A blood purification membrane and a preparation method thereof

Abstract

The present application relates to the technical field of membrane separation, and particularly relates to a blood purification membrane and a preparation method thereof. The blood purification membrane comprises a porous polymer base film and a functional layer covering at least one surface of the porous polymer base film. In the film-forming base material of the porous polymer base film, a hydrophilic porogen is locked in the polymer network of the film-forming base material through physical entanglement, and the functional layer comprises polydopamine and a zwitterionic polymer, and the zwitterionic polymer is covalently anchored to the surface of the porous polymer base film through the polydopamine. The beneficial effect is that the zwitterionic polymer is covalently anchored to the surface of the base film through the polydopamine, compared with the existing technology of physical coating fixation, the problem of easy peeling of the functional layer and poor long-term stability is solved, the service life of the blood purification membrane is prolonged, meanwhile, the safety risk caused by the peeling of the functional components into the blood is avoided, and the clinical application requirement of the blood purification material is met.

Description

Technical Field

[0001] This invention relates to the field of membrane separation technology, and in particular to a blood purification membrane and its preparation method. Background Technology

[0002] Blood purification technology is a core supporting technology for the treatment of critical illnesses such as end-stage renal disease, acute kidney injury, sepsis, and multiple organ failure. As a core functional component that comes into direct contact with blood, the screening performance, antifouling performance, and biocompatibility of the blood purification membrane directly determine the treatment effect, treatment continuity, and patient clinical prognosis.

[0003] Currently, the mainstream blood purification membrane substrates used in clinical practice are mainly polyethersulfone (PES) and polysulfone (PSF). These materials possess excellent mechanical strength, chemical stability, and sterilization resistance. However, their strong hydrophobicity makes them highly susceptible to non-specific protein adsorption upon contact with blood, thereby initiating a coagulation cascade reaction, activating platelets and the complement system, and ultimately leading to thrombosis and membrane pore blockage. To address these issues, extensive modification research has been conducted in the industry, but existing technologies all suffer from core defects that are difficult to overcome simultaneously, failing to meet the clinical needs of blood purification. Specifically: (1) Currently, the nominal pore size of commonly used hemodialysis membranes in clinical practice is mostly 1-10 nm, which only allows small molecule toxins such as creatinine and urea to pass through, while retaining beneficial plasma proteins such as albumin and immunoglobulins; the nominal pore size of plasma separation membranes is mostly 0.2-0.5 μm, which only allows plasma components to pass through, while retaining all blood cells. The pore size design of the above two types of membranes is guided by their respective clinical solute clearance targets, but there is a contradiction between pore size and permeability. Although small-pore dialysis membranes can effectively retain beneficial proteins, they limit the clearance of large and medium molecule toxins; although large-pore plasma separation membranes allow plasma proteins to pass through freely, they cannot selectively retain specific harmful components. More importantly, when attempting to expand the membrane pore size to the micrometer level to achieve high-flux permeation of plasma proteins, the hydrophobic properties of the membrane material cause plasma proteins to be rapidly adsorbed on the membrane surface and in the pores. In addition, due to the limitations of existing hydrophilic modification technology, the membrane pores are easily blocked by protein fouling layers, resulting in rapid flux decay and loss of separation performance. How to maintain the long-term patency of the membrane channels and stable separation performance while increasing the membrane pore size to ensure high-flux permeation of beneficial plasma proteins is a core technical problem that existing technologies have failed to solve effectively.

[0004] (2) Existing hydrophilic modification technologies suffer from poor long-term stability and functional degradation. Currently, the mainstream approach in the industry is to use a hydrophilic modification scheme that blends polyvinylpyrrolidone (PVP) with polyethersulfone (PES). This reduces the hydrophobicity of the membrane surface and decreases protein adsorption through the hydrophilic effect of PVP. However, in this scheme, there is a lack of covalent bonds between PVP and the PES substrate. The fixation mainly relies on physical entanglement and hydrogen bonding. During long-term blood contact, PVP will still slowly dissolve, leading to a gradual decrease in the hydrophilicity of the membrane surface and the hydrophilicity of the inner wall of the membrane pores. This results in increased protein adsorption and a gradual decrease in flux. Excessive PVP addition can also lead to a decrease in the mechanical strength of the membrane and collapse of the membrane pore structure, making it unable to meet the pressure resistance requirements for long-term circulation. Therefore, the existing PVP blend hydrophilic modification scheme cannot provide long-lasting and stable anti-protein adsorption protection for large-pore blood purification membranes, and it is difficult to meet the dual requirements of high-flux protein permeation and long-term stable operation.

