High-blood-compatibility PMP (Polymethyl Phthalate) film as well as preparation method and application thereof

Abstract

The invention relates to the technical field of medical polymer materials, and provides a high-blood-compatibility PMP (polymethylpyrrolidone) membrane as well as a preparation method and application thereof in order to solve the technical problems of serious protein adhesion and poor blood compatibility caused by hydrophobicity of an existing PMP (poly-4-methyl-1-pentene) membrane. The preparation method comprises the following steps: firstly, carrying out plasma activation treatment on the PMP base film; then, a stable hydrophilic coating is constructed on the surface of the membrane through coordination of tannic acid and ferric ions and electrostatic adsorption of polyethyleneimine; and finally, carrying out low surface energy grafting modification by using methyl triethoxysilane. According to the invention, the PMP membrane with excellent anticoagulant property and high gas flux is successfully prepared through synergistic modification of the three steps. The hemolysis rate is less than or equal to 0.7%, the BSA adsorption quantity is less than or equal to 320 ng / cm < 2 >, the platelet adhesion quantity is obviously reduced, meanwhile, the oxygen flux retention rate is more than or equal to 92% (140-155 mL * min <-1 > * m <-2 >), and the core performance requirements of ECMO and other medical equipment on the membrane material are completely met. The method is simple in process, easily available in raw materials and suitable for large-scale production.

Description

Technical Field

[0001] This invention relates to the field of medical polymer membrane materials technology, specifically to a highly blood-compatible poly(4-methyl-1-pentene) (PMP) membrane, its preparation method and application, and is particularly suitable as a core material for extracorporeal life support systems that come into direct contact with blood. Background Technology

[0002] PMP membranes are the preferred gas exchange membrane material for devices such as extracorporeal membrane oxygenation (ECMO) due to their excellent gas permeability, mechanical strength, and chemical stability. However, the inherent hydrophobicity of PMP membranes makes them prone to non-specific protein adsorption upon contact with blood, thereby activating platelet adhesion and coagulation cascade reactions, leading to thrombus formation. Although existing technologies have modified PMP membranes through various strategies, the following limitations still exist: (1) The synergy of surface modification strategies is insufficient. For example, patent CN114749032A prepares PMP hollow fiber membranes by thermally induced phase separation. Although the membrane pore structure is optimized, its surface modification still depends on a single hydrophilic coating or heparin immobilization strategy. Such methods only resist the initial adsorption of proteins through hydrophilic groups and lack a "desorption promotion" mechanism for adsorbed pollutants. In long-term use, the risk of thrombosis is easily increased due to coating failure.

[0003] (2) There is a contradiction between the structure and biocompatibility of composite functional materials. For example, patent CN120242764A proposes to use metal-organic framework (MOF) based porous liquid to modify PMP membranes in order to improve gas exchange efficiency. However, the biocompatibility of MOF materials in the blood environment is not yet fully understood, and its nanoparticles may detach from the membrane surface and trigger an immune response. At the same time, the interfacial bonding force between MOF and PMP matrix is ​​weak, and interlayer delamination is prone to occur during long-term blood circulation, leading to functional decline.

[0004] (3) Low surface energy materials pose a risk to biosafety. Some studies have used materials such as perfluorooctylsilane (PFOTS) to construct hydrophobic surfaces, but perfluorinated compounds have bioaccumulation and blood toxicity, which do not meet the safety standards for medical materials.

[0005] To address this, the present invention proposes a three-step modification strategy of "plasma pretreatment - hydrophilic coating construction - biosafe low surface energy group grafting". By combining a hydrophilic bottom layer of tannic acid / polyethyleneimine (TA / PEI) with a low surface energy surface layer of methyltriethoxysilane (MTES), a "non-adhesive-easy desorption" synergistic interface is formed, which improves blood compatibility while ensuring coating firmness and biosafety. Summary of the Invention

[0006] To address the shortcomings of existing PMP membranes, such as limited hydrophilic modification strategies, poor long-term stability of coatings under dynamic blood flow, and insufficient biocompatibility of composite functional materials, this invention provides a modified PMP membrane with improved blood compatibility and its preparation method, the specific steps of which are as follows: (1) Surface activation treatment Poly(4-methylpentene) (PMP) hollow fiber membranes were placed in a plasma treatment instrument and treated with air as the discharge gas at a power of 80-120 W for 3-8 min to obtain surface-activated PMP pretreated membranes. (2) Construction of hydrophilic coating The pretreated membrane obtained in step (1) was sequentially immersed in tannic acid (TA) aqueous solution, ferric chloride aqueous solution and polyethyleneimine aqueous solution, and the adsorption and reaction were carried out stepwise at 25-35℃ to form a stable tannic acid-iron ion-polyethyleneimine composite coating, and then rinsed clean with deionized water. (3) Low surface energy modification The membrane obtained in step (2) is immersed in a 2-5% (v / v) methyltriethoxysilane ethanol (MTES) solution and reacted at a constant temperature of 35-55°C for 6-10 hours. After the reaction is completed, it is rinsed with ethanol and deionized water and dried under vacuum for 4-6 hours to obtain the modified PMP membrane.

