A multi-layer composite bionic structure oxygenation membrane and its preparation method and application

Abstract

The present invention relates to the technical field of biomedical membranes, and in particular to a multilayer composite bionic structure oxygenation membrane and its preparation method and application, comprising the steps of preparing a coating liquid; scraping or spraying the coating liquid on the surface of a support membrane to obtain a hydrophobic porous layer; preparing an organic phase solution; contacting the organic phase solution with the hydrophobic porous layer to obtain a composite membrane for adsorbing aldehyde / acyl chloride monomers; preparing an aqueous phase solution; contacting the aqueous phase solution with the composite membrane for adsorbing aldehyde / acyl chloride monomers to prepare a polyimide / polyamide layer; preparing a grafting solution; contacting the grafting solution with the polyimide / polyamide layer to obtain a nascent oxygenation membrane, and drying the nascent oxygenation membrane to obtain a multilayer composite bionic structure oxygenation membrane. The multilayer structure oxygenation membrane provided by the present invention meets the multiple properties required by the oxygenation membrane, and the prepared multilayer composite membrane has good gas exchange and biocompatibility, and can not only realize the rapid two-way exchange of blood CO2 and extracorporeal O2, but also effectively prevent blood leakage.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedical membranes, and in particular to a multi-layer composite bionic structure oxygenation membrane and a preparation method and application thereof. Background Art

[0002] Extracorporeal membrane oxygenation (ECMO) is a life support system that can temporarily replace cardiopulmonary function. It is mainly used to provide extracorporeal respiration and blood circulation for patients with severe cardiopulmonary failure. The oxygenation membrane in the ECMO system can realize the bidirectional exchange of CO2 in the blood and extracorporeal O2, playing a similar function to the alveoli of the human body. Therefore, good gas transfer capacity is an essential structural feature of the oxygenation membrane. In addition, since the oxygenation membrane is in direct contact with the blood, it faces the risk of hemolysis of red blood cells and thrombosis. Therefore, surface properties with excellent biocompatibility are the development direction of oxygenation membrane applications. However, current oxygenation membrane materials face various performance trade-offs. For example, polydimethylsiloxane is considered to be the first generation of oxygenation membrane materials, with hydrophobic and dense surface properties, good blood leakage resistance and long-term operation stability. However, the mechanical properties of polydimethylsiloxane are poor, resulting in its low gas transfer rate. Therefore, the development of oxygenation membranes with excellent blood compatibility, sufficient gas exchange capacity and sufficient plasma leakage resistance is of great significance to achieve efficient blood oxygenation. Summary of the invention

[0003] The purpose of the present invention is to provide a multi-layer composite bionic structure oxygenation membrane and a preparation method and application thereof. The provided multi-layer composite bionic structure oxygenation membrane meets the multiple properties required of the oxygenation membrane. The prepared multi-layer composite bionic structure oxygenation membrane has good gas exchange and biocompatibility, and can not only realize the rapid two-way exchange of blood CO2 and extracorporeal O2, but also effectively prevent blood leakage.

[0004] To achieve the above object, the present invention provides a method for preparing a multi-layer composite bionic structure oxygenation membrane, comprising the following steps:

[0005] (1) preparing a coating liquid containing a porous organic framework, polydimethylsiloxane, tetraethyl orthosilicate, dibutyltin dilaurate and an organic solvent; applying the coating liquid by scraping or spraying on the surface of the support film, and placing the coating liquid in a constant temperature and humidity chamber for drying for 1 to 60 hours to obtain a hydrophobic porous layer, i.e., a porous organic framework / polydimethylsiloxane layer having hydrophobic porous properties;

[0006] (2) preparing an organic phase solution containing binary or polybasic aldehyde molecules, binary or polybasic acyl chloride molecules and an organic solvent; contacting the organic phase solution with the hydrophobic porous layer obtained in step (1) for 1 to 60 minutes, allowing the aldehyde / acyl chloride monomers to be fully adsorbed on the surface of the hydrophobic porous layer, and then removing excess organic phase solution to prepare a composite membrane adsorbing aldehyde / acyl chloride monomers;