[0005] (3) Existing technologies for directly preparing large-pore membranes via phase inversion often rely on increasing the amount of pore-forming agent or changing the coagulation bath conditions to expand the pore size. However, this method is prone to widening of the pore size distribution, large pores failing to pass through the sieve, and small pores becoming clogged, resulting in a significant decrease in sieving accuracy. Post-processing methods such as pore enlargement or etching are not only complex and costly, but may also damage the membrane substrate structure and reduce mechanical strength. Existing technologies, such as CN113230898A, disclose a method for preparing an extracorporeal circulation anticoagulant modified membrane, which covalently grafts the Xa factor inhibitor apixaban onto carboxylated polysulfone / polyethersulfone. This scheme improves the anticoagulant performance of the membrane, but after bulk grafting, the functional molecules are largely embedded inside the substrate, resulting in low surface utilization. Furthermore, strong acid and strong oxidation modification conditions may reduce the mechanical strength of the membrane substrate, which is not conducive to maintaining the large-pore membrane structure. More importantly, the proposed solution does not address the construction of membrane pore size regulation and hydrophilic antifouling functions, and therefore cannot solve the problems of membrane pore blockage and flux decay in large-pore membranes under high-flux protein permeation conditions.

[0006] In summary, current blood purification membrane technologies, whether traditional PVP hydrophilic blending modification, direct phase inversion to prepare large-pore membranes, or novel drug bulk grafting modification, all struggle to maintain long-term membrane patency and stable separation performance while simultaneously increasing membrane pore size to ensure high-flux permeation of beneficial plasma proteins. The problems of protein adsorption blockage and rapid flux decay faced by large-pore membranes, coupled with the limitation of small-pore membranes in achieving high-flux permeation of beneficial proteins, constitute the core contradiction that is difficult to reconcile with existing technologies, making it difficult to meet the comprehensive requirements of clinical blood purification for membrane material separation performance and operational reliability. Summary of the Invention

[0007] (a) Technical problems to be solved In view of the above-mentioned shortcomings and deficiencies of the prior art, the present invention provides a blood purification membrane and its preparation method, which solves the technical problem that when the existing blood purification membrane expands the pore size to achieve high-flux permeation of beneficial plasma proteins, the membrane pore flux rapidly declines and the separation performance is difficult to maintain for a long time due to unstable hydrophilic modification and protein adsorption blockage.

[0008] (II) Technical Solution To achieve the above objectives, the main technical solutions adopted by the present invention include: In a first aspect, the present invention provides a blood purification membrane, comprising a porous polymer base membrane and a functional layer covering at least one surface of the porous polymer base membrane; In the film-forming substrate of the porous polymer-based membrane, the hydrophilic pore-forming agent is physically entangled and locked within the polymer network of the film-forming substrate; The functional layer comprises polydopamine and a zwitterionic polymer, wherein the zwitterionic polymer is covalently anchored to the surface of the porous polymer base film via the polydopamine.

[0009] Alternatively, the film-forming substrate is a blend of sulfonated polyethersulfone with a molecular weight of 40,000-60,000 and polyethersulfone with a molecular weight of 40,000-60,000, wherein the mass ratio of the sulfonated polyethersulfone to the polyethersulfone is (1-2):(8-9), and the degree of sulfonation of the sulfonated polyethersulfone is 8%-12%. The sulfonic acid groups introduced by the sulfonated polyethersulfone impart negative charge to the surface of the substrate film, which can reduce the adsorption of negatively charged plasma proteins through electrostatic repulsion, thereby helping to improve the anti-protein contamination ability.

[0010] The amount of the hydrophilic porogen added is 20%-30% of the total mass of the film-forming substrate; The porous polymer-based membrane has a pore size of 0.5-5 μm. A single human red blood cell has a diameter of 6-8 μm and can freely pass through pores larger than 2 μm through elastic deformation. Beneficial proteins such as plasma albumin and immunoglobulins have hydrodynamic diameters <100 nm and can pass through freely without obstruction. This pore size range allows beneficial plasma proteins to pass through freely and be reinfused into the body, while effectively retaining blood cell components such as red blood cells and white blood cells, preventing cell loss.

[0011] Alternatively, the hydrophilic porogen may be one or more of polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, or polyethylene oxide.

[0012] In a further technical solution, the hydrophilic porogen is a combination of a high molecular weight porogen and a low molecular weight porogen.

[0013] In a further technical solution, the high molecular weight porogen is PVP K90, the low molecular weight porogen is PVPK30, and the mass ratio of PVP K90 to PVP K30 is 2:1.

[0014] The pore-forming agents are a combination of PVP K90 and PVP K30. The large-molecule PVP K90 is responsible for constructing the macroporous support structure, increasing the membrane's porosity and flux, while the small-molecule PVP K30 regulates the phase transformation rate and narrows the pore size distribution. The long-chain PVP K90 has a stronger entanglement effect with the PES / SPES backbone, while the short-chain PVP K30 can fill the network gaps. This combination further enhances the locking effect of PVP, reducing the risk of dissolution during long-term use, while also improving membrane flexibility and reducing the fiber breakage rate during spinning.

[0015] Alternatively, the polydopamine forms a polydopamine layer in the functional layer, and the thickness of the polydopamine layer is 50-100 nm. This 50-100 nm polydopamine layer thickness ensures sufficient active quinone sites to provide ample grafting sites for the zwitterionic polymer, while completely preventing blockage of the 0.5-5 μm sieve channels of the base membrane.

[0016] The grafting amount of the zwitterionic polymer is 5-10 μg / cm. 2 ; The zwitterionic polymer is one or more of polycarboxybetaine, polysulfonate betaine, or polyphosphocholine.

