Hollow fiber filter membrane, and preparation method therefor and use thereof

Abstract

A hollow fiber filter membrane, and a preparation method therefor and the use thereof, which relate to the technical field of separation membrane materials. By using in-situ gas generation combined with ultrasonic-assisted phase separation technology, and by means of adjusting the ratio of each component in spinning dope, core liquid and coagulation bath formulations and adjusting a spinning process, a hollow fiber filter membrane having a unique structure and surface morphology is obtained. The cross section of the hollow fiber filter membrane is of an asymmetric gradient sponge-like pore structure, with the pore size increasing first and then decreasing from the inside to the outside. The inner surface has smooth and loosely arranged slit-shaped pores, and the outer surface has round pores. The membrane has a PMI pore size of 0.1-0.45 μm, and is a microfiltration membrane. The membrane has a water flux of up to 300-650 LMH@Psi and a low shear force during tangential flow filtration, and exhibits a good anti-fouling performance, strong alkali resistance, good biocompatibility, and adequate mechanical properties for use.

Description

A hollow fiber filter membrane and its preparation method and application

[0001] This application claims priority to a prior application, patent application number 202410033865.1, filed with the State Intellectual Property Office of China on January 9, 2024, entitled “A Hollow Fiber Filter Membrane, Preparation Method, and Application Thereof.” The entire text of the prior application is incorporated herein by reference. Technical Field

[0002] The present application relates to the technical field of separation membrane materials, and in particular to a hollow fiber filter membrane and a preparation method and application thereof. Background Art

[0003] In recent years, large-scale cell culture technology and bioreactor engineering have been widely used in the research, development, and industrial production of biopharmaceutical products such as antibodies, recombinant protein drugs, and viral vaccines. To meet the stringent quality requirements and increasing demand for biopharmaceuticals, cell-scale expansion processes have evolved from simple fed-batch culture to perfusion culture technology.

[0004] Continuous perfusion cell culture processes maintain bioreactor volume and cell density through the continuous addition of nutrients, the continuous removal of product (and soluble impurities), and periodic removal of cells and debris. In this process, cell circulation and clarification are typically accomplished using tangential flow filtration (TFF) or alternating tangential flow (ATF) filtration using hollow fiber membranes with large inner diameters. This process utilizes the permselective properties of the hollow fiber membranes to separate cells and secreted products. Cells and culture medium continuously flow through and around the hollow fiber membranes. The permselective properties of the hollow fiber membranes allow the cell secretions and metabolic waste to be collected on the other side of the membranes. After further purification, the biopharmaceutical product is obtained. Compared to batch and fed-batch processes, perfusion culture maintains a stable cell growth and proliferation environment for extended periods, even at high cell densities, reducing product residence time within the reactor. This is beneficial for product consistency, cost-effectiveness, and scalability, particularly for products with unstable properties.

[0005] Most separation membranes used in the biomedical field are organic membranes. Organic membranes are primarily categorized by their form factor into flat membranes and hollow fiber membranes. Hollow fiber membranes, with their large surface area and self-supporting properties, are particularly suitable for processing high-concentration liquids. Therefore, hollow fiber membranes are commonly used in cell perfusion culture. Among the various membrane-forming materials, polyethersulfone (PES) has been widely used in biomedical membranes due to its excellent film-forming properties, flexibility, biocompatibility, chemical resistance, and mechanical properties.

[0006] Commercially, the main preparation processes for polyethersulfone hollow fiber membranes are non-solvent induced phase inversion (NIPS) and (steam induced phase inversion) VIPS-NIPS coupling process. However, the membrane fibers prepared by these two processes have disadvantages such as poor membrane pore permeability and low flux during phase separation. That is, when the feed liquid passes through the membrane, the bending factor is high, the resistance is large, and the membrane pores are more easily clogged, which reduces the service life. In order to improve the permeability of the membrane fibers, researchers have made a lot of efforts. Usually, blending or chemical modification is used to regulate the hydrophilicity and pore structure of the membrane. Due to compatibility issues, the pore size uniformity, chemical dissolution and production cost of the membrane face challenges.

[0007] In order to solve the above problems, researchers have developed some new assisted phase separation technologies.

[0008] China's authorized invention patent CN102512987A improves the permeability of PVDF hollow fiber membranes by blending a gas porogen into the fiber solution. After the membrane fibers are formed, a chemical reaction between the chemical treatment solution and the gas porogen occurs, strengthening the membrane and forming pores. However, the as-spun fibers must be soaked in the chemical treatment solution for 6-12 hours, and then the membrane fibers must be rinsed and cured in room temperature tap water. This process is cumbersome and cannot be used in continuous production.

