A hydrogel-coated oxygen membrane and its preparation method

Abstract

This invention relates to a hydrogel-coated oxygenation membrane and its preparation method. A polyolefin resin and a modifier are added to a diluent, and the mixture is heated and stirred to obtain a casting solution. Using the casting solution as a raw material, a sheet membrane or hollow fiber membrane is obtained by thermally induced phase separation and film scraping or spinning. The hydrogel solution is irradiated under ultraviolet light to reach a semi-solid state, obtaining a prepolymerized hydrogel solution. The obtained prepolymerized hydrogel solution is coated onto the sheet membrane or hollow fiber membrane. The membrane coated with the prepolymerized hydrogel solution is then irradiated under ultraviolet light until the hydrogel solution is completely cured. After drying at room temperature, a hydrogel-coated oxygenation membrane is obtained, wherein the hydrogel layer thickness is 0.5-3 μm. The hydrogel-coated oxygenation membrane is used as a medium for blood gas exchange during extracorporeal membrane oxygenation (ECMO); the anti-plasma leakage time is 180-560 h, and the protein adhesion is 0.3-1.1 μg / cm³. 2 The hemolysis rate was 0.79-1.01%.

Description

Technical Field

[0001] This application belongs to the field of membrane technology, specifically relating to a hydrogel-coated oxygen membrane and its preparation method. Background Technology

[0002] Extracorporeal membrane oxygenation (ECMO) is an important treatment for patients with severe cardiopulmonary dysfunction. While assisting blood circulation, it simultaneously increases blood oxygen saturation and removes carbon dioxide from the blood. As a barrier between blood and gas, the gas permeability, blood compatibility, and resistance to plasma leakage of the oxygenation membrane are key factors affecting the long-term performance of the oxygenator.

[0003] Commercially available oxygenation membranes are primarily made of polypropylene (PP) and poly(4-methyl-1-pentene) (PMP), with polypropylene being a representative material for hollow fiber oxygenation membranes. Because medical-grade PP raw materials are inexpensive and readily available, and PP membranes exhibit good gas permeability, with CO2 and O2 permeation rates of 7.12 and 8.33 ml / (min·cm²), respectively. 2 ·bar)[1], although the presence of surface micropores increases the risk of air embolism and plasma leakage during oxygenation, and plasma leakage occurs in PP membranes after about 8 hours, it is suitable for short-term cardiac surgery and can provide temporary respiratory support, resulting in a large market capacity for PP oxygenators. PMP membranes have low gas permeability, with CO2 and O2 permeation rates of 1.69 and 0.59 ml / (min·cm) respectively. 2 ·bar)[2], its structure is a dense surface and porous inner layer asymmetric structure, which makes its anti-plasma leakage time greater than 168h, and it is suitable for long-term respiratory support for patients with cardiopulmonary failure, etc. After plasma treatment, the surface of the commercial membrane is coated with an anticoagulant heparin coating, a heparin-like coating or a zwitterionic coating, which can improve the blood compatibility of the membrane surface. However, a large amount of heparin anticoagulant needs to be injected in the application, and if the coating pore blockage occurs, it will easily lead to a decrease in the gas exchange rate of the membrane, which is not conducive to clinical application.

[0004] PMP and PP contain only methyl and methylene groups, lacking active groups. Plasma technology for membrane surface modification is typically used to create oxygen-containing active groups on the membrane surface, but its processes are complex and require high precision, posing a significant barrier to large-scale application. Other researchers mostly use strong acids, strong bases, and toxic chemical reagents for activation and modification. Based on current market demands, providing an oxygenation membrane with a simple and efficient modification process, good leakage resistance, good blood compatibility, and while maintaining high blood gas exchange performance is a pressing issue for researchers in this field.

[0005] [1]J.Li,T.He,H.Chen,Y.Cheng,E.Drioli,Z.Wang,Z.Cui,Preparation ofHyflon AD / Polypropylene Blend Membrane for Artificial Lung,Membranes 13(2023).https: / / doi.org / 10.3390 / membranes13070665.

[0006] [2]T.He, application,J.Membr.Sci.704(2024)122891.https: / / doi.org / https: / / doi.org / 10.1016 / j.memsci.2024.122891. Summary of the Invention

[0007] To address the aforementioned shortcomings of the prior art, this invention provides a hydrogel-coated oxygenation membrane and its preparation method. This invention designs and prepares a series of hydrogel-coated oxygenation membranes. Utilizing the high water content, good biocompatibility, and network polymer structure of hydrogels, this invention solves the problems of high modification barriers and insignificant coating effects in existing oxygenation membranes, resulting in poor anti-plasma leakage performance and blood compatibility, as well as coating pore blockage hindering gas exchange.

[0008] To address the aforementioned technical problems, this invention provides a hydrogel-coated oxygenation membrane. The process involves a one-step modification of the polyolefin (20-40 wt%), diluent (60-80 wt%), and a modifier (5-15 wt% of the polyolefin mass) during the preparation of the oxygenation membrane to obtain a flat sheet membrane or hollow fiber membrane with a microporous structure. This promotes the migration of oxygen-containing functional groups to the membrane surface, thus solving the modification problem of the polyolefin and strengthening the interaction between the membrane substrate and the hydrogel layer. A 0.5-3 μm hydrogel layer is coated onto the surface of the flat sheet membrane using a spin-coating method at 500-3000 rpm or onto the surface of the hollow fiber membrane using a dip-coating method at 500-1500 mm / min. This overcomes the technical bottleneck in hydrogel membrane fabrication, enabling a highly efficient blood gas exchange process.

[0009] To achieve the above objectives, the technical solution adopted in this application is as follows:

[0010] A method for preparing a hydrogel-coated oxygen membrane includes the following steps:

[0011] 1) Add 20-40 wt% polyolefin resin and 5-15 wt% modifier to 60-80 wt% diluent, heat and stir evenly, and let stand to obtain casting solution.

[0012] 2) Using the casting solution as raw material, a flat sheet membrane or hollow fiber membrane is obtained by thermally induced phase separation method for coating or spinning.