[0017] Alternatively, the functional layer further comprises an organoselenium catalyst, which is covalently anchored to the surface of the porous polymer-based membrane via the polydopamine, and the grafting amount of the organoselenium catalyst is 0.5-2 μg / cm³. 2 .

[0018] In a further technical solution, the organic selenium catalyst has glutathione peroxidase-like activity, which can catalyze the generation of nitric oxide from endogenous nitrosothiols and remove reactive oxygen species. The organoselenium catalyst is one or more of selenocystamine, ibuselenline derivatives, or selenium-containing amino acid polymers.

[0019] Organoselenium catalysts possess both glutathione peroxidase-like activity and NO catalytic activity. This dual catalytic function endows membrane surfaces with synergistic protective capabilities against oxidation and platelets. On one hand, they block the initiation of the vicious cycle of oxidative stress-inflammation-coagulation by scavenging excess reactive oxygen species (ROS); on the other hand, they directly inhibit platelet activation and aggregation by catalyzing NO generation.

[0020] In a further technical solution, the porous polymer-based membrane is further loaded with dabigatran ester particles, the amount of which is 0.5%-1% of the total mass of the film-forming substrate.

[0021] Dabigatran ester particles are uniformly dispersed in the basement membrane matrix. Upon contact with blood, they slowly dissolve and release dabigatran, directly inhibiting the activity of free thrombin and thrombin bound to fibrin, further blocking the formation of fibrin network, and providing additional chemical anticoagulation protection for the membrane material.

[0022] Secondly, the present invention provides a method for preparing a blood purification membrane, comprising the following steps: S1. Preparation of porous polymer-based membrane: The film-forming substrate and the hydrophilic pore-forming agent are dissolved in an organic solvent to prepare a casting solution. After degassing, a porous polymer-based membrane with a pore size of 0.5-5μm is obtained by phase inversion method. S2. Construct a functional layer on at least one surface of the porous polymer-based membrane: S2.1 Place the porous polymer base membrane in a buffer solution containing dopamine hydrochloride at pH 8.0-8.5 and react at room temperature in the dark to form a uniform polydopamine layer on the surface of the base membrane. After the reaction is complete, remove the membrane and wash it to remove unreacted impurities. S2.2 Place the base film with the polydopamine layer obtained in step S2.1 in a buffer solution containing zwitterionic polymer at pH 8.0-8.5 and react at room temperature in the dark to covalently graft the zwitterionic polymer onto the polydopamine layer. S3. The membrane material obtained in step S2.2 is washed with pure water and dried to obtain the blood purification membrane.

[0023] Optionally, in step S2.1, the buffer solution is a Tris-HCl buffer solution, the concentration of dopamine hydrochloride is 1.5-2.5 mg / mL, and the reaction time is 1.5-2 h, so as to form a polydopamine layer with a thickness of 50-100 nm. In step S2.2, the buffer solution is Tris-HCl buffer solution, the concentration of the zwitterionic polymer is 5-10 mg / mL, and the reaction time is 10-14 h.

[0024] Optionally, in step S2.2, the buffer solution further contains an organoselenium catalyst with a concentration of 1-3 mg / mL. After the reaction is completed, the organoselenium catalyst is covalently grafted onto the polydopamine layer with the zwitterionic polymer.

[0025] In a further technical solution, the phase transformation method in step S1 is a dry-wet spinning process, the coagulation bath of the dry-wet spinning process is deionized water, and the coagulation bath temperature is 40-60℃.

[0026] In a further technical solution, in step S1, the organic solvent is one or more of N,N-dimethylacetamide, N-methylpyrrolidone, or dimethyl sulfoxide.

[0027] In a further technical solution, during the preparation of the casting solution in step S1, dabigatran ester particles are added at a rate of 0.5%-1% of the total mass of the film-forming substrate. After ultrasonic pre-dispersion, the particles are added to the casting solution and stirred at low speed until homogeneous.

[0028] A further technical solution, the dry-wet spinning process, specifically comprises: the casting solution and the core solution are simultaneously extruded through a hollow fiber spinneret, pre-cured in a 5-8cm air section, and then sequentially enter a primary coagulation bath and a secondary coagulation bath to complete phase transformation and curing, and are then drawn and wound to obtain a hollow fiber base film; the core solution is an aqueous solution of N,N-dimethylacetamide with a mass ratio of 35% at a temperature of 30℃; the primary coagulation bath is an aqueous solution of N,N-dimethylacetamide with a mass ratio of 25% at a temperature of 28-32℃; the secondary coagulation bath is pure medical injection water at a temperature of 38-42℃; and the spinning traction speed is 15-25m / min.

[0029] (III) Beneficial Effects The beneficial effects of this invention are as follows: A blood purification membrane of this invention comprises a porous polymer base membrane and a functional layer, wherein the functional layer comprises polydopamine and a zwitterionic polymer, and the zwitterionic polymer is covalently anchored to the surface of the base membrane via polydopamine, and the zwitterionic polymer reacts with polydopamine through its terminal amino groups. This structure integrates the adhesion and anchoring functions of polydopamine with the superhydrophilic and antifouling functions of the zwitterionic polymer.