[0009] Chinese invention patent CN 2018126540A discloses a high-flux braided tube-reinforced hollow fiber membrane and its preparation method. This method increases the flux of the membrane by pressurizing the silk solution to distribute tiny bubbles within the solution, forming a "steamed cake" structure during the curing process. However, during processing, a large number of bubbles in the silk solution tend to coalesce, forming larger bubbles. These bubbles form defects after curing, reducing the strength and retention rate of the membrane, making industrialization difficult.

[0010] China's authorized invention patent CN 113019159 A uses the meshing action of a gear pump to circulate and bubble the core liquid. The silk liquid and core liquid are then extruded simultaneously. After a period of air flow, the fibers are immersed in an ultrasonic coagulation bath. Ultrasonic action is used to aggregate and break up the bubble-containing core liquid within the nascent fibers, increasing the porosity of the inner surface of the membrane fibers and subsequently transferring it to the membrane wall. The formed fibers are then passed through a rinsing tank and wound for collection. The bubbles generated in the core liquid by the meshing action of the gear pump may be of uneven size, and the nascent fibers undergo extremely rapid phase separation in the coagulation bath. This may result in bubbles in the core liquid not being transferred to the membrane wall, causing the membrane fibers to solidify, thus failing to improve the permeability of the membrane fibers.

[0011] Summary of the Invention

[0012] In response to the shortcomings of the existing technology, the hollow fiber microfiltration membrane provided by this application utilizes in-situ gas generation combined with ultrasonic-assisted phase separation technology from the perspective of improving membrane permeability, reducing cultured cell shear force and improving anti-pollution performance. Through innovation in formulation and spinning process, a hollow fiber microfiltration membrane for continuous cell perfusion culture and its preparation method are obtained. The average pore size of the hollow fiber microfiltration membrane is 0.1-0.45 μm, and it has the advantages of high flux, good permeability and strong anti-pollution ability. It can meet the following requirements in biopharmaceuticals: (a) continuous perfusion culture of cells; (b) dialysis of proteins; (c) clarification and filtration of cells and bacteria in fermentation broth; (d) retention and concentration of cells and bacteria; (e) nanoparticle coating, filtration, fractionation / dehydration; (f) rinsing of latex, polystyrene and other diagnostic particles to remove unreacted / unbound drug substrates.

[0013] In order to solve the problems of the prior art, the technical solutions of the present invention are as follows:

[0014] A method for preparing a hollow fiber filter membrane comprises: simultaneously extruding a core liquid and a silk liquid that have been vacuumed through a coaxial double-hole spinneret to form a primary hollow fiber; the primary hollow fiber is sequentially passed through an air gap and an ultrasonic vibration coagulation bath to be solidified and formed; and then washed, dried, and wound to obtain a hollow fiber filter membrane; the silk liquid contains a gas generator, which is a substance that can react with a protonic acid to generate gas; and the coagulation bath contains a protonic acid.

[0015] Furthermore, the silk liquid includes: a main resin, a pore-forming agent, a gas generator, a solvent and an additive, the main resin is a polysulfone material, and the additive is a non-solvent for regulating the phase separation rate; the core liquid is a mixed solution of at least one of the solvents and water; the coagulation bath is a mixed solution of at least one of the solvents, a protonic acid and water.

[0016] In some embodiments of the present invention, the main resin is one of polyethersulfone (PES) or polysulfone (PSF); the pore-forming agent is at least one of polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), Tween, polylactic acid and polyethylene glycol; the solvent is at least one of dimethyl sulfoxide (DMSO), dimethylformamide (DMF), N-ethylpyrrolidone (NEP), dimethylacetamide (DMAC) and N-methylpyrrolidone (NMP); the additive is a small molecule non-solvent, specifically at least one of ethanol, ethylene glycol, 1,2-propylene glycol, glycerol, formic acid, ethanol, water, tetrahydrofuran and acetone; the gas generator is at least one of sodium bicarbonate and sodium borohydride; the protonic acid is one or more of hydrochloric acid, sulfuric acid, nitric acid, citric acid and oxalic acid.

[0017] In some embodiments of the present invention, the silk solution comprises the following material compositions in parts by weight: 15-25 parts of main resin, 5-15 parts of pore-forming agent, 0-5 parts of gas generator, 55-85 parts of solvent, and 2-20 parts of additives.

[0018] In some embodiments of the present invention, during the preparation of the silk solution, the dissolution temperature is 30-80° C., the stirring rate is 50-500 r / min, and the stirring time is 8-24 h.

[0019] In some embodiments of the present invention, the silk liquid and the core liquid are subjected to vacuum treatment.

[0020] In some embodiments of the present invention, the protonic acid in the coagulation bath is specifically hydrochloric acid with a concentration of 0.001-0.003 wt %. Within a certain range, the higher the protonic acid concentration, the faster and more complete the reaction, which is beneficial to improving the membrane permeability and pore size.

[0021] In some embodiments of the present invention, the humidity of the air section is controlled at a relative humidity of 70±5 and a temperature of 55±5°C.