[0007] (3) preparing an aqueous solution containing amino acid molecules, diamine or polyamine molecules and deionized water; contacting the aqueous solution with the composite membrane for adsorbing aldehyde / acyl chloride monomers obtained in step (2) for 1 to 60 minutes, allowing the aldehyde / acyl chloride monomers to undergo interfacial polymerization with the amino acid / amine monomers, and then removing excess aqueous solution to prepare a polyimide / polyamide layer having hydrophilic and dense properties;

[0008] (4) preparing a grafting solution containing vinyl carboxylic acid / sulfonic acid or vinyl carboxylic acid / sulfonate, a redox initiator and deionized water; contacting the grafting solution with the polyimine / polyamide layer obtained in step (3), standing for 5 minutes to 24 hours to allow a redox free radical grafting reaction to occur, and then removing excess grafting solution to prepare a bionic functional layer with heparin-like properties to obtain a nascent oxygenation membrane;

[0009] (5) The primary oxygenation membrane obtained in step (4) is placed in a constant temperature and humidity chamber for drying for 1 to 60 hours to obtain a multilayer composite bionic structure oxygenation membrane.

[0010] Preferably, in step (1), the porous organic framework includes one or more of NH2-Uio-66, MIL-101-NH2, MIL-125-NH2, ZIF-8-PEI, TpPa, TpBD, and TpDp; and the organic solvent includes one or more of n-heptane, n-hexane, and cyclohexane.

[0011] Preferably, in step (1), the support membrane is an inorganic or organic porous membrane; the type of the porous membrane includes one of a flat plate, a tubular type and a hollow fiber type.

[0012] More preferably, the material of the inorganic porous membrane includes one of molecular sieve and ceramic; the material of the organic porous membrane includes one of polysulfone, polyethersulfone, polyacrylonitrile, polyimide, polytetrafluoroethylene, polypropylene, polyvinylidene fluoride and polyethylene.

[0013] More preferably, the support membrane is one of polysulfone, polyethersulfone and polypropylene ultrafiltration membrane.

[0014] Preferably, in step (2), the binary or polyvalent aldehyde molecule includes one or more of trimesic acid, terephthalaldehyde, biphenyldicarboxaldehyde, 1,3,5-trialdehyde benzene, 2,4,6-trihydroxybenzene-1,3,5-tricarboxaldehyde, 1,3,5-tris(4-formylphenyl)amine, 2,5-dihydroxyterephthalaldehyde, 2,5-dibromoterephthalaldehyde, and 2,4,6-trimethoxy-trimesic acid;

[0015] The binary or polybasic acid chloride molecules include one or more of phthaloyl chloride, isophthaloyl chloride, terephthaloyl chloride, trimesoyl chloride, malonyl chloride, succinyl chloride, glutaryl chloride, adipoyl chloride, pimeloyl chloride, suberyl chloride, azelayl chloride, sebacoyl chloride, 4,4'-oxybis(benzoyl chloride), phthaloyl disulfonyl chloride, isophthaloyl disulfonyl chloride, terephthaloyl disulfonyl chloride, 1,3,5-benzenetrisulfonyl chloride, mesitylene disulfonyl chloride, 4,4'-biphenyl disulfonyl chloride, and methylene disulfonyl chloride;

[0016] The second organic solvent is selected from one or more C5-C10 alkanes.

[0017] More preferably, the mass ratio of the dibasic or polybasic aldehyde molecules to the dibasic or polybasic acyl chloride molecules is 1:1 to 1:3.

[0018] Preferably, in step (3), the amino acid molecules include one or more of arginine, lysine, histidine, serine, tyrosine, tryptophan, glutamine, asparagine, cystine, and proline;

[0019] The diamine or polyamine molecule is a small molecule or polymer containing a diamine or polyamine group in the structural formula, including one or more of piperazine, p-phenylenediamine, m-phenylenediamine, o-phenylenediamine, benzyl diamine and its derivatives, C2-C12 alkyl straight-chain diamines and their derivatives, urea, oxalyl diamine, dithiooxalyl diamine, 2,5-diaminoterephthalic acid, 2-sulfonic acid-1,4-phenylenediamine, 2-isopropyl-1,4-phenylenediamine, diethylenetriamine, dipropylenetriamine, dihexylenetriamine, melamine, oxalic acid dihydrazide, succinic acid dihydrazide, tetrakis(4-aminophenyl)methane, polyethyleneimine, and polyethyleneamine.

