A hollow fiber membrane with good biocompatibility and its application

Abstract

The present invention discloses a hollow fiber membrane with excellent biocompatibility. The components of the hollow fiber membrane include a polysulfone / polyethersulfone matrix component and a grafted aromatic hydrophobic polymer containing 30% to 100% by weight of the matrix component. The preparation method of the grafted aromatic hydrophobic polymer comprises the following steps: dissolving an aromatic diamine in an organic solvent, then adding an aromatic dianhydride, and conducting a polymerization reaction for 4 to 10 hours. Then, adding a polyamine and stirring and dissolving the mixture to conduct a secondary reaction for 2 to 4 hours. Finally, adding a carboxyl-containing anticoagulant and conducting a grafting reaction for 12 to 48 hours to obtain the grafted aromatic hydrophobic polymer. The hollow fiber membrane of the present invention has stable performance, can effectively reduce the deposition of prothrombin and fibrin, etc., significantly improves the anticoagulant effect, and greatly enhances biocompatibility.

Description

Technical Field

[0001] The present invention relates to the field of biomaterials, and in particular to a hollow fiber membrane with good biocompatibility and applications thereof. Background Art

[0002] Polysulfone / polyethersulfone is a polymer material with excellent overall performance, including excellent heat resistance, physical and mechanical properties, insulation properties, and relatively good biocompatibility. It has been widely used in many fields. Polysulfone / polyethersulfone also has excellent membrane-forming and filtration properties, making it one of the most common materials for preparing hollow fiber membranes.

[0003] However, since the polysulfone / polyethersulfone membrane material itself has a strong hydrophobic effect and the sulfur and oxygen atoms in its structure have a strong polarity, when it is used in clinical contact with blood, it has a strong adhesion effect on platelets, etc. In addition, the porous structure of the fiber membrane itself makes it easy for prothrombin and fibrin to deposit in the pores of the fiber membrane, thereby activating the coagulation system and inducing the formation of thrombus. Long-term use is very likely to cause protein contamination, and then the "pore blocking" phenomenon occurs.

[0004] In order to improve the anticoagulant and anti-fouling properties of polysulfone / polyethersulfone membrane materials, three main methods are used: (1) bulk modification, that is, anticoagulant modification of the polysulfone / polyethersulfone material bulk, and then preparing fiber membrane; (2) surface modification, grafting self-anticoagulant polymers on the fiber surface by chemical methods, photochemical methods or plasma technology, or coating the surface with self-anticoagulant polymers by physical methods; (3) blending modification, forming a spinning solution by blending polysulfone / polyethersulfone with self-anticoagulant functional polymers, and finally spinning into a membrane.

[0005] Polysulfone / polyethersulfone (PS / PES) bulk materials offer stable properties and are difficult to modify. Surface grafting and coating modifications are generally applied to smaller-diameter hollow fiber membranes, making them difficult to implement in large-scale production. Currently, physical blending modification is the primary approach to improving the anticoagulant properties of PS / PES fiber membranes. For example, polyvinylpyrrolidone (PVP), zwitterionic compounds (MPC, a polyphospholipid), and sulfonated functional polymers are incorporated into the PS / PES membrane-forming solution, followed by spinning into membranes. However, during use, the hydrophilic additives in hollow fiber membranes obtained using these modification methods gradually precipitate, resulting in low performance stability. Even when amphiphilic polymers are used, significant phase separation issues can still occur, which can reduce the strength and mechanical properties of the membranes, and consequently, the membrane's filtration stability. Summary of the Invention

[0006] The object of the present invention is to overcome at least one deficiency of the prior art and to provide a hollow fiber membrane with good biocompatibility and applications thereof.

[0007] The technical solution adopted by the present invention is:

[0008] In a first aspect, the present invention provides a hollow fiber membrane with good biocompatibility, wherein the components of the hollow fiber membrane include a polysulfone / polyethersulfone matrix component and a grafted aromatic hydrophobic polymer containing 30% to 100% by weight of the matrix component, wherein the preparation method of the grafted aromatic hydrophobic polymer comprises the following steps:

[0009] 1) dissolving an aromatic diamine in an organic solvent, then adding aromatic dianhydride, and carrying out a polymerization reaction for 4 to 10 hours to obtain a polyamic acid solution;

[0010] 2) adding polyamine to the polyamic acid solution prepared in step 1) and stirring to dissolve, and performing a secondary reaction for 2 to 4 hours;

[0011] 3) adding a carboxyl-containing anticoagulant to the solution obtained in step 2) and performing a grafting reaction for 12 to 48 hours to obtain a grafted aromatic hydrophobic polymer.

