Preparation method and application of polyethylene glycol heat crosslinking modified polyether sulfone asymmetric membrane

Abstract

A preparation method and application of a polyethylene glycol heat crosslinking modified polyether sulfone asymmetric membrane. Polyether sulfone is dissolved in N, N-dimethylacetamide, polyethylene glycol-400, azobis isobutyronitrile and N, N'-methylene bisacrylamide are added to form a uniform solution. The reaction solution is fully mixed by stirring under a nitrogen atmosphere through thermal initiation of polymerization, and ultrasonic defoaming is performed. The solution is scraped on a glass plate, and the temperature and humidity are controlled. After the glass plate is immersed in isopropyl alcohol and then in water, the membrane is completely separated from the glass plate, and finally the membrane is dried. The polyethylene glycol is crosslinked on the polyether sulfone membrane by thermal initiation in the solution, and the material is modified as a whole. The application is mainly applied to the preparation of gas-blood contact membrane, and has high blood compatibility, biological safety, good stability and asymmetric membrane material. At the same time, the preparation process is simple, the raw materials are cheap and easy to obtain, the prepared membrane has excellent performance, and has great application potential.

Description

Technical Field

[0001] This invention belongs to the field of biomedicine and relates to a method for preparing a polyethylene glycol thermally crosslinked modified polyethersulfone asymmetric membrane and its use in gas separation processes and immune reactions in special liquid phases during gas-blood contact. Background Technology

[0002] Respiratory diseases are among the most common diseases in the world. Taking my country as an example, there are currently over 100 million lung disease patients and over 30 million asthma patients in my country. About 13.6% of people over 40 years old in my country suffer from COPD. More than 90% of patients are missed in diagnosis. About 1 million people die from COPD in my country every year. COPD has become the third leading cause of death after cardiovascular and cerebrovascular diseases and malignant tumors.

[0003] ECMO, as the core facility for treating severe cardiopulmonary failure, is known as the "last straw" and "golden weapon" for critically ill patients. ECMO is essentially a modified artificial heart-lung machine, mainly composed of a membrane oxygenator and a blood pump. The former primarily replaces the body's lung function to achieve external respiration, while the latter replaces the body's heart function. When a patient's lung function is severely impaired and they cannot breathe independently, the membrane oxygenator can undertake the task of external gas exchange, buying precious time for the patient's treatment and lung function recovery. Currently, the two most commonly used oxygenation membranes on the market are PMP asymmetric membranes and PP microporous membranes. PP microporous membranes have many micropores on their surface, which can lead to blood leakage after short-term use, even endangering the patient's life. Although PMP material has a dense surface, its irregular crystalline and amorphous regions have a low density, and the pore size is small, making PMP membrane fabrication technology challenging. Due to their inherent hydrophobicity, PP and PMP membranes can lead to protein adsorption and platelet deposition and activation on the membrane surface during long-term use, ultimately resulting in thrombus formation and severely reducing the efficiency of the oxygenation membrane.

[0004] Polyethersulfone (PES) has become a commonly used material for preparing gas separation membranes due to its excellent tensile properties, good thermal stability, and excellent chemical stability. However, its hydrophobic nature and lack of good biocompatibility (blood compatibility) limit its application in the biological field. Essentially, the hydrophobicity of PES stems from the lack of hydrophilic groups. Therefore, introducing hydrophilic groups into PES can effectively improve the material's hydrophilicity, enhance its blood compatibility, and further expand its application areas.

[0005] Common hydrophilic modification methods are mainly divided into chemical grafting (photo-initiated grafting, plasma grafting, and thermally initiated grafting) and physical blending, each with its own advantages and disadvantages. Physical blending simply mixes two substances together without chemical bonds between them, resulting in highly unstable modification and poor modification effects. Photo-initiated grafting and plasma grafting both modify the material surface, leading to incomplete modification and potential damage to the material surface, and the operations are complex.

[0006] Polyethylene glycol (PEG) is a water-soluble polymer compound with helical chains and hydroxyl groups at both ends. It is non-toxic, non-irritating, and inexpensive, and is widely used in biomedicine, cosmetics, and other fields. Introducing PEG into PES materials can effectively improve the material's hydrophilicity, thereby improving its blood compatibility.