[0020] More preferably, the mass fraction of the amino acid molecules in the aqueous solution is 0.1-5.0%, the mass fraction of the diamine or polyamine is 0.003-0.1%, and the mass ratio of the amino acid molecules to the diamine or polyamine is 100:1-20:1.

[0021] More preferably, the amino acid molecule is one or more of arginine, lysine and histidine.

[0022] More preferably, the diamine or polyamine molecule is one or more of piperazine, ethylenediamine, polyethyleneimine and polyvinylamine.

[0023] Preferably, in step (4), the grafting solution comprises vinyl carboxylic acid / sulfonic acid or vinyl carboxylic acid / sulfonate with a molar concentration of 0.02 to 3.0 M, a redox initiator with a molar concentration of 0.005 to 2.0 M, and the balance of deionized water.

[0024] More preferably, the molar concentration of vinyl carboxylic acid / sulfonic acid or vinyl carboxylic acid / sulfonate is 0.2-1.0M, and the molar concentration of the redox initiator is 0.01-0.5M.

[0025] Preferably, in step (4), the vinyl sulfonic acid or vinyl sulfonate includes one or more of vinyl sulfonic acid, vinylbenzenesulfonic acid, propylene sulfonic acid, 2-acrylamido-2-methylpropanesulfonic acid, sodium vinyl sulfonate, sodium p-styrenesulfonate, potassium p-styrenesulfonate, sodium propylene sulfonate, sodium methyl propylene sulfonate, sodium methacrylate 2-ethanesulfonate sodium salt, methacrylate 3-sulfonate propyl ester potassium salt, 2-acrylamido-2-methylpropanesulfonic acid sodium salt, methacrylate sulfobetaine, 3-((2-(acryloyloxy)ethyl)dimethylammonium)propane-1-sulfonic acid inner salt, and 1-(3-thiopropyl)-2-vinylpyridine betaine.

[0026] More preferably, the vinyl sulfonic acid or vinyl sulfonate is one of sodium vinyl sulfonate, sodium p-styrene sulfonate and methacrylate sulfobetaine.

[0027] Preferably, in step (4), the vinyl carboxylic acid or vinyl carboxylate comprises one or more of acrylic acid, methacrylic acid, butenoic acid, pentenoic acid, hexenoic acid, aminohexenoic acid, heptenoic acid, 1-vinyl-1H-pyrrole-2-carboxylic acid, 5-p-toluene-1-vinyl-1H-pyrrole-2-carboxylic acid, sodium acrylate, potassium acrylate, sodium methacrylate, and potassium methacrylate.

[0028] More preferably, the vinyl carboxylic acid or vinyl carboxylate is one of acrylic acid and sodium methacrylate.

[0029] Preferably, in step (4), the redox initiator comprises potassium persulfate and sodium pyrosulfite.

[0030] Preferably, in step (2), the temperature of the organic phase solution is 10 to 50°C.

[0031] More preferably, the temperature of the organic phase solution is 20-40°C.

[0032] Preferably, in step (3), the temperature of the aqueous solution is 10 to 80°C.

[0033] More preferably, the temperature of the aqueous solution is 20-60°C.

[0034] Preferably, in step (4), the temperature of the grafting solution is 10 to 80°C.

[0035] More preferably, the grafting solution temperature is 20-60°C.

[0036] Preferably, in step (5), the drying temperature is 30 to 80° C. and the drying time is 1 to 24 hours.

[0037] More preferably, the drying temperature is 40-80° C. and the drying time is 5-8 hours.

[0038] A multi-layer composite bionic structure oxygenation membrane is prepared by a multi-layer composite bionic structure oxygenation membrane preparation method.

[0039] The invention discloses an application of a multi-layer composite bionic structure oxygenation membrane, which is applied to blood oxygenation or extracorporeal membrane oxygenation system.