[0012] In some examples, the aromatic dianhydride in step 1) is selected from any one of 3,3',4,4'-benzophenonetetracarboxylic dianhydride, 4,4'-hexafluoroisopropylidenephthalic anhydride, 3,3',4,4'-biphenyltetracarboxylic dianhydride, 1,2',4,5'-pyromellitic anhydride, 3,3',4,4'-diphenylsulfonetetracarboxylic dianhydride or phthalic anhydride.

[0013] In some examples, the aromatic diamine in step 1) is selected from any one of 3,3'-dimethyl-4,4'-diphenylmethanediamine, 4,4'-diaminodiphenylmethane, 4,4'-diphenylmethane diisocyanate, 4,4'-diaminodiphenyl ether, and p-phenylenediamine.

[0014] In some examples, the molar ratio of the aromatic dianhydride to the aromatic diamine is (1-1.05):1.

[0015] In some examples, the polyamine in step 2) is selected from one or more of ethylenediamine, propylenediamine, tris(2-aminoethyl)amine, and pentaerythritol.

[0016] In some examples, the molar ratio of the polyamine to the aromatic dianhydride is (2-2.05):1.

[0017] In some examples, the organic solvent in step 1) is at least one selected from dimethyl sulfoxide, N-methyl-2-pyrrolidone, N,N-dimethylformamide and N,N-dimethylacetamide.

[0018] In some examples, the carboxyl group-containing anticoagulant is selected from heparin or a heparin analog.

[0019] In some instances, the method for preparing the hollow fiber membrane includes the following steps: stirring and dissolving polysulfone / polyethersulfone, grafted aromatic hydrophobic polymer, water-soluble porogen and spinning solution solvent at 80-180°C, centrifugally filtering, standing at 40-80°C for 2-24 hours to degas to obtain a spinning solution, and the spinning solution is subjected to dry or wet spinning, water washing, stretching and drying to obtain a modified hollow fiber membrane.

[0020] In some examples, the mass ratio of the components in the spinning solution is: 20-60 parts of polysulfone / polyethersulfone, 20-40 parts of grafted aromatic hydrophobic polymer, 0.1-10 parts of water-soluble porogen, and 100-300 parts of spinning solution solvent.

[0021] In a second aspect, the present invention provides an application of the hollow fiber membrane with good biocompatibility in the preparation of blood purification materials.

[0022] The beneficial effects of the present invention are:

[0023] In some examples of the present invention, an aromatic hydrophobic polymer grafted with an anticoagulant is blended and modified with polysulfone / polyethersulfone, and anticoagulant groups are directly obtained on the surface of the prepared hollow fiber membrane, eliminating the need for subsequent anticoagulant modification of the hollow fiber membrane, thereby achieving the purpose of continuous anticoagulant modification.

[0024] In some embodiments of the present invention, the grafted aromatic hydrophobic polymer has obvious hydrophobicity, has good blending effect with polysulfone / polyethersulfone, is not prone to phase separation, and has stable hollow fiber membrane performance;

[0025] In some embodiments of the present invention, a large number of amino groups are branched on the surface of the grafted aromatic hydrophobic polymer after blending with polysulfone / polyethersulfone. According to the principle of like dissolves like, the hydrophilicity of the hollow fiber membrane can be further enhanced, thereby improving biocompatibility. DETAILED DESCRIPTION

[0026] A hollow fiber membrane with good biocompatibility, wherein the components of the hollow fiber membrane include a polysulfone / polyethersulfone matrix component and a grafted aromatic hydrophobic polymer containing 30% to 100% by mass of the matrix component, wherein the preparation method of the grafted aromatic hydrophobic polymer comprises the following steps:

[0027] 1) dissolving an aromatic diamine in an organic solvent, then adding aromatic dianhydride, and carrying out a polymerization reaction for 4 to 10 hours to obtain a polyamic acid solution;

[0028] 2) adding polyamine to the polyamic acid solution prepared in step 1) and stirring to dissolve, and performing a secondary reaction for 2 to 4 hours;

[0029] 3) adding a carboxyl-containing anticoagulant to the solution obtained in step 2) and performing a grafting reaction for 12 to 48 hours to obtain a grafted aromatic hydrophobic polymer.

[0030] In some examples, the aromatic dianhydride in step 1) is selected from any one of 3,3',4,4'-benzophenonetetracarboxylic dianhydride, 4,4'-hexafluoroisopropylidenephthalic anhydride, 3,3',4,4'-biphenyltetracarboxylic dianhydride, 1,2',4,5'-pyromellitic anhydride, 3,3',4,4'-diphenylsulfonetetracarboxylic dianhydride, or phthalic anhydride. These raw materials are widely available and have good stability.