[0013] 3) Irradiate the hydrogel solution under ultraviolet light to achieve a semi-solid state, thus obtaining a prepolymerized hydrogel solution;

[0014] 4) Coat the prepolymer hydrogel solution obtained in step 3) onto the flat sheet membrane or hollow fiber membrane obtained in step 2); then irradiate the membrane after coating with the prepolymer hydrogel solution under ultraviolet light to completely solidify the hydrogel solution; after drying at room temperature, a hydrogel-coated oxygen membrane is obtained, wherein the thickness of the hydrogel layer is 0.5-3 μm.

[0015] In step 1), the diluent includes one or more combinations of soybean oil, paraffin oil, diisooctyl adipate, dibutyl phthalate, dioctyl phthalate, palm wax, triacetin, castor oil, tributyl acetyl citrate, trioctyl acetyl citrate, tributyl citrate, and oleic acid; the polyolefin includes one of polypropylene, polyethylene, and poly(4-methyl-1-pentene); the modifying material is polyethylene-b-polyethylene glycol (PE-b-PEG) or polyoxyethylene-polyoxypropylene ether (Pluronic acid). One of F-127), which is a hydrophilic-hydrophobic block copolymer, with one end being an oxygen-containing hydrophilic segment and the other end being a hydrophobic segment with good compatibility with polyolefins; the hydrogel includes one of poly(acrylamide-co-3-(trimethoxyphenyl)methacrylate)(p(AAm-co-TMSPMA)), poly(acrylic acid-co-3-(trimethoxyphenyl)methacrylate)(p(AAc-co-TMSPMA)) or poly((ethylene glycol)diacrylate-co-poly(ethylene glycol)methacrylate)(p(PEGDA-co-PEGMA)).

[0016] In step 1), the step of heating and stirring until uniform and then letting stand is specifically to heat to 160-180°C and stir until uniform, then raise the temperature to 170-190°C and let stand until there are no bubbles to obtain the casting solution.

[0017] In step 2), the method of scraping the film using thermally induced phase separation is as follows: the casting solution is poured onto a quartz glass plate with a tape thickness of 120-360 μm, and scraped uniformly with a scraper at a speed of 1-10 cm / s. The glass plate with the casting solution is placed in a water coagulation bath at room temperature to solidify and form the film, and then introduced into the extractant. After extraction for 24-48 hours, the diluent is removed, and the extractant is replaced during the extraction process. The film is then dried until there is no moisture, resulting in a flat sheet membrane with microporous distribution. The extractant includes one or more of n-hexane, n-pentane, anhydrous ethanol, isopropanol, and diethyl ether.

[0018] In step 2), the method of spinning using thermally induced phase separation is as follows: the casting solution is extruded through a spinneret at a spinning speed of 41-62 m / min and a core liquid flow rate of 8-20 ml / min. After solidification in a water coagulation bath at room temperature, the solution is introduced into an extractant and extracted for 24-48 hours. The diluent is removed, and the extractant is replaced during this period. The solution is then dried until no moisture is present, resulting in a hollow fiber membrane with microporous distribution. The extractant includes one or more of n-hexane, n-pentane, anhydrous ethanol, isopropanol, and diethyl ether.

[0019] In step 3), the prepolymerized hydrogel solution is irradiated with ultraviolet light at 10-20W, 365nm to reach a semi-cured state, wherein the semi-cured state is an adhesive state between the fully fluid state of the hydrogel solution and the rigid state of the cured hydrogel. The irradiation time is preferably 50-70% of the hydrogel solution's complete curing time.

[0020] In step 4), the method of coating the prepolymer hydrogel solution onto the flat sheet membrane is as follows: the flat sheet membrane is attached to a glass plate and the prepolymer hydrogel solution is spin-coated using a spin coater at a speed of 500-3000 rpm. The membrane after hydrogel coating is then polymerized under ultraviolet light at 10-20W and 365nm to completely solidify the hydrogel solution. After drying at room temperature, the hydrogel-coated oxygen membrane is obtained.

[0021] In step 4), the method of coating the prepolymer hydrogel solution onto the hollow fiber membrane is as follows: the hollow fiber membrane is coated with the prepolymer hydrogel solution using a traction device at a speed of 500-1500 mm / min, and then the membrane after hydrogel coating is polymerized under ultraviolet light at 10-20W and 365nm to completely solidify the hydrogel solution. After drying at room temperature, the hydrogel-coated oxygen membrane is obtained.

[0022] The hydrogel-coated oxygen membrane prepared by the method of this invention includes a flat oxygen membrane or a hollow fiber oxygen membrane; the thickness of the flat oxygen membrane is 100-300 μm, and the diameter and wall thickness of the hollow fiber oxygen membrane are 276-632 μm and 66-153 μm, respectively; both the flat oxygen membrane and the hollow fiber oxygen membrane exhibit a bilayer structure, including a loose microporous layer and a dense non-porous layer, wherein the flat membrane or hollow fiber membrane composed of polyolefin and modified substances is loosely microporous, and the hydrogel layer composed of hydrogel and coating the outer surface of the flat membrane or hollow fiber membrane is dense and non-porous; the thickness of the dense non-porous hydrogel layer is 0.5-3 μm. The bilayer structure of the flat oxygen membrane and the hollow fiber oxygen membrane is shown in the attached figure. Figure 2 Appendix Figure 4 As shown, layer 1 is a dense, non-porous hydrogel layer, and layer 2 is a loosely porous sheet membrane or hollow fiber membrane layer; the thickness of the dense, non-porous hydrogel layer is 0.5-3 μm.

[0023] The hydrogel-coated oxygenation membrane of the present invention is used as a medium for blood gas exchange during extracorporeal membrane oxygenation.