[0040] Reaction mechanism of the present invention:

[0041] In the present invention, porous organic framework and polydimethylsiloxane are loaded on the surface of supporting film to form a functional layer with hydrophobic porous characteristics, which can not only avoid interfacial polymerization monomers from penetrating into supporting film, but also provide good blood barrier effect. The interfacial polymerization reaction of organic phase monomers (binary or polyaldehyde molecules and binary or polyvalent acyl chloride molecules) and aqueous phase monomers (amino acids and binary or polyvalent amine molecules) forms a polyimide / polyamide layer with hydrophilic compact characteristics, and the cross-linked structure of the formed polyimide / polyamide can be regulated by adjusting the mass ratio of the monomers. Meanwhile, the amino acid in the aqueous phase solution of the present invention is the basic component unit of human protein, and amidation reaction occurs in the interfacial polymerization process between the amine group and the acyl chloride group in the amino acid molecule to form a cross-linked polymer network, and the trace binary or polyvalent amine molecules added help to enhance the crosslinking degree and hydrophilicity of the polymer network, giving oxygenated membrane good CO2 and O2 exchange rate. A large amount of amine groups remaining in the polymer network can promote the dissolution and reaction of CO2 molecules in the film, and efficient gas exchange capacity is obtained by promoting the transfer mechanism. Finally, a biomimetic functional layer with heparin-like properties rich in carboxyl or sulfonic acid groups is formed through a redox radical grafting process, which has an anticoagulant effect, is beneficial to improve the biocompatibility of the oxygenated membrane, and reduces the formation of thrombus on the membrane surface.

[0042] Beneficial effects of the present invention:

[0043] (1) The present invention provides a multi-layer composite bionic structure oxygenation membrane, which is composed of a support layer, a hydrophobic porous layer, a hydrophilic dense layer (polyimide / polyamide layer) and a heparin-like bionic layer, and has good CO2 and O2 gas exchange rate, biocompatibility and blood compatibility, and can effectively prevent blood leakage;

[0044] (2) The present invention provides a method for preparing a multi-layer composite bionic structure oxygenation membrane, which has a simple process, mild preparation conditions, a wide range of applications, and is easy to scale up and promote.

[0045] The technical solution of the present invention is further described in detail below through the accompanying drawings and embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Figure 1 is a surface scanning electron microscope image of the support membrane (polysulfone ultrafiltration membrane) in Example 1 of the present invention;

[0047] Figure 2 This is a surface scanning electron microscope image of the multilayer composite bionic structure oxygenated membrane in Example 1 of the present invention. DETAILED DESCRIPTION

[0048] The present invention is further described below in conjunction with the accompanying drawings and embodiments. Unless otherwise defined, the technical terms or scientific terms used in the present invention should be the common meanings understood by people with ordinary skills in the field to which the present invention belongs. The above-mentioned features or features mentioned in the specific examples mentioned in the present invention can be combined arbitrarily, and these specific embodiments are only used to illustrate the present invention and are not used to limit the scope of the present invention.

[0049] Materials used in the present invention: There is no particular limitation on the sources of all raw materials in the present invention and the following examples, and any raw materials may be commercially available.

[0050] Gas permeation flux detection method: The permeation rate of CO2 and O2 is tested using a membrane permeation performance test system. The test system includes a pump, a membrane tank, a pipeline, a regulating valve, a pressure gauge and a soap film flow meter. The test pressure is 1.0 bar.

[0051] The calculation formula of gas permeation rate is: p i =Q i / (A·ΔP i ), where p i is the penetration rate of CO2 or O2, in GPU (1GPU = 1×10 -6 cm 3 (STP) cm -2 ·s -1 cm Hg -1 ), Q i is the gas volume flow rate under standard conditions, in cm 3 (STP) s -1 ); A is the effective membrane area, in cm 2 , ΔP i is the partial pressure difference of component i on both sides of the membrane, in mmHg. The test uses pure gas, CO2 and O2 to permeate from the opposite sides of the membrane respectively.

[0052] The gas permeation rate ratio of CO2 and O2 is calculated as: R p =p C / p O , where R p is the gas permeation rate ratio of CO2 and O2, p C and p OThey are the gas permeation rates of CO2 and O2 respectively, in GPU.

[0053] Membrane surface water contact angle detection method: The membrane surface water contact angle is detected using a contact angle meter. The sample is cut into 1cm×3cm, placed on the sample table, and 3μL of deionized water is dripped. The contact angle value is obtained by the software, and the test is repeated 3 times to obtain the average value.

[0054] Method for detecting the amount of protein adhesion on the membrane surface: bovine serum albumin was used to evaluate the amount of protein adsorption on the membrane surface. The sample was immersed in a 5 mg / L bovine serum albumin-phosphate solution and incubated at 37°C for 1 hour, then placed in a sodium dodecyl sulfate solution and shaken for 1 hour, the absorbance of the solution was read using an ELISA reader, and the amount of protein adhesion was calculated using the standard curve.