[0022] In some embodiments of the present invention, the silk liquid temperature is 55-60°C, the pressure is 0.1-0.3 MPa, the flow rate is 3.5-7.5 g / min, the core liquid temperature is 55-60°C, and the flow rate is 1.5-3.5 g / min.

[0023] Furthermore, in some embodiments of the present invention, the length of the air gap is 5-60 cm, the temperature of the coagulation bath is 40-80° C., and the ultrasonic power of the ultrasonic vibration is 100-800 KW.

[0024] Furthermore, in some embodiments of the present invention, the water washing temperature is 60-80° C., and the winding (receiving) speed is 10-40 m / min.

[0025] The hollow fiber filter membrane prepared by any of the above methods.

[0026] A hollow fiber membrane filter is made by cutting the above-mentioned hollow fiber membrane and packaging it in a shell.

[0027] The hollow fiber membrane filter can be applied in one or more of the following ways in the form of unidirectional / alternating tangential flow:

[0028] (a) Continuous perfusion culture of cells; (b) Dialysis of proteins; (c) Clarification and filtration of cells and bacteria in fermentation broth; (d) Retention and concentration of cells and bacteria; (e) Nanoparticle coating, filtration, fractionation / dehydration; (f) Rinsing of latex, polystyrene and other diagnostic particles to remove unreacted / unbound drug substrates.

[0029] The principle of the hollow fiber membrane formation process and the method for preparing the hollow fiber membrane filter prepared by the method of the present invention are as follows:

[0030] The prepared core liquid and silk liquid are vacuum degassed; then, after being extruded simultaneously through a coaxial double-hole spinneret, the core liquid containing a certain pressure contacts the silk liquid, supporting the silk liquid to form, and forming a nascent hollow fiber with an inner surface and an outer surface; the nascent fiber passes through an air gap and is formed in an ultrasonic coagulation bath; wherein, in the air section, the solvent on the outer surface of the nascent fiber undergoes a slow double diffusion process with the water molecules (non-solvent) in the air, and a similar solvent-water double diffusion process also occurs on the inner surface. Due to the high spinning speed and the limited length of the air gap, the phase separation cannot be complete, and the nascent fiber in the air The phase separation process of the segment can also be called the pre-phase separation process; then the nascent fiber is immersed in a coagulation bath with ultrasonic function to carry out a rapid solvent-water non-solvent double diffusion process, and at the same time the gas generator in the nascent fiber reacts with the acid in the coagulation bath to quickly generate a large number of tiny bubbles, which are caused to aggregate, move and break inside the nascent fiber through ultrasonic vibration to improve the permeability of the membrane filament; the formed fiber is passed through a water washing tank to remove residual solvents and additives, etc.; and is dried online in a drying section; the dried membrane filament is wound, cut, and packaged in a shell to make a hollow fiber membrane filter for standby use.

[0031] The hollow fiber membrane prepared by the method of the present invention has an inner diameter of 0.3-1.5 mm, a single-side wall thickness of 80-140 μm, and a porosity of 60%-75% (dry-wet weighing method). The inner surface of the membrane has a loose, slit-shaped pore structure, which is relatively smooth, unlike the rough, grooved inner surface structure of traditional microfiltration hollow fiber membranes. The slit-shaped pores have a short diameter of 0.01-0.05 μm and a long diameter of 0.5-5 μm. Due to the slit-shaped pore structure on the inner surface, it is conducive to cell retention while maintaining a high filtration flux. The outer surface of the membrane has a cell-like open pore structure with a pore size of 0.05-0.5 μm. The cross-section of the membrane is an asymmetric gradient sponge pore structure, which consists of a separation layer and a support layer. Along the wall thickness direction, from the inside to the outside, the pore size first increases and then decreases: the separation layer is on the side close to the inner surface, and its structure is a "relatively dense" sponge pore structure. The thickness of the separation layer is 2-8μm, accounting for 5%-15% of the total wall thickness, and the pore size is 0.02-0.4μm; the support layer includes a first transition layer and a second transition layer. The thickness of the first transition layer is 15-180μm, accounting for 20%-80% of the total wall thickness, and the pore size is 0.4-2.5μm. The thickness of the second transition layer is 40-80μm on the side close to the outer surface, accounting for 35%-50% of the total wall thickness, and the pore size is 0.2-0.4μm.

[0032] The hollow fiber membrane prepared by the method of the present invention has a PMI pore size of 0.1-0.45 μm, belongs to the category of microfiltration membrane, has a dead-end test burst pressure (compressed air-ethanol infiltration) ≥ 0.20 MPa, and a pure water flux of 300-650 LMH@Psi.