[0024] The advantages of this invention, which differ from existing technologies, are:

[0025] 1. The hydrogel-coated oxygenation membrane of this invention utilizes the high water content, good biocompatibility, and network polymer structure of hydrogel to solve the problems of high modification threshold and insignificant coating effects in existing oxygenation membranes, resulting in poor anti-plasma leakage performance and blood compatibility, as well as coating blockage hindering gas exchange. By functionalizing the surface of the difficult-to-modify oxygenation membrane with oxygen-containing groups through hydrophobic interactions, the interaction between the membrane substrate and the hydrogel is strengthened, avoiding defects and coating peeling. The functional groups within the hydrogel can enhance the transport performance of carbon dioxide and oxygen; furthermore, the highly cross-linked hydrogel surface is dense, ensuring excellent anti-plasma leakage and blood compatibility. The carbon dioxide and oxygen permeability of the hydrogel-coated flat oxygenation membrane of this application can reach 163.58-208.94 ml / min and 110.77-208.89 ml / min, respectively. -1 ·cm -2 ·bar -1 The hydrogel-coated hollow fiber oxygen membrane has O2 and CO2 permeability of 67.54-100.31 ml / min and 56.66-86.02 ml / min, respectively. -1 ·cm -2 ·bar -1 The hydrogel-coated oxygen membrane exhibited plasma leakage resistance for 180-560 hours and protein adhesion of 0.3-1.1 μg / cm³. 2 The hemolysis rate was 0.79%-1.01%, which was significantly lower than that of commercial PMP and PP films. The final hydrogel-coated oxygenated membrane had good blood compatibility.

[0026] 2. The preparation method of this application involves uniformly dispersing the modifier in the casting solution, scraping and spinning the film using thermally induced phase separation, and coating the hydrogel using spin coating and dip coating methods. The film-making process is simple and efficient, greatly reducing the difficulty of film-making and coating. The prepared hydrogel-coated oxygenation membrane is highly competitive as a blood gas exchange medium in extracorporeal membrane oxygenation (ECMO). Attached Figure Description

[0027] Figure 1 This is a scanning electron microscope image of the surface of the hydrogel-coated flat oxygen membrane of Embodiment 2 of this application.

[0028] Figure 2 This is a cross-sectional scanning electron microscope image of the hydrogel-coated flat oxygen membrane of Embodiment 2 of this application, wherein layer 1 is a dense, non-porous hydrogel layer and layer 2 is a loose, microporous membrane layer.

[0029] Figure 3 This is a scanning electron microscope image of the surface of the hydrogel-coated hollow fiber oxygen membrane of Example 5 of this application.

[0030] Figure 4 This is a cross-sectional scanning electron microscope (SEM) image of the hollow fiber oxygen membrane coated with hydrogel according to Example 5 of this application, including an overall cross-sectional view (a) and a cross-sectional SEM image (b) within the black dashed area in Figure (a). In Figure (b), layer 1 is a dense, non-porous hydrogel layer, and layer 2 is a loose, microporous membrane layer. Detailed Implementation

[0031] The present application will now be described in detail with reference to the embodiments shown in the accompanying drawings. However, these embodiments do not limit the present application, and any structural, methodological, or functional modifications made by those skilled in the art based on these embodiments are included within the protection scope of the present application.

[0032] This invention utilizes hydrophobic interactions to modify a membrane substrate with a microporous structure in one step, promoting the migration of oxygen-containing functional groups to the membrane surface and strengthening the interaction between the membrane substrate and the hydrogel layer, thereby solving the modification problem of polyolefins. The hydrogel is coated onto the surface of the modified flat sheet membrane by spin coating or onto the surface of the modified hollow fiber membrane by dip coating, overcoming the technical bottleneck of hydrogel membrane fabrication and achieving a highly efficient blood gas exchange process. The functional groups within the hydrogel reduce the resistance to carbon dioxide and oxygen transport in the membrane, significantly improving the gas permeability of the oxygenation membrane while ensuring excellent resistance to plasma leakage and blood compatibility; this avoids the complex manufacturing process of controlling the membrane structure to improve blood compatibility, resistance to plasma leakage, and gas transport properties in current oxygenation membrane production.

[0033] The technical solution of this application will be further explained in detail below with reference to specific embodiments.

[0034] The hydrogels involved in the following embodiments include:

[0035] The hydrogels include poly(acrylamide-co-3-(trimethoxyphenyl)methacrylate) (p(AAm-co-TMSPMA)), poly(acrylic acid-co-3-(trimethoxyphenyl)methacrylate) (p(AAc-co-TMSPMA)), and poly((ethylene glycol)diacrylate-co-poly(ethylene glycol)methacrylate) (p(PEGDA-co-PEGMA)), and the hydrogels are prepared by any method.

[0036] The technical solution of the present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments. The specific examples described are only for explanation and illustration of the present invention and are not intended to limit the present invention.

[0037] Example 1:

[0038] A hydrogel-coated flat oxygenation membrane is prepared using the following steps:

[0039] Step 1): Add 4g of poly(4-methyl-1-pentene) resin and 0.20g of PE-PEG to 3.6g of trioctyl citrate and 2.4g of tributyl citrate, and stir at 160°C in a three-necked flask until homogeneous. Then heat to 170°C and let stand until no bubbles remain to obtain the casting solution.

[0040] Step 2): Using the casting solution as raw material, a film is formed by thermally induced phase separation. The casting solution is poured onto a quartz glass plate with a 120 μm thick adhesive tape, and scraped uniformly at a speed of 1 cm / s with a scraper. The glass plate with the casting solution is placed in a water coagulation bath at room temperature to solidify and form the film. Then, it is introduced into anhydrous ethanol as the extraction solvent and extracted for 24 hours to ensure the removal of trioctyl acetyl citrate and tributyl citrate. The ethanol is replaced twice during the extraction. Afterward, it is dried at room temperature until no moisture remains to obtain a flat sheet membrane.

[0041] Step 3): Irradiate the p(AAm-co-TMSPMA) hydrogel solution under 10W, 365nm ultraviolet light until it reaches a semi-cured state to obtain a prepolymer hydrogel solution. The irradiation condition is that the irradiation time of the hydrogel solution is 50% of its complete curing time.

[0042] Step 4): Use a spin coating method at a speed of 500 rpm to coat a 10 cm layer. 2 A 2 ml prepolymer hydrogel solution was coated onto the surface of a flat membrane. The membrane, after coating with the prepolymer hydrogel solution, was irradiated with 10 W, 365 nm UV light for the remaining 50% of the time required for the hydrogel solution to fully cure. After drying at room temperature, a hydrogel-coated oxygen membrane was obtained, wherein the hydrogel layer thickness was 0.5 μm.