[0055] Example 1

[0056] Figure 1 is a surface scanning electron microscope image of the support film in Example 1 of the present invention, Figure 2 This is a surface scanning electron microscope image of the multilayer composite bionic structure oxygenation membrane in Example 1 of the present invention. As shown in the figure, the present invention provides a method for preparing a multilayer composite bionic structure oxygenation membrane, and a mixed solution containing 0.02% NH2-Uio-66, 0.3% polydimethylsiloxane, 0.2% ethyl orthosilicate, 0.2% dibutyltin dilaurate and the balance of n-hexane is prepared as a coating liquid. A mixed solution containing 0.1% terephthalaldehyde, 0.2% trimesoyl chloride and the balance of n-hexane is prepared as an organic phase solution. A mixed solution containing 0.3% arginine, 0.01% piperazine and the balance of deionized water is prepared as an aqueous phase solution. A mixed solution containing 0.25M sodium vinyl sulfonate, 0.01M potassium persulfate and sodium pyrosulfite and the balance of deionized water is prepared as a grafting solution.

[0057] The coating liquid was scraped onto the surface of the polysulfone ultrafiltration membrane, and dried in a constant temperature and humidity chamber at 50°C and 30% relative humidity for 2 hours to obtain a hydrophobic porous layer; the organic phase solution was placed on the surface of the hydrophobic porous layer for adsorption for 5 minutes, and the excess organic phase solution was removed to obtain a composite membrane for adsorbing aldehyde / acyl chloride monomers; the aqueous phase solution was placed on the surface of the composite membrane for adsorbing aldehyde / acyl chloride monomers for interfacial polymerization reaction for 3 minutes, and the excess aqueous phase solution was removed to obtain a polyimide / polyamide layer; the grafting solution was placed on the surface of the polyimide / polyamide layer for grafting reaction for 1 hour, and the excess grafting solution was removed to obtain a bionic functional layer with heparin-like properties, and after repeated washing with deionized water, a nascent oxygenation membrane was obtained. The nascent oxygenation membrane was placed in a constant temperature and humidity chamber at 30°C and 40% relative humidity for 12 hours to obtain a multilayer composite structure oxygenation membrane.

[0058] After testing, the CO2 permeation rate of the multilayer composite membrane at 1.0 bar is 3520 GPU, the O2 permeation rate is 220 GPU, and the CO2:O2 permeation rate ratio is 16. The water contact angle is 42°, and the protein adhesion amount is 7 μg / cm 2 .

[0059] Example 2

[0060] A mixed solution containing 0.02% ZIF-8-PEI, 0.6% polydimethylsiloxane, 0.3% ethyl orthosilicate, 0.3% dibutyltin dilaurate and the balance n-hexane was prepared as a coating solution. A mixed solution containing 0.2% 2,5-dihydroxyterephthalaldehyde, 0.3% glutaryl chloride and the balance n-hexane was prepared as an organic phase solution. A mixed solution containing 0.3% lysine, 0.01% benzyl diamine and the balance deionized water was prepared as an aqueous phase solution. A mixed solution containing 0.25M methacrylic acid sulfobetaine, 0.01M potassium persulfate and sodium pyrosulfite and the balance deionized water was prepared as a grafting solution.

[0061] The coating liquid was scraped onto the surface of the polyethersulfone ultrafiltration membrane, and dried in a constant temperature and humidity chamber at 50°C and a relative humidity of 30% for 2 hours to obtain a hydrophobic porous layer; the organic phase solution was placed on the surface of the hydrophobic porous layer for adsorption for 15 minutes, and the excess organic phase solution was removed to obtain a composite membrane for adsorbing aldehyde / acyl chloride monomers; the aqueous phase solution was placed on the surface of the composite membrane for adsorbing aldehyde / acyl chloride monomers for interfacial polymerization reaction for 10 minutes, and the excess aqueous phase solution was removed to obtain a polyimide / polyamide layer; the grafting solution was placed on the surface of the polyimide / polyamide layer for grafting reaction for 2 hours, and the excess grafting solution was removed to obtain a bionic functional layer with heparin-like properties, and after repeated washing with deionized water, a nascent oxygenation membrane was obtained. The nascent oxygenation membrane was placed in a constant temperature and humidity chamber at 30°C and a relative humidity of 40% and dried for 12 hours to obtain a multilayer composite structure oxygenation membrane.