[0007] Preferably, the PMP membrane in step (1) has a pore size of 0.1-0.5 μm and a porosity of 40-60%.

[0008] Preferably, in step (2): The concentration of the TA aqueous solution is 0.5-1.5 mg / mL, and the shaking adsorption time is 10-20 min; The concentration of the ferric chloride aqueous solution is 0.3-0.8 mg / mL, and the reaction time is 5-10 min; The PEI aqueous solution has a concentration of 5-15 mg / mL, a molecular weight of 8000-10000, a pH value of 8.0-9.0, and a reaction time of 12-18 h.

[0009] Preferably, the modified PMP membrane obtained in step (3) has a surface water contact angle of 62-73° and an oxygen flux of 140-155 mL·min. -1 ·m -2 .

[0010] Preferably, the modified PMP membrane obtained in step (3) has the following blood compatibility parameters: hemolysis rate ≤ 0.7%, bovine serum albumin (BSA) adsorption capacity ≤ 320 ng / cm³. 2 Fibrinogen (BFG) adsorption capacity ≤200 ng / cm³2 Platelet adhesion amount ≤2.5×10 4 pcs / mm 2 .

[0011] Beneficial effects 1. Excellent blood compatibility By constructing a TA / Fe³⁺ / PEI hydrophilic coating and combining it with MTES low surface energy modification, the resulting modified PMP membrane exhibits excellent anti-biofouling properties. Its hemolysis rate is ≤0.7%, meeting the ISO 10993-4 biocompatibility standard for medical materials. Compared to the unmodified membrane, protein adsorption is reduced by more than 73%, and platelet adhesion is reduced by more than 71%, effectively reducing the risk of thrombosis.

[0012] 2. Ideal gas exchange performance The functional coating layer formed during the modification process is dense and uniform, significantly improving surface properties without clogging the membrane pore structure. The oxygen flux of the modified membrane remains at 140-155 mL·min. -1 ·m -2 Compared to the original membrane, the retention rate is over 92%, fully meeting the core requirements for gas flux (≥120 mL·min) for medical applications such as extracorporeal membrane oxygenation. -1 ·m -2 ).

[0013] 3. Excellent process and material feasibility The tannic acid, ferric chloride, polyethyleneimine, and methyltriethoxysilane used in this invention are all conventional and readily available chemical raw materials, with low cost and stable supply. The entire preparation process is based on mature technologies such as plasma treatment, solution soaking, and isothermal grafting, with mild conditions, low equipment requirements, and no complex or harsh synthesis steps, providing a good foundation for large-scale industrial production. Attached Figure Description

[0014] Figure 1 Schematic diagram of the preparation mechanism of PMP-TA / PEI-MTES membrane.

[0015] Performance testing methods (1) Water contact angle: The static contact angle of deionized water on the membrane surface was measured at 25°C using an optical contact angle meter. Five sites were tested for each sample, and the average value was taken. Oxygen flux: The oxygen permeation flux was measured using a gas permeation testing system (C130H) at 25°C and a pressure difference of 1 atm. The effective membrane area was 12.56 cm². (2) Hemolysis rate: According to ISO 10993-4 standard, the membrane sample was incubated with rabbit red blood cell suspension at 37℃ for 1 h, and the absorbance was measured by ultraviolet spectrophotometer (540 nm) to calculate the hemolysis rate; (3) Platelet adhesion test: The membrane sample was incubated with platelet-rich plasma (PRP) at 37°C for 1 h, rinsed with PBS, fixed, dehydrated, sputtered with gold, and the platelet morphology was observed and counted by SEM (average of 5 fields of view). (4) Protein adsorption capacity: The adsorption capacity of the membrane after incubation at 37°C for 1 h in 1 mg / mL BSA solution and 0.5 mg / mL BFG solution was determined using the Micro BCA kit, and the test was performed in triplicate. Detailed Implementation

[0016] The present invention will be further described below with reference to specific embodiments.