[0043] The hydrogel-coated oxygen membrane has a thickness of 100 μm, and its O2 and CO2 permeabilities are 110.77 and 163.58 ml·min, respectively. -1 ·cm -2 ·bar -1 The anti-plasma leakage time was 180 h, and the protein adhesion amount was 0.3 μg cm. 2 The hemolysis rate was 0.79%.

[0044] Example 2:

[0045] A hydrogel-coated flat oxygenation membrane is prepared using the following steps:

[0046] Step 1): Add 3g of polypropylene resin and 0.30g of Pluronic F-127 to 4.2g of paraffin oil and 2.8g of acetylated tributyl citrate, and stir at 170°C in a three-necked flask until homogeneous. Then heat to 180°C and let stand until no bubbles remain to obtain the casting solution.

[0047] Step 2): Using the casting solution as raw material, a film is formed by thermally induced phase separation. The casting solution is poured onto a quartz glass plate with a 240 μm thick adhesive tape, and scraped uniformly at a speed of 6 cm / s with a scraper. The glass plate with the casting solution is placed in a water coagulation bath at room temperature to solidify and form the film. Then, it is introduced into a mixture of extractant n-pentane and isopropanol and extracted for 36 hours to ensure the removal of paraffin oil and tributyl acetylacetic acid. During this period, n-pentane and isopropanol are replaced twice. Then, it is dried at room temperature until there is no moisture, and a flat sheet membrane is obtained.

[0048] Step 3): Irradiate the p(AAc-co-TMSPMA) hydrogel solution under ultraviolet light at 15W and 365nm until it reaches a semi-cured state to obtain a prepolymerized hydrogel solution. The irradiation condition is that the irradiation time of the hydrogel solution is 60% of its complete curing time.

[0049] Step 4): Use a spin coating method at a speed of 1500 rpm to coat a 10 cm layer. 2 A 4 ml prepolymer hydrogel solution was coated onto the surface of a flat membrane. The membrane, after coating with the prepolymer hydrogel solution, was irradiated with 15 W, 365 nm UV light for the remaining 40% of the time required for the hydrogel solution to fully cure. After drying at room temperature, a hydrogel-coated oxygen membrane was obtained, with a hydrogel layer thickness of 2.25 μm.

[0050] like Figure 1 , Figure 2 As shown, the hydrogel-coated flat plate oxygenation membrane includes a flat plate membrane with micropores and a dense, non-porous hydrogel layer wrapped around the surface of the flat plate membrane. Figure 2The membrane consists of two layers: a dense, non-porous hydrogel layer and a loosely porous microporous sheet membrane layer. The hydrogel-coated sheet oxygen membrane has a thickness of approximately 150 μm, and the hydrogel layer has a thickness of approximately 2.3 μm.

[0051] The hydrogel-coated oxygenation membrane exhibited O2 and CO2 permeabilities of 165.53 and 176.55 ml·min, respectively. -1 ·cm -2 ·bar -1 The anti-plasma leakage time was 240 h, and the protein adhesion amount was 0.7 μg cm. 2 The hemolysis rate was 0.91%.

[0052] Example 3:

[0053] A hydrogel-coated flat oxygenation membrane is prepared using the following steps:

[0054] Step 1): Add 2g of polyethylene resin and 0.30g of PE-PEG to 4.8g of diisooctyl adipate and 3.2g of castor oil, and stir at 180°C in a three-necked flask until homogeneous. Then, heat to 190°C and let stand until no bubbles remain to obtain the casting solution.

[0055] Step 2): Using the casting solution as raw material, a film is formed by thermally induced phase separation. The casting solution is poured onto a quartz glass plate with a 360 μm thick adhesive tape, and scraped uniformly at a speed of 10 cm / s with a scraper. The glass plate with the casting solution is placed in a water coagulation bath at room temperature to solidify and form the film. Then, it is introduced into anhydrous ethanol as the extraction solvent and extracted for 48 hours to ensure the removal of diisooctyl adipate and castor oil. During this period, hexane and anhydrous ethanol are replaced twice. Subsequently, the film is dried at room temperature until no moisture remains to obtain a flat sheet membrane.

[0056] Step 3): Irradiate the p(PEGDA-co-PEGMA) hydrogel solution under 20W, 365nm ultraviolet light to achieve a semi-cured state and obtain a prepolymer hydrogel solution. The irradiation time is 70% of the time required for the hydrogel solution to fully cure.

[0057] Step 4): Use a spin coating method at a speed of 3000 rpm to coat a 10 cm layer. 2 A 3 ml prepolymer hydrogel solution was coated onto the surface of a flat membrane. The membrane, after coating with the prepolymer hydrogel solution, was irradiated with UV light at 20 W, 365 nm for the remaining 30% of the time required for the hydrogel solution to fully cure. After drying at room temperature, a hydrogel-coated oxygen membrane was obtained, wherein the hydrogel layer thickness was 3.0 μm.

[0058] The hydrogel-coated oxygen membrane has a thickness of 300 μm, and its O2 and CO2 permeabilities are 208.89 and 208.94 ml·min, respectively. -1·cm -2 ·bar -1 The anti-plasma leakage time was 560 h, and the protein adhesion amount was 1.1 μg cm. 2 The hemolysis rate was 1.01%.

[0059] Example 4:

[0060] A hydrogel-coated hollow fiber oxygenation membrane is prepared using the following steps:

[0061] Step 1): Add 240g of poly(4-methyl-1-pentene) resin and 12g of Pluronic F-127 to 360g of dioctyl phthalate, and stir at 160℃ in the reactor of a twin-screw spinning machine until homogeneous. Then raise the temperature to 170℃ and let it stand until no bubbles are present to obtain the casting solution.

[0062] Step 2): Using the casting solution as raw material, the film is spun using a twin-screw spinning machine via thermally induced phase separation. The casting solution is extruded through a spinneret at a spinning speed of 41 m / min and a core liquid flow rate of 8 ml / min. After solidification in a water coagulation bath at room temperature, the film is introduced into anhydrous ethanol as the extraction agent and extracted for 24 hours to ensure the removal of dioctyl phthalate. The anhydrous ethanol is replaced twice during the extraction process. Subsequently, the film is dried at room temperature until no moisture remains, yielding a hollow fiber membrane.