[0031] In some examples, the aromatic diamine in step 1) is selected from any one of 3,3'-dimethyl-4,4'-diphenylmethane diamine, 4,4'-diaminodiphenylmethane, 4,4'-diphenylmethane diisocyanate, 4,4'-diaminodiphenyl ether, and p-phenylenediamine. These aromatic diamines are relatively widely available and have good stability.

[0032] In some examples, the molar ratio of the aromatic dianhydride to the aromatic diamine is (1-1.05):1, which can ensure sufficient reaction.

[0033] In some examples, the polyamine in step 2) is selected from one or more of ethylenediamine, propylenediamine, tris(2-aminoethyl)amine, and pentaerythritol.

[0034] In some examples, the molar ratio of the polyamine to the aromatic dianhydride is (2-2.05):1.

[0035] In some examples, the organic solvent in step 1) is at least one selected from dimethyl sulfoxide, N-methyl-2-pyrrolidone, N,N-dimethylformamide and N,N-dimethylacetamide.

[0036] The presence of a carboxyl group further facilitates the grafting reaction of the anticoagulant. In some embodiments, the anticoagulant containing a carboxyl group is selected from heparin or a heparin analog. Heparin or a heparin analog has good anticoagulant effect and its safety has been verified during long-term use.

[0037] In some instances, the method for preparing the hollow fiber membrane includes the following steps: stirring and dissolving polysulfone / polyethersulfone, grafted aromatic hydrophobic polymer, water-soluble porogen and spinning solution solvent at 80-180°C, centrifugally filtering, standing at 40-80°C for 2-24 hours to degas to obtain a spinning solution, and the spinning solution is subjected to dry or wet spinning, water washing, stretching and drying to obtain a modified hollow fiber membrane.

[0038] In some examples, the mass ratio of the components in the spinning solution is: 20-60 parts of polysulfone / polyethersulfone, 20-40 parts of grafted aromatic hydrophobic polymer, 0.1-10 parts of water-soluble porogen, and 100-300 parts of spinning solution solvent.

[0039] The following disclosure provides many different embodiments or examples for implementing different solutions of the present invention.

[0040] The preparation methods of the grafted aromatic hydrophobic polymers of Examples 1 to 3 of the present invention are as follows:

[0041] 1. Measure a certain amount of a strong polar solvent and gradually add a certain amount of diamine under nitrogen protection. Stir for 2 hours until completely dissolved. Then gradually add dianhydride and stir for 4-10 hours to obtain a polyamic acid stock solution. The substances and their contents are shown in Table 1 below.

[0042] 2. Add polyamine to the solution obtained in step (1), with the molar ratio of polyamine to the aromatic dianhydride in step (1) being 2.05:1, stir for 2 hours to dissolve, and then continue stirring to react for 4-10 hours.

[0043] 3. Add 10 mg of heparin / heparin analog to the solution obtained in step (2), stir thoroughly to dissolve, and soak for 12-48 hours to obtain an aromatic hydrophobic polymer solution.

[0044] Table 1

[0045]

[0046] The preparation methods of the modified hollow fiber membranes in the examples and comparative examples of the present invention are as follows:

[0047] 1) According to the raw material composition and mass ratio in Table 2, polysulfone / polyethersulfone, blended resin, water-soluble porogen and spinning solution solvent were weighed respectively, stirred and dissolved at 100°C to form a transparent solution, centrifuged and filtered, and allowed to stand at 80°C for 4 hours to degas to obtain a spinning solution.

[0048] 2) The spinning solution prepared in step 1 is extruded from a spinneret at an extrusion rate of 3-15 mL / min using a spinning device. After passing through an air bath of 5-50 cm in air, the solution is placed in a water bath of 20-50°C for coagulation and molding. The solution is then wound at a speed of 5-50 m / min to form the formed fiber. The formed fiber is immersed in water to remove the residual solvent and unreacted raw materials, and then dried to obtain a hollow fiber membrane.

[0049] Among them, the water-soluble porogen can be selected from at least one of polyethylene imine, polyethylene glycol 800, polyethylene glycol 1000, polyethylene glycol 2000, polyvinyl pyrrolidone, polyacrylic acid, polyvinyl alcohol, Tween-20, Tween-60, Tween-80, sodium sorbate, potassium sorbate, sodium citrate, sodium laurate, sodium alginate, sodium lysine, sodium ethylenediaminetetraacetic acid, sodium tetradecanoate, sodium dodecylsulfonate, sodium octanoate, sodium hexanoate, sodium propionate, sodium acetate, sodium oxalate, lithium acetate, sodium chloride, lithium chloride, calcium chloride or copper chloride, and the spinning solution solvent is selected from at least one of dimethyl sulfoxide, N-methyl-2-pyrrolidone, N,N-dimethylformamide and N,N-dimethylacetamide.