[0062] After testing, the CO2 permeation rate of the multilayer composite membrane at 1.0 bar is 1630 GPU, the O2 permeation rate is 112 GPU, and the CO2:O2 permeation rate ratio is 15. The water contact angle is 36°, and the protein adhesion amount is 7 μg / cm 2 .

[0063] Example 3

[0064] A mixed solution containing 0.03% TpPa, 0.4% polydimethylsiloxane, 0.3% ethyl orthosilicate, 0.3% dibutyltin dilaurate and the balance n-heptane was prepared as a coating solution. A mixed solution containing 0.2% trimesaldehyde, 0.3% 1,3,5-benzenetrisulfonyl chloride and the balance cyclohexane was prepared as an organic phase solution. A mixed solution containing 0.3% tyrosine, 0.01% p-phenylenediamine and the balance deionized water was prepared as an aqueous phase solution. A mixed solution containing 0.5M sodium vinyl sulfonate, 0.02M potassium persulfate and sodium pyrosulfite and the balance deionized water was prepared as a grafting solution.

[0065] The coating liquid is sprayed on the surface of the polypropylene hollow fiber membrane, and dried in a constant temperature and humidity chamber at 50°C and a relative humidity of 30% for 3 hours to obtain a hydrophobic porous layer; the organic phase solution is placed on the surface of the hydrophobic porous layer for adsorption for 10 minutes, and the excess organic phase solution is removed to obtain a composite membrane for adsorbing aldehyde / acyl chloride monomers; the aqueous phase solution is placed on the surface of the composite membrane for adsorbing aldehyde / acyl chloride monomers for interfacial polymerization reaction for 10 minutes, and the excess aqueous phase solution is removed to obtain a polyimide / polyamide layer; the grafting solution is placed on the surface of the polyimide / polyamide layer for grafting reaction for 2 hours, and the excess grafting solution is removed to obtain a bionic functional layer with heparin-like properties, which is repeatedly washed with deionized water to obtain a nascent oxygenation membrane; the nascent oxygenation membrane is placed in a constant temperature and humidity chamber at 50°C and a relative humidity of 40% for drying for 12 hours to obtain an oxygenation membrane with a multi-layer composite structure.

[0066] After testing, the CO2 permeation rate of the multilayer composite membrane at 1.0 bar is 3530 GPU, the O2 permeation rate is 210 GPU, and the CO2:O2 permeation rate ratio is 17. The water contact angle is 50°, and the protein adhesion amount is 8 μg / cm 2 .

[0067] Example 4

[0068] A mixed solution containing 0.02% TpBD, 0.4% polydimethylsiloxane, 0.2% ethyl orthosilicate, 0.2% dibutyltin dilaurate and the balance n-hexane was prepared as a coating solution. A mixed solution containing 0.2% 2,4,6-trimethoxy-benzene trimesic acid aldehyde, 0.3% benzyl chloride and the balance n-hexane was prepared as an organic phase solution. A mixed solution containing 0.6% histidine, 0.02% polyethyleneimine and the balance deionized water was prepared as an aqueous phase solution. A mixed solution containing 0.5M sodium vinyl sulfonate, 0.01M potassium persulfate and sodium pyrosulfite and the balance deionized water was prepared as a grafting solution.

[0069] The coating liquid is scraped onto the surface of the polyvinylidene fluoride porous membrane, and dried in a constant temperature and humidity chamber at 50°C and a relative humidity of 30% for 1 hour to obtain a hydrophobic porous layer; the organic phase solution is placed on the surface of the hydrophobic porous layer for adsorption for 5 minutes, and the excess organic phase solution is removed to obtain a composite membrane for adsorbing aldehyde / acyl chloride monomers; the aqueous phase solution is placed on the surface of the composite membrane for adsorbing aldehyde / acyl chloride monomers for interfacial polymerization reaction for 15 minutes, and the excess aqueous phase solution is removed to obtain a polyimide / polyamide layer; the grafting solution is placed on the surface of the polyimide / polyamide layer for grafting reaction for 1 hour, and the excess grafting solution is removed to obtain a bionic functional layer with heparin-like properties, which is repeatedly washed with deionized water to obtain a nascent oxygenated membrane; the nascent oxygenated membrane is placed in a constant temperature and humidity chamber at 30°C and a relative humidity of 40% for drying for 12 hours to obtain a multi-layer composite structure oxygenated membrane.