[0063] Step 3): Irradiate the p(AAm-co-TMSPMA) hydrogel solution under 10W, 365nm ultraviolet light until it reaches a semi-cured state to obtain a prepolymer hydrogel solution. The irradiation condition is that the irradiation time of the hydrogel solution is 50% of its complete curing time.

[0064] Step 4): Using a dip-coating method at a rotation speed of 500 mm / min, 8 ml of prepolymer hydrogel solution was coated onto the surface of a 1.5 m long, 275.5 μm diameter hollow fiber membrane. After coating with the prepolymer hydrogel solution, the membrane was irradiated under 10 W, 365 nm UV light for the remaining 50% of the time required for complete curing of the hydrogel solution. After drying at room temperature, a hydrogel-coated oxygen membrane was obtained, with a hydrogel layer thickness of 0.5 μm.

[0065] The hydrogel-coated oxygen membrane has a diameter of 276 μm and a wall thickness of 66 μm, with O2 and CO2 permeabilities of 67.54 and 56.66 ml·min, respectively. -1 ·cm -2 ·bar -1 The anti-plasma leakage time was 180 h, and the protein adhesion amount was 0.3 μg cm. 2 The hemolysis rate was 0.79%.

[0066] Example 5:

[0067] A hydrogel-coated hollow fiber oxygenation membrane is prepared using the following steps:

[0068] Step 1): Add 100g of polypropylene resin and 15g of PE-PEG to 250g of soybean oil and 150g of tributyl acetylacetate. Stir the mixture at 180℃ in the reactor of a twin-screw spinning machine until homogeneous. Then, raise the temperature to 190℃ and let it stand until no bubbles remain to obtain the casting solution.

[0069] Step 2): Using the casting solution as raw material, the film is spun using a twin-screw spinning machine via thermally induced phase separation. The casting solution is extruded through a spinneret at a spinning speed of 62 m / min and a core liquid flow rate of 20 ml / min. After solidification in a water coagulation bath at room temperature, the film is introduced into an extraction solvent of n-pentane and anhydrous ethanol and extracted for 48 hours to ensure the removal of soybean oil and tributyl acetyl citrate. During this period, the n-pentane and anhydrous ethanol are replaced twice. The film is then dried at room temperature until no moisture remains, yielding a hollow fiber membrane.

[0070] Step 3): Irradiate the p(AAc-co-TMSPMA) hydrogel solution under 20W, 365nm ultraviolet light until it reaches a semi-cured state to obtain a prepolymerized hydrogel solution. The irradiation condition is that the irradiation time of the hydrogel solution is 70% of its complete curing time.

[0071] Step 4): Using a dip-coating method at a rotation speed of 1500 mm / min, 6 ml of prepolymer hydrogel solution was coated onto the surface of a 1.0 m long, 629 μm diameter hollow fiber membrane. After coating with the prepolymer hydrogel solution, the membrane was irradiated under UV light at 20 W, 365 nm for the remaining 30% of the time required for complete curing of the hydrogel solution. After drying at room temperature, a hydrogel-coated oxygen membrane was obtained, with a hydrogel layer thickness of 3.00 μm.

[0072] like Figure 3 , Figure 4 As shown, the prepared hydrogel-coated hollow fiber oxygenated membrane has an internal hollow structure, including a hollow fiber membrane with micropores distributed and a dense, non-porous hydrogel layer wrapped around the surface of the hollow fiber membrane. Figure 4 (b) consists of a dense, non-porous hydrogel layer in layer 1 and a loose, microporous hollow fiber membrane layer in layer 2. The diameter and wall thickness of the hydrogel-coated hollow fiber oxygen membrane are approximately 632 μm and 153 μm, respectively, and the hydrogel layer is approximately 3.00 μm thick.

[0073] The hydrogel-coated oxygenation membrane exhibited O2 and CO2 permeabilities of 100.31 and 86.02 ml·min, respectively. -1 ·cm -2 ·bar -1 The anti-plasma leakage time was 560 h, and the protein adhesion amount was 1.1 μg cm.2 The hemolysis rate was 1.01%.

[0074] Example 6:

[0075] A hydrogel-coated hollow fiber oxygenation membrane is prepared using the following steps:

[0076] Step 1): Add 180g of polyethylene resin and 18g of PE-PEG to 252g of paraffin oil and 168g of oleic acid, and stir at 170℃ in the reactor of a twin-screw spinning machine until homogeneous. Then, heat to 180℃ and let stand until no bubbles remain to obtain the casting solution.

[0077] Step 2): Using the casting solution as raw material, the film is spun using a twin-screw spinning machine via thermally induced phase separation. The casting solution is extruded through a spinneret at a spinning speed of 52 m / min and a core liquid flow rate of 15 ml / min. After solidification in a water coagulation bath at room temperature, the film is introduced into an extraction solvent of hexane and diethyl ether and extracted for 36 hours to ensure the removal of paraffin oil and oleic acid. During this period, the hexane and diethyl ether are replaced twice. The film is then dried at room temperature until no moisture remains, yielding a hollow fiber membrane.

[0078] Step 3): Irradiate the p(PEGDA-co-PEGMA) hydrogel solution under ultraviolet light at 15W and 365nm until it reaches a semi-cured state to obtain a prepolymer hydrogel solution. The irradiation condition is that the irradiation time of the hydrogel solution is 60% of its complete curing time.

[0079] Step 4): Using a dip-coating method at a rotation speed of 1000 mm / min, 4 ml of prepolymer hydrogel solution was coated onto the surface of a 1.3 m long, 340 μm diameter hollow fiber membrane. After coating with the prepolymer hydrogel solution, the membrane was irradiated under 15 W, 365 nm UV light for the remaining 40% of the time required for complete curing of the hydrogel solution. After drying at room temperature, a hydrogel-coated oxygen membrane was obtained, with a hydrogel layer thickness of 1.0 μm.

[0080] The hydrogel-coated oxygen membrane has a diameter of 340 μm and a wall thickness of 96 μm, and its O2 and CO2 permeabilities are 79.74 and 86.66 ml·min, respectively. -1 ·cm -2 ·bar -1 The anti-plasma leakage time was 300 h, and the protein adhesion amount was 0.6 μg cm. 2 The hemolysis rate was 0.96%.