[0033] Compared with the prior art, the present invention has the following beneficial effects:

[0034] (1) The present invention provides a method for preparing a hollow fiber filter membrane from the perspective of improving membrane permeability, reducing shear force of cultured cells and improving anti-pollution performance. By utilizing in-situ gas generation combined with ultrasonic-assisted phase separation technology, and adjusting the types and ratios of the main resin, pore-forming agent, gas generator, and small molecule additives in the silk liquid formula, and adjusting the types and ratios of the core liquid and coagulation bath and adjusting the process parameters of each spinning stage, a high-throughput hollow fiber filter membrane with a unique structure and surface morphology is prepared. The cross-section of the filter membrane is an asymmetric gradient sponge pore structure in which the pore diameter first increases and then decreases from the inside to the outside, the inner surface is a smooth and loose slit-shaped pore structure, and the outer surface is a cellular pore structure. The pure water flux of the hollow fiber filter membrane can reach 300-650LMH@Psi.

[0035] (2) The hollow fiber filter membrane prepared by the method of the present invention has an internal pressure type, unidirectional / alternating tangential flow filtration mode. Since the inner surface is a smooth, loose slit-shaped pore structure with a pore size in the range of 0.01-5 μm and a water contact angle of 45-70°, it is applied to continuous perfusion cell culture. The smoother the filtration surface of the membrane, the better the hydrophilicity, and the less likely protein pollutants are to accumulate on the membrane surface to form a filter cake layer, which is beneficial to reducing the shear force during liquid filtration, protecting cells and reducing membrane fouling. Experiments show that the hollow fiber membrane prepared by the present invention has a retention rate of 100% for CHO cells, a retention rate of more than 99% for Escherichia coli, and a retention rate of 0% for bovine serum albumin (BSA).

[0036] (3) The hollow fiber membranes prepared by the present invention exhibit excellent anti-fouling properties. Conventional filters have unacceptable permeability when their flux recovery rate falls below 80%. However, filters made from the hollow fiber membranes prepared by the present invention, after undergoing a 30-day cell perfusion culture cycle and then washing with 0.1 mol / L NaOH for 1 hour, exhibited a water flux recovery rate exceeding 90%. Even after 10 reuses, the water flux was still able to recover to over 80% of its initial value.

[0037] In summary, the hollow fiber membrane provided by the present invention can be widely used in biomedical fields such as continuous perfusion culture of cells, dialysis of proteins, clarification and filtration of cells and bacteria in fermentation broth, and retention and concentration of cells and bacteria, and has extremely high social value and economic benefits. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] FIG1 is a scanning electron microscope (SEM) image of the entire cross-section of the PES hollow fiber membrane prepared in Example 1, wherein the magnification is 100×;

[0039] FIG2 is a scanning electron microscope (SEM) image of one side of the cross section of the PES hollow fiber membrane prepared in Example 1, wherein the magnification is 500×;

[0040] FIG3 is a scanning electron microscope (SEM) image of the inner surface of the PES hollow fiber membrane prepared in Example 1, wherein the magnification is 1K×;

[0041] FIG4 is a scanning electron microscope (SEM) image of the outer surface of the PES hollow fiber membrane prepared in Example 1, wherein the magnification is 5K×;

[0042] FIG5 is a scanning electron microscope (SEM) image of the entire cross-section of the PES hollow fiber membrane prepared in Example 2, wherein the magnification is 60×;

[0043] FIG6 is a scanning electron microscope (SEM) image of one side of the cross section of the PES hollow fiber membrane prepared in Example 2, wherein the magnification is 500×;

[0044] FIG7 is a scanning electron microscope (SEM) image of the inner surface of the PES hollow fiber membrane prepared in Example 2, wherein the magnification is 1K×;

[0045] FIG8 is a scanning electron microscope (SEM) image of the outer surface of the PES hollow fiber membrane prepared in Example 2, wherein the magnification is 5K×;

[0046] FIG9 is a scanning electron microscope (SEM) image of one side of the cross section of the PES hollow fiber membrane prepared in Comparative Example 1, wherein the magnification is 500×;

[0047] FIG10 is a scanning electron microscope (SEM) image of the inner surface of the PES hollow fiber membrane prepared in Comparative Example 1, wherein the magnification is 2K×;

[0048] FIG11 is a scanning electron microscope (SEM) image of the outer surface of the PES hollow fiber membrane prepared in Comparative Example 1, wherein the magnification is 5K×;

[0049] FIG12 is a scanning electron microscope (SEM) image of one side of the cross section of the PES hollow fiber membrane prepared in Comparative Example 2, wherein the magnification is 500×;

[0050] FIG13 is a scanning electron microscope (SEM) image of the inner surface of the PES hollow fiber membrane prepared in Comparative Example 2, wherein the magnification is 1K×;

[0051] FIG14 is a scanning electron microscope (SEM) image of the outer surface of the PES hollow fiber membrane prepared in Comparative Example 2, wherein the magnification is 5K×. DETAILED DESCRIPTION

[0052] To facilitate the technical solution of the application, some concepts involved in this application are first explained below.