[0007] Currently, most scholars employ photografting and radiation grafting methods to graft polyethylene glycol (PEG) onto the surface of membrane materials to improve their blood compatibility. For example, Xiangpu Qin, in "Improving the Blood Compatibility and the Gas Permeability of Polyether Ether Ketone Hollow Fiber Membrane Used for Membrane Oxygenator via Grafting Hydrophilic Components," used ultraviolet light as a light source to photoinitiate the grafting of hydrophilic substances such as PEG. Atiye Sadat Abednejad, in "Surface modification of polypropylene membrane by polyethylene glycol graft polymerization," used H2 plasma to treat the membrane material, generating free radicals on the membrane surface, and then immersed it in a PEG solution to graft PEG. These modification methods only modify the membrane surface, and the modified layer is prone to detachment, making it difficult to maintain the modification effect for a long time. However, stability is precisely what oxygenated membranes require, so a novel PEG modification method is urgently needed.

[0008] Therefore, this invention proposes a new approach to the preparation of modified membranes by co-constructing membrane networks with PEG and PES. By using thermal crosslinking to entangle PEG molecular chain segments with PES molecular chain segments, the modified membrane is endowed with good stability and a hydrophilic layer with good biocompatibility is established. Summary of the Invention

[0009] Addressing the shortcomings of existing methods for hydrophilic modification of PES materials, such as complexity, difficulty in industrialization, unstable modification effects, and high modification costs, this invention proposes for the first time a method for hydrophilic modification of polyethersulfone (PES) using PEG as a modifier via thermally initiated crosslinking polymerization. This method, employing a two-bath process, produces a dense, asymmetric membrane. This approach is simple to operate, yields good modification results, and is cost-effective. Through thermally initiated crosslinking polymerization in a nitrogen atmosphere, using polyethylene glycol-400 and PES as raw materials, and adding a crosslinking agent and initiator, modification is completed in a PES casting solution. This results in a tight entanglement between the modifier and the material, exhibiting excellent stability and preventing the modifier from easily detaching during prolonged use. Furthermore, the introduction of hydroxyl groups enhances the membrane's affinity for CO2 gas, increasing its gas permeability.

[0010] The technical solution of the present invention: A method for preparing a polyethylene glycol (PEG) thermally crosslinked modified polyethersulfone (PES) asymmetric membrane is disclosed. PEG undergoes thermal crosslinking-initiated polymerization in a PES casting solution to construct a three-dimensional crosslinked network, entangled with the PES molecular chains. The modified PES asymmetric membrane is then prepared via a dual coagulation bath. The thickness of the dense layer of the membrane can be controlled by the immersion time in the first coagulation bath. The modified membrane exhibits a typical sponge-like structure in its cross-section, with a smooth, defect-free surface. The specific steps are as follows: (1) Preparation of casting solution: Using N,N-dimethylacetamide (DMAC) as solvent, add 20wt% PES and 5wt% polyethylene glycol (PEG) of total solution mass, 10% N,N'-methylenebisacrylamide (MBA) of polyethylene glycol as crosslinking agent, and 10% azobisisobutyronitrile (AIBN) of crosslinking agent as initiator. Stir magnetically until the solution is homogeneous. (2) In-situ crosslinking polymerization to modify PES: Place the casting solution from step (1) in an oil bath, add a magnetic stir bar, turn on mechanical stirring, raise the temperature to 85℃ and react for 10h, then let it stand and cool, and continue stirring for 12h to obtain the casting solution. (3) Preparation of modified membrane: The casting solution in step (2) was ultrasonically allowed to stand to remove micro bubbles. The membrane was then coated on a glass plate using a tabletop flatbed coating machine. Finally, the coated membrane was placed in isopropanol for 3 minutes until it turned from transparent to white. The membrane was then removed from the isopropanol and quickly transferred to deionized water until it floated on the surface. The membrane was then transferred to fresh deionized water and placed for 48 hours. The membrane was then removed and vacuum dried at 60°C for 12 hours to obtain a polyethylene glycol thermally crosslinked modified polyethersulfone asymmetric membrane.

[0011] A polyethylene glycol thermally crosslinked modified polyethersulfone asymmetric membrane is used as a membrane material for gas exchange at the gas-blood interface.