[0081] Example 7:

[0082] A hydrogel-coated hollow fiber oxygenation membrane is prepared using the following steps:

[0083] Step 1): Add 180g of poly(4-methyl-1-pentene) resin and 24g of PE-PEG to 210g of palm wax and 210g of castor oil, and stir at 160℃ in the reactor of a twin-screw spinning machine until homogeneous. Then raise the temperature to 170℃ and let it stand until no bubbles are present to obtain the casting solution.

[0084] Step 2): Using the casting solution as raw material, the film is spun using a twin-screw spinning machine via thermally induced phase separation. The casting solution is extruded through a spinneret at a spinning speed of 41 m / min and a core liquid flow rate of 8 ml / min. After solidification in a water coagulation bath at room temperature, the film is introduced into anhydrous ethanol and diethyl ether as extraction agents and extracted for 24 hours to ensure the removal of palm wax and castor oil. During this period, the anhydrous ethanol and diethyl ether are replaced twice. The film is then dried at room temperature to obtain a hollow fiber membrane.

[0085] Step 3): Irradiate the p(AAm-co-TMSPMA) hydrogel solution under ultraviolet light at 17W and 365nm until it reaches a semi-cured state to obtain a prepolymerized hydrogel solution. The irradiation condition is that the irradiation time of the hydrogel solution is 50% of its complete curing time.

[0086] Step 4): Using a dip-coating method at a rotation speed of 500 mm / min, 3 ml of prepolymer hydrogel solution was coated onto the surface of a 1.0 m long, 385.4 μm diameter hollow fiber membrane. After coating with the prepolymer hydrogel solution, the membrane was irradiated under ultraviolet light (17 W, 365 nm) for the remaining 50% of the time required for the hydrogel solution to fully cure. After drying at room temperature, a hydrogel-coated oxygen membrane was obtained, with a hydrogel layer thickness of 0.6 μm.

[0087] The hydrogel-coated oxygen membrane has a diameter of 386 μm and a wall thickness of 130 μm, with O2 and CO2 permeabilities of 72.36 and 80.32 ml·min, respectively. -1 ·cm -2 ·bar -1 The anti-plasma leakage time was 520 h, and the protein adhesion amount was 0.5 μg cm. 2 The hemolysis rate was 0.83%.

[0088] Example 8:

[0089] A hydrogel-coated hollow fiber oxygenation membrane is prepared using the following steps:

[0090] Step 1): Add 140g of polypropylene resin and 14g of PE-PEG to 250g of triacetin, 170g of dibutyl phthalate, and stir at 170℃ in the reactor of a twin-screw spinning machine until homogeneous. Then raise the temperature to 180℃ and let it stand until no bubbles remain to obtain the casting solution.

[0091] Step 2): Using the casting solution as raw material, the film is spun using a twin-screw spinning machine via thermally induced phase separation. The casting solution is extruded through a spinneret at a spinning speed of 51 m / min and a core liquid flow rate of 14 ml / min. After solidification in a water coagulation bath at room temperature, the film is introduced into an extraction solvent of n-pentane and anhydrous ethanol and extracted for 36 h to ensure the removal of triacetin and dibutyl phthalate. During this period, the n-pentane and anhydrous ethanol are replaced twice. The film is then dried at room temperature to obtain a hollow fiber membrane.

[0092] Step 3): Irradiate the p(AAm-co-TMSPMA) hydrogel solution under 20W, 365nm ultraviolet light to achieve a semi-cured state and obtain a prepolymer hydrogel solution. The irradiation condition is that the irradiation time of the hydrogel solution is 60% of its complete curing time.

[0093] Step 4): Using a dip-coating method at a rotation speed of 1000 mm / min, 5 ml of prepolymer hydrogel solution was coated onto the surface of a 2.0 m long, 418.2 μm diameter hollow fiber membrane. After coating with the prepolymer hydrogel solution, the membrane was irradiated under UV light at 20 W, 365 nm for the remaining 40% of the time required for the hydrogel solution to fully cure. After drying at room temperature, a hydrogel-coated oxygen membrane was obtained, with a hydrogel layer thickness of 1.8 μm.

[0094] The hydrogel-coated oxygen membrane has a diameter of 420 μm and a wall thickness of 115 μm, with O2 and CO2 permeabilities of 89.66 and 69.79 ml·min, respectively. -1 ·cm -2 ·bar -1 The anti-plasma leakage time was 480 h, and the protein adhesion amount was 0.3 μg cm. 2 The hemolysis rate was 0.94%.

[0095] Example 9:

[0096] A hydrogel-coated hollow fiber oxygenation membrane is prepared using the following steps:

[0097] Step 1): Add 220g of polyethylene resin and 33g of Pluronic F-127 to 270g of tributyl citrate and 270g of trioctyl citrate, and stir at 180°C in the reactor of a twin-screw spinning machine until homogeneous. Then, raise the temperature to 190°C and let it stand until no bubbles remain to obtain the casting solution.

[0098] Step 2): Using the casting solution as raw material, the film is spun using a twin-screw spinning machine via thermally induced phase separation. The casting solution is extruded through a spinneret at a spinning speed of 62 m / min and a core liquid flow rate of 20 ml / min. After solidification in a water coagulation bath at room temperature, the film is introduced into anhydrous ethanol as the extraction agent and extracted for 24 hours to ensure the removal of tributyl citrate and trioctyl citrate. The anhydrous ethanol is replaced twice during this period. The film is then dried at room temperature until no moisture remains, yielding a hollow fiber membrane.

[0099] Step 3): Irradiate the p(PEGDA-co-PEGMA) hydrogel solution under 10W, 365nm ultraviolet light to achieve a semi-cured state, and obtain a prepolymer hydrogel solution. The irradiation condition is that the irradiation time of the hydrogel solution is 70% of its complete curing time.