[0030] Among them, the zwitterionic polymer forms a dense hydration layer on the membrane surface through the ionic solvation of anionic and cationic groups, which can repel the non-specific adsorption of plasma proteins at the source and effectively prevent protein deposition and blockage in the membrane pores. Polydopamine, as a covalent anchoring platform, can form stable covalent bonds with the amino-containing zwitterionic polymer through Michael addition and Schiff base reactions with its catechol / quinone groups in its molecular structure, firmly binding the functional molecules to the membrane surface. This avoids the problems of easy detachment of the functional layer and rapid decline in hydrophilicity caused by traditional physical coating or physical blending methods, ensuring the antifouling stability and flux maintenance capability of the blood purification membrane during long-term use.

[0031] The porous polymer-based membrane consists of a film-forming substrate, namely a blend of sulfonated polyethersulfone (SPES) and polyethersulfone (PES), with a hydrophilic porogen physically entangled and locked within the polymer network of the substrate. During film formation, some of the porogen is washed out, forming interconnected channels, while the remaining porogen is physically locked within the substrate network, continuously providing hydrophilicity. Compared to the shortcomings of traditional PVP physical blending schemes, where PVP is prone to dissolution leading to hydrophilicity degradation, this invention significantly reduces the risk of porogen dissolution through the physical entanglement and spatial confinement of polymer chains, enabling the base membrane to possess high flux, high permeability, and long-term hydrophilic stability.

[0032] This invention discloses a method for preparing a blood purification membrane. Through a two-step process—first preparing a polydopamine anchoring layer, then covalently grafting zwitterionic polymers—the method ensures the orderly anchoring of functional molecules on the membrane surface and high grafting efficiency. This avoids the disordered competitive reactions and functional molecule inactivation issues that may occur when all components are co-deposited in a single step, resulting in long-term stable performance. This method employs the industry-standard phase inversion film formation process and can be directly integrated into existing industrial production lines for blood purification membranes. It requires no additional large-scale equipment or adjustments to the core production process, significantly reducing industrialization costs. Detailed Implementation

[0033] To better explain and facilitate understanding of the invention, specific embodiments are described in detail. However, it should be understood that the invention can be implemented in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided to enable a clearer and more thorough understanding of the invention and to fully convey its scope to those skilled in the art.

[0034] Example 1: This embodiment provides a method for preparing a blood purification membrane. All raw materials used in this embodiment are medical grade (USP Class VI), and the method specifically includes the following steps: (1) Preparation of casting solution: N,N-dimethylacetamide (DMAc) was added to a closed reactor and heated to 50°C under nitrogen protection. PVP K90 3.0g and PVP K30 1.5g were added in sequence and stirred for 2h until completely dissolved. A mixture of polyethersulfone (PES, molecular weight 50000) 16.2g and sulfonated polyethersulfone (SPES, molecular weight 50000, sulfonation degree 10%) 1.8g was added in 3 batches and stirred continuously at 50°C and 300rpm for 8h until completely dissolved to obtain a uniform and transparent casting solution.

[0035] (2) Degassing and curing: The casting solution was allowed to stand at 50℃ and -0.095MPa vacuum for 12 hours to degas, and then cured at 50℃ under nitrogen atmosphere for 4 hours after the vacuum was turned off.

[0036] (3) Dry-wet spinning: A ring-shaped hollow fiber spinneret (slit inner diameter 180μm, outer diameter 320μm) was used. The casting solution extrusion rate was 1.3mL / min, the core solution was 35wt% DMAc aqueous solution (30℃), and the extrusion rate was 0.9mL / min. After pre-curing in a 6cm air section (25℃, relative humidity 40%), the fiber was sequentially introduced into the first coagulation bath (25wt% DMAc aqueous solution, 30℃) and the second coagulation bath (pure medical injection water, 40℃). The traction speed was 20m / min, and the hollow fiber membrane was obtained by winding.

[0037] (4) Post-treatment of the base membrane: The membrane fibers were rinsed countercurrently with 45℃ medical injection water for 48h, and the rinsing water was changed every 6h; then soaked in 0.5wt% medical glycerol aqueous solution for 12h, and dried in clean air at 25℃ until the water content was ≤3% to obtain a porous polymer base membrane with a nominal pore size of 2μm.

[0038] (5) Preparation of polydopamine anchoring solution and functional grafting solution: Prepare a 10mM Tris-HCl buffer solution with a pH of 8.5, add dopamine hydrochloride to it and stir until completely dissolved to obtain a polydopamine anchoring solution with a dopamine hydrochloride concentration of 2mg / mL; use the same batch of 10mM Tris-HCl buffer solution with a pH of 8.5, add zwitterionic polymer (terminated amino polycarboxylic betaine, PCBMA), stir until completely dissolved to obtain a functional grafting solution with a zwitterionic polymer concentration of 8mg / mL.

[0039] (6) Preparation of polydopamine layer: The base membrane is placed in a special modified fixture and sealed and fixed so that only the inner cavity of the membrane fiber can be circulated. The polydopamine anchoring solution is circulated into the inner cavity of the membrane fiber at a flow rate of 2 mL / min using a constant flow pump. The reaction is carried out at room temperature in the dark for 2 hours to form a polydopamine layer with a thickness of 80 nm. After the reaction is completed, the membrane is rinsed with medical water for injection three times for 5 minutes each time to remove unreacted impurities.