[0017] Example 1 (1) Surface activation treatment Poly(4-methylpentene) (PMP) hollow fiber membrane (pore size 0.3 μm, porosity 50%) was cut into 2 cm × 2 cm samples, placed in a plasma treatment instrument, and treated with air as the discharge gas at a power of 100 W for 5 min to obtain a surface-activated PMP pretreated membrane. (2) Construction of hydrophilic coating Prepare a 1.0 mg / mL TA aqueous solution, immerse the pretreated membrane in it, and shake and adsorb at 30℃ for 15 min; after removal, immerse it in a 0.5 mg / mL FeCl3·6H2O aqueous solution and react at 30℃ for 8 min; then immerse it in a 10 mg / mL PEI aqueous solution (pH=8.5) and shake and react at 30℃ for 15 h to form a stable tannic acid-iron ion-polyethyleneimine composite coating. Rinse with deionized water 3 times (5 min each time) to obtain a PMP-TA / PEI membrane; (3) Low surface energy modification A 3% (v / v) MTES ethanol solution was prepared, and the PMP-TA / PEI membrane was immersed in it. The reaction was carried out at 45°C for 8 hours. After the reaction was completed, the membrane was washed three times with ethanol and three times with deionized water (5 min each time). The membrane was then dried under vacuum at 60°C for 5 hours to obtain the modified PMP membrane (PMP-TA / PEI-MTES).

[0018] The prepared PMP membrane had a water contact angle of 65.3° and an oxygen flux of 145 mL·min. -1 ·m -2 Its blood compatibility parameters are: hemolysis rate 0.6%, BSA adsorption capacity 305 ng / cm³. 2BFG adsorption capacity: 195 ng / cm³ 2 Platelet adhesion amount 2.4×10 4 pcs / mm 2 .

[0019] Example 2 (1) Surface activation treatment Poly(4-methylpentene) (PMP) hollow fiber membrane (pore size 0.2 μm, porosity 45%) was cut into 2 cm × 2 cm samples and placed in a plasma treatment instrument. Air was used as the discharge gas, the power was 80 W, and the treatment time was 8 min to obtain a surface-activated PMP pretreated membrane. (2) Construction of hydrophilic coating Prepare a 0.8 mg / mL TA aqueous solution, immerse the pretreated membrane in it, and shake and adsorb at 28℃ for 18 min; after removal, immerse it in a 0.4 mg / mL FeCl3·6H2O aqueous solution and react at 28℃ for 10 min; then immerse it in an 8 mg / mL PEI aqueous solution (pH=8.2) and shake and react at 28℃ for 16 h to form a stable tannic acid-iron ion-polyethyleneimine composite coating. Rinse with deionized water 3 times (5 min each time) to obtain a PMP-TA / PEI membrane; (3) Low surface energy modification A 2% (v / v) MTES ethanol solution was prepared, and the PMP-TA / PEI membrane was immersed in it. The reaction was carried out at 40°C for 10 h. After the reaction was completed, the membrane was washed three times with ethanol and three times with deionized water (5 min each time). The membrane was then dried under vacuum at 60°C for 4 h to obtain the modified PMP membrane (PMP-TA / PEI-MTES).

[0020] The prepared PMP membrane had a water contact angle of 68.7° and an oxygen flux of 152 mL·min. -1 ·m -2 Its blood compatibility parameters are: hemolysis rate 0.7%, BSA adsorption capacity 318 ng / cm³. 2 BFG adsorption capacity: 203 ng / cm³ 2 Platelet adhesion amount 2.5×10 4 pcs / mm 2 .

[0021] Example 3 (1) Surface activation treatment Poly(4-methylpentene) (PMP) hollow fiber membrane (pore size 0.4 μm, porosity 55%) was cut into 2 cm × 2 cm samples, placed in a plasma treatment instrument, and treated with air as the discharge gas at a power of 120 W for 3 min to obtain a surface-activated PMP pretreated membrane. (2) Construction of hydrophilic coating A 1.5 mg / mL TA aqueous solution was prepared, and the pretreated membrane was immersed in it and shaken for 12 min at 32 °C for adsorption. After removal, it was immersed in a 0.7 mg / mL FeCl3·6H2O aqueous solution and reacted at 32 °C for 6 min. Subsequently, it was immersed in a 14 mg / mL PEI aqueous solution (pH=8.8) and shaken for 13 h at 32 °C to form a stable tannic acid-iron ion-polyethyleneimine composite coating. The membrane was rinsed three times with deionized water (5 min each time) to obtain the PMP-TA / PEI membrane. (3) Low surface energy modification A 4% (v / v) MTES ethanol solution was prepared, and the PMP-TA / PEI membrane was immersed in it. The reaction was carried out at 50°C for 7 hours. After the reaction was completed, the membrane was washed three times with ethanol and three times with deionized water (5 min each time). The membrane was then dried under vacuum at 60°C for 6 hours to obtain the modified PMP membrane (PMP-TA / PEI-MTES).