[0070] After testing, the CO2 permeation rate of the multilayer composite membrane at 1.0 bar is 1820 GPU, the O2 permeation rate is 125 GPU, and the CO2:O2 permeation rate ratio is 15. The water contact angle is 32°, and the protein adhesion amount is 7 μg / cm 2 .

[0071] Comparative Example 1

[0072] The difference from Example 1 is that the support membrane is not treated with the coating solution, and the rest is the same as Example 1.

[0073] After testing, the CO2 permeation rate of the multilayer composite membrane at 1.0 bar is 5500 GPU, the O2 permeation rate is 1130 GPU, and the CO2:O2 permeation rate ratio is 5. The water contact angle is 45°, and the protein adhesion amount is 7 μg / cm 2 .

[0074] By comparing the test results of Example 1 and Comparative Example 1, it can be seen that the CO2:O2 permeation rate ratio of the multilayer composite membrane obtained in Example 1 is higher than that of Comparative Example 1, indicating that the coating treatment in the preparation process is conducive to the uniform formation of the hydrophilic dense layer.

[0075] Comparative Example 2

[0076] The difference from Example 1 is that no grafting solution treatment is performed, and the rest is the same as Example 1.

[0077] After testing, the CO2 permeation rate of the multilayer composite membrane at 1.0 bar is 3620 GPU, the O2 permeation rate is 260 GPU, and the CO2:O2 permeation rate ratio is 14. The water contact angle is 65°, and the protein adhesion amount is 11 μg / cm 2 .

[0078] By comparing the test results of Example 1 and Comparative Example 2, it can be seen that the CO2:O2 permeation rate ratio of the multilayer composite membrane obtained in Example 1 is higher than that in Comparative Example 2, and the amount of protein adhesion is reduced. This indicates that grafting treatment during the preparation process helps to improve the gas exchange performance and biocompatibility of the membrane.

[0079] In summary, the present invention prepares a multilayer composite bionic structure having a hydrophobic porous layer, a hydrophilic dense layer and a heparin-like surface characteristic layer through coating modification, interfacial polymerization reaction and grafting treatment of the support membrane, thereby achieving synergistic enhancement of multiple functions. The prepared multilayer composite bionic structure oxygenation membrane has good CO2 and O2 gas exchange rate, good biocompatibility and blood compatibility.

[0080] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that they can still modify or replace the technical solution of the present invention with equivalents, and these modifications or equivalent replacements cannot cause the modified technical solution to deviate from the spirit and scope of the technical solution of the present invention.

Claims

1. A method for preparing a multi-layer composite bionic structure oxygenation membrane, characterized in that: The following steps are involved: (1) preparing a coating liquid containing a porous organic framework, polydimethylsiloxane, tetraethyl orthosilicate, dibutyltin dilaurate and an organic solvent; applying the coating liquid by scraping or spraying on the surface of the support film, and drying it in a constant temperature and humidity chamber for 1 to 60 hours to obtain a hydrophobic porous layer; the organic solvent comprises one or more of n-heptane, n-hexane and cyclohexane; (2) preparing an organic phase solution containing dibasic or polybasic aldehyde molecules, dibasic or polybasic acyl chloride molecules and an organic solvent; The organic phase solution is contacted with the hydrophobic porous layer obtained in step (1) for 1 to 60 minutes, and then the excess organic phase solution is removed to prepare a composite membrane for adsorbing aldehyde / acyl chloride monomers; the second organic solvent is selected from one or more of C5 to C10 alkanes; (3) preparing an aqueous solution containing amino acid molecules, diamine or polyamine molecules and deionized water; contacting the aqueous solution with the composite membrane for adsorbing aldehyde / acyl chloride monomers obtained in step (2) for 1 to 60 minutes, allowing the aldehyde / acyl chloride monomers to undergo interfacial polymerization with the amino acid / amine monomers, and then removing excess aqueous solution to prepare a polyimide / polyamide layer; The mass ratio of amino acid molecules to diamine or polyamine in the aqueous solution is 100:1 to 20:1; (4) preparing a grafting solution containing vinyl sulfonate, a redox initiator and deionized water; contacting the grafting solution with the polyimine / polyamide layer obtained in step (3), standing for 5 minutes to 24 hours to allow a redox free radical grafting reaction to occur, and then removing excess grafting solution to prepare a nascent oxygenated membrane; the redox initiator includes potassium persulfate and sodium pyrosulfite; (5) placing the nascent oxygenated membrane obtained in step (4) in a constant temperature and humidity chamber and drying for 1 to 60 hours to obtain a multilayer composite bionic structure oxygenated membrane; The multi-layer composite bionic structure oxygenation membrane is applied to blood oxygenation or extracorporeal membrane oxygenation system.