[0040] (7) Covalent grafting of functional components: The functional grafting solution was circulated into the membrane fiber lumen at a flow rate of 2 mL / min using a constant flow pump and reacted at room temperature in the dark for 12 h. The zwitterionic polymer was covalently grafted onto the polydopamine layer through Michael addition reaction and Schiff base reaction.

[0041] (8) Finished product post-processing: The modified membrane fibers were rinsed with pure water three times, ultrasonically cleaned twice, and vacuum dried at 25°C for 6 hours to obtain the blood purification membrane of this embodiment.

[0042] The resulting blood purification membrane is denoted as E1.

[0043] Example 2: This embodiment provides a method for preparing a blood purification membrane. The difference between this embodiment and Embodiment 1 is that: in step (5), when preparing the functional grafting solution, an organic selenium catalyst (selenocysteine) and a zwitterionic polymer (terminated amino polycarboxylic acid betaine, PCBMA) are added sequentially and stirred until completely dissolved to obtain a functional grafting solution with an organic selenium catalyst concentration of 2 mg / mL and a zwitterionic polymer concentration of 8 mg / mL; in step (7), the organic selenium catalyst and the zwitterionic polymer are covalently grafted onto the polydopamine layer through Michael addition reaction and Schiff base reaction; the remaining steps are the same and are denoted as E2.

[0044] Example 3: This embodiment provides a method for preparing a blood purification membrane. The difference between this embodiment and embodiment 2 is that: step (1): the mass ratio of SPES to PES is 2:8, that is, SPES 3.6g and PES 14.4g. The remaining steps are the same, and it is denoted as E3.

[0045] Example 4: This embodiment provides a method for preparing a blood purification membrane. The difference between this embodiment and embodiment 2 is that: Step (1): The total amount of pore-forming agent added is 30% of the total mass of the film-forming substrate, that is, 3.6g of PVP K90 and 1.8g of PVP K30 (the mass ratio of K90:K30 is still 2:1). The remaining steps are the same and are denoted as E4.

[0046] Example 5: This embodiment provides a method for preparing a blood purification membrane. The difference between this embodiment and embodiment 2 is that: in step (6): the concentration of the organic selenium catalyst in the functional grafting solution is 3 mg / mL, the concentration of the zwitterionic polymer is 10 mg / mL, and the rest of the steps are the same, which is denoted as E5.

[0047] Example 6: This embodiment provides a method for preparing a blood purification membrane. The difference between this embodiment and embodiment 2 is as follows: In step (1): In the preparation of the casting solution, after the PES and SPES mixed powders are completely dissolved, 0.18g of dabigatran ester particles (drug loading 10%) are added. The amount added is 1% of the total mass of the film-forming substrate. The dabigatran ester particles are pre-dispersed in a small amount of DMAc by ultrasound for 30min in advance. After adding the casting solution, the mixture is stirred at low speed for 1h until it is uniformly dispersed. The remaining steps are the same and are referred to as E6.

[0048] Example 7: This embodiment provides a method for preparing a blood purification membrane. The difference between this embodiment and embodiment 5 is as follows: In step (1): In the preparation of the casting solution, after the PES and SPES mixed powders are completely dissolved, 0.18g of dabigatran ester particles (drug loading 10%) are added. The amount added is 1% of the total mass of the film-forming substrate. The drug-loaded dabigatran ester particles are pre-dispersed in a small amount of DMAc by ultrasound for 30min in advance. After adding the casting solution, the mixture is stirred at low speed for 1h until it is uniformly dispersed. The remaining steps are the same and are referred to as E7.

[0049] Comparative Example 1: This comparative example provides a method for preparing a blood purification membrane. The difference between this example and Example 2 is that: step (5): no zwitterionic polymer is added to the functional grafting solution, only 2 mg / mL of organic selenium catalyst is contained, and the rest of the steps are the same, which is denoted as C1.

[0050] Comparative Example 2: This comparative example provides a method for preparing a blood purification membrane. The difference between this comparative example and Example 1 is that in steps (6) and (7), the preparation of the polydopamine layer and the grafting of functional components are not carried out, that is, the base membrane is not subjected to any surface functionalization modification. The remaining steps are the same, and it is referred to as C2.

[0051] Comparative Example 3: This comparative example provides a method for preparing a blood purification membrane. The difference between this example and Example 2 is that the functional layer is prepared by a one-step co-deposition method. Specifically, the base membrane is loaded into a modification fixture, and a 10mM Tris-HCl buffer solution (pH 8.5) containing 2mg / mL dopamine hydrochloride, 2mg / mL selenocysteine, and 8mg / mL PCBMA is circulated into the membrane fiber lumen at a flow rate of 2mL / min using a constant flow pump. The reaction is carried out at room temperature in the dark for 12 hours, and the membrane is washed and dried to obtain the modified membrane. The remaining steps are the same and are referred to as C3.