[0053] Example 1

[0054] S1: Preparation of silk solution, core solution and coagulation bath:

[0055] 16wt% polyethersulfone, 10wt% PVA, 5wt% PVP, 0.2wt% sodium borohydride, 8wt% 1,2-propylene glycol, 60.8wt%

[0056] NMP was heated and stirred uniformly, with a dissolving temperature of 80°C, a stirring rate of 100 rpm, and a stirring time of 24 h. The membrane solution was vacuum degassed for 8 h to obtain a silk solution;

[0057] 68 wt% DMAC and 32 wt% pure water were mixed and stirred evenly, and vacuum degassed for 1 h to obtain the core liquid;

[0058] 40 wt % DMAC, 0.001 wt % HCl, and 59.999 wt % pure water were mixed and stirred to obtain a coagulation bath.

[0059] S2: Spinning:

[0060] The core liquid and silk liquid after vacuum degassing (removing dissolved air, the same below) are pressurized and transported to the main spinning section through a gear pump and a metering pump respectively; then, after being extruded simultaneously through a coaxial double-hole spinneret, the core liquid containing a certain pressure contacts the silk liquid, supporting the silk liquid to form, and forming a nascent hollow fiber with an inner surface and an outer surface; the nascent fiber passes through an air gap and is formed in an ultrasonic coagulation bath; the formed fiber passes through a water washing tank to remove residual solvents and additives; and is dried online by a drying equipment; the dried membrane filaments are wound, cut, and packaged in a shell to make a hollow fiber membrane filter for use.

[0061] Among them, the silk liquid temperature is 60℃, the core liquid temperature is 60℃, the air section length is 40cm, the coagulation bath temperature is 65℃, the ultrasonic power is 200KW, the water washing bath temperature is 80℃, the spinning speed is 28m / min, the inner diameter of the hollow fiber membrane is 1.0mm, and the outer diameter is 1.3mm.

[0062] Figures 1 and 2 are SEM images of the entire cross-section and one side of the hollow fiber microfiltration membrane prepared by the method described in Example 1, respectively. The cross-section of the membrane fiber is an asymmetric gradient sponge pore structure. Along the wall thickness direction, from the inside to the outside, the pore size first increases and then decreases; the separation layer has a thickness of 5 μm, accounting for 8.3% of the total wall thickness, and a pore size of 0.02-0.25 μm; the first transition layer in the support layer close to the separation layer has a thickness of 30 μm, accounting for 50% of the total wall thickness, and a pore size of 0.25-2 μm; the second transition layer in the support layer close to the outer surface has a thickness of 25 μm, accounting for 41.7% of the total wall thickness, and a pore size of 2-0.3 μm.

[0063] Figure 3 is a SEM image of the inner surface of the hollow fiber microfiltration membrane prepared by the method described in Example 1. The inner surface of the membrane filament is a loose slit-shaped pore structure with a pore size of 0.01-0.6 μm. The inner surface is relatively smooth, which is beneficial to reducing the shear force during feed liquid filtration and alleviating membrane fouling.

[0064] FIG4 is a SEM image of the outer surface of the hollow fiber microfiltration membrane prepared by the method described in Example 1. The outer surface of the membrane fiber has a common cell-like pore structure with a pore size of 0.05-0.5 μm.

[0065] Testing showed that the hollow fiber microfiltration membrane prepared in this embodiment had an average PMI pore size of 0.20 μm, a pure water flux of 390 LMH@Psi, a BSA permeability of 100%, a CHO cell retention rate of 100%, and an E. coli retention rate greater than 99.9%. After a 30-day cell perfusion culture cycle, the filter made of the hollow fiber membrane was washed with 0.1 mol / L NaOH for 1 hour, and the pure water flux recovery rate was 95%. After 10 uses, the pure water flux recovery rate was 82%.

[0066] Example 2

[0067] S1: Preparation of silk solution, core solution and coagulation bath:

[0068] 15 wt% polyethersulfone, 12 wt% PVA, 3 wt% PVP, 1 wt% Tween 20, 0.3 wt% sodium borohydride, 9 wt% 1,2-propylene glycol, and 59.7 wt% NMP were heated and stirred uniformly; the dissolution temperature was 80°C, the stirring rate was 100 rpm, and the stirring time was 24 h. The membrane solution was vacuum degassed for 8 h to obtain a silk solution;

[0069] 70 wt% DMAC and 30 wt% pure water were mixed and stirred evenly, and vacuum degassed for 1 h to obtain the core solution;

[0070] 43 wt % DMAC, 0.001 wt % HCl, and 56.999 wt % pure water were mixed and stirred uniformly to obtain a coagulation bath.

