane prepared by the present invention has significantly enhanced adsorption capacity for common toxins, can more effectively remove metabolic waste from the patient's body, improve the effect of dialysis treatment, and help improve the patient's health.

[0057] Biocompatibility Testing: The biocompatibility of the resin membranes was evaluated through cytotoxicity and hemolysis tests. In the cytotoxicity test, extracts from the resin membranes prepared in Examples 1 and 2, as well as those prepared in the prior art, were co-incubated with cultured cell lines (e.g., L929 mouse fibroblasts). Cell viability was assessed using the MTT assay, and the cytotoxicity level was determined based on cell viability. In the hemolysis test, the resin membranes were mixed with fresh blood and incubated at 37°C for a specified period of time. The supernatant was then centrifuged, the hemoglobin content was measured, and the hemolysis rate was calculated. The experimental results showed that the cytotoxicity levels of Examples 1 and 2 were both 0-1, with hemolysis rates below 0.5%. The prior art test had a cytotoxicity level of 1-2 and a hemolysis rate of 0.8%. The lower cytotoxicity levels and hemolysis rates of Example 1 and Example 2 indicate that the resin membrane prepared by the present invention causes less damage to cells, is less likely to induce a hemolytic reaction when in contact with blood, has better biocompatibility, is safer in clinical applications, can reduce adverse reactions in patients during dialysis, and improve the treatment comfort of patients.

[0058] The above shows and describes the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The above embodiments and descriptions are merely preferred examples of the present invention and are not intended to limit the present invention. Various changes and improvements may be made to the present invention without departing from the spirit and scope of the present invention. Such changes and improvements fall within the scope of the present invention. The scope of protection claimed in the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing a hemodialysis resin, characterized in that: The following steps are involved: S1. Pretreatment: Immerse the polymethyl methacrylate porous resin membrane in a 10%-12% sodium hydroxide solution containing 0.5%-1.5% polyoxyethylene sorbitan fatty acid ester (i.e., Tween-80) by mass at a temperature of 40-50°C for 20-30 minutes to allow the surfactant to effectively reduce the interfacial tension between the solution and the resin membrane, promote the alkaline solution to evenly penetrate the pores of the resin membrane, fully expand the pore structure, and increase the surface active sites; S2. Grafting reaction: Polyethylene glycol with a hydroxyl value in the range of 450-500 is selected as the grafting raw material and dissolved in water to prepare a solution with a mass fraction of 35%-40%. At the same time, 0.3%-0.6% dibutyltin dilaurate is added as a catalyst, and 0.1%-0.2% of antioxidant 1010 is added. Subsequently, the pretreated resin film is completely immersed in the grafting reaction solution and reacted at a temperature of 45-50°C for 60-90 minutes to ensure that the polyethylene glycol forms a stable, uniform and strong chemical bond with the resin film surface; S3. Cross-linking modification: Prepare a specific mixed solution in which the citric acid concentration is 150-180g / L, the sodium citrate concentration is maintained at 500-550g / L, and nano-titanium dioxide with a mass concentration of 0.5g / L-1g / L and a particle size of 20-50nm is added. Then, the resin film that has completed the grafting reaction is immersed in the mixed solution and reacted at a temperature of 85-90℃ for 50-70min. With the help of the cross-linking reaction, rich sodium carboxylate groups are accurately introduced on the surface of the resin film. At the same time, the unique physical and chemical properties of nano-titanium dioxide are utilized to improve the comprehensive performance of the resin film.

2. The method for preparing a hemodialysis resin according to claim 1, wherein: After the pretreatment step is completed, the pretreated resin membrane is rinsed with deionized water for no less than 5 times until the pH value of the rinse liquid is neutral, so as to completely remove the alkaline solution and other impurities remaining on the surface of the resin membrane and provide a clean surface environment for the subsequent grafting reaction.

3. The method for preparing a hemodialysis resin according to claim 1, wherein: After the grafting reaction step is completed, the resin film after the grafting reaction needs to be quality tested, and the coverage of the polyethylene glycol grafted area is observed using a scanning electron microscope, and the coverage difference is required to be controlled within 10%; the tensile strength of the grafted product is tested using tensile testing equipment, and the tensile strength should be no less than 90% of the tensile strength of existing products of the same type. If the above-mentioned test standards cannot be met, the relevant parameters of the subsequent cross-linking modification steps shall be adjusted accordingly to ensure the stability of product quality.

4. The method for preparing a hemodialysis resin according to claim 1, wherein: It also covers post-processing steps, specifically removing the cross-linked modified resin film from the mixed solution, first rinsing it with deionized water 3-5 times to remove the residual mixed solution components on the surface, and then placing it in a vacuum environment and drying it at a temperature range of 50-60°C for 2-3 hours to reduce the water content of the resin film to less than 5%, creating good conditions for subsequent packaging, storage and clinical use.

5. The method for preparing a hemodialysis resin according to claim 1, wherein: In the cross-linking modification step, the nano-titanium dioxide particle size is between 20-50nm, which can be evenly dispersed in the mixed solution, fully contacting and synergistically acting with other components, so that the resin film has an antibacterial rate of more than 90% against common pathogens such as Escherichia coli and Staphylococcus aureus, and can photocatalytically degrade some toxins under light conditions.

6. The method for preparing a hemodialysis resin according to any one of claim 1, wherein: The coverage difference of the polyethylene glycol grafted area on the resin membrane surface is reduced by more than 50%, and the anticoagulation time is improved by 30%-50% by the technology of grafting polyethylene glycol and cross-linking sodium citrate on the surface of the polymethyl methacrylate porous resin membrane.

7. The method for preparing a hemodialysis resin according to claim 6, wherein: The anticoagulation time of the prepared dialysis resin membrane is increased by 30%-50%, and the adsorption rate of common toxins such as creatinine and urea nitrogen is increased by 20%-30%. Evaluations through cytotoxicity and hemolysis experiments show that the cytotoxicity level is 0-1 and the hemolysis rate is less than 0.5%.

8. The method for preparing a hemodialysis resin according to claim 1, wherein: In the pretreatment step, the mass fraction of Tween-80 is 1%, the mass fraction of the sodium hydroxide solution is 10%, the treatment temperature is 45° C., and the treatment time is 25 minutes.

9. The method for preparing a hemodialysis resin according to claim 1, wherein: The hydroxyl value of the polyethylene glycol is 480, the mass fraction of the solution is 35%, the mass fraction of the catalyst dibutyltin dilaurate is 0.3%, the mass fraction of the antioxidant 1010 is 0.1%, the grafting reaction temperature is 45° C., and the reaction time is 90 min.

10. The method for preparing a hemodialysis resin according to claim 1, wherein: The mixed solution has a citric acid concentration of 150 g / L, a sodium citrate concentration of 500 g / L, a nano-titanium dioxide mass concentration of 0.5 g / L, a cross-linking reaction temperature of 85° C., and a reaction time of 70 min.