[0052] Verification example: This verification example systematically tests the performance of the above embodiments and comparative examples. The test environment temperature is 25°C and the relative humidity is 40%.

[0053] (1) Water contact angle test: The static droplet method was used to flatten and fix the membrane sample, add 2 μL of deionized water, and read the contact angle value after the droplet stabilized (30s after addition) using a contact angle meter. Five different positions were tested for each sample and the average value was taken.

[0054] (2) Protein adsorption test: The membrane sample was immersed in phosphate buffer (PBS, pH 7.4) containing 1 mg / mL bovine serum albumin (BSA) and incubated at 37°C for 2 h. After removal, the membrane was rinsed 3 times with PBS, and the amount of BSA adsorbed on the membrane surface was determined using a BCA protein quantification kit.

[0055] (3) Albumin permeate test: The membrane was assembled into a small component, and filtration was performed using a PBS solution containing 1 mg / mL BSA as the feed solution under a transmembrane pressure difference of 50 mmHg. The permeate was collected, and the BSA concentration was determined by the BCA method to calculate the permeate rate.

[0056] (4) Coating stability test: The membrane sample was placed in PBS buffer (pH 7.4) and oscillated at 37°C (100 rpm) to simulate the blood flow shear environment. Samples were taken on days 1, 7, 14 and 30 to test the change in water contact angle.

[0057] (5) Membrane filtration performance stability test: using an effective filtration area of ​​0.01m 2 Small hollow fiber membrane modules containing bovine serum albumin (4 g / dL), fibrinogen (0.3 g / dL), and human platelets (1.0 × 10⁻⁶). 8 Simulated blood (number of cells / mL) was used as the test medium, and horizontal filtration was performed at 37℃ and a constant filtration pressure of 0.1 MPa. Filtrate was collected at time intervals of 0-5 min, 25-30 min, 45-50 min, and 85-90 min, and the average outflow rate was recorded for each time interval. The protein concentration in the filtrate was determined using the BCA protein quantification method, and the protein permeation rate was calculated. The long-term filtration stability of the membrane module was evaluated by the retention rate at the 90-min outflow rate and the protein permeation rate retention rate.

[0058] The test results of the membranes prepared in Examples 1-7 and Comparative Examples 1-3 are shown in Tables 1 to 3.

[0059] Table 1 Basic Performance Test Results

[0060] Table 2 Coating stability test

[0061] Table 3. Results of membrane filtration performance stability test

[0062] Based on the performance test results in Tables 1 to 3, the following analytical conclusions can be drawn: As shown in Table 1, the water contact angles in Examples 1 to 7 were all within the range of 10.5°–13.2°, and the BSA adsorption capacity was all below 4.1 μg / cm³. 2 It exhibits excellent superhydrophilicity and low protein adsorption properties. Example 1 (containing only the zwitterionic polymer PCBMA) showed a water contact angle of 12.5° and a BSA adsorption capacity of 3.8 μg / cm³. 2It is significantly superior to Comparative Example 2 (unmodified base membrane, water contact angle 85.6°, BSA adsorption capacity 52.3 μg / cm³). 2 This demonstrates that the superhydrophilic antifouling layer formed by PDA covalently anchoring to zwitterionic polymers inherently possesses excellent antifouling properties. Example 2 (containing an organoselenium catalyst) showed a water contact angle of 11.8° and a BSA adsorption capacity of 3.5 μg / cm³. 2 Similar to Example 1, this indicates that the introduction of the organoselenium catalyst did not negatively affect the hydrophilicity of the antifouling layer. Comparative Example 1 (which does not contain zwitterionic polymers in its functional layer) showed a water contact angle as high as 42.3° and a BSA adsorption capacity of 25.6 μg / cm³. 2 This contrasts sharply with the examples. The results indicate that even with a polydopamine layer and an organoselenium catalyst on the membrane surface, a dense hydration layer cannot form without zwitterionic polymers, resulting in high protein adsorption. This demonstrates that zwitterionic polymers in the functional layer are essential components for imparting superhydrophilicity and physical antifouling properties to the membrane surface. Comparative Example 3 (one-step co-deposition method) showed a water contact angle of 18.7° and a BSA adsorption capacity of 7.8 μg / cm³. 2 While superior to Comparative Examples 1 and 2, it is significantly inferior to the two-step method. This demonstrates that the two-step method, which first constructs a polydopamine anchoring layer and then covalently grafts functional molecules, can more orderly and efficiently fix the zwitterionic polymers to the membrane surface, fully leveraging their antifouling performance. In contrast, the one-step method involves disordered competitive reactions among the components, and some zwitterionic polymers may be embedded in the polydopamine or fail to be effectively exposed on the surface, leading to a decrease in antifouling effect.

[0063] As shown in Table 1, the albumin permeability of Examples 1 to 7 was between 93% and 96%, significantly better than that of Comparative Example 2 (unmodified base membrane, 82.5%). The high albumin permeability of these examples indicates that the 0.5-5 μm pore size design of this invention effectively ensures the free permeation of beneficial plasma proteins such as albumin, meeting the requirements of blood purification for the reinfusion of beneficial components. Simultaneously, the 50-100 nm polydopamine layer and covalently grafted functional molecules did not clog the membrane pores and did not affect the membrane's separation performance. The slightly lower albumin permeability of Comparative Example 3 (88.5%) was due to the deposition of some polydopamine / polymer aggregates into the membrane pores or at the pore openings during the one-step formation of the functional layer, causing localized blockage and affecting protein permeation.