[0012] The beneficial effects of this application are as follows: This invention is mainly used to prepare organic composite materials with good blood compatibility, certain CO2 / O2 selectivity, and long-term stability. Firstly, the asymmetric membrane prepared by the two-bath method has advantages such as a dense, thin skin and good density. Secondly, PES material with high mechanical strength (tensile and compressive strength) is used as the framework, giving the membrane excellent mechanical properties. Finally, PEG is introduced into the PES framework through in-situ crosslinking polymerization, which modifies the membrane as a whole, resulting in good modification stability and preventing the modifier from easily detaching or peeling off. Simultaneously, this invention uses two inexpensive raw materials, greatly reducing manufacturing costs. The method is simple and has the potential for large-scale industrial manufacturing. Attached Figure Description

[0013] Figure 1 These are SEM images of the PEG-modified PES asymmetric membrane. Among them, (a) is the SEM image of the modified membrane surface at a scale of 50 μm; (b) is the SEM image of the modified membrane surface at a scale of 1 μm; (c) is the overall cross-sectional view of the modified membrane; and (d) is a magnified view of the dense skin layer of the modified membrane cross-section.

[0014] Figure 2 This is the Fourier transform infrared spectrum of the prepared modified membrane.

[0015] Figure 3 These are hydrophilicity and hydrophobicity test results for the PES asymmetric membrane and the prepared modified PES asymmetric membrane. Among them, (a) shows the measurement results of the PES asymmetric membrane; (b) shows the measurement results of the acrylic acid modified PES asymmetric membrane in the comparative example; and (c) shows the measurement results of the polyethylene glycol modified PES asymmetric membrane in Example 1.

[0016] Figure 4 These are the results of a 14-day anti-leakage test on the modified membrane. (a) is a simplified diagram of the device; (b) is a detailed diagram of the device; and (c) is a bottom view of the membrane after the 14-day test.

[0017] Figure 5 These are the results of the membrane platelet adhesion test. Among them, (a) and (d) are platelet adhesion maps of PES asymmetric membrane at different scales; (b) and (e) are platelet adhesion maps of acrylic modified PES asymmetric membrane at different scales; (e) and (f) are platelet adhesion maps of polyethylene glycol modified PES asymmetric membrane at different scales. Detailed Implementation

[0018] The specific embodiments of the present invention will be further described below with reference to the accompanying drawings and technical solutions.

[0019] Example 1: A method for preparing a polyethylene glycol thermally crosslinked modified polyethersulfone asymmetric film includes the following steps: (1) Preparation of casting solution: Take 8g of dried PES, add 30g of DMAC, 2g of PEG-400, 200mg of MBA and 20mg of AIBN, stir evenly and the casting solution is successfully prepared.

[0020] (2) Thermal crosslinking modified PES: Place the casting solution from step (1) into a three-necked flask, add a magnetic stir bar, turn on the mechanical stirrer, raise the temperature to 85℃ and react for 10h, then let it stand and cool, transfer it to a glass bottle and continue stirring for 12h.

[0021] (3) Preparation of modified membrane: The casting solution of (2) above was ultrasonically allowed to stand to remove micro bubbles. The glass plate was heated using a tabletop flatbed film scraper. The casting solution was immediately scraped onto the heated glass plate. Finally, the film after scraping was placed in isopropanol for 2 minutes. When the film changed from transparent to white, the film was removed from the isopropanol and quickly transferred to deionized water until it floated on the water surface. The film was then transferred to fresh deionized water and placed for 48 hours. It was then removed and placed in the air for 5 hours for preliminary drying. Then, it was vacuum dried at 60°C for 12 hours to obtain the modified membrane.

[0022] Comparative Example 1: A method for preparing a control group of polyethylene glycol thermally crosslinked modified polyethersulfone asymmetric membrane and acrylic acid thermally crosslinked modified membrane includes the following steps: (1) Preparation of casting solution: Mix 0.8g of acrylic acid (AA), 80mg of MBA, 8mg of AIBN, 8g of PES, and 32g of DMAC and stir mechanically to prepare the casting solution.

[0023] (2) AA thermal crosslinking modified PES: The above casting solution was poured into a three-necked flask, placed in an oil bath, and the temperature was raised to 80°C for 10 hours under a nitrogen atmosphere. After standing and cooling, it was transferred to a glass bottle and stirred for another 12 hours.

[0024] (3) Preparation of modified membrane: The casting solution of (2) above was ultrasonically allowed to stand to remove micro bubbles. Using a flat plate coating machine, the glass plate was heated and the casting solution was immediately coated on the heated glass plate. Finally, the coated membrane was placed in isopropanol for 2 minutes. When the membrane changed from transparent to white, it was removed from the isopropanol and quickly transferred to deionized water until it floated on the water surface. The membrane was then transferred to fresh deionized water and placed for 48 hours. It was then removed and placed in the air for 5 hours for preliminary drying. Then it was vacuum dried at 60°C for 12 hours to obtain the modified membrane.