[0071] S2: Spinning:

[0072] The core liquid and silk liquid after vacuum degassing are pressurized and transported to the main spinning section through a gear pump and a metering pump; then, after being extruded simultaneously through a coaxial double-hole spinneret, the core liquid containing a certain pressure contacts with the silk liquid, supporting the silk liquid to form, and forming a nascent hollow fiber with an inner surface and an outer surface; the nascent fiber passes through an air gap and is formed in an ultrasonic coagulation bath; the formed fiber passes through a water washing tank to remove residual solvents and additives; and is dried online by a drying equipment; the dried membrane filaments are wound, cut, and packaged in a shell to make a hollow fiber membrane filter for standby use.

[0073] Among them, the silk liquid temperature is 55℃, the core liquid temperature is 55℃, the air section length is 35cm, the coagulation bath temperature is 65℃, the ultrasonic power is 200KW, the water washing bath temperature is 80℃, the spinning speed is 25m / min, the inner diameter of the hollow fiber membrane is 0.85mm, and the outer diameter is 1.31mm.

[0074] Figures 5 and 6 are SEM images of the entire cross-section and one side of the hollow fiber microfiltration membrane prepared by the method described in Example 2, respectively. The cross-section of the membrane fiber is an asymmetric gradient sponge pore structure. Along the wall thickness direction, from the inside to the outside, the pore size first increases and then decreases; the separation layer has a thickness of 15 μm, accounting for 6.0% of the total wall thickness, and a pore size of 0.02-0.45 μm; the first transition layer in the support layer close to the separation layer has a thickness of 165 μm, accounting for 71.7% of the total wall thickness, and a pore size of 0.45-2.5 μm; the second transition layer in the support layer close to the outer surface has a thickness of 50 μm, accounting for 21.7% of the total wall thickness, and a pore size of 1-0.5 μm.

[0075] Figure 7 is a SEM image of the inner surface of the hollow fiber microfiltration membrane prepared by the method described in Example 2. The inner surface of the membrane filament has a loose slit-shaped pore structure with a pore size of 0.05-3 μm. The inner surface is relatively smooth, which is beneficial to reducing the shear force during feed liquid filtration and alleviating membrane fouling.

[0076] FIG8 is a SEM image of the outer surface of the hollow fiber microfiltration membrane prepared by the method described in Example 2. The outer surface of the membrane fiber has a common cell-like pore structure with a pore size of 0.05-0.5 μm.

[0077] Testing showed that the hollow fiber microfiltration membrane prepared in this embodiment had an average PMI pore size of 0.37 μm, a pure water flux of 633 LMH@Psi, a BSA permeability of 100%, a CHO cell retention rate of 100%, and an E. coli retention rate greater than 99.9%. After a 30-day cell perfusion culture cycle, the filter made of the hollow fiber membrane was cleaned with 0.1 mol / L NaOH for 1 hour, and the pure water flux recovery rate was 97%. After 15 uses, the pure water flux recovery rate was 80.5%.

[0078] Comparative Example 1

[0079] S1: Preparation of silk solution, core solution and coagulation bath:

[0080] 15 wt% polyethersulfone, 12 wt% PVA, 3 wt% PVP, 1 wt% Tween 20, 9 wt% 1,2-propylene glycol, and 60 wt% NMP were heated and stirred uniformly; the dissolution temperature was 80°C, the stirring rate was 100 rpm, and the stirring time was 24 h. The membrane solution was vacuum degassed for 8 h to obtain a silk solution;

[0081] 70 wt% DMAC and 30 wt% pure water were mixed and stirred evenly, and vacuum degassed for 1 h to obtain the core solution;

[0082] 43 wt % DMAC, 0.001 wt % HCl, and 56.999 wt % pure water were mixed and stirred uniformly to obtain a coagulation bath.

[0083] S2: Spinning:

[0084] The core liquid and silk liquid after vacuum degassing are pressurized and transported to the main spinning section through a gear pump and a metering pump; then, after being extruded simultaneously through a coaxial double-hole spinneret, the core liquid containing a certain pressure contacts with the silk liquid, supporting the silk liquid to form, and forming a nascent hollow fiber with an inner surface and an outer surface; the nascent fiber passes through an air gap and is formed in an ultrasonic coagulation bath; the formed fiber passes through a water washing tank to remove residual solvents and additives; and is dried online by a drying equipment; the dried membrane filaments are wound, cut, and packaged in a shell to make a hollow fiber membrane filter for standby use.

[0085] Among them, the silk liquid temperature is 55℃, the core liquid temperature is 55℃, the air section length is 35cm, the coagulation bath temperature is 65℃, the ultrasonic power is 200KW, the water washing bath temperature is 80℃, the spinning speed is 25m / min, the inner diameter of the hollow fiber membrane is 0.85mm, and the outer diameter is 1.17mm.