[0064] As shown in Table 2, the water contact angles of Examples 1 and 2 prepared by the two-step method increased only slightly after 30 days of oscillation in a simulated blood flow shear environment (Example 1 increased from 12.5° to 14.5°, and Example 2 increased from 11.8° to 13.6°), demonstrating excellent long-term hydrophilic stability. Example 5, with increased grafting of functional components, showed even better stability, with its water contact angle only increasing to 12.5° after 30 days. In stark contrast, the water contact angle of Comparative Example 3 prepared by the one-step method increased from 18.7° to 35.6° under the same conditions, indicating that the coating gradually detached and failed. The water contact angles of Comparative Examples 1 and 2 remained high for 30 days, showing no significant improvement trend. The two-step method of this invention first forms a polydopamine anchoring layer, and then covalently grafts functional molecules through Michael addition and Schiff base reaction. This strategy enables zwitterionic polymers to be anchored to the membrane surface with stable covalent bonds, avoiding the problem of physical adsorption or weakly bound coatings falling off under long-term blood flow shear forces, and significantly improving the durability and reliability of the functional layer.

[0065] As shown in Table 3, after 90 minutes of simulated continuous blood filtration, Examples 1 and 2 achieved flow rate retention rates of 88.5% and 90.2%, respectively, with protein permeability retention rates both exceeding 95%, demonstrating excellent long-term filtration stability. Example 6, containing dabigatran etexilate, further improved the flow rate retention rate to 92.8%. Example 5 (high grafting density) achieved a flow rate retention rate of 92.5%, indicating that appropriately increasing the grafting density of functional molecules can further enhance antifouling capabilities.

[0066] Comparative Example 2 (unmodified base membrane) showed an outflow rate retention rate of only 45.2% and a protein permeability retention rate reduced to 72.8%, indicating that the unmodified hydrophobic PES base membrane rapidly became clogged in the presence of proteins and platelets, resulting in a significant decrease in filtration performance. Comparative Example 3 (one-step method) showed an outflow rate retention rate of 68.5%, significantly lower than the two-step method example, further confirming that the one-step coating lacked stability under dynamic shear conditions, gradually detaching and failing, leading to decreased hydrophilicity of the membrane surface, increased protein adsorption, and membrane pore clog.

[0067] In summary, the comparison between Example 1 (containing only zwitterionic polymers) and Comparative Example 2 (unmodified base membrane) demonstrates that the superhydrophilic antifouling layer formed by PDA covalently anchoring the zwitterionic polymer is key to imparting low protein adsorption, high-flux protein permeation, and long-term flux stability to the membrane. The comparison between Example 1 and Example 2 shows that the basic scheme itself already possesses excellent antifouling and separation performance. The comparison results of Comparative Example 1 demonstrate the irreplaceable role of zwitterionic polymers in antifouling function, and the comparison results between Comparative Example 3 and the examples demonstrate the significant advantages of the two-step method over the one-step method in terms of coating stability and antifouling durability.

[0068] In summary, the blood purification membrane and its preparation method provided by this invention lock in a hydrophilic pore-forming agent through a semi-interpenetrating polymer network structure to construct a large-pore sieving base membrane, and construct a superhydrophilic antifouling layer by covalently anchoring amphoteric polymers with polydopamine. This achieves a balance between high protein permeability and long-term flux stability in the large-pore blood purification membrane, and its comprehensive performance is significantly better than that of existing technical solutions, possessing outstanding substantive features and significant progress.

[0069] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to 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 or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

[0070] The "range" disclosed in this application is defined by a lower limit and an upper limit. A given range is defined by selecting a lower limit and an upper limit, which define the boundaries of a particular range. Ranges defined in this way can include or exclude endpoints and can be arbitrarily combined; that is, any lower limit can be combined with any upper limit to form a range. For example, if ranges of 60-120 and 80-110 are listed for a specific parameter, it is expected that ranges of 60-110 and 80-120 are also included. Furthermore, if minimum range values ​​of 1 and 2 are listed, and if maximum range values ​​of 3, 4, and 5 are listed, then the following ranges are all expected: 1-3, 1-4, 1-5, 2-3, 2-4, and 2-5. In this application, unless otherwise stated, the numerical range "ab" represents a shortened representation of any combination of real numbers between a and b, where a and b are real numbers. For example, the numerical range "0-5" indicates that all real numbers between "0-5" have been listed in this article; "0-5" is simply a shortened representation of these numerical combinations. Furthermore, when a parameter is stated as an integer ≥2, it is equivalent to disclosing that the parameter is, for example, an integer such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, etc.

[0071] Unless otherwise specified, all embodiments and optional embodiments of this application can be combined to form new technical solutions.

[0072] Unless otherwise specified, all technical features and optional technical features of this application may be combined to form new technical solutions.