[0025] Comparative Example 2: A method for preparing a modified PES asymmetric membrane control group PES asymmetric membrane material includes the following steps: (1) Preparation of casting solution: Mix 2g of PES and 8g of DMAC, stir evenly, and let stand ultrasonically for 1 hour to obtain the casting solution. (2) Preparation of asymmetric membrane: The casting solution of (1) above was ultrasonically allowed to stand to remove microbubbles. A tabletop flatbed film scraper was used to heat the glass plate and coat the casting solution onto the glass plate. The film was then scraped by the flatbed film scraper. Finally, the coated membrane was placed in isopropanol for 2 minutes. When the membrane changed from transparent to white, it was removed from the isopropanol and quickly transferred to deionized water until it floated on the water surface. The membrane was then transferred to fresh deionized water and placed for 48 hours. It was then removed and placed in the air for 5 hours for preliminary drying. Finally, it was vacuum dried at 60°C for 12 hours to obtain the PES asymmetric membrane.

[0026] Characterization of asymmetric film materials: (1) The modified film prepared in Example 1 was characterized using field emission scanning electron microscopy (SEM). The film was cryogenically quenched in liquid nitrogen to observe the asymmetric film morphology. The treated modified film material was fixed on the sample stage using conductive adhesive, and the sample was sputtered with gold to enhance conductivity. The morphology of its surface and cross-section was observed. As can be seen from the scanning electron microscope images, as... Figure 1 As shown in (a) and (b), the SEM images of the modified PES asymmetric membrane surface at both large and small scales indicate that the membrane surface is dense and free of micropores, suggesting that the modified membrane surface is dense and can effectively resist blood leakage. Figure 1 As shown in (c), the cross-section of the modified membrane exhibits a typical asymmetric structure and has sponge-like pores inside without penetrating finger-like macropores. This is because a cross-linked network was constructed, which suppressed the overflow of hydrophilic modifiers during the phase transformation process and formed sponge-like pores. Figure 1 (d) The modified PES asymmetric membrane shown has a thin, dense layer on its surface with a thickness of 310.6 nm, forming a separation functional layer with anti-leakage and gas selectivity. The extremely thin dense layer thickness can ensure good gas permeability.

[0027] (2) The original PES film and the modified PES asymmetric film were characterized using Fourier transform infrared spectroscopy (FITR) to detect the functional groups within the films. Figure 2 It can be observed that, compared to the PES membrane, the infrared curve of the acrylic modified membrane is at 2878 cm⁻¹. -1 A CH2 stretching vibration peak appeared at 1680 cm⁻¹. -1 A characteristic peak of carbonyl (C=O) appeared at 2878 cm⁻¹; while in the spectrum of the polyethylene glycol-modified PES asymmetric film, a characteristic peak of carbonyl (C=O) appeared at 2878 cm⁻¹. -1 The presence of the characteristic peak of CH2 indicates that PEG was introduced into the membrane, and the modified membrane was successfully prepared.

[0028] (3) Fix the membrane to the test stage using tape, draw deionized water using a microsyringe, randomly select 3 locations on the membrane surface, and add 5 μL of deionized water to each selected location. Observe the spread of the water droplets on the membrane surface using a camera, and calculate the water contact angle of the material using circle fitting to characterize the hydrophilic and hydrophobic properties of the material. The contact angles of the polyethylene glycol-modified PES asymmetric membrane prepared in Example 1, the PES asymmetric membrane prepared in Comparative Example 2, and the acrylic acid-modified PES asymmetric membrane prepared in Comparative Example 1 were tested, and the test results are as follows: Figure 3 As shown, the water contact angle of the PES asymmetric membrane surface in Example 2 is 96°, which is determined by the intrinsic hydrophobic nature of PES material. In contrast, the contact angle of the polyethylene glycol-modified PES asymmetric membrane in Example 1 is 65°, while the contact angle of the acrylic acid-modified PES asymmetric membrane in Comparative Example 1 is 61°. By introducing hydrophilic substances into the membrane through hydrophilic modification, the hydrophilic properties of the membrane are improved.