[0086] Figure 9 is an SEM image of one side of the cross section of the hollow fiber microfiltration membrane prepared by the method described in Comparative Example 1. The cross section of the membrane filament is an asymmetric gradient sponge pore structure. Along the wall thickness direction, from the inside to the outside, the pore size first increases and then decreases; the separation layer has a thickness of 13 μm, accounting for 8.13% of the total wall thickness, and a pore size of 0.02-0.45 μm; the first transition layer in the support layer close to the separation layer has a thickness of 127 μm, accounting for 79.38% of the total wall thickness, and a pore size of 0.45-2.5 μm; the second transition layer in the support layer close to the outer surface has a thickness of 20 μm, accounting for 12.5% ​​of the total wall thickness, and a pore size of 1-0.5 μm.

[0087] Figures 10 and 11 are SEM images of the inner and outer surfaces of the hollow fiber microfiltration membrane prepared by the method described in Comparative Example 1. Since no gas generating agent is added, there are more closed pores on the inner and outer surfaces of the membrane fibers and the inner surface is relatively rough. The membrane fibers of such a structure have poor permeability and anti-pollution ability.

[0088] Testing showed that the hollow fiber microfiltration membrane prepared in this example had an average PMI pore size of 0.21 μm, a pure water flux of 328 LMH@Psi, a BSA permeability of 99%, a CHO cell retention rate of 100%, and an E. coli retention rate greater than 99.9%. After a 30-day cell perfusion culture cycle, the filter made of the hollow fiber membrane was cleaned with 0.1 mol / L NaOH for 1 hour, and the pure water flux recovery rate was 78%.

[0089] Comparative Example 2

[0090] S1: Preparation of silk solution, core solution and coagulation bath:

[0091] 15 wt% polyethersulfone, 12 wt% PVA, 3 wt% PVP, 1 wt% Tween 20, 0.3 wt% sodium borohydride, 9 wt% 1,2-propylene glycol, and 59.7 wt% NMP were heated and stirred uniformly; the dissolution temperature was 80°C, the stirring rate was 100 rpm, and the stirring time was 24 h. The membrane solution was vacuum degassed for 8 h to obtain a silk solution;

[0092] 70 wt% DMAC and 30 wt% pure water were mixed and stirred evenly, and vacuum degassed for 1 h to obtain the core solution;

[0093] 43 wt % DMAC, 0.003 wt % HCl, and 56.997 wt % pure water were mixed and stirred to obtain a coagulation bath.

[0094] S2: Spinning:

[0095] The core liquid and silk liquid after vacuum degassing are pressurized and transported to the main spinning section through a gear pump and a metering pump; then, after being extruded simultaneously through a coaxial double-hole spinneret, the core liquid containing a certain pressure contacts with the silk liquid, supporting the silk liquid to form a primary hollow fiber with an inner surface and an outer surface; the primary fiber passes through an air gap and is formed in a coagulation bath; the formed fiber passes through a water washing tank to remove residual solvents and additives; and is dried online by a drying equipment; the dried membrane filaments are wound, cut, and packaged in a shell to make a hollow fiber membrane filter for standby use.

[0096] Among them, the silk liquid temperature is 55℃, the core liquid temperature is 55℃, the air section length is 35cm, the coagulation bath temperature is 65℃, there is no ultrasound, the water washing bath temperature is 80℃, the spinning speed is 25m / min, the inner diameter of the hollow fiber membrane is 0.50mm, and the outer diameter is 0.70mm.

[0097] Figure 12 is an SEM image of one side of the cross section of the hollow fiber microfiltration membrane prepared by the method described in Comparative Example 2. The cross section of the membrane filament is an asymmetric gradient sponge pore structure. Along the wall thickness direction, from the inside to the outside, the pore size first increases and then decreases; the separation layer has a thickness of 6 μm, accounting for 6% of the total wall thickness, and a pore size of 0.02-0.25 μm; the first transition layer in the support layer close to the separation layer has a thickness of 77.8 μm, accounting for 77.8% of the total wall thickness, and a pore size of 0.25-2 μm; the second transition layer in the support layer close to the outer surface has a thickness of 16.2 μm, accounting for 16.2% of the total wall thickness, and a pore size of 0.05-0.25 μm.

[0098] Figures 13 and 14 are SEM images of the inner and outer surfaces of the hollow fiber microfiltration membrane prepared by the method described in Comparative Example 2. Since ultrasound is not turned on in the coagulation bath, the sizes of the inner and outer pores of the membrane filaments are relatively small, with the pore size of the inner surface being 0.05-0.8μm and the pore size of the outer surface being 0.05-0.3μm. Although the inner surface is relatively smooth, the porosity is not high, and the membrane filaments of such a structure have poor permeability.