[0100] Step 4): Using a dip-coating method at a rotation speed of 500 mm / min, 1 ml of prepolymer hydrogel solution was coated onto the surface of a 0.8 m long, 537.6 μm diameter hollow fiber membrane. After coating with the prepolymer hydrogel solution, the membrane was irradiated under ultraviolet light (15 W, 365 nm) for the remaining 30% of the time required for the hydrogel solution to fully cure. After drying at room temperature, a hydrogel-coated oxygen membrane was obtained, with a hydrogel layer thickness of 2.4 μm.

[0101] The hydrogel-coated oxygen membrane has a diameter of 540 μm and a wall thickness of 136 μm, with O2 and CO2 permeabilities of 95.47 and 73.14 ml·min, respectively. -1 ·cm -2 ·bar -1 The anti-plasma leakage time was 360 hours, and the protein adhesion amount was 0.8 μg / cm³. 2 The hemolysis rate was 0.99%.

[0102] Performance Test 1:

[0103] To characterize the CO2 and O2 permeation rates of the hydrogel-coated oxygen membranes prepared in Examples 1 to 9, oxygen or carbon dioxide at 1 bar was introduced into a self-made flat sheet membrane module or a hollow fiber membrane module encapsulated with epoxy resin AB glue. The gas flow rate was measured using a soap membrane flow meter. The CO2 and O2 permeation rates of the hydrogel-coated oxygen membranes were calculated using the following formula (1). To characterize the plasma leakage resistance time of the hydrogel-coated oxygen membranes prepared in Examples 1 to 9, the plasma leakage resistance time was tested according to the method suggested in patent CN 112403289 A. The prepared membrane was encapsulated in a membrane module, and the shell side or near-hydrogel layer of the module was filled with phosphate buffered saline (PBS) solution and kept at a constant temperature of 37°C. Nitrogen gas was introduced into the tube side of the membrane module for purging, and the purging gas outlet was connected to a drying tube containing anhydrous copper sulfate. The time elapsed after the anhydrous copper sulfate in the drying tube began to change color was defined as the plasma leakage resistance time.

[0104]

[0105] P: Gas permeability of the hydrogel-coated oxygen membrane (ml / (min·cm)) 2 ·bar));Q i (ml / min) is the volumetric flow rate of gas "i", A(cm³) 2 Δp refers to the effective membrane area of ​​the hydrogel-coated oxygen membrane. i (bar) represents the partial pressure difference of gas "i" between the feed end and the permeation end, where "i" is CO2 or O2.

[0106] Performance Test 2:

[0107] To characterize the protein adhesion and hemolysis rate of the hydrogel-coated oxygenated membranes prepared in Examples 1 to 9, the membranes were added to phosphate-buffered saline (PBS, pH 7.4) and equilibrated at room temperature for 2 hours. Then, they were immersed in bovine serum albumin (BSA, 4.5 mg / mL) for 2 hours and stored in a humidified water-jacketed incubator, equilibrated with 5% carbon dioxide in air for 2 hours. After rinsing five times with PBS, the membranes were placed in a beaker containing 2 mL of 1% (w / v%) sodium dodecyl sulfate (SDS) aqueous solution and sonicated at room temperature for 20 min. Adsorbed proteins were separated from the surface, and a protein detection reagent called diachondroitin (BCA) was added. The membranes were incubated at 60°C for 1 hour. After cooling the beaker to room temperature, the absorbance was measured at 562 nm compared to a blank sample. The amount of protein adsorbed on the sample surface was calculated using a standard curve. In addition, the erythrocyte compatibility of the membranes was evaluated by a hemolysis rate test. 10 ml of whole blood diluted with 60 ml of physiological saline and 60 ml of deionized water were used as negative and positive controls, respectively. The membrane was incubated with 5 ml of whole blood diluted with physiological saline at 37°C for 3 hours. Blood samples were collected, centrifuged at 3000 rpm for 10 min, and the supernatant was collected. The hemoglobin absorbance was analyzed at 545 nm. The hemolysis rate of the membrane material (H) was determined. r The following formula (2) is used to determine the result:

[0108]

[0109] A s It is the absorbance of the sample group, A n It is the absorbance of the negative group, A p It is the absorbance of the sample group.

[0110] The CO2 and O2 permeation rates, anti-plasma leakage time, membrane thickness or diameter, hydrogel layer thickness, protein adhesion amount and hemolysis rate of the oxygenated membranes coated with hydrogels prepared in Examples 1 to 9 of this invention are summarized in Table 1.

[0111] Table 1. Gas permeability, plasma leakage resistance, membrane thickness, and blood compatibility of hydrogel-coated oxygen membranes.

[0112] Table 1

[0113]

[0114]

[0115] As shown in the table above, the hydrogel-coated flat oxygenation membranes prepared in Examples 1 to 3 exhibit significantly better CO2 permeation rates, O2 permeation rates, and anti-plasma leakage time compared to commercial PMP and PP membranes. In Example 3, the CO2 permeation rate of the hydrogel-coated flat oxygenation membrane was 208.94 ml / (min·cm). 2The O2 permeation rate was 208.89 ml / (min·cm) (bar). 2 (·bar); and the CO2 permeation rate, O2 permeation rate, and anti-plasma leakage time of the hydrogel-coated hollow fiber oxygen membranes prepared in Examples 4 to 9 are significantly better than those of PMP and PP commercial membranes. The CO2 permeation rate of the hydrogel-coated hollow fiber oxygen membrane in Example 5 is 86.02 ml / (min·cm). 2 The O2 permeation rate was 100.31 ml / (min·cm) (bar). 2 (bar). In addition, the protein adhesion amounts in Examples 1 to 9 were 0.3-1.1 μg cm⁻¹. 2 The hemolysis rate was 0.79%-1.01%, which was significantly lower than that of commercial PMP and PP films. The final hydrogel-coated oxygenated membrane had good blood compatibility.

[0116] The hydrogel-coated oxygenation membranes prepared in Examples 1 to 9 utilize the characteristics of hydrogels, including their high water content, good biocompatibility, and network polymer structure, to coat modified oxygenation membranes, thereby enhancing the effective coupling between the oxygenation membrane and the hydrogel. The functional groups within the hydrogel can increase the gas permeability of carbon dioxide and oxygen molecules through the oxygenation membrane while ensuring excellent resistance to plasma leakage and blood compatibility, solving the problem of dense coatings blocking gas permeability. This avoids the complex manufacturing process of controlling the membrane structure to improve blood compatibility, resistance to plasma leakage, and gas transport properties in current oxygenation membrane production.