[0029] (4) The modified membrane was subjected to a long-term anti-leakage test using a self-made anti-leakage device. The membrane was placed between two hollow gaskets with the dense layer facing inward. 5 ml of anticoagulated rabbit blood and 5 ml of physiological saline were added to the device and placed under normal pressure for 14 days. The condition of the bottom of the membrane was observed to determine whether the blood had permeated through the dense layer of the membrane and wetted it. Figure 4 (a) A simplified diagram of a laboratory-made anti-leakage testing device, which mainly consists of a gas cylinder, an ultrafiltration cup, a pressure gauge, and a pressure reducing valve; Figure 4 (b) is a detailed view of the ultrafiltration cup, with 13mm thick blood spread evenly on the membrane surface. Figure 4 (c) is a view of the membrane bottom surface after 14 days. As can be seen from the figure, the membrane bottom surface is smooth and clean, with no red marks, indicating that there was no blood leakage during the 14 days.

[0030] (5) The platelet morphology of the membranes prepared in Example 1, Comparative Example 1, and Comparative Example 2 was characterized using field emission scanning electron microscopy (SEM). The membranes were cut into 1 cm diameter sheets and soaked in physiological saline and PBS buffer for 48 h each. After adding 3 ml of platelet-rich plasma, the membranes were incubated in a 37°C water bath for 2 h. The plasma was then discarded, and 3 ml of 2.5 wt% glutaraldehyde / physiological saline solution was added. The membranes were stored at 4°C for 2 h. The membrane surface was then washed with a series of concentrations of ethanol / physiological saline solution and isoamyl acetate / ethanol solution. The membranes were then freeze-dried for 12 h to preserve their morphology. The treated membrane material was fixed onto the sample stage using conductive adhesive. The sample was sputter-coated with gold to enhance conductivity, and the morphology and number of platelets on its surface were observed. Figure 5 (a) and (d) Platelet adhesion maps of unmodified PES asymmetric surface. As can be seen from the map, there is a large amount of platelet adhesion on the membrane surface. The platelets are aggregated together and change from round to irregular shape, indicating that the platelets have been activated and the coagulation pathway has been activated. Figure 5(b) and (e) are platelet adhesion diagrams of acrylic acid modified asymmetric membrane. Compared with the unmodified PES membrane, the number of platelets on the modified membrane is drastically reduced, and the activation level is also significantly reduced. Figure 5 (c) and (f) are platelet adhesion maps of polyethylene glycol modified PES membranes. No substances resembling platelets were found on the membrane surface at the 100 μm and 50 μm scales, indicating that polyethylene glycol modified membranes can effectively inhibit platelet adsorption and prolong the time required for coagulation compared to common acrylic acid (containing C=O double bond functional groups) modifiers.

[0031] This invention prepares an asymmetric membrane by introducing polyethylene glycol (PEG) into a PES membrane. PEG is firmly fixed within the PES membrane through thermal crosslinking polymerization. The sponge-like pores ensure the membrane's impact resistance, while the ultra-thin, dense skin layer prevents blood leakage and ensures good gas permeability. Hydrophilic modification significantly improves the membrane's blood compatibility, resulting in a smaller immune response during blood-gas contact, thus reducing the occurrence of adverse phenomena such as thrombosis during application and providing new insights for the research of biomedical materials.

Claims

1. A method for preparing a polyethylene glycol thermally crosslinked modified polyethersulfone asymmetric film, characterized in that, The steps are as follows: (1) Preparation of casting solution: N,N-dimethylacetamide is used as solvent, and 20wt% of PES and 5wt% of polyethylene glycol are added. 10% of N,N'-methylenebisacrylamide is used as crosslinking agent and 10% of azobisisobutyronitrile is used as initiator. The solution is stirred magnetically until it is homogeneous. (2) In-situ crosslinking polymerization to modify PES: Place the casting solution from step (1) in an oil bath, add a magnetic stir bar, turn on mechanical stirring, raise the temperature to 85℃ and react for 10h, then let it stand and cool, and continue stirring for 12h to obtain the casting solution. (3) Preparation of modified membrane: The casting solution in step (2) was ultrasonically allowed to stand to remove micro bubbles. The membrane was then coated on a glass plate using a tabletop flatbed coating machine. Finally, the coated membrane was placed in isopropanol for 3 minutes until it turned from transparent to white. The membrane was then removed from the isopropanol and quickly transferred to deionized water until it floated on the surface. The membrane was then transferred to fresh deionized water and placed for 48 hours. The membrane was then removed and vacuum dried at 60°C for 12 hours to obtain a polyethylene glycol thermally crosslinked modified polyethersulfone asymmetric membrane.

2. The polyethylene glycol thermally crosslinked modified polyethersulfone asymmetric membrane obtained by the preparation method of claim 1 is used as a membrane material for gas exchange at the gas-blood contact interface.

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