[0022] The prepared PMP membrane had a water contact angle of 62.1° and an oxygen flux of 142 mL·min. -1 ·m -2 Its blood compatibility parameters are: hemolysis rate 0.5%, BSA adsorption capacity 292 ng / cm³. 2 BFG adsorption capacity: 188 ng / cm³ 2 Platelet adhesion amount 2.1×10 4 pcs / mm 2 .

[0023] Example 4 (1) Surface activation treatment Poly(4-methylpentene) (PMP) hollow fiber membrane (pore size 0.3 μm, porosity 50%) was cut into 2 cm × 2 cm samples, placed in a plasma treatment instrument, and treated with air as the discharge gas at a power of 110 W for 6 min to obtain a surface-activated PMP pretreated membrane. (2) Construction of hydrophilic coating Prepare a 0.5 mg / mL TA aqueous solution, immerse the pretreated membrane in it, and shake and adsorb at 35℃ for 10 min; after removal, immerse it in a 0.3 mg / mL FeCl3·6H2O aqueous solution and react at 35℃ for 5 min; then immerse it in a 15 mg / mL PEI aqueous solution (pH=9.0) and shake and react at 35℃ for 12 h to form a stable tannic acid-iron ion-polyethyleneimine composite coating. Rinse with deionized water 3 times (5 min each time) to obtain a PMP-TA / PEI membrane; (3) Low surface energy modification A 5% (v / v) MTES ethanol solution was prepared, and the PMP-TA / PEI membrane was immersed in it. The reaction was carried out at 55°C for 6 hours. After the reaction was completed, the membrane was washed three times with ethanol and three times with deionized water (5 min each time). The membrane was then dried under vacuum at 60°C for 5 hours to obtain the modified PMP membrane (PMP-TA / PEI-MTES).

[0024] The prepared PMP membrane had a water contact angle of 72.5° and an oxygen flux of 140 mL·min. -1 ·m -2 Its blood compatibility parameters are: hemolysis rate 0.6%, BSA adsorption capacity 315 ng / cm³. 2 BFG adsorption capacity: 198 ng / cm³ 2 Platelet adhesion amount 2.3×10 4 pcs / mm 2 .

Claims

1. A method for preparing a high hemocompatible PMP membrane, characterized in that, The method comprises the following steps: (1) surface activation treatment Poly-4-methylpentene (PMP) hollow fiber membranes are placed in a plasma treatment instrument, and treated for 3-8 min at a power of 80-120 W with air as the discharge gas to obtain surface-activated PMP pretreated membranes; (2) hydrophilic coating construction The pretreated membranes obtained in step (1) are sequentially immersed in a tannic acid (TA) aqueous solution, a ferric chloride aqueous solution and a polyethyleneimine aqueous solution, and subjected to stepwise oscillation adsorption and reaction at 25-35°C to form a stable tannic acid-iron ion-polyethyleneimine composite coating, which is then washed with deionized water; (3) low surface energy modification The membranes obtained in step (2) are immersed in a methyltriethoxysilane ethanol (MTES) solution with a volume fraction of 2-5%, and subjected to constant temperature reaction at 35-55°C for 6-10 h, after which the membranes are washed with ethanol and deionized water and vacuum dried for 4-6 h to obtain the modified PMP membranes.

2. The production method according to claim 1, characterized by, The PMP membranes in step (1) have a pore size of 0.1-0.5 μm and a porosity of 40-60%.

3. The preparation method according to claim 1, characterized in that, In step (2): (1) the TA aqueous solution has a concentration of 0.5-1.5 mg / mL, and the oscillation adsorption time is 10-20 min; (2) the ferric chloride aqueous solution has a concentration of 0.3-0.8 mg / mL, and the reaction time is 5-10 min; (3) the PEI aqueous solution has a concentration of 5-15 mg / mL, a molecular weight of 8000-10000, a pH value of 8.0-9.0, and a reaction time of 12-18 h.

4. The high hemocompatible PMP membrane prepared according to the method of any one of claims 1 to 3, characterized in that, The surface water contact angle is 62-73°, and the oxygen flux is 140-155 mL min -1 ·m -2 .

5. The high hemocompatible PMP membrane according to claim 4, characterized in that, The blood compatibility parameters are as follows: hemolysis rate ≤ 0.7%, bovine serum albumin (BSA) adsorption amount ≤ 320 ng / cm 2 , fibrinogen (BFG) adsorption amount ≤ 200 ng / cm 2 , platelet adhesion amount ≤ 2.5 × 10 4 / mm 2 .

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