[0050] Table 2

[0051]

[0052] Then, performance tests were conducted on Examples 4-7 and Comparative Examples 1-2. The test results are shown in Table 3 below:

[0053] Table 3

[0054]

[0055] in conclusion:

[0056] It can be seen that the ultrafiltration coefficient of the hollow fiber membrane prepared by the present invention is not significantly changed compared with the fiber membrane of Example 1 which has not been hydrophilically modified, and the dialysis performance is not affected; the water contact angle is significantly reduced and the hydrophilicity is significantly improved; the pure water flux recovery rate after hemodialysis is significantly improved, indicating that the modified hollow fiber membrane reduces the deposition of prothrombin and fibrin, etc.; the APTT (activated partial thromboplastin time) is significantly prolonged, and the anticoagulant effect is significantly improved.

[0057] Compared with hollow fiber membranes modified only with polyvinyl pyrrolidone, their hydrophilicity and anticoagulant effect are also increased to a certain extent.

[0058] The above is a further detailed description of the present invention and should not be considered as a limitation on the specific implementation of the present invention. For those skilled in the art, simple deductions or substitutions that do not depart from the concept of the present invention are within the scope of protection of the present invention.

Claims

1. A hollow fiber membrane with good biocompatibility, characterized in that: The components of the hollow fiber membrane include a polysulfone / polyethersulfone matrix component and a grafted aromatic hydrophobic polymer with a matrix component mass content of 30% to 100%, and the polysulfone / polyethersulfone matrix component and the grafted aromatic hydrophobic polymer are composited by blending. The preparation method of the grafted aromatic hydrophobic polymer includes the following steps: 1) dissolving an aromatic diamine in an organic solvent, then adding aromatic dianhydride, and carrying out a polymerization reaction for 4 to 10 hours to obtain a polyamic acid solution; 2) adding a polyamine to the polyamic acid solution prepared in step 1) and stirring and dissolving the polyamine to carry out a secondary reaction for 2 to 4 hours, wherein the polyamine is selected from one or more of ethylenediamine, propylenediamine, tris(2-aminoethyl)amine, and pentaerythritol; 3) adding a carboxyl-containing anticoagulant to the solution obtained in step 2), wherein the carboxyl-containing anticoagulant is selected from heparin or a heparin analogue, and performing a grafting reaction for 12 to 48 hours to obtain a grafted aromatic hydrophobic polymer.

2. The hollow fiber membrane according to claim 1, characterized in that The aromatic dianhydride in step 1) is selected from any one of 3,3',4,4'-benzophenonetetracarboxylic dianhydride, 4,4'-hexafluoroisopropylidenephthalic anhydride, 3,3',4,4'-biphenyltetracarboxylic dianhydride, 1,2',4,5'-pyromellitic anhydride, 3,3',4,4'-diphenylsulfonetetracarboxylic dianhydride or phthalic anhydride.

3. The hollow fiber membrane according to claim 1, characterized in that The aromatic diamine in step 1) is selected from any one of 3,3'-dimethyl-4,4'-diphenylmethanediamine, 4,4'-diaminodiphenylmethane, 4,4'-diphenylmethane diisocyanate, 4,4'-diaminodiphenyl ether, and p-phenylenediamine.

4. The hollow fiber membrane according to claim 2 or 3, characterized in that The molar ratio of the aromatic dianhydride to the aromatic diamine is (1-1.05):

1.

5. The hollow fiber membrane according to claim 1 or 2, characterized in that The molar ratio of the polyamine to the aromatic dianhydride is (2-2.05):

1.

6. The hollow fiber membrane according to claim 1, characterized in that The organic solvent in step 1) is at least one selected from dimethyl sulfoxide, N-methyl-2-pyrrolidone, N,N-dimethylformamide and N,N-dimethylacetamide.

7. The hollow fiber membrane according to claim 1, characterized in that The preparation method of the hollow fiber membrane comprises the following steps: dissolving polysulfone / polyethersulfone, a grafted aromatic hydrophobic polymer, a water-soluble porogen and a spinning solution solvent by stirring at 80 to 180° C., centrifugally filtering, standing at 40 to 80° C. for 2 to 24 hours to degas, and obtaining a spinning solution; and obtaining a modified hollow fiber membrane by dry or wet spinning, washing, stretching and drying the spinning solution.

8. The hollow fiber membrane according to claim 7, characterized in that The mass ratio of the components in the spinning solution is: 20-60 parts of polysulfone / polyethersulfone, 20-40 parts of grafted aromatic hydrophobic polymer, 0.1-10 parts of water-soluble porogen, and 100-300 parts of spinning solution solvent.

9. Use of the hollow fiber membrane with good biocompatibility according to any one of claims 1 to 8 in the preparation of blood purification materials.

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