2. The method for preparing a multi-layer composite bionic structure oxygenation membrane according to claim 1, characterized in that: In step (1), the porous organic framework includes one or more of NH2-Uio-66, MIL-101-NH2, MIL-125-NH2, ZIF-8-PEI, TpPa, TpBD, and TpDp.

3. The method for preparing a multi-layer composite bionic structure oxygenation membrane according to claim 1, characterized in that: In step (1), the supporting membrane is an inorganic or organic porous membrane; the type of the porous membrane includes one of a flat plate, a tubular type and a hollow fiber type.

4. The method for preparing a multi-layer composite bionic structure oxygenation membrane according to claim 1, characterized in that: In step (2), the binary or polyvalent aldehyde molecule includes one or more of trimesic acid, terephthalaldehyde, biphenyldicarboxaldehyde, 2,4,6-trihydroxybenzene-1,3,5-tricarboxaldehyde, 1,3,5-tris(4-formylphenyl)amine, 2,5-dihydroxyterephthalaldehyde, 2,5-dibromoterephthalaldehyde, and 2,4,6-trimethoxy-trimesic acid; The binary or polybasic acid chloride molecules include one or more of phthaloyl chloride, isophthaloyl chloride, terephthaloyl chloride, trimesoyl chloride, malonyl chloride, succinyl chloride, glutaryl chloride, adipoyl chloride, pimeloyl chloride, suberyl chloride, azelayl chloride, sebacoyl chloride, 4,4'-oxybis(benzoyl chloride), phthaloyl disulfonyl chloride, isophthaloyl disulfonyl chloride, terephthaloyl disulfonyl chloride, 1,3,5-benzenetrisulfonyl chloride, mesitylene disulfonyl chloride, 4,4'-biphenyl disulfonyl chloride, and methylene disulfonyl chloride.

5. The method for preparing a multi-layer composite bionic structure oxygenation membrane according to claim 1, characterized in that: In step (3), the amino acid molecules include one or more of arginine, lysine, histidine, serine, tyrosine, tryptophan, glutamine, asparagine, cystine, and proline; The diamine or polyamine molecule is a small molecule or polymer containing a diamine or polyamine group in the structural formula, including one or more of piperazine, p-phenylenediamine, m-phenylenediamine, o-phenylenediamine, benzyl diamine and its derivatives, C2-C12 alkyl straight-chain diamines and their derivatives, urea, oxalyl diamine, dithiooxalyl diamine, 2,5-diaminoterephthalic acid, 2-sulfonic acid-1,4-phenylenediamine, 2-isopropyl-1,4-phenylenediamine, diethylenetriamine, dipropylenetriamine, dihexylenetriamine, melamine, oxalic acid dihydrazide, succinic acid dihydrazide, tetrakis(4-aminophenyl)methane, polyethyleneimine, and polyethyleneamine.

6. The method for preparing a multi-layer composite bionic structure oxygenation membrane according to claim 1, characterized in that: In step (4), the vinyl sulfonate includes one or more of sodium vinyl sulfonate, sodium p-styrene sulfonate, potassium p-styrene sulfonate, sodium propylene sulfonate, sodium methpropylene sulfonate, sodium methacrylate 2-ethanesulfonate, potassium methacrylate 3-sulfonate propyl ester, sodium 2-acrylamido-2-methylpropanesulfonate, methacrylate sulfobetaine, 3-((2-(acryloyloxy)ethyl)dimethylammonium)propane-1-sulfonic acid inner salt, and 1-(3-thiopropyl)-2-vinylpyridine betaine.

7. A multi-layer composite bionic structure oxygenation membrane, characterized in that: A multi-layer composite bionic structure oxygenation membrane prepared by the method for preparing a multi-layer composite bionic structure oxygenation membrane according to any one of claims 1 to 6.

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