[0099] Testing showed that the hollow fiber microfiltration membrane prepared in this example had an average PMI pore size of 0.26 μm, a pure water flux of 437 LMH@Psi, a BSA permeability of 99.4%, a CHO cell retention rate of 100%, and an E. coli retention rate greater than 99.9%. After a 30-day cell perfusion culture cycle, the filter made of the hollow fiber membrane was cleaned with 0.1 mol / L NaOH for 1 hour, and the pure water flux recovery rate was 89%.

[0100] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above and that the invention can be embodied in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the embodiments should be considered in all respects as illustrative and non-restrictive, and the scope of the invention is defined by the appended claims, not the foregoing description, and all variations within the meaning and range of equivalents of the claims are intended to be included therein. Any reference sign in a claim should not be construed as limiting the claim to which it relates.

[0101] In addition, it should be understood that although this specification is described in terms of implementation methods, not every implementation method contains only one independent technical solution. This narrative method of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment can also be appropriately combined to form other implementation methods that can be understood by those skilled in the art.

Claims

1. A method for preparing a hollow fiber filter membrane, characterized in that, Including: The degassed core liquid and spinning solution are simultaneously extruded through a coaxial double-hole spinneret to form nascent hollow fibers. The nascent hollow fibers are successively solidified and formed after passing through an air gap and a coagulation bath with ultrasonic vibration, and then are washed with water, dried, and wound to obtain a hollow fiber filter membrane. The spinning solution contains a gas generating agent, which is a substance capable of reacting with a protonic acid to generate gas, and the coagulation bath contains a protonic acid.

2. The method for preparing a hollow fiber filter membrane according to claim 1, wherein: The spinning solution includes: a main resin, a pore-forming agent, a gas generating agent, a solvent, and an additive. The main resin is a polysulfone material, and the additive is a non-solvent for regulating the phase separation rate; The core liquid is a mixed solution of at least one of the solvents and water; The coagulation bath is a mixed solution of at least one of the solvents, a protonic acid, and water.

3. The method for preparing a hollow fiber filter membrane according to claim 2, wherein: The main resin is one of polyethersulfone or polysulfone; the pore-forming agent is at least one of polyethylene glycol, polyvinylpyrrolidone, Tween, polylactic acid, and polyvinyl alcohol; the solvent is at least one of dimethyl sulfoxide, dimethylformamide, N-ethylpyrrolidone, dimethylacetamide, and N-methylpyrrolidone; the additive is specifically at least one of ethanol, ethylene glycol, 1,2-propanediol, glycerol, formic acid, water, tetrahydrofuran, and acetone; the gas generating agent is at least one of sodium borohydride and sodium bicarbonate; the protonic acid is one or more of hydrochloric acid, sulfuric acid, nitric acid, citric acid, and oxalic acid.

4. The preparation method of the hollow fiber filter membrane according to claim 3, characterized in that, The spinning solution consists of the following components in parts by weight: 15-25 parts of main resin, 5-15 parts of pore-forming agent, 0-5 parts of gas generating agent, 55-85 parts of solvent, and 2-20 parts of additive.

5. The preparation method of the hollow fiber filter membrane according to any one of claims 1-4, characterized in that, In the coagulation bath, the protonic acid is specifically hydrochloric acid, and the concentration is 0.001-0.003 wt%.

6. The method for preparing a hollow fiber filter membrane according to any one of claims 1-4, wherein: The temperature of the spinning solution is 55-60 °C, the pressure is 0.1-0.3 MPa, and the flow rate is 3.5-7.5 g / min; The temperature of the core liquid is 55 °C-60 °C, and the flow rate is 1.5-3.5 g / min; The concentration of the protonic acid solution is 0.0001-0.003 wt%.

7. The method for preparing a hollow fiber filter membrane according to any one of claims 1-4, wherein: The length of the air gap is 5-60 cm; The temperature of the coagulation bath is 40-80 °C, and the ultrasonic power of the ultrasonic vibration is 100-800 KW; The temperature of the water washing is 60-80 °C, and the winding speed is 10-40 m / min.

8. A hollow fiber filter membrane prepared by the method according to any one of claims 1-7.

9. A hollow fiber membrane filter, characterized in that, The hollow fiber membrane filter is obtained by cutting and encapsulating the hollow fiber filter membrane according to claim 8 in a housing.

10. Use of the hollow fiber membrane filter according to claim 9, characterized in that, The hollow fiber filter membrane filter is applied in one or more of the following ways in a unidirectional / alternating tangential flow form: (a) Continuous perfusion culture of cells; (b) Dialysis of proteins; (c) Clarification and filtration of cells and bacteria in the fermentation broth; (d) Retention and concentration of cells and bacteria; (e) Nanoparticle coating, diafiltration, fractionation / dehydration; (f) Rinsing of latex, polystyrene and other diagnostic particles to remove unreacted / unbound drug substrates.

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