[0117] The foregoing description of this disclosure is provided to enable any person skilled in the art to implement or use this disclosure. Various modifications to this disclosure will be apparent to those skilled in the art, and the general principles applicable herein can be applied to other variations without departing from the scope of this disclosure. Therefore, this disclosure is not limited to the examples and designs described herein, but is consistent with the widest scope of the principles and novel features disclosed herein.

Claims

1. A method for preparing a hydrogel-coated oxygen membrane, characterized in that: Includes the following steps: 1) Add 20-40 wt% polyolefin resin and 5-15 wt% modifier to 60-80 wt% diluent, heat and stir evenly, and let stand to obtain casting solution. 2) Using the casting solution as raw material, a flat sheet membrane or hollow fiber membrane is obtained by thermally induced phase separation method for coating or spinning. 3) Irradiate the hydrogel solution under ultraviolet light to achieve a semi-solid state, thus obtaining a prepolymerized hydrogel solution; 4) Coat the prepolymer hydrogel solution obtained in step 3) onto the flat sheet membrane or hollow fiber membrane obtained in step 2); then irradiate the membrane after coating with the prepolymer hydrogel solution under ultraviolet light to completely solidify the hydrogel solution; after drying at room temperature, a hydrogel-coated oxygen membrane is obtained. In step 1), the diluent includes one or more combinations of soybean oil, paraffin oil, diisooctyl adipate, dibutyl phthalate, dioctyl phthalate, palm wax, triacetyl triacetate, castor oil, acetylated tributyl citrate, acetylated trioctyl citrate, tributyl citrate, and oleic acid; the polyolefin includes one of polypropylene, polyethylene, and poly(4-methyl-1-pentene); the modifier is one of polyethylene-b-polyethylene glycol and polyoxyethylene-polyoxypropylene ether; the hydrogel includes one of poly(acrylamide-co-3-(trimethoxyylphenyl)methacrylate), poly(acrylic acid-co-3-(trimethoxyylphenyl)methacrylate), or poly((ethylene glycol)diacrylate-co-poly(ethylene glycol)methacrylate). In step 3), the prepolymer hydrogel solution is irradiated with ultraviolet light at 10-20 W and 365 nm to reach a semi-cured state, and the irradiation time is 50-70% of its complete curing time. The prepared hydrogel-coated oxygen membrane includes a flat oxygen membrane or a hollow fiber oxygen membrane; the thickness of the flat oxygen membrane is 100-300 μm, and the diameter and wall thickness of the hollow fiber oxygen membrane are 276-632 μm and 66-153 μm, respectively; the flat oxygen membrane and the hollow fiber oxygen membrane exhibit a bilayer structure, including a loose microporous layer and a dense non-porous layer, wherein the flat membrane or hollow fiber membrane composed of polyolefin and modified substances is loose microporous, and the hydrogel layer composed of hydrogel and coated on the outer surface of the flat membrane or hollow fiber membrane is dense and non-porous; the thickness of the dense non-porous hydrogel layer is 0.5-3 μm.

2. The method for preparing the hydrogel-coated oxygen membrane as described in claim 1, characterized in that: In step 1), the step of heating and stirring evenly and then letting it stand is specifically to heat to 160~180℃ and stir until it is uniform, then raise the temperature to 170~190℃ and let it stand until there are no bubbles to obtain the casting solution.

3. The method for preparing the hydrogel-coated oxygen membrane as described in claim 1, characterized in that: In step 2), the method of scraping the film using thermally induced phase separation is as follows: the casting solution is poured onto a quartz glass plate with a tape thickness of 120-360 μm, and scraped uniformly with a scraper at a speed of 1-10 cm / s. The glass plate with the casting solution is placed in a water coagulation bath at room temperature to solidify and shape, and then introduced into the extractant. After extraction for 24-48 h, the diluent is removed, and the extractant is replaced during the extraction process. Then, it is dried until there is no moisture, and a flat plate membrane with microporous distribution is obtained. The extractant includes one or more of n-hexane, n-pentane, anhydrous ethanol, isopropanol, and diethyl ether.

4. The method for preparing the hydrogel-coated oxygen membrane as described in claim 1, characterized in that: In step 2), the method of spinning using thermally induced phase separation is as follows: the casting solution is extruded through a spinneret at a spinning speed of 41-62 m / min and a core liquid flow rate of 8-20 ml / min. After solidification in a water coagulation bath at room temperature, the solution is introduced into an extractant and extracted for 24-48 h. The diluent is removed, and the extractant is replaced during this period. The solution is then dried until no moisture is present, resulting in a hollow fiber membrane with microporous distribution. The extractant includes one or more of n-hexane, n-pentane, anhydrous ethanol, isopropanol, and diethyl ether.

5. The method for preparing the hydrogel-coated oxygen membrane as described in claim 1, characterized in that: In step 4), the method for coating the prepolymer hydrogel solution onto the flat sheet membrane is as follows: the flat sheet membrane is attached to a glass plate and the prepolymer hydrogel solution is spin-coated using a spin coater at a speed of 500-3000 rpm. The membrane after hydrogel coating is then polymerized under ultraviolet light at 10-20 W and 365 nm to completely solidify the hydrogel solution. After drying at room temperature, the hydrogel-coated oxygen membrane is obtained.

6. The method for preparing the hydrogel-coated oxygen membrane as described in claim 1, characterized in that: In step 4), the method for coating the prepolymer hydrogel solution onto the hollow fiber membrane is as follows: the hollow fiber membrane is coated with the prepolymer hydrogel solution using a traction device at a speed of 500-1500 mm / min, and then the membrane after hydrogel coating is polymerized under ultraviolet light at 10-20 W and 365 nm to completely solidify the hydrogel solution. After drying at room temperature, the hydrogel-coated oxygen membrane is obtained.

7. The hydrogel-coated oxygenation membrane as described in claim 1 is used as a medium for blood gas exchange during extracorporeal membrane oxygenation.

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