[0073] Unless otherwise specified, all steps in this application may be performed sequentially or randomly, for example, sequentially. For instance, the method includes steps (a) and (b), indicating that the method may include steps (a) and (b) performed sequentially, or it may include steps (b) and (a) performed sequentially. For instance, the method may also include step (c), indicating that step (c) may be added to the method in any order; for example, the method may include steps (a), (b), and (c), or it may include steps (a), (c), and (b), or it may include steps (c), (a), and (b), etc.

[0074] Unless otherwise specified, the terms "comprising" and "including" as used in this application can be open-ended or closed-ended. For example, "comprising" and "including" can mean that other components not listed may also be included, or that only the listed components may be included.

[0075] Unless otherwise specified, the term "or" is inclusive in this application. For example, the phrase "A or B" means "A, B, or both A and B". More specifically, the condition "A or B" is satisfied by any of the following conditions: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); or both A and B are true (or exist).

Claims

1. A blood purification membrane, characterized in that, It includes a porous polymer base film and a functional layer covering at least one surface of the porous polymer base film; In the film-forming substrate of the porous polymer-based membrane, the hydrophilic pore-forming agent is physically entangled and locked within the polymer network of the film-forming substrate; The functional layer comprises polydopamine and a zwitterionic polymer, wherein the zwitterionic polymer is covalently anchored to the surface of the porous polymer base film via the polydopamine.

2. The blood purification membrane as described in claim 1, characterized in that, The film-forming substrate is a blend of sulfonated polyethersulfone with a molecular weight of 40,000-60,000 and polyethersulfone with a molecular weight of 40,000-60,000, wherein the mass ratio of the sulfonated polyethersulfone to the polyethersulfone is (1-2):(8-9), and the degree of sulfonation of the sulfonated polyethersulfone is 8%-12%. The amount of the hydrophilic porogen added is 20%-30% of the total mass of the film-forming substrate; The porous polymer-based membrane has a pore size of 0.5-5 μm.

3. The blood purification membrane as described in claim 1, characterized in that, The hydrophilic porogen is one or more of polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, or polyethylene oxide.

4. The blood purification membrane according to claim 3, characterized in that, The hydrophilic porogen is a combination of a high molecular weight porogen and a low molecular weight porogen; The high molecular weight porogen is PVP K90, the low molecular weight porogen is PVP K30, and the mass ratio of PVP K90 to PVP K30 is 2:

1.

5. The blood purification membrane as described in claim 1, characterized in that, The polydopamine forms a polydopamine layer in the functional layer, and the thickness of the polydopamine layer is 50-100 nm; The grafting amount of the zwitterionic polymer is 5-10 μg / cm. 2 ; The zwitterionic polymer is one or more of polycarboxybetaine, polysulfonate betaine, or polyphosphocholine.

6. The blood purification membrane as described in claim 5, characterized in that, The functional layer further comprises an organoselenium catalyst, which is covalently anchored to the surface of the porous polymer-based membrane through the polydopamine layer. The grafting amount of the organoselenium catalyst is 0.5-2 μg / cm³. 2 .

7. A method for preparing a blood purification membrane as described in any one of claims 1-6, characterized in that, Includes the following steps: S1. Preparation of porous polymer-based membrane: The film-forming substrate and the hydrophilic pore-forming agent are dissolved in an organic solvent to prepare a casting solution. After degassing, a porous polymer-based membrane is prepared by phase inversion method. S2. Construct a functional layer on at least one surface of the porous polymer-based membrane: S2.1 Place the porous polymer base membrane in a buffer solution containing dopamine hydrochloride at pH 8.0-8.5 and react at room temperature in the dark to form a uniform polydopamine layer on the surface of the base membrane. After the reaction is complete, remove the membrane and wash it to remove unreacted impurities. S2.2 Place the base film with the polydopamine layer obtained in step S2.1 in a buffer solution containing zwitterionic polymer at pH 8.0-8.5 and react at room temperature in the dark to covalently graft the zwitterionic polymer onto the polydopamine layer. S3. The membrane material obtained in step S2.2 is washed with pure water and dried to obtain the blood purification membrane.

8. The method for preparing the blood purification membrane as described in claim 7, characterized in that, In step S2.1, the buffer solution is Tris-HCl buffer, the concentration of dopamine hydrochloride is 1.5-2.5 mg / mL, and the reaction time is 1.5-2 h, so as to form a polydopamine layer with a thickness of 50-100 nm. In step S2.2, the buffer solution is Tris-HCl buffer solution, the concentration of the zwitterionic polymer is 5-10 mg / mL, and the reaction time is 10-14 h.

9. The method for preparing the blood purification membrane according to claim 8, characterized in that, In step S2.2, the buffer solution also contains an organoselenium catalyst with a concentration of 1-3 mg / mL. After the reaction is completed, the organoselenium catalyst is covalently grafted onto the polydopamine layer with the zwitterionic polymer.

10. The method for preparing the blood purification membrane according to claim 7, characterized in that, The phase inversion method described in step S1 is a dry-wet spinning process. The coagulation bath for dry-wet spinning is deionized water, and the coagulation bath temperature is 40℃-